pubmed_id
stringlengths 39
43
| abstract
stringlengths 3
18k
|
|---|---|
http://www.ncbi.nlm.nih.gov/pubmed/7595741
|
1. J Clin Oncol. 1995 Nov;13(11):2796-804. doi: 10.1200/JCO.1995.13.11.2796.
Very-high-dose short-term chemotherapy for poor-risk peripheral primitive
neuroectodermal tumors, including Ewing's sarcoma, in children and young adults.
Kushner BH(1), Meyers PA, Gerald WL, Healey JH, La Quaglia MP, Boland P, Wollner
N, Casper ES, Aledo A, Heller G, et al.
Author information:
(1)Department of Medical Imaging, Memorial Sloan-Kettering Cancer Center New
York, NY 10021, USA.
PURPOSE: To improve the prognosis of patients with poor-risk peripheral
primitive neuroectodermal tumors (pPNETs; including peripheral neuroepithelioma
and Ewing's sarcoma), while testing the feasibility of intensive use in
adolescents and young adults of high-dose cyclophosphamide, doxorubicin, and
vincristine (HD-CAV).
PATIENTS AND METHODS: This report concerns previously untreated patients with
newly diagnosed pPNET deemed poor-risk because of a tumor volume more than 100
cm3 or metastases to bone or bone marrow. The P6 protocol consists of seven
courses of chemotherapy. Courses 1, 2, 3, and 6 include 6-hour infusions of
cyclophosphamide on days 1 and 2 for a total of 4,200 mg/m2 per course (140
mg/kg per course for patients < 10 years old), plus 72-hour infusions of
doxorubicin 75 mg/m2 and vincristine 2.0 mg/m2 beginning on day 1 (HD-CAV).
Courses 4, 5, and 7 consist of 1-hour infusions of ifosfamide 1.8 g/m2/d and
etoposide (VP-16) 100 mg/m2/d, for 5 days. Granulocyte colony-stimulating factor
(G-CSF) and mesna are used. Courses start after neutrophil counts reach
500/microL and platelet counts reach 100,000/uL. Surgical resection follows
course 3 and radiotherapy follows completion of all chemotherapy.
RESULTS: Among the first 36 consecutive assessable patients (median age, 17
years), HD-CAV achieved excellent histopathologic or clinical responses in 34
patients and partial responses (PRs) in two patients. For 24 patients with
locoregional disease, the 2-year event-free survival rate was 77%; adverse
events were two locoregional relapses, one distant relapse, and one secondary
leukemia. All six patients with metastatic disease limited to lungs achieved a
complete response (CR) and did not relapse; one is in remission 36+ months from
diagnosis, but the other patients are not assessable in terms of long-term
efficacy of the P6 protocol because of short follow-up time (n = 3), additional
systemic therapy (bone marrow transplantation), or septic death (autopsy showed
no residual pPNET). All six patients with widespread metastases had major
responses, including eradication of extensive bone marrow involvement, but
distant relapses ensued. Myelosuppression was severe, but most patients received
the first three courses of HD-CAV within 6 to 7 weeks. Major nonhematologic
toxicities were mucositis and peripheral neuropathy.
CONCLUSION: Excellent antitumor efficacy and manageable toxicity support the
dose-intensive use of HD-CAV for pPNET in children, as well as in young adults.
Consolidation of remissions of pPNET metastatic to bone and bone marrow remains
a therapeutic challenge.
DOI: 10.1200/JCO.1995.13.11.2796
PMID: 7595741 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/7513503
|
1. Am J Surg Pathol. 1994 May;18(5):486-94.
Immunohistochemical profile of monoclonal antibody O13: antibody that recognizes
glycoprotein p30/32MIC2 and is useful in diagnosing Ewing's sarcoma and
peripheral neuroepithelioma.
Weidner N(1), Tjoe J.
Author information:
(1)Department of Pathology, University of California, San Francisco 94143-0102.
Comment in
Am J Surg Pathol. 1995 Jun;19(6):732-4. doi:
10.1097/00000478-199506000-00018.
Am J Surg Pathol. 1995 Jul;19(7):851-2. doi:
10.1097/00000478-199507000-00016.
Ewing's sarcoma (ES) and peripheral neuroepithelioma (PN) are closely related
tumors, and it can be difficult to distinguish them from other small-round-cell
tumors (SRCTs). The glycoprotein p30/32MIC2 is highly, but not exclusively,
expressed in both ES and PN. Although the monoclonal antibody (Mab) HBA71, which
reacts with P30/32MIC2, has been reported to be relatively specific and highly
sensitive for both neoplasms, it is not readily available. Yet, Mab O13 is
commercially available, and it purportedly displays the same immunostaining
characteristics as HBA71. Because O13 has not been studied extensively, we
immunostained 21 ES/PNs and 147 other tumors or lesions that might show
SRCT-like features with O13. The results were similar to those reported for
HBA71. We found O13 to be 100% sensitive for ES/PN; and, no immunostaining was
noted on the SRCTs often included in the differential diagnosis of ES/PN (i.e.,
conventional neuroblastoma, rhabdomyosarcoma, and non-lymphoblastic lymphomas).
But, O13 immunoreacted with lymphoblastic lymphomas and some other tumors and
normal tissues. Nonetheless, this nonspecific reactivity should not cause
diagnostic problems, if an antibody panel containing anti-desmin and
anti-leukocyte common antigen is used in conjunction with O13. We conclude that,
within the proper diagnostic context, strong immunoreactivity of a SRCT tumor
for O13 should be considered good evidence that the tumor is ES/PN.
PMID: 7513503 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22328099
|
1. Oncology. 2012;82(2):114-8. doi: 10.1159/000336479. Epub 2012 Feb 11.
Expression levels of transcribed ultraconserved regions uc.73 and uc.388 are
altered in colorectal cancer.
Sana J(1), Hankeova S, Svoboda M, Kiss I, Vyzula R, Slaby O.
Author information:
(1)Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute,
Brno, Czech Republic.
OBJECTIVES: The development of colorectal cancer (CRC) is characterized by
multiple genetic alterations. Transcribed ultraconserved regions (T-UCRs) are a
subset of 481 sequences longer than 200 bp, which are absolutely conserved
between orthologous regions of human, rat and mouse genomes, and are actively
transcribed. It has recently been proven in cancer systems that differentially
expressed T-UCRs could alter the functional characteristics of malignant cells.
Genome-wide profiling revealed that T-UCRs have distinct signatures in human
leukemia and carcinoma.
METHODS: In our study, we examined the expression levels of uc.43, uc.73,
uc.134, uc.230, uc.339, uc.388 and uc.399 in 54 samples of primary colorectal
carcinomas and 15 samples of non-tumoral adjacent tissues by real-time PCR.
T-UCR expression levels were also correlated with commonly used
clinicopathological features of CRC.
RESULTS: Expression levels of uc.73 (p = 0.0139) and uc.388 (p = 0.0325) were
significantly decreased in CRC tissue, and uc.73 indicated a positive
correlation with overall survival (p = 0.0315). The lower expression of uc.388
was associated with the distal location of CRC (p = 0.0183), but no correlation
of any evaluated T-UCR with clinical stage, grade and tumor diameter was
observed.
CONCLUSION: Our preliminary results suggest that uc.73 and uc.388 could be
potential diagnostic and prognostic biomarkers in CRC patients.
Copyright © 2012 S. Karger AG, Basel.
DOI: 10.1159/000336479
PMID: 22328099 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24509273
|
1. J Am Coll Cardiol. 2014 Apr 8;63(13):1278-1288. doi:
10.1016/j.jacc.2014.01.006. Epub 2014 Feb 5.
Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145):
a pooled analysis of more than 1,300 patients in 4 phase II trials.
Raal FJ(1), Giugliano RP(2), Sabatine MS(2), Koren MJ(3), Langslet G(4), Bays
H(5), Blom D(6), Eriksson M(7), Dent R(8), Wasserman SM(8), Huang F(8), Xue
A(8), Albizem M(8), Scott R(8), Stein EA(9).
Author information:
(1)Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences,
University of Witwatersrand, Johannesburg, South Africa.
(2)TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital,
Boston, Massachusetts.
(3)Jacksonville Center For Clinical Research, Jacksonville, Florida.
(4)Lipid Clinic, Oslo University Hospital, Oslo, Norway.
(5)Louisville Metabolic and Atherosclerosis Research Center, Louisville,
Kentucky.
(6)Department of Medicine, University of Cape Town, Cape Town, South Africa.
(7)Karolinska University Hospital, Stockholm, Sweden.
(8)Amgen Inc., Thousand Oaks, California.
(9)EVLIN Consultants, Chicago, Illinois. Electronic address: [email protected].
OBJECTIVES: The purpose of this study was assess the effect of evolocumab (AMG
145) on lipoprotein (Lp)(a) from a pooled analysis of 4 phase II trials.
BACKGROUND: Lp(a), a low-density lipoprotein (LDL) particle linked to the
plasminogen-like glycoprotein apolipoprotein(a), shows a consistent and
independent positive association with cardiovascular disease risk in
epidemiological studies. Current therapeutic options to reduce Lp(a) are
limited.
METHODS: A pooled analysis of data from 1,359 patients in 4 phase II trials
assessed the effects of evolocumab, a fully human monoclonal antibody to PCSK9,
on Lp(a), the relationship between Lp(a) and lowering of low-density lipoprotein
cholesterol (LDL-C) and apolipoprotein B, and the influence of background statin
therapy. Lp(a) was measured using a standardized isoform-independent method.
RESULTS: Evolocumab treatment for 12 weeks resulted in significant (p < 0.001)
mean (95% confidence interval) dose-related reductions in Lp(a) compared to
control: 29.5% (23.3% to 35.7%) and 24.5% (20.4% to 28.7%) with 140 mg and 420
mg, dosed every 2 and 4 weeks, respectively, with no plateau of effect. Lp(a)
reductions were significantly correlated with percentages of reductions in LDL-C
(Spearman correlation coefficient, 0.5134; p < 0.001) and apolipoprotein B
(Spearman correlation coefficient, 0.5203; p < 0. 001). Mean percentage
reductions did not differ based on age or sex but the trend was greater in those
patients taking statins.
CONCLUSIONS: Inhibition of PCSK9 with evolocumab resulted in significant
dose-related reductions in Lp(a). While the mean percentage of reduction was
significantly greater in those patients with baseline Lp(a) of ≤125 nmol/l, the
absolute reduction was substantially larger in those with levels >125 nmol/l.
Copyright © 2014 American College of Cardiology Foundation. Published by
Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jacc.2014.01.006
PMID: 24509273 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8065896
|
1. Nucleic Acids Res. 1994 Aug 11;22(15):2876-81. doi: 10.1093/nar/22.15.2876.
Self-methylation of BspRI DNA-methyltransferase.
Szilák L(1), Finta C, Patthy A, Venetianer P, Kiss A.
Author information:
(1)Institute of Biochemistry, Hungarian Academy of Sciences, Szeged.
Erratum in
Nucleic Acids Res 1994 Oct 25;22(21):4552.
The DNA (cytosine-5)-methyltransferase (m5C-MTase) M.BspRI is able to accept the
methyl group from the methyl donor S-adenosyl-L-methionine (AdoMet) in the
absence of DNA. Transfer of the methyl group to the enzyme is a slow reaction
relative to DNA methylation. Self-methylation is dependent on the native
conformation of the enzyme and is inhibited by S-adenosyl-L-homocysteine, DNA
and sulfhydryl reagents. Amino acid sequencing of proteolytic peptides obtained
from M.BspRI, which had been methylated with [methyl-3H]AdoMet, and thin layer
chromatography of the modified amino acid identified two cysteines, Cys156 and
Cys181 that bind the methyl group in form of S-methylcysteine. One of the
acceptor residues, Cys156 is the highly conserved cysteine which plays the role
of the catalytic nucleophile of m5C-MTases.
DOI: 10.1093/nar/22.15.2876
PMCID: PMC310249
PMID: 8065896 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16705037
|
1. Genes Dev. 2006 Jun 1;20(11):1470-84. doi: 10.1101/gad.1416106. Epub 2006 May
16.
The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region
and functions as a Dlx-2 transcriptional coactivator.
Feng J(1), Bi C, Clark BS, Mady R, Shah P, Kohtz JD.
Author information:
(1)Program in Neurobiology and Department of Pediatrics, Children's Memorial
Hospital and Feinberg School of Medicine, Northwestern University, Chicago,
Illinois 60614, USA.
The identification of ultraconserved noncoding sequences in vertebrates has been
associated with developmental regulators and DNA-binding proteins. One of the
first of these was identified in the intergenic region between the Dlx-5 and
Dlx-6 genes, members of the Dlx/dll homeodomain-containing protein family. In
previous experiments, we showed that Sonic hedgehog treatment of forebrain
neural explants results in the activation of Dlx-2 and the novel noncoding RNA
(ncRNA), Evf-1. In this report, we show that the Dlx-5/6 ultraconserved region
is transcribed to generate an alternatively spliced form of Evf-1, the ncRNA
Evf-2. Evf-2 specifically cooperates with Dlx-2 to increase the transcriptional
activity of the Dlx-5/6 enhancer in a target and homeodomain-specific manner. A
stable complex containing the Evf-2 ncRNA and the Dlx-2 protein forms in vivo,
suggesting that the Evf-2 ncRNA activates transcriptional activity by directly
influencing Dlx-2 activity. These experiments identify a novel mechanism whereby
transcription is controlled by the cooperative actions of an ncRNA and a
homeodomain protein. The possibility that a subset of vertebrate ultraconserved
regions may function at both the DNA and RNA level to control key developmental
regulators may explain why ultraconserved sequences exhibit 90% or more
conservation even after 450 million years of vertebrate evolution.
DOI: 10.1101/gad.1416106
PMCID: PMC1475760
PMID: 16705037 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24825642
|
1. JAMA. 2014 May 14;311(18):1870-82. doi: 10.1001/jama.2014.4030.
Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin
therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2
randomized clinical trial.
Robinson JG(1), Nedergaard BS(2), Rogers WJ(3), Fialkow J(4), Neutel JM(5),
Ramstad D(6), Somaratne R(7), Legg JC(7), Nelson P(7), Scott R(7), Wasserman
SM(7), Weiss R(8); LAPLACE-2 Investigators.
Collaborators: Hamilton A, Lehman R, Proietto J, Simons L, Bous JP, Cornelli K,
De Munck L, Vantroyen, Vermeersch L, Vileyn G, Akhras R, Cha J, Chehayeb R,
Chilvers M, Collette R, Dowell A, Dzongowski P, Gupta A, Halperin F, Hart R,
Heaton K, Henein S, Kanani S, Kornder J, Lamy A, OMahony M, Pandey A,
Sabe-Affaki G, St Maurice F, Adamkova V, Cermak O, Ceska R, Frana P, Hala T,
Kellnerova I, Machkova M, Petrzelkova J, Pojsl S, Stankova V, Vaclavik J,
Zemanek J, Krogsaa A, Nedergaard BS, Wermuth S, Clavel S, Cohen AA, Davy JM,
Joubert M, Mansourati J, Probst V, Verges B, Degtyareva E, Förster A, Horacek T,
Kasperk C, Kohler E, Laufs U, Meissner G, Schenkenberger I, Stoessel J, Trenk D,
Winkler K, Lau EM, Yeung CY, Bajnok L, Bod E, Harcsa E, Lippai J, Mohacsi A,
Palinkas A, Poor F, Szakal I, Sziegl Z, Borghi C, Bucci M, Cattin L, Iannuzzi A,
Miccoli R, Passaro A, Pintus P, Pirro M, Sirtori C, Zambon S, De Graaf J,
Donders S, Imholz B, Klessens-Godfroy F, Kooy A, Stroes E, Van Leendert R,
Viergever P, Helder D, Vincent H, Barbarash O, Chumakova G, Demchenko E,
Kotelnikov M, Litvin A, Lukyanov Y, Shvarts Y, Susekov A, Treshkur T, Yakhontova
P, Gimilio JF, Gimeno EJ, Raya PM, Nuñez-Cortes JM, Prieto JM, Sala XP, Ros E,
Borgencrantz B, Bosson P, Curiac D, Dahlén G, Delavaran C, Lindholm CJ, Burnier
M, Eberli F, Gallino A, Mach F, Rickli H, Widmer F, Abdulhakim EE, Adler L,
Blagden M, D'Costa R, Falk R, Fisher M, Hassanin H, Horvathova V, Kerrane J,
Mackay J, McCormack T, McKinnon C, Oyesile B, Pavel-Knox I, Soran H, Thomas H,
Abraham W, Aronoff S, Atassi K, Awasty V, Bailey K, Baron S, Bear R, Bertolet B,
Bhagwat R, Coburn N, Connery L, Dauber I, Davis M, Diederich C, Eaton G, Fialkow
J, Fishbein G, French W, Friedlander I, Fuchs-Ertman D, Ginsberg D, Hagan M,
Hage-Korban E, Halpern S, Henderson D, Houser P, Ibrahim H, Jennings W, Kivitz
A, Kozlowski L, Loh I, Malone M, McConnehey B, McCullum K, Miller M, Napoli M,
Neutel J, Purdy D, Qureshi M, Ramstad D, Raoof T, Reichman A, Rich K, Robinson
J, Rogers W, Salazar J, Shaoulian E, Stringer J, Tarleton G, Throne M, Webb C,
Weiss R, Wiseman A.
Author information:
(1)Department of Epidemiology, College of Public Health, University of Iowa,
Iowa City2Department of Medicine, College of Public Health, University of Iowa,
Iowa City.
(2)Center for Clinical and Basic Research, Aalborg, Denmark.
(3)Division of Cardiovascular Disease, University of Alabama Medical Center,
Birmingham.
(4)Department of Medicine, Herbert Wertheim College of Medicine, Florida
International University, Miami.
(5)Orange County Research Center, Tustin, California.
(6)Hampton Roads Center for Clinical Research, Suffolk, Virginia.
(7)Amgen Inc, Thousand Oaks, California.
(8)Maine Research Associates, Auburn.
IMPORTANCE: In phase 2 studies, evolocumab, a fully human monoclonal antibody to
PCSK9, reduced LDL-C levels in patients receiving statin therapy.
OBJECTIVE: To evaluate the efficacy and tolerability of evolocumab when used in
combination with a moderate- vs high-intensity statin.
DESIGN, SETTING, AND PATIENTS: Phase 3, 12-week, randomized, double-blind,
placebo- and ezetimibe-controlled study conducted between January and December
of 2013 in patients with primary hypercholesterolemia and mixed dyslipidemia at
198 sites in 17 countries.
INTERVENTIONS: Patients (n = 2067) were randomized to 1 of 24 treatment groups
in 2 steps. Patients were initially randomized to a daily, moderate-intensity
(atorvastatin [10 mg], simvastatin [40 mg], or rosuvastatin [5 mg]) or
high-intensity (atorvastatin [80 mg], rosuvastatin [40 mg]) statin. After a
4-week lipid-stabilization period, patients (n = 1899) were randomized to
compare evolocumab (140 mg every 2 weeks or 420 mg monthly) with placebo (every
2 weeks or monthly) or ezetimibe (10 mg or placebo daily; atorvastatin patients
only) when added to statin therapies.
MAIN OUTCOMES AND MEASURES: Percent change from baseline in low-density
lipoprotein cholesterol (LDL-C) level at the mean of weeks 10 and 12 and at week
12.
RESULTS: Evolocumab reduced LDL-C levels by 66% (95% CI, 58% to 73%) to 75% (95%
CI, 65% to 84%) (every 2 weeks) and by 63% (95% CI, 54% to 71%) to 75% (95% CI,
67% to 83%) (monthly) vs placebo at the mean of weeks 10 and 12 in the moderate-
and high-intensity statin-treated groups; the LDL-C reductions at week 12 were
comparable. For moderate-intensity statin groups, evolocumab every 2 weeks
reduced LDL-C from a baseline mean of 115 to 124 mg/dL to an on-treatment mean
of 39 to 49 mg/dL; monthly evolocumab reduced LDL-C from a baseline mean of 123
to 126 mg/dL to an on-treatment mean of 43 to 48 mg/dL. For high-intensity
statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 89
to 94 mg/dL to an on-treatment mean of 35 to 38 mg/dL; monthly evolocumab
reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of
33 to 35 mg/dL. Adverse events were reported in 36%, 40%, and 39% of
evolocumab-, ezetimibe-, and placebo-treated patients, respectively. The most
common adverse events in evolocumab-treated patients were back pain, arthralgia,
headache, muscle spasms, and pain in extremity (all <2%).
CONCLUSIONS AND RELEVANCE: In this 12-week trial conducted among patients with
primary hypercholesterolemia and mixed dyslipidemia, evolocumab added to
moderate- or high-intensity statin therapy resulted in additional LDL-C
lowering. Further studies are needed to evaluate the longer-term clinical
outcomes and safety of this approach for LDL-C lowering.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01763866.
DOI: 10.1001/jama.2014.4030
PMID: 24825642 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/11749045
|
1. Mol Genet Metab. 2001 Dec;74(4):403-12. doi: 10.1006/mgme.2001.3259.
The 4N cell cycle delay in Fanconi anemia reflects growth arrest in late S
phase.
Akkari YM(1), Bateman RL, Reifsteck CA, D'Andrea AD, Olson SB, Grompe M.
Author information:
(1)Department of Molecular and Medical Genetics, Oregon Health Sciences
University, 3181 SW Sam Jackson Park Road L103, Portland, Oregon 97201, USA.
[email protected]
Fanconi anemia (FA) is a human genetic disorder characterized by
hypersensitivity to DNA crosslinking agents. Its cellular phenotypes include
increased chromosome breakage and a marked cell-cycle delay with 4N DNA content
after introduction of interstrand DNA crosslinks (ICL). To further understand
the nature of this delay previously described as a G2/M arrest, we introduced
ICL specifically during G2 and monitored the cells for passage into mitosis. Our
results showed that, even at the highest doses, postreplication ICL produced
neither G2/M arrest nor chromosome breakage in FA-A or FA-C cells. This suggests
that, similar to wild-type cells, DNA replication is required to trigger both
responses. Therefore, the 4N cell DNA content observed in FA cells after ICL
treatment also represents incomplete DNA replication and arrest in late S phase.
FA fibroblasts from complementation groups A and C were able to recover from the
ICL-induced cell-cycle arrest, but took approximately 3 times longer than
controls. These results indicate that the FA pathway is required for the
efficient resolution of ICL-induced S-phase arrest.
Copyright 2001 Elsevier Science.
DOI: 10.1006/mgme.2001.3259
PMID: 11749045 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8441638
|
1. Nucleic Acids Res. 1993 Jan 25;21(2):303-9. doi: 10.1093/nar/21.2.303.
Sequence-specific and mechanism-based crosslinking of Dcm DNA cytosine-C5
methyltransferase of E. coli K-12 to synthetic oligonucleotides containing
5-fluoro-2'-deoxycytidine.
Hanck T(1), Schmidt S, Fritz HJ.
Author information:
(1)Institut für Molekulare Genetik, Georg-August-Universität Göttingen, Germany.
The product of the dcm gene is the only DNA cytosine-C5 methyltransferase of
Escherichia coli K-12; it catalyses transfer of a methyl group from S-adenosyl
methionine (SAM) to the C-5 position of the inner cytosine residue of the
cognate sequence CCA/TGG. Sequence-specific, covalent crosslinking of the enzyme
to synthetic oligonucleotides containing 5-fluoro-2'-deoxycytidine is
demonstrated. This reaction is abolished if serine replaces the cysteine at
residue #177 of the enzyme. These results lend strong support to a catalytic
mechanism in which an enzyme sulfhydryl group undergoes Michael addition to the
C5-C6 double bond, thus activating position C-5 of the substrate DNA cytosine
residue for electrophilic attack by the methyl donor SAM. The enzyme is capable
of self-methylation in a DNA-independent reaction requiring SAM and the presence
of cysteine at position #177.
DOI: 10.1093/nar/21.2.303
PMCID: PMC309107
PMID: 8441638 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25303625
|
1. J Obstet Gynaecol Res. 2015 Mar;41(3):478-82. doi: 10.1111/jog.12552. Epub
2014 Oct 10.
Ewing's sarcoma/peripheral primitive neuroectodermal tumors of the uterus
confirmed with fluorescence in situ hybridization in a 29-year-old Chinese
female: a case report and published work review.
Yi T(1), Wang P, Lin L, Jiang W.
Author information:
(1)Department of Gynecology, West China Second University Hospital of Sichuan
University, Chengdu, China.
Ewing's sarcoma/peripheral primitive neuroectodermal tumors (ES/pPNET) are a
group of small round cell sarcomas that show varying degrees of neuroectodermal
differentiation characterized by translocation involving the EWS gene. Uterine
ES/pPNET is a rare entity. A 29-year-old Chinese female who presented with
abdominal swelling and pain was diagnosed with a primary uterine ES/pPNET on the
basis of clinicopathologic, immunohistochemical and fluorescence in situ
hybridization (FISH) data. She was given a multimodal treatment, including
neoadjuvant, 95% cytoreductive, chemotherapy and radiotherapy. The patient is
currently alive with persistent disease after 18 months of follow-up. We
emphasized the crucial role of molecular techniques in the differential
diagnosis of small round cell tumors in this unusual location. Multimodal
therapy may improve the outcomes of patients.
© 2014 The Authors. Journal of Obstetrics and Gynaecology Research © 2014 Japan
Society of Obstetrics and Gynecology.
DOI: 10.1111/jog.12552
PMID: 25303625 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16793409
|
1. Methods Enzymol. 2006;409:316-29. doi: 10.1016/S0076-6879(05)09018-X.
Detection and structural analysis of R-loops.
Yu K(1), Roy D, Huang FT, Lieber MR.
Author information:
(1)Department of Pathology, Norris Comprehensive Cancer Center, University of
Southern California Keck School of Medicine, Los Angeles, USA.
R-loops are structures where an RNA strand is base paired with one DNA strand of
a DNA duplex, leaving the displaced DNA strand single-stranded. Stable R-loops
exist in vivo at prokaryotic origins of replication, the mitochondrial origin of
replication, and mammalian immunoglobulin (Ig) class switch regions in activated
B lymphocytes. All of these R-loops arise upon generation of a G-rich RNA strand
by an RNA polymerase upon transcription of a C-rich DNA template strand. These
R-loops are of significant length. For example, the R-loop at the col E1 origin
of replication appears to be about 140 bp. Our own lab has focused on class
switch regions, where the R-loops can extend well over a kilobase in length.
Here, methods are described for detection and analysis of R-loops in vitro and
in vivo.
DOI: 10.1016/S0076-6879(05)09018-X
PMID: 16793409 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24843019
|
1. Elife. 2014 Apr 29;3:e02190. doi: 10.7554/eLife.02190.
Periodic DNA patrolling underlies diverse functions of Pif1 on R-loops and
G-rich DNA.
Zhou R(1), Zhang J(2), Bochman ML(3), Zakian VA(3), Ha T(4).
Author information:
(1)Center for the Physics of Living Cells, Department of Physics, University of
Illinois at Urbana-Champaign, Urbana, United States.
(2)Center for the Physics of Living Cells, Department of Physics, University of
Illinois at Urbana-Champaign, Urbana, United States Materials Science and
Engineering, University of Illinois at Urbana-Champaign, Urbana, United States.
(3)Department of Molecular Biology, Princeton University, Princeton, United
States.
(4)Center for the Physics of Living Cells, Department of Physics, University of
Illinois at Urbana-Champaign, Urbana, United States Howard Hughes Medical
Institute, University of Illinois at Urbana-Champaign, Urbana, United States
[email protected].
Comment in
Elife. 2014 Apr 29;3:e02854. doi: 10.7554/eLife.02854.
Pif1 family helicases are conserved from bacteria to humans. Here, we report a
novel DNA patrolling activity which may underlie Pif1's diverse functions: a
Pif1 monomer preferentially anchors itself to a 3'-tailed DNA junction and
periodically reel in the 3' tail with a step size of one nucleotide, extruding a
loop. This periodic patrolling activity is used to unfold an intramolecular
G-quadruplex (G4) structure on every encounter, and is sufficient to unwind
RNA-DNA heteroduplex but not duplex DNA. Instead of leaving after G4 unwinding,
allowing it to refold, or going beyond to unwind duplex DNA, Pif1 repeatedly
unwinds G4 DNA, keeping it unfolded. Pif1-induced unfolding of G4 occurs in
three discrete steps, one strand at a time, and is powerful enough to overcome
G4-stabilizing drugs. The periodic patrolling activity may keep Pif1 at its site
of in vivo action in displacing telomerase, resolving R-loops, and keeping G4
unfolded during replication, recombination and repair.DOI:
http://dx.doi.org/10.7554/eLife.02190.001.
Copyright © 2014, Zhou et al.
DOI: 10.7554/eLife.02190
PMCID: PMC3999857
PMID: 24843019 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that no competing interests
exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/25981810
|
1. Lancet Oncol. 2015 Jun;16(6):716-28. doi: 10.1016/S1470-2045(15)70100-2. Epub
2015 May 14.
Treatment with two different doses of sonidegib in patients with locally
advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised,
double-blind phase 2 trial.
Migden MR(1), Guminski A(2), Gutzmer R(3), Dirix L(4), Lewis KD(5), Combemale
P(6), Herd RM(7), Kudchadkar R(8), Trefzer U(9), Gogov S(10), Pallaud C(10), Yi
T(11), Mone M(12), Kaatz M(13), Loquai C(14), Stratigos AJ(15), Schulze HJ(16),
Plummer R(17), Chang AL(18), Cornélis F(19), Lear JT(20), Sellami D(21), Dummer
R(22).
Author information:
(1)Mohs Surgery Center, Department of Dermatology, University of Texas MD
Anderson Cancer Center, Houston, TX, USA. Electronic address:
[email protected].
(2)Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW,
Australia.
(3)Department of Dermatology and Allergy, Medizinische Hochschule Hannover,
Hannover, Germany.
(4)Department of Medical Oncology, Sint-Augustinus Ziekenhuis, Antwerp, Belgium.
(5)Division of Medical Oncology, University of Colorado School of Medicine,
Aurora, CO, USA.
(6)Department of Onco-Dermatology, Anticancer Institute, Lyon, France.
(7)Department of Dermatology, Glasgow Royal Infirmary, Glasgow, UK.
(8)Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA.
(9)Dermatologikum Berlin, Berlin, Germany.
(10)Oncology Clinical Development, Novartis Pharma, Basel, Switzerland.
(11)Biometrics and Data Management, Oncology Business Unit, Novartis
Pharmaceuticals Corporation, East Hanover, NJ, USA.
(12)Oncology Clinical Development, Novartis Pharmaceuticals Corporation, East
Hanover, NJ, USA.
(13)Department of Dermatology and Allergology, University Hospital Jena, Jena,
Germany; SRH Wald-Klinikum Gera, Gera, Germany.
(14)Deparment of Dermatology, University Medical Center Mainz, Mainz, Germany.
(15)Deparment of Dermatology, Andreas Sygros Hospital, University of Athens,
Athens, Greece.
(16)Fachklinik Hornheide, Münster, Germany.
(17)Northern Centre for Cancer Care, Freeman Hospital, Newcastle upon Tyne, UK.
(18)Deparment of Dermatology, Stanford University School of Medicine, Redwood
City, CA, USA.
(19)Cliniques Universitaires Saint-Luc, Université Catholique de Louvain,
Brussels, Belgium.
(20)Manchester Academic Health Science Centre, University of Manchester,
Manchester, UK.
(21)Oncology Global Development, Novartis Pharmaceuticals Corporation, East
Hanover, NJ, USA.
(22)Universitätsspital Zürich-Skin Cancer Center University Hospital, Zürich,
Switzerland.
Comment in
Lancet Oncol. 2015 Jun;16(6):608-10. doi: 10.1016/S1470-2045(15)70233-0.
BACKGROUND: Patients with advanced basal cell carcinoma have limited treatment
options. Hedgehog pathway signalling is aberrantly activated in around 95% of
tumours. We assessed the antitumour activity of sonidegib, a Hedgehog signalling
inhibitor, in patients with advanced basal cell carcinoma.
METHODS: BOLT is an ongoing multicentre, randomised, double-blind, phase 2
trial. Eligible patients had locally advanced basal cell carcinoma not amenable
to curative surgery or radiation or metastatic basal cell carcinoma. Patients
were randomised via an automated system in a 1:2 ratio to receive 200 mg or 800
mg oral sonidegib daily, stratified by disease, histological subtype, and
geographical region. The primary endpoint was the proportion of patients who
achieved an objective response, assessed in the primary efficacy analysis
population (patients with fully assessable locally advanced disease and all
those with metastatic disease) with data collected up to 6 months after
randomisation of the last patient. This trial is registered with
ClinicalTrials.gov, number NCT01327053.
FINDINGS: Between July 20, 2011, and Jan 10, 2013, we enrolled 230 patients, 79
in the 200 mg sonidegib group, and 151 in the 800 mg sonidegib group. Median
follow-up was 13·9 months (IQR 10·1-17·3). In the primary efficacy analysis
population, 20 (36%, 95% CI 24-50) of 55 patients receiving 200 mg sonidegib and
39 (34%, 25-43) of 116 receiving 800 mg sonidegib achieved an objective
response. In the 200 mg sonidegib group, 18 (43%, 95% CI 28-59) patients who
achieved an objective response, as assessed by central review, were noted among
the 42 with locally advanced basal cell carcinoma and two (15%, 2-45) among the
13 with metastatic disease. In the 800 mg group, 35 (38%, 95% CI 28-48) of 93
patients with locally advanced disease had an objective response, as assessed by
central review, as did four (17%, 5-39) of 23 with metastatic disease. Fewer
adverse events leading to dose interruptions or reductions (25 [32%] of 79
patients vs 90 [60%] of 150) or treatment discontinuation (17 [22%] vs 54 [36%])
occurred in patients in the 200 mg group than in the 800 mg group. The most
common grade 3-4 adverse events were raised creatine kinase (five [6%] in the
200 mg group vs 19 [13%] in the 800 mg group) and lipase concentration (four
[5%] vs eight [5%]). Serious adverse events occurred in 11 (14%) of 79 patients
in the 200 mg group and 45 (30%) of 150 patients in the 800 mg group.
INTERPRETATION: The benefit-to-risk profile of 200 mg sonidegib might offer a
new treatment option for patients with advanced basal cell carcinoma, a
population that is difficult to treat.
FUNDING: Novartis Pharmaceuticals Corporation.
Copyright © 2015 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(15)70100-2
PMID: 25981810 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25147206
|
1. Nucleic Acids Res. 2014;42(16):10473-87. doi: 10.1093/nar/gku658. Epub 2014
Aug 21.
Processing of double-R-loops in (CAG)·(CTG) and C9orf72 (GGGGCC)·(GGCCCC)
repeats causes instability.
Reddy K(1), Schmidt MH(1), Geist JM(2), Thakkar NP(1), Panigrahi GB(1), Wang
YH(3), Pearson CE(4).
Author information:
(1)Department of Genetics, The Hospital for Sick Children, Peter Gilgan Centre
for Research & Learning, 686 Bay Street, Toronto, Ontario M5G 0A4, Canada
Program of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 0A4,
Canada.
(2)Department of Genetics, The Hospital for Sick Children, Peter Gilgan Centre
for Research & Learning, 686 Bay Street, Toronto, Ontario M5G 0A4, Canada
Department of Biology, Laurentian University, Sudbury, Ontario P3E 2C6, Canada.
(3)Department of Biochemistry & Molecular Genetics, University of Virginia
School of Medicine, Charlottesville, VA 22908, USA.
(4)Department of Genetics, The Hospital for Sick Children, Peter Gilgan Centre
for Research & Learning, 686 Bay Street, Toronto, Ontario M5G 0A4, Canada
Program of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 0A4,
Canada [email protected].
R-loops, transcriptionally-induced RNA:DNA hybrids, occurring at repeat tracts
(CTG)n, (CAG)n, (CGG)n, (CCG)n and (GAA)n, are associated with diseases
including myotonic dystrophy, Huntington's disease, fragile X and Friedreich's
ataxia. Many of these repeats are bidirectionally transcribed, allowing for
single- and double-R-loop configurations, where either or both DNA strands may
be RNA-bound. R-loops can trigger repeat instability at (CTG)·(CAG) repeats, but
the mechanism of this is unclear. We demonstrate R-loop-mediated instability
through processing of R-loops by HeLa and human neuron-like cell extracts.
Double-R-loops induced greater instability than single-R-loops. Pre-treatment
with RNase H only partially suppressed instability, supporting a model in which
R-loops directly generate instability by aberrant processing, or via slipped-DNA
formation upon RNA removal and its subsequent aberrant processing. Slipped-DNAs
were observed to form following removal of the RNA from R-loops. Since
transcriptionally-induced R-loops can occur in the absence of DNA replication,
R-loop processing may be a source of repeat instability in the brain.
Double-R-loop formation and processing to instability was extended to the
expanded C9orf72 (GGGGCC)·(GGCCCC) repeats, known to cause amyotrophic lateral
sclerosis and frontotemporal dementia, providing the first suggestion through
which these repeats may become unstable. These findings provide a mechanistic
basis for R-loop-mediated instability at disease-associated repeats.
© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gku658
PMCID: PMC4176329
PMID: 25147206 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20080737
|
1. Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):692-7. doi:
10.1073/pnas.0909740107. Epub 2009 Dec 22.
R loops stimulate genetic instability of CTG.CAG repeats.
Lin Y(1), Dent SY, Wilson JH, Wells RD, Napierala M.
Author information:
(1)Baylor College of Medicine, Verna and Marrs McLean Department of Biochemistry
and Molecular Biology, One Baylor Plaza, Houston, TX 77030, USA.
Transcription stimulates the genetic instability of trinucleotide repeat
sequences. However, the mechanisms leading to transcription-dependent repeat
length variation are unclear. We demonstrate, using biochemical and genetic
approaches, that the formation of stable RNA.DNA hybrids enhances the
instability of CTG.CAG repeat tracts. In vitro transcribed CG-rich repeating
sequences, unlike AT-rich repeats and nonrepeating sequences, form stable,
ribonuclease A-resistant structures. These RNA.DNA hybrids are eliminated by
ribonuclease H treatment. Mutation in the rnhA1 gene that decreases the activity
of ribonuclease HI stimulates the instability of CTG.CAG repeats in E. coli.
Importantly, the effect of ribonuclease HI depletion on repeat instability
requires active transcription. We also showed that transcription-dependent
CTG.CAG repeat instability in human cells is stimulated by siRNA knockdown of
RNase H1 and H2. In addition, we used bisulfite modification, which detects
single-stranded DNA, to demonstrate that the nontemplate DNA strand at
transcribed CTG.CAG repeats remains partially single-stranded in human genomic
DNA, thus indicating that it is displaced by an RNA.DNA hybrid. These studies
demonstrate that persistent hybrids between the nascent RNA transcript and the
template DNA strand at CTG.CAG tracts promote instability of DNA trinucleotide
repeats.
DOI: 10.1073/pnas.0909740107
PMCID: PMC2818888
PMID: 20080737 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/24743386
|
1. PLoS Genet. 2014 Apr 17;10(4):e1004294. doi: 10.1371/journal.pgen.1004294.
eCollection 2014 Apr.
Transcription-associated R-loop formation across the human FMR1 CGG-repeat
region.
Loomis EW(1), Sanz LA(2), Chédin F(2), Hagerman PJ(3).
Author information:
(1)Department of Biochemistry and Molecular Medicine, University of California,
Davis, School of Medicine, Davis, California, United States of America.
(2)Department of Molecular and Cellular Biology, University of California,
Davis, Davis, California, United States of America; The Genome Center,
University of California, Davis, Davis, California, United States of America.
(3)Department of Biochemistry and Molecular Medicine, University of California,
Davis, School of Medicine, Davis, California, United States of America; MIND
Institute, University of California, Davis, Health System, Sacramento,
California, United States of America.
Expansion of a trinucleotide (CGG) repeat element within the 5' untranslated
region (5'UTR) of the human FMR1 gene is responsible for a number of heritable
disorders operating through distinct pathogenic mechanisms: gene silencing for
fragile X syndrome (>200 CGG) and RNA toxic gain-of-function for FXTAS (∼ 55-200
CGG). Existing models have focused almost exclusively on post-transcriptional
mechanisms, but co-transcriptional processes could also contribute to the
molecular dysfunction of FMR1. We have observed that transcription through the
GC-rich FMR1 5'UTR region favors R-loop formation, with the nascent (G-rich) RNA
forming a stable RNA:DNA hybrid with the template DNA strand, thereby displacing
the non-template DNA strand. Using DNA:RNA (hybrid) immunoprecipitation (DRIP)
of genomic DNA from cultured human dermal fibroblasts with both normal (∼ 30 CGG
repeats) and premutation (55<CGG<200 repeats) alleles, we provide evidence for
FMR1 R-loop formation in human genomic DNA. Using a doxycycline (DOX)-inducible
episomal system in which both the CGG-repeat and transcription frequency can be
varied, we further show that R-loop formation increases with higher expression
levels. Finally, non-denaturing bisulfite mapping of the displaced
single-stranded DNA confirmed R-loop formation at the endogenous FMR1 locus and
further indicated that R-loops formed over CGG repeats may be prone to
structural complexities, including hairpin formation, not commonly associated
with other R-loops. These observations introduce a new molecular feature of the
FMR1 gene that is directly affected by CGG-repeat expansion and is likely to be
involved in the associated cellular dysfunction.
DOI: 10.1371/journal.pgen.1004294
PMCID: PMC3990486
PMID: 24743386 [Indexed for MEDLINE]
Conflict of interest statement: I have read the journal's policy and have the
following conflicts. I, Dr. Hagerman, hold patents for quantification of
CGG-repeat number and for measurement of FMRP levels. I have submitted, with
Pacific Biosciences, a patent application for SMRT-sequencing methodology. I
collaborate with Pacific Biosciences without compensation; Pacific Biosciences
and I are co-recipients of an STTR grant from the NICHD.
|
http://www.ncbi.nlm.nih.gov/pubmed/15531884
|
1. Nat Immunol. 2004 Dec;5(12):1275-81. doi: 10.1038/ni1137. Epub 2004 Nov 7.
An evolutionarily conserved target motif for immunoglobulin class-switch
recombination.
Zarrin AA(1), Alt FW, Chaudhuri J, Stokes N, Kaushal D, Du Pasquier L, Tian M.
Author information:
(1)Howard Hughes Medical Institute, The Children's Hospital, CBR Institute for
Biomedical Research, and Department of Genetics, Harvard University Medical
School, Boston, Massachusetts 02115, USA.
Comment in
Nat Immunol. 2004 Dec;5(12):1203-4. doi: 10.1038/ni1204-1203.
Immunoglobulin H class-switch recombination (CSR) occurs between switch regions
and requires transcription and activation-induced cytidine deaminase (AID).
Transcription through mammalian switch regions, because of their GC-rich
composition, generates stable R-loops, which provide single-stranded DNA
substrates for AID. However, we show here that the Xenopus laevis switch region
S(mu), which is rich in AT and not prone to form R-loops, can functionally
replace a mouse switch region to mediate CSR in vivo. X. laevis S(mu)-mediated
CSR occurred mostly in a region of AGCT repeats targeted by the AID-replication
protein A complex when transcribed in vitro. We propose that AGCT is a
primordial CSR motif that targets AID through a non-R-loop mechanism involving
an AID-replication protein A complex.
DOI: 10.1038/ni1137
PMID: 15531884 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18986989
|
1. J Biol Chem. 2008 Dec 26;283(52):36743-51. doi: 10.1074/jbc.M806174200. Epub
2008 Nov 5.
Native R-loops persist throughout the mouse mitochondrial DNA genome.
Brown TA(1), Tkachuk AN, Clayton DA.
Author information:
(1)Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn,
Virginia 20147-2408, USA.
Mammalian mtDNA has been found here to harbor RNA-DNA hybrids at a variety of
locations throughout the genome. The R-loop, previously characterized in vitro
at the leading strand replication origin (OH), is isolated as a native RNA-DNA
hybrid copurifying with mtDNA. Surprisingly, other mitochondrial transcripts
also form stable partial R-loops. These are abundant and affect mtDNA
conformation. Current models regarding the mechanism of mammalian mtDNA
replication have been expanded by recent data and discordant hypotheses. The
presence of stable, nonreplicative, and partially hybridized RNA on the mtDNA
template is significant for the reevaluation of replication models based on
two-dimensional agarose gel analyses. In addition, the close association of a
subpopulation of mtRNA with the DNA template has further implications regarding
the structure, maintenance, and expression of the mitochondrial genome. These
results demonstrate that variously processed and targeted mtRNAs within
mammalian mitochondria likely have multiple functions in addition to their
conventional roles.
DOI: 10.1074/jbc.M806174200
PMCID: PMC2605977
PMID: 18986989 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8321753
|
1. Pathol Res Pract. 1993 Mar;189(2):235-41; discussion 241-4. doi:
10.1016/S0344-0338(11)80104-4.
Cytogenetics of Askin's tumour. Case report and review of the literature.
Füzesi L(1), Heller R, Schreiber H, Mertens R.
Author information:
(1)Department of Pathology, Medical Faculty, Technical University of Aachen,
FRG.
The eleventh cytogenetically analyzed Askin's tumour, diagnosed in a
two-year-old girl, is reported. Chromosomal analysis revealed a pseudodiploid
karyotype of tumour cells with translocations of t(11;22)(q24;q12) and
der(4)t(2;4)(q24;q35). The observed t(11;22)(q24;q12) is not only a unique
characteristic of all cytogenetically analyzed Askin's tumours but it also
occurs in 92-100% of peripheral neuroepithelioma and of Ewing's sarcoma,
irrespective of its osseous or extraosseous localization. This genetical
similarity further supports a nosological concept according to which Askin's
tumour, Ewing's sarcoma and peripheral neuroepithelioma represent phenotypic
variations of the same tumour, namely the peripheral primitive neuroectodermal
tumour.
DOI: 10.1016/S0344-0338(11)80104-4
PMID: 8321753 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24050928
|
1. Eur J Endocrinol. 2013 Oct 23;169(6):867-84. doi: 10.1530/EJE-13-0442. Print
2013 Dec.
Screening for AIP gene mutations in a Han Chinese pituitary adenoma cohort
followed by LOH analysis.
Cai F(1), Zhang YD, Zhao X, Yang YK, Ma SH, Dai CX, Liu XH, Yao Y, Feng M, Wei
JJ, Xing B, Jiao YH, Wei ZQ, Yin ZM, Zhang B, Gu F, Wang RZ.
Author information:
(1)Department of Neurosurgery, Peking Union Medical College, Chinese Academy of
Medical Sciences, Peking Union Medical College Hospital, Beijing 100730,
People's Republic of China.
OBJECTIVE: The aryl hydrocarbon receptor interacting protein gene (AIP) is
associated with pituitary adenoma (PA). AIP has not been sequenced in East Asian
PA populations, so we performed this study in a Han Chinese cohort.
DESIGN: Our study included six familial PA pedigrees comprising 16 patients and
27 unaffected relatives, as well as 216 sporadic PA (SPA) patients and 100
unrelated healthy controls.
METHODS: AIP sequencing was carried out on genomic DNA isolated from blood
samples. Multiplex ligation-dependent probe amplification and microsatellite
marker analyses on DNA from the paired tumor tissues were performed for loss of
heterozygosity analysis.
RESULTS: We identified three common and four rare single nucleotide
polymorphisms (SNPs), one intron insertion, one novel synonymous variant, four
novel missense variants, and a reported nonsense mutation in three familial
isolated PA (FIPA) cases from the same family. Large genetic deletions were not
observed in the germline but were seen in the sporadic tumor DNA from three
missense variant carriers. The prevalence of AIP pathogenic variants in PA
patients here was low (3.88%), but was higher in somatotropinoma patients
(9.30%), especially in young adults (≤30 years) and pediatric (≥18 years)
paients (17.24% and 25.00% respectively). All AIP variant patients suffered from
macroadenomas. However, the AIP mutation rate in FIPA families was low in this
cohort (16.67%, 1/6 families).
CONCLUSION: AIP gene mutation may not be frequent in FIPA or SPA from the Han
Chinese population. AIP sequencing and long-term follow-up investigations should
be performed for young patients with large PAs and their families with PA
predisposition.
DOI: 10.1530/EJE-13-0442
PMID: 24050928 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25646180
|
1. Clin Cancer Res. 2015 Feb 1;21(3):505-13. doi: 10.1158/1078-0432.CCR-14-0507.
Molecular pathways: novel approaches for improved therapeutic targeting of
Hedgehog signaling in cancer stem cells.
Justilien V(1), Fields AP(2).
Author information:
(1)Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center,
Jacksonville, Florida.
(2)Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center,
Jacksonville, Florida. [email protected].
The Hedgehog (Hh) signaling pathway is critical for embryonic development. In
adult tissues, Hh signaling is relatively quiescent with the exception of roles
in tissue maintenance and repair. Aberrant activation of Hh signaling is
implicated in multiple aspects of transformation, including the maintenance of
the cancer stem cell (CSC) phenotype. Preclinical studies indicate that CSCs
from many tumor types are sensitive to Hh pathway inhibition and that
Hh-targeted therapeutics block many aspects of transformation attributed to
CSCs, including drug resistance, relapse, and metastasis. However, to date, Hh
inhibitors, specifically those targeting Smoothened [such as vismodegib,
BMS-833923, saridegib (IPI-926), sonidegib/erismodegib (LDE225), PF-04449913,
LY2940680, LEQ 506, and TAK-441], have demonstrated good efficacy as monotherapy
in patients with basal cell carcinoma and medulloblastoma, but have shown
limited activity in other tumor types. This lack of success is likely due to
many factors, including a lack of patient stratification in early trials,
cross-talk between Hh and other oncogenic signaling pathways that can modulate
therapeutic response, and a limited knowledge of Hh pathway activation
mechanisms in CSCs from most tumor types. Here, we discuss Hh signaling
mechanisms in the context of human cancer, particularly in the maintenance of
the CSC phenotype, and consider new therapeutic strategies that hold the
potential to expand considerably the scope and therapeutic efficacy of
Hh-directed anticancer therapy.
©2015 American Association for Cancer Research.
DOI: 10.1158/1078-0432.CCR-14-0507
PMCID: PMC4316382
PMID: 25646180 [Indexed for MEDLINE]
Conflict of interest statement: Disclosure of Potential Conflicts of Interest:
A.P. Fields reports receiving a commercial research grant from Teva
Pharmaceuticals. No potential conflicts of interest were disclosed by the other
author.
|
http://www.ncbi.nlm.nih.gov/pubmed/23743763
|
1. Pituitary. 2014 Jun;17(3):220-6. doi: 10.1007/s11102-013-0493-1.
Familial acromegaly due to aryl hydrocarbon receptor-interacting protein (AIP)
gene mutation in a Turkish cohort.
Niyazoglu M(1), Sayitoglu M, Firtina S, Hatipoglu E, Gazioglu N, Kadioglu P.
Author information:
(1)Division of Endocrinology and Metabolism, Department of Internal Medicine,
Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.
Aryl hydrocarbon receptor-interacting protein (AIP) is associated with 15-20% of
familial isolated pituitary adenomas and 50-80% of cases with AIP mutation
exhibit a somatotropinoma. Herein we report clinical characteristics of a large
family where AIP R304X variants have been identified. AIP mutation analysis was
performed on a large (n = 52) Turkish family across six generations. Sella MRIs
of 30 family members were obtained. Basal pituitary hormone levels were
evaluated in 13 family members harboring an AIP mutation. Thirteen of 52 family
members (25%) were found to have a heterozygous nonsense germline R304X mutation
in the AIP gene. Seven of the 13 mutation carriers (53.8%) had current or
previous history of pituitary adenoma. Of these 7 mutation carriers, all but one
had somatotropinoma/somatolactotropinoma (85.7% of the pituitary adenomas). Of
the 6 acromegaly patients with AIP mutation (F/M: 3/3) the mean age at diagnosis
of acromegaly was 32 ± 10.3 years while the mean age of symptom onset was 24.8 ±
9.9 years. Three of the six (50%) acromegaly cases with AIP mutation within the
family presented with a macroadenoma and none presented with gigantism.
Biochemical disease control was achieved in 66.6% (4/6) of the mutation carriers
with acromegaly after a mean follow-up period of 18.6 ± 17.6 years. Common
phenotypic characteristics of familial pituitary adenoma or somatotropinoma due
to AIP mutation vary between families or even between individuals within a
family.
DOI: 10.1007/s11102-013-0493-1
PMID: 23743763 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/7771924
|
1. Arkh Patol. 1995 Jan-Feb;57(1):16-22.
[Peripheral primitive neuroectodermal tumors of the soft tissues and bones].
[Article in Russian]
Smirnov AV, Solov'ev IuN.
Large group of small-round-cell tumours of soft tissues and bone represents a
complex diagnostic problem for the pathologists. Neuronal nature of many tumours
from this group is proven by means of new methods--immunophenotypic analysis,
tissue culture, cytogenetics. Peripheral neuroepithelioma, Ewing tumour,
primitive neuroectodermal tumour (PNET), Askin tumour belong to these neoplasms.
These tumours anatomically have no connection with the structures of the central
nervous system or autonomous sympathetic nervous system.
PMID: 7771924 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22464440
|
1. Mol Cell. 2012 Mar 30;45(6):708-9. doi: 10.1016/j.molcel.2012.03.014.
R loops: lassoing DNA methylation at CpGi.
Vertino PM(1), Wade PA.
Author information:
(1)Department of Radiation Oncology and the Winship Cancer Institute, Emory
University School of Medicine, Atlanta, GA 30307, USA. [email protected]
Comment on
Mol Cell. 2012 Mar 30;45(6):814-25. doi: 10.1016/j.molcel.2012.01.017.
In this issue of Molecular Cell, Ginno et al. (2012) describe unusual sequence
features at promoter CpG islands that can lead to formation of persistent
RNA-DNA hybrids (R loops), which are proposed to prevent genomic DNA
methylation.
Copyright © 2012 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.molcel.2012.03.014
PMID: 22464440
|
http://www.ncbi.nlm.nih.gov/pubmed/24523439
|
1. Clin Cancer Res. 2014 Apr 1;20(7):1900-9. doi: 10.1158/1078-0432.CCR-13-1710.
Epub 2014 Feb 12.
A phase I, multicenter, open-label, first-in-human, dose-escalation study of the
oral smoothened inhibitor Sonidegib (LDE225) in patients with advanced solid
tumors.
Rodon J(1), Tawbi HA, Thomas AL, Stoller RG, Turtschi CP, Baselga J,
Sarantopoulos J, Mahalingam D, Shou Y, Moles MA, Yang L, Granvil C, Hurh E, Rose
KL, Amakye DD, Dummer R, Mita AC.
Author information:
(1)Authors' Affiliations: Vall d'Hebron Institut d'Oncologia and Universitat
Autonoma of Barcelona, Barcelona, Spain; University of Pittsburgh Cancer
Institute and University of Pittsburgh School of Medicine, Pittsburgh,
Pennsylvania; University of Leicester, Leicester, United Kingdom; University
Hospital of Zürich, Zürich, Switzerland; Memorial Sloan-Kettering Cancer Center,
New York, New York; Institute for Drug Development, Cancer Therapy and Research
Center, University of Texas Health Science Center, San Antonio, Texas; Novartis
Institutes for BioMedical Research, Cambridge, Massachusetts; and Novartis
Pharmaceuticals Corporation, East Hanover, New Jersey.
PURPOSE: This phase I trial was undertaken to determine the maximum tolerated
dose (MTD), dose-limiting toxicities (DLT), safety, tolerability,
pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the
novel smoothened inhibitor sonidegib (LDE225), a potent inhibitor of hedgehog
signaling, in patients with advanced solid tumors.
EXPERIMENTAL DESIGN: Oral sonidegib was administered to 103 patients with
advanced solid tumors, including medulloblastoma and basal cell carcinoma (BCC),
at doses ranging from 100 to 3,000 mg daily and 250 to 750 mg twice daily,
continuously, with a single-dose pharmacokinetics run-in period. Dose
escalations were guided by a Bayesian logistic regression model. Safety,
tolerability, efficacy, pharmacokinetics, and biomarkers in skin and tumor
biopsies were assessed.
RESULTS: The MTDs of sonidegib were 800 mg daily and 250 mg twice daily. The
main DLT of reversible grade 3/4 elevated serum creatine kinase (18% of
patients) was observed at doses ≥ the MTD in an exposure-dependent manner.
Common grade 1/2 adverse events included muscle spasm, myalgia, gastrointestinal
toxicities, increased liver enzymes, fatigue, dysgeusia, and alopecia. Sonidegib
exposure increased dose proportionally up to 400 mg daily, and displayed
nonlinear pharmacokinetics at higher doses. Sonidegib exhibited
exposure-dependent reduction in GLI1 mRNA expression. Tumor responses observed
in patients with medulloblastoma and BCC were associated with evidence of
hedgehog pathway activation.
CONCLUSIONS: Sonidegib has an acceptable safety profile in patients with
advanced solid tumors and exhibits antitumor activity in advanced BCC and
relapsed medulloblastoma, both of which are strongly associated with activated
hedgehog pathway, as determined by gene expression.
©2014 AACR.
DOI: 10.1158/1078-0432.CCR-13-1710
PMID: 24523439 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24817600
|
1. Cancer Chemother Pharmacol. 2014 Jul;74(1):63-75. doi:
10.1007/s00280-014-2468-y. Epub 2014 May 10.
Absorption, distribution, metabolism, and excretion (ADME) of ¹⁴C-sonidegib
(LDE225) in healthy volunteers.
Zollinger M(1), Lozac'h F, Hurh E, Emotte C, Bauly H, Swart P.
Author information:
(1)Drug Metabolism and Pharmacokinetics (DMPK), Novartis Institutes for
BioMedical Research, Fabrikstrasse 14, 4002, Basel, Switzerland,
[email protected].
PURPOSE: The absorption, distribution, metabolism, and excretion of the hedgehog
pathway inhibitor sonidegib (LDE225) were determined in healthy male subjects.
METHODS: Six subjects received a single oral dose of 800 mg ¹⁴C-sonidegib (74
kBq, 2.0 µCi) under fasting conditions. Blood, plasma, urine, and fecal samples
were collected predose, postdose in-house (days 1-22), and during 24-h visits
(weekly, days 29-43; biweekly, days 57-99). Radioactivity was determined in all
samples using accelerator mass spectrometry (AMS). Liquid chromatography-tandem
mass spectrometry (LC-MS/MS) was used to determine concentrations of sonidegib
and its main circulating metabolite in plasma. Metabolite profiles and
structures were determined in pooled plasma, urine, and fecal samples using
high-performance LC-AMS and LC-MS/MS, respectively.
RESULTS: A single dose of ¹⁴C-sonidegib was well tolerated in healthy subjects.
Unchanged sonidegib and total radioactivity reached peak concentration in plasma
by 2 and 3 h, respectively, and demonstrated similarly long half-lives of 319
and 331 h, respectively. Absorbed sonidegib (estimated 6-7 %) was extensively
distributed, and the approximate terminal volume of distribution was 2,500 L.
Unchanged sonidegib and a metabolite resulting from amide hydrolysis were the
major circulating components (36.4 and 15.4 % of radioactivity area under the
curve, respectively). Absorbed sonidegib was eliminated predominantly through
oxidative metabolism of the morpholine part and amide hydrolysis. Unabsorbed
sonidegib was excreted through the feces. Metabolites in excreta accounted for
4.49 % of the dose (1.20 % in urine, 3.29 % in feces). The recovery of
radioactivity in urine and feces was essentially complete (95.3 ± 1.93 % of the
dose in five subjects; 56.9 % of the dose in one subject with incomplete feces
collection suspected).
CONCLUSIONS: Sonidegib exhibited low absorption, was extensively distributed,
and was slowly metabolized. Elimination of absorbed sonidegib occurred largely
by oxidative and hydrolytic metabolism.
DOI: 10.1007/s00280-014-2468-y
PMID: 24817600 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24598114
|
1. J Hematol Oncol. 2014 Mar 5;7:18. doi: 10.1186/1756-8722-7-18.
Targeting hedgehog signaling in myelofibrosis and other hematologic
malignancies.
Tibes R(1), Mesa RA.
Author information:
(1)Mayo Clinic Cancer Center, NCI Designated Comprehensive Cancer Center, 13400
E, Shea Blvd, Scottsdale, AZ 85259, USA. [email protected].
Treatment of myelofibrosis (MF), a BCR-ABL-negative myeloproliferative neoplasm,
is challenging. The only current potentially curative option, allogeneic
hematopoietic stem cell transplant, is recommended for few patients. The
remaining patients are treated with palliative therapies to manage MF-related
anemia and splenomegaly. Identification of a mutation in the Janus kinase 2
(JAK2) gene (JAK2 V617F) in more than half of all patients with MF has prompted
the discovery and clinical development of inhibitors that target JAK2. Although
treatment with JAK2 inhibitors has been shown to improve symptom response and
quality of life in patients with MF, these drugs do not alter the underlying
disease; therefore, novel therapies are needed. The hedgehog (Hh) signaling
pathway has been shown to play a role in normal hematopoiesis and in the
tumorigenesis of hematologic malignancies. Moreover, inhibitors of the Hh
pathway have been shown to inhibit growth and self-renewal capacity in
preclinical models of MF. In a mouse model of MF, combined inhibition of the Hh
and JAK pathways reduced JAK2 mutant allele burden, reduced bone marrow
fibrosis, and reduced white blood cell and platelet counts. Preliminary clinical
data also suggest that inhibition of the Hh pathway, alone or in combination
with JAK2 inhibition, may enable disease modification in patients with MF.
Future studies, including one combining the Hh pathway inhibitor sonidegib and
the JAK2 inhibitor ruxolitinib, are underway in patients with MF and will inform
whether this combination approach can lead to true disease modification.
DOI: 10.1186/1756-8722-7-18
PMCID: PMC3975838
PMID: 24598114 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24423289
|
1. J Clin Endocrinol Metab. 2014 Apr;99(4):1122-31. doi: 10.1210/jc.2013-2868.
Epub 2013 Jan 1.
Clinical experience in the screening and management of a large kindred with
familial isolated pituitary adenoma due to an aryl hydrocarbon receptor
interacting protein (AIP) mutation.
Williams F(1), Hunter S, Bradley L, Chahal HS, Storr HL, Akker SA, Kumar AV,
Orme SM, Evanson J, Abid N, Morrison PJ, Korbonits M, Atkinson AB.
Author information:
(1)Regional Center for Endocrinology and Diabetes (F.W., S.H., A.B.A.), Royal
Victoria Hospital, Belfast BT12 6BA, Northern Ireland, United Kingdom;
Department of Medical Genetics (L.B., P.J.M.), Belfast Health and Social Care
Trust, Belfast BT9 7AB, Northern Ireland, United Kingdom; Department of
Endocrinology (H.S.C., H.L.S., S.A.A., M.K.), Barts and London School of
Medicine, Queen Mary University of London, London EC1A 6BQ, United Kingdom;
North East Thames Regional Genetics Service (A.V.K.), Great Ormond Street
Hospital, London WC1N 3JH, United Kingdom; Department of Endocrinology (S.M.O.),
St James University Hospital, Leeds LS9 7TF, United Kingdom; Department of
Radiology (J.E.), St Bartholomew Hospital, London EC1A 7BE, United Kingdom; and
Department of Endocrinology (N.A.), Royal Belfast Hospital for Sick Children,
Belfast, BT12 6BA, United Kingdom.
CONTEXT: Germline AIP mutations usually cause young-onset acromegaly with low
penetrance in a subset of familial isolated pituitary adenoma families. We
describe our experience with a large family with R304* AIP mutation and discuss
some of the diagnostic dilemmas and management issues.
OBJECTIVE: The aim of the study was to identify and screen mutation carriers in
the family.
PATIENTS: Forty-three family members participated in the study.
SETTING: The study was performed in university hospitals.
OUTCOME: We conducted genetic and endocrine screening of family members.
RESULTS: We identified 18 carriers of the R304* mutation, three family members
with an AIP-variant A299V, and two family members who harbored both changes. One
of the two index cases presented with gigantism and pituitary apoplexy, the
other presented with young-onset acromegaly, and both had surgery and
radiotherapy. After genetic and clinical screening of the family, two R304*
carriers were diagnosed with acromegaly. They underwent transsphenoidal surgery
after a short period of somatostatin analog treatment. One of these two patients
is in remission; the other achieved successful pregnancy despite suboptimal
control of acromegaly. One of the A299V carrier family members was previously
diagnosed with a microprolactinoma; we consider this case to be a phenocopy.
Height of the unaffected R304* carrier family members is not different compared
to noncarrier relatives.
CONCLUSIONS: Families with AIP mutations present particular problems such as the
occurrence of large invasive tumors, poor response to medical treatment,
difficulties with fertility and management of pregnancy, and the finding of AIP
sequence variants of unknown significance. Because disease mostly develops at a
younger age and penetrance is low, the timing and duration of the follow-up of
carriers without overt disease requires further study. The psychological and
financial impact of prolonged clinical screening must be considered. Excellent
relationships between the family, endocrinologists, and geneticists are
essential, and ideally these families should be managed in centers with
specialist expertise.
DOI: 10.1210/jc.2013-2868
PMID: 24423289 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17961654
|
1. Ann Endocrinol (Paris). 2007 Jun;68 Suppl 1:9-11. doi:
10.1016/s0003-4266(07)80003-5.
[Familial pituitary adenomas: clinical and genetic aspects].
[Article in French]
Bricaire L(1), Brue T.
Author information:
(1)Service d'endocrinologie, CHU St Antoine, 184 rue du Fbg St. Antoine, 75571
Paris 12, France. [email protected]
Erratum in
Ann Endocrinol (Paris). 2008 Nov;69(5):459-60.
Pituitary adenomas can occur in a familial context, or they can be isolated
cases, sometimes due to a predisposing syndrome. In multiple endocrine neoplasia
type 1, they often associate with a mutation of the menin gene, a
tumor-suppressing gene. A new germinal mutation predisposing to the development
of multiple endocrine neoplasias has recently been identified in MENI-negative
subjects on the gene CDKN1B encoding for p27(kip1)protein. Carney Complex
syndrome--a rare disease--is in more than 60% of the cases linked to the
inactivation mutation of a gene located on 17q22-24 that encodes the regulatory
subunit 1 of protein kinase A, PRKARIA. Isolated familial pituitary adenomas
represent 1.9 to 3.2% of the population of subjects presenting a pituitary
adenoma. Low penetrance non-sense mutations, Q14X, IVS3-IG>A and R304X, in
11q12-11q13 region encoding AIP protein, (Aryl hydrocarbon receptor Interacting
Protein), have been described by Vierimaa et al, in Finish patients with
pituitary adenoma predispositions.
DOI: 10.1016/s0003-4266(07)80003-5
PMID: 17961654 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22915287
|
1. Pituitary. 2013 Jun;16(2):238-44. doi: 10.1007/s11102-012-0409-5.
Should aip gene screening be recommended in family members of FIPA patients with
R16H variant?
Zatelli MC(1), Torre ML, Rossi R, Ragonese M, Trimarchi F, degli Uberti E,
Cannavò S.
Author information:
(1)Department of Biomedical Sciences and Advanced Therapies, Section of
Endocrinology, University of Ferrara, Ferrara, Italy.
Germline mutations of aryl-hydrocarbon-receptor interacting protein (AIP) are
associated with pituitary adenoma predisposition. They occur in 20 % of familial
isolated pituitary adenoma (FIPA) and in about 3-5 % of sporadic pituitary
adenomas, especially in early onset somatotropinomas and prolactinomas. Our aim
was to evaluate the clinical and genetic features of a large Italian FIPA
family, where an AIP variant was identified. AIP direct sequencing from genomic
DNA was carried out in 16 available family members. AIP R16H carriers also
underwent magnetic resonance imaging and hormonal assessments. AIP mutations
were also searched in 16 patients with sporadic growth hormone-secreting
pituitary adenoma and in 6 unrelated patients in whom pituitary adenoma was
excluded. We found an AIP R16H variation in two family members harbouring a
pituitary adenoma and in 6 unaffected family members. No AIP mutation was found
neither in growth hormone-secreting pituitary adenoma patients, nor in the
unrelated patients without pituitary adenoma. We report a FIPA family harbouring
an AIP R16H change, supporting the hypothesis that the latter represents a
variant of unknown significance.
DOI: 10.1007/s11102-012-0409-5
PMID: 22915287 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24787137
|
1. PLoS Genet. 2014 May 1;10(5):e1004318. doi: 10.1371/journal.pgen.1004318.
eCollection 2014 May.
R-loops associated with triplet repeat expansions promote gene silencing in
Friedreich ataxia and fragile X syndrome.
Groh M(1), Lufino MM(2), Wade-Martins R(2), Gromak N(1).
Author information:
(1)Sir William Dunn School of Pathology, University of Oxford, Oxford, United
Kingdom.
(2)Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford,
United Kingdom.
Friedreich ataxia (FRDA) and Fragile X syndrome (FXS) are among 40 diseases
associated with expansion of repeated sequences (TREDs). Although their
molecular pathology is not well understood, formation of repressive chromatin
and unusual DNA structures over repeat regions were proposed to play a role. Our
study now shows that RNA/DNA hybrids (R-loops) form in patient cells on expanded
repeats of endogenous FXN and FMR1 genes, associated with FRDA and FXS. These
transcription-dependent R-loops are stable, co-localise with repressive H3K9me2
chromatin mark and impede RNA Polymerase II transcription in patient cells. We
investigated the interplay between repressive chromatin marks and R-loops on the
FXN gene. We show that decrease in repressive H3K9me2 chromatin mark has no
effect on R-loop levels. Importantly, increasing R-loop levels by treatment with
DNA topoisomerase inhibitor camptothecin leads to up-regulation of repressive
chromatin marks, resulting in FXN transcriptional silencing. This provides a
direct molecular link between R-loops and the pathology of TREDs, suggesting
that R-loops act as an initial trigger to promote FXN and FMR1 silencing. Thus
R-loops represent a common feature of nucleotide expansion disorders and provide
a new target for therapeutic interventions.
DOI: 10.1371/journal.pgen.1004318
PMCID: PMC4006715
PMID: 24787137 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/23371967
|
1. Endocr Rev. 2013 Apr;34(2):239-77. doi: 10.1210/er.2012-1013. Epub 2013 Jan
31.
Familial isolated pituitary adenomas (FIPA) and the pituitary adenoma
predisposition due to mutations in the aryl hydrocarbon receptor interacting
protein (AIP) gene.
Beckers A(1), Aaltonen LA, Daly AF, Karhu A.
Author information:
(1)Department of Endocrinology, Centre Hospitalier Universitaire de Liège,
University of Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, Belgium.
[email protected]
Pituitary adenomas are one of the most frequent intracranial tumors and occur
with a prevalence of approximately 1:1000 in the developed world. Pituitary
adenomas have a serious disease burden, and their management involves
neurosurgery, biological therapies, and radiotherapy. Early diagnosis of
pituitary tumors while they are smaller may help increase cure rates. Few
genetic predictors of pituitary adenoma development exist. Recent years have
seen two separate, complimentary advances in inherited pituitary tumor research.
The clinical condition of familial isolated pituitary adenomas (FIPA) has been
described, which encompasses the familial occurrence of isolated pituitary
adenomas outside of the setting of syndromic conditions like multiple endocrine
neoplasia type 1 and Carney complex. FIPA families comprise approximately 2% of
pituitary adenomas and represent a clinical entity with homogeneous or
heterogeneous pituitary adenoma types occurring within the same kindred. The
aryl hydrocarbon receptor interacting protein (AIP) gene has been identified as
causing a pituitary adenoma predisposition of variable penetrance that accounts
for 20% of FIPA families. Germline AIP mutations have been shown to associate
with the occurrence of large pituitary adenomas that occur at a young age,
predominantly in children/adolescents and young adults. AIP mutations are
usually associated with somatotropinomas, but prolactinomas, nonfunctioning
pituitary adenomas, Cushing disease, and other infrequent clinical adenoma types
can also occur. Gigantism is a particular feature of AIP mutations and occurs in
more than one third of affected somatotropinoma patients. Study of pituitary
adenoma patients with AIP mutations has demonstrated that these cases raise
clinical challenges to successful treatment. Extensive research on the biology
of AIP and new advances in mouse Aip knockout models demonstrate multiple
pathways by which AIP may contribute to tumorigenesis. This review assesses the
current clinical and therapeutic characteristics of more than 200 FIPA families
and addresses research findings among AIP mutation-bearing patients in different
populations with pituitary adenomas.
DOI: 10.1210/er.2012-1013
PMCID: PMC3610678
PMID: 23371967 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25972891
|
1. Front Genet. 2015 Apr 28;6:158. doi: 10.3389/fgene.2015.00158. eCollection
2015.
R-loops and initiation of DNA replication in human cells: a missing link?
Lombraña R(1), Almeida R(1), Álvarez A(1), Gómez M(1).
Author information:
(1)Functional Organization of the Genome Group, Centro de Biología Molecular
"Severo Ochoa", Consejo Superior de Investigaciones Científicas/Universidad
Autónoma de Madrid , Madrid, Spain.
The unanticipated widespread occurrence of stable hybrid DNA/RNA structures
(R-loops) in human cells and the increasing evidence of their involvement in
several human malignancies have invigorated the research on R-loop biology in
recent years. Here we propose that physiological R-loop formation at CpG island
promoters can contribute to DNA replication origin specification at these
regions, the most efficient replication initiation sites in mammalian cells.
Quite likely, this occurs by the strand-displacement reaction activating the
formation of G-quadruplex structures that target the origin recognition complex
(ORC) in the single-stranded conformation. In agreement with this, we found that
R-loops co-localize with the ORC within the same CpG island region in a
significant fraction of these efficient replication origins, precisely at the
position displaying the highest density of G4 motifs. This scenario builds on
the connection between transcription and replication in human cells and suggests
that R-loop dysregulation at CpG island promoter-origins might contribute to the
phenotype of DNA replication abnormalities and loss of genome integrity detected
in cancer cells.
DOI: 10.3389/fgene.2015.00158
PMCID: PMC4412123
PMID: 25972891
|
http://www.ncbi.nlm.nih.gov/pubmed/25296254
|
1. Nature. 2014 Dec 18;516(7531):436-9. doi: 10.1038/nature13787. Epub 2014 Oct
5.
R-loops induce repressive chromatin marks over mammalian gene terminators.
Skourti-Stathaki K(1), Kamieniarz-Gdula K(1), Proudfoot NJ(1).
Author information:
(1)Sir William Dunn School of Pathology, South Parks Road, University of Oxford,
Oxford OX1 3RE, UK.
The formation of R-loops is a natural consequence of the transcription process,
caused by invasion of the DNA duplex by nascent transcripts. These structures
have been considered rare transcriptional by-products with potentially harmful
effects on genome integrity owing to the fragility of the displaced DNA coding
strand. However, R-loops may also possess beneficial effects, as their
widespread formation has been detected over CpG island promoters in human genes.
Furthermore, we have previously shown that R-loops are particularly enriched
over G-rich terminator elements. These facilitate RNA polymerase II (Pol II)
pausing before efficient termination. Here we reveal an unanticipated link
between R-loops and RNA-interference-dependent H3K9me2 formation over pause-site
termination regions in mammalian protein-coding genes. We show that R-loops
induce antisense transcription over these pause elements, which in turn leads to
the generation of double-stranded RNA and the recruitment of DICER, AGO1, AGO2
and the G9a histone lysine methyltransferase. Consequently, an H3K9me2
repressive mark is formed and heterochromatin protein 1γ (HP1γ) is recruited,
which reinforces Pol II pausing before efficient transcriptional termination. We
predict that R-loops promote a chromatin architecture that defines the
termination region for a substantial subset of mammalian genes.
DOI: 10.1038/nature13787
PMCID: PMC4272244
PMID: 25296254 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22291433
|
1. Endocr Relat Cancer. 2012 May 3;19(3):233-41. doi: 10.1530/ERC-11-0362. Print
2012 Jun.
Cyclin-dependent kinase inhibitor 1B (CDKN1B) gene variants in AIP
mutation-negative familial isolated pituitary adenoma kindreds.
Tichomirowa MA(1), Lee M, Barlier A, Daly AF, Marinoni I, Jaffrain-Rea ML, Naves
LA, Rodien P, Rohmer V, Faucz FR, Caron P, Estour B, Lecomte P, Borson-Chazot F,
Penfornis A, Yaneva M, Guitelman M, Castermans E, Verhaege C, Wémeau JL, Tabarin
A, Fajardo Montañana C, Delemer B, Kerlan V, Sadoul JL, Cortet Rudelli C,
Archambeaud F, Zacharieva S, Theodoropoulou M, Brue T, Enjalbert A, Bours V,
Pellegata NS, Beckers A.
Author information:
(1)Department of Endocrinology, Centre Hospitalier Universitaire de Liège,
Domaine Universitaire du Sart-Tilman, University of Liège, 4000 Liège, Belgium.
Familial isolated pituitary adenoma (FIPA) occurs in families and is unrelated
to multiple endocrine neoplasia type 1 and Carney complex. Mutations in AIP
account only for 15-25% of FIPA families. CDKN1B mutations cause MEN4 in which
affected patients can suffer from pituitary adenomas. With this study, we wanted
to assess whether mutations in CDKN1B occur among a large cohort of AIP
mutation-negative FIPA kindreds. Eighty-eight AIP mutation-negative FIPA
families were studied and 124 affected subjects underwent sequencing of CDKN1B.
Functional analysis of putative CDKN1B mutations was performed using in silico
and in vitro approaches. Germline CDKN1B analysis revealed two nucleotide
changes: c.286A>C (p.K96Q) and c.356T>C (p.I119T). In vitro, the K96Q change
decreased p27 affinity for Grb2 but did not segregate with pituitary adenoma in
the FIPA kindred. The I119T substitution occurred in a female patient with
acromegaly. p27(I119T) shows an abnormal migration pattern by SDS-PAGE. Three
variants (p.S56T, p.T142T, and c.605+36C>T) are likely nonpathogenic because In
vitro effects were not seen. In conclusion, two patients had germline sequence
changes in CDKN1B, which led to functional alterations in the encoded p27
proteins in vitro. Such rare CDKN1B variants may contribute to the development
of pituitary adenomas, but their low incidence and lack of clear segregation
with affected patients make CDKN1B sequencing unlikely to be of use in routine
genetic investigation of FIPA kindreds. However, further characterization of the
role of CDKN1B in pituitary tumorigenesis in these and other cases could help
clarify the clinicopathological profile of MEN4.
DOI: 10.1530/ERC-11-0362
PMID: 22291433 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20570174
|
1. Trends Endocrinol Metab. 2010 Jul;21(7):419-27. doi:
10.1016/j.tem.2010.02.007. Epub 2010 Jun 1.
Clinical, genetic and molecular characterization of patients with familial
isolated pituitary adenomas (FIPA).
Chahal HS(1), Chapple JP, Frohman LA, Grossman AB, Korbonits M.
Author information:
(1)Department of Endocrinology, Barts and the London School of Medicine, Queen
Mary University of London, London EC1M 6BQ, UK.
Familial pituitary adenomas can occur in MEN1 and Carney complex, as well as in
the recently characterized familial isolated pituitary adenoma (FIPA) syndrome.
FIPA is an autosomal dominant disease with incomplete penetrance, characterized
by early-onset disease, often aggressive tumor growth and a predominance of
somatotroph and lactotroph adenomas. In 20% of FIPA families, heterozygous
mutations have been described in the aryl hydrocarbon receptor interacting (AIP)
gene, whereas in other families the causative gene(s) are unknown. It has been
suggested that AIP is a tumor suppressor gene and although experimental data
support this hypothesis, the exact molecular mechanism by which its disruption
leads to tumorigenesis is unclear. Here we discuss the clinical, genetic and
molecular features of patients with FIPA.
Copyright 2010 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.tem.2010.02.007
PMID: 20570174 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23633209
|
1. J Clin Endocrinol Metab. 2013 Jul;98(7):2800-10. doi: 10.1210/jc.2012-4029.
Epub 2013 Apr 30.
Aryl hydrocarbon receptor interacting protein (AIP) mutations occur rarely in
sporadic parathyroid adenomas.
Pardi E(1), Marcocci C, Borsari S, Saponaro F, Torregrossa L, Tancredi M,
Raspini B, Basolo F, Cetani F.
Author information:
(1)Department of Clinical and Experimental Medicine, University of Pisa, 56124
Pisa, Italy.
CONTEXT: The molecular pathogenesis of primary hyperparathyroidism is still
largely unknown. The aryl hydrocarbon receptor interacting protein (AIP) gene
has a major role in the pathogenesis of familial isolated pituitary adenoma.
OBJECTIVE: We evaluated the involvement of the AIP gene in sporadic parathyroid
adenomas.
PATIENTS AND DESIGN: We performed direct sequencing and multiplex
ligation-dependent probe amplification analyses of the AIP gene in a large
series of sporadic parathyroid adenomas. Loss of heterozygosity (LOH) at the AIP
locus was studied, and aryl hydrocarbon receptor interacting protein
immunostaining was also performed. In addition, alterations in the MEN1 gene
were studied.
RESULTS: A somatic AIP mutation, substitution of arginine with glutamine at
codon 304 (R304Q), was identified in 2 of 132 tumors. The mutation was germline
in both cases despite the nonfamilial presentation. Heterozygous AIP large
deletions were detected in 29 cases including 1 of the 2 mutated tumors,
confirming a biallelic inactivation of the AIP gene. The AIP-mutated tumor with
LOH showed decreased AIP immunostaining compared with normal parathyroid. LOH at
the MEN1 locus, which often shared LOH at the AIP locus, was found in one third
of tumors. Somatic MEN1 mutations were found in the 1 of the 2 AIP-mutated
tumors and in 22 parathyroid adenomas. In addition, multiplex ligation-dependent
probe amplification analysis revealed 1 large deletion of the MEN1 gene in 1
patient.
CONCLUSIONS: The AIP gene is rarely involved in parathyroid adenomas, but the
germline nature of the mutations suggests that it might predispose to primary
hyperparathyroidism. MEN1 gene alterations occur in a substantial proportion of
sporadic parathyroid adenomas.
DOI: 10.1210/jc.2012-4029
PMID: 23633209 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17244780
|
1. J Clin Endocrinol Metab. 2007 May;92(5):1891-6. doi: 10.1210/jc.2006-2513.
Epub 2007 Jan 23.
Aryl hydrocarbon receptor-interacting protein gene mutations in familial
isolated pituitary adenomas: analysis in 73 families.
Daly AF(1), Vanbellinghen JF, Khoo SK, Jaffrain-Rea ML, Naves LA, Guitelman MA,
Murat A, Emy P, Gimenez-Roqueplo AP, Tamburrano G, Raverot G, Barlier A, De
Herder W, Penfornis A, Ciccarelli E, Estour B, Lecomte P, Gatta B, Chabre O,
Sabaté MI, Bertagna X, Garcia Basavilbaso N, Stalldecker G, Colao A, Ferolla P,
Wémeau JL, Caron P, Sadoul JL, Oneto A, Archambeaud F, Calender A, Sinilnikova
O, Montañana CF, Cavagnini F, Hana V, Solano A, Delettieres D, Luccio-Camelo DC,
Basso A, Rohmer V, Brue T, Bours V, Teh BT, Beckers A.
Author information:
(1)Department of Endocrinology, Centre Hospitalier Universitaire de Liège,
University of Liège, Domaine Universitaire du Sart Tilman, 4000 Liège, Belgium.
Comment in
J Clin Endocrinol Metab. 2007 May;92(5):1617-9. doi: 10.1210/jc.2007-0595.
CONTEXT: An association between germline aryl hydrocarbon receptor-interacting
protein (AIP) gene mutations and pituitary adenomas was recently shown.
OBJECTIVE: The objective of the study was to assess the frequency of AIP gene
mutations in a large cohort of patients with familial isolated pituitary adenoma
(FIPA).
DESIGN: This was a multicenter, international, collaborative study.
SETTING: The study was conducted in 34 university endocrinology and genetics
departments in nine countries.
PATIENTS: Affected members from each FIPA family were studied. Relatives of
patients with AIP mutations underwent AIP sequence analysis.
MAIN OUTCOME MEASURES: Presence/absence and description of AIP gene mutations
were the main outcome measures.
INTERVENTION: There was no intervention.
RESULTS: Seventy-three FIPA families were identified, with 156 patients with
pituitary adenomas; the FIPA cohort was evenly divided between families with
homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10
germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift,
Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described
previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a
younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative
subjects. Somatotropinomas predominated among FIPA families with AIP mutations,
but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting
adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those
with familial somatotropinomas were negative for AIP mutations.
CONCLUSIONS: AIP mutations, of which nine new mutations have been described
here, occur in approximately 15% of FIPA families. Although pituitary tumors
occurring in association with AIP mutations are predominantly somatotropinomas,
other tumor types are also seen. Further study of the impact of AIP mutations on
protein expression and activity is necessary to elucidate their role in
pituitary tumorigenesis in FIPA.
DOI: 10.1210/jc.2006-2513
PMID: 17244780 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18285522
|
1. Physiol Genomics. 2008 Apr 22;33(2):257-66. doi:
10.1152/physiolgenomics.00154.2007. Epub 2008 Feb 19.
Familial hypertrophic cardiomyopathy-related cardiac troponin C mutation L29Q
affects Ca2+ binding and myofilament contractility.
Liang B(1), Chung F, Qu Y, Pavlov D, Gillis TE, Tikunova SB, Davis JP, Tibbits
GF.
Author information:
(1)Cardiac Membrane Research Laboratory, Kinesiology, Simon Fraser University,
Burnaby, Canada.
The cardiac troponin C (cTnC) mutation, L29Q, has been found in a patient with
familial hypertrophic cardiomyopathy. We previously showed that L29, together
with neighboring residues, Asp2, Val28, and Gly30, plays an important role in
determining the Ca(2+) affinity of site II, the regulatory site of mammalian
cardiac troponin C (McTnC). Here we report on the Ca(2+) binding characteristics
of L29Q McTnC and D2N/V28I/L29Q/G30D McTnC (NIQD) utilizing the Phe(27) --> Trp
(F27W) substitution, allowing one to monitor Ca(2+) binding and release. We also
studied the effect of these mutants on Ca(2+) activation of force generation in
single mouse cardiac myocytes using cTnC replacement, together with sarcomere
length (SL) dependence. The Ca(2+)-binding affinity of site II of L29Q
McTnC(F27W) and NIQD McTnC(F27W) was approximately 1.3- and approximately
1.9-fold higher, respectively, than that of McTnC(F27W). The Ca(2+)
disassociation rate from site II of L29Q McTnC(F27W) and NIQD McTnC(F27W) was
not significantly different than that of control (McTnC(F27W)). However, the
rate of Ca(2+) binding to site II was higher in L29Q McTnC(F27W) and NIQD
McTnC(F27W) relative to control (approximately 1.5-fold and approximately
2.0-fold respectively). The Ca(2+) sensitivity of force generation was
significantly higher in myocytes reconstituted with L29Q McTnC (approximately
1.4-fold) and NIQD McTnC (approximately 2-fold) compared with those
reconstituted with McTnC. Interestingly, the change in Ca(2+) sensitivity of
force generation in response to an SL change (1.9, 2.1, and 2.3 mum) was
significantly reduced in myocytes containing L29Q McTnC or NIQD McTnC. These
results demonstrate that the L29Q mutation enhances the Ca(2+)-binding
characteristics of cTnC and that when incorporated into cardiac myocytes, this
mutant alters myocyte contractility.
DOI: 10.1152/physiolgenomics.00154.2007
PMID: 18285522 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24100689
|
1. Cancer Biol Ther. 2014 Feb;15(2):149-55. doi: 10.4161/cbt.26724. Epub 2013 Nov
1.
Beyond abiraterone: new hormonal therapies for metastatic castration-resistant
prostate cancer.
Pinto Á(1).
Author information:
(1)Medical Oncology Department; University Hospital La Paz; IdiPAZ; Madrid,
Spain.
Prostate cancer is a heterogeneous disease where the previous concept of
"hormone resistance" has been changed by a new generation of hormonal therapies
that have proven efficacy in the castration-resistant setting. The fact is that
androgens play a crucial role in the whole clinical course of prostate cancer,
even when a patient meets castration-resistance criteria. The development of
abiraterone showed how important and clinically meaningful can be to achieve the
lowest possible levels of testosterone, and androgen receptor overexpression,
mutation, or enhanced crosstalk with other pathways, which can also be targeted
with new agents tested in the last few years. New androgen biosynthesis
inhibitors have been developed, such as orteronel (TAK-700), but also new
antiandrogens (enzalutamide, ARN-509, ODM-201) or even agents with a dual
mechanism of action (galeterone). In this review the development of new hormonal
therapies following the arrival of abiraterone for the treatment of prostate
cancer will be summarized.
DOI: 10.4161/cbt.26724
PMCID: PMC3928129
PMID: 24100689 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17893250
|
1. Eur J Endocrinol. 2007 Oct;157(4):371-82. doi: 10.1530/EJE-07-0348.
The clinical, pathological, and genetic features of familial isolated pituitary
adenomas.
Beckers A(1), Daly AF.
Author information:
(1)Department of Endocrinology, Centre Hospitalier Universitaire de Liège,
Domaine Universitaire du Sart Tilman, University of Liège, 4000 Liège, Belgium.
[email protected]
Pituitary adenomas occur in a familial setting in multiple endocrine neoplasia
type 1 (MEN1) and Carney's complex (CNC), which occur due to mutations in the
genes MEN1 and PRKAR1A respectively. Isolated familial somatotropinoma (IFS) is
also a well-described clinical syndrome related only to patients with
acrogigantism. Pituitary adenomas of all types--not limited to IFS--can occur in
a familial setting in the absence of MEN1 and CNC; this phenotype is termed
familial isolated pituitary adenomas (FIPA). Over the past 7 years, we have
described over 90 FIPA kindreds. In FIPA, both homogeneous and heterogeneous
pituitary adenoma phenotypes can occur within families; virtually all FIPA
kindreds contain at least one prolactinoma or somatotropinoma. FIPA differs from
MEN1 in terms of a lower proportion of prolactinomas and more frequent
somatotropinomas in the FIPA cohort. Patients with FIPA are significantly
younger at diagnosis and have significantly larger pituitary adenomas than
matched sporadic pituitary adenoma counterparts. A minority of FIPA families
overall (15%) exhibit mutations in the aryl hydrocarbon receptor-interacting
protein (AIP) gene; AIP mutations are present in only half of IFS kindreds
occurring as part of the FIPA cohort. In families with AIP mutations, pituitary
adenomas have a penetrance of over 50%. AIP mutations are extremely rare in
patients with sporadic pituitary adenomas. This review deals with pituitary
adenomas that occur in a familial setting, describes in detail the clinical,
pathological, and genetic features of FIPA, and addresses aspects of the
clinical approach to FIPA families with and without AIP mutations.
DOI: 10.1530/EJE-07-0348
PMID: 17893250 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20833337
|
1. Best Pract Res Clin Endocrinol Metab. 2010 Jun;24(3):461-76. doi:
10.1016/j.beem.2010.03.001.
The genetics of pituitary adenomas.
Vandeva S(1), Jaffrain-Rea ML, Daly AF, Tichomirowa M, Zacharieva S, Beckers A.
Author information:
(1)Department of Endocrinology, University of Liège, Domaine Universitaire du
Sart-Tilman, 4000 Liège, Belgium.
Pituitary adenomas are one of the most frequent intracranial tumors with a
prevalence of clinically-apparent tumors close to 1:1000 of the general
population. They are clinically significant because of hormone overproduction
and/or tumor mass effects in addition to the need for neurosurgery, medical
therapies and radiotherapy. The majority of pituitary adenomas have a sporadic
origin with recognized genetic mutations seldom being found; somatotropinomas
are an exception, presenting frequent somatic GNAS mutations. In this and other
phenotypes, tumorigenesis could possibly be explained by altered function of
genes implicated in cell cycle regulation, growth factors or their receptors,
cell-signaling pathways, specific hormonal factors or other molecules with still
unclear mechanisms of action. Genetic changes, such as allelic loss or gene
amplification, and epigenetic changes, usually by promoter methylation, have
been implicated in abnormal gene expression, but alternative mechanisms may be
present. Familial cases of pituitary adenomas represent 5% of all pituitary
tumors. MEN1 mutations cause multiple endocrine neoplasia type 1 (MEN1), while
the Carney complex (CNC) is characterized by mutations in the protein kinase A
regulatory subunit-1alpha (PRKAR1A) gene or changes in a locus at 2p16.
Recently, a MEN1-like condition, MEN4, was found to be related to mutations in
the CDKN1B gene. The clinical entity of familial isolated pituitary adenomas
(FIPA) is characterized by genetic defects in the aryl hydrocarbon receptor
interacting protein (AIP) gene in about 15% of all kindreds and 50% of
homogenous somatotropinoma families. Identification of familial cases of
pituitary adenomas is important as these tumors may be more aggressive than
their sporadic counterparts.
Copyright 2010 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.beem.2010.03.001
PMID: 20833337 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21450940
|
1. Endocr Relat Cancer. 2011 Jun 8;18(3):347-56. doi: 10.1530/ERC-11-0059. Print
2011 Jun.
Hyperplasia-adenoma sequence in pituitary tumorigenesis related to aryl
hydrocarbon receptor interacting protein gene mutation.
Villa C(1), Lagonigro MS, Magri F, Koziak M, Jaffrain-Rea ML, Brauner R,
Bouligand J, Junier MP, Di Rocco F, Sainte-Rose C, Beckers A, Roux FX, Daly AF,
Chiovato L.
Author information:
(1)Unit of Neuropathology, INSERM U984 Laboratory of Glial Plasticity, Centre
Hospitalier Sainte Anne, University of Paris Descartes, 1 Rue Cabanis, 75014
Paris, France. [email protected]
Mutations of the aryl hydrocarbon receptor interacting protein (AIP) gene are
associated with pituitary adenomas that usually occur as familial isolated
pituitary adenomas (FIPA). Detailed pathological and tumor genetic data on AIP
mutation-related pituitary adenomas are not sufficient. Non-identical twin
females presented as adolescents to the emergency department with severe
progressive headache caused by large pituitary macroadenomas require emergency
neurosurgery; one patient had incipient pituitary apoplexy. Post-surgically, the
patients were found to have silent somatotrope adenomas on pathological
examination. Furthermore, the light microscopic, immunohistochemical, and
electron microscopic studies demonstrated tumors of virtually identical
characteristics. The adenomas were accompanied by multiple areas of pituitary
hyperplasia, which stained positively for GH, indicating somatotrope
hyperplasia. Genetic analyses of the FIPA kindred revealed a novel E216X
mutation of the AIP gene, which was present in both the affected patients and
the unaffected father. Molecular analysis of surgical specimens revealed loss of
heterozygosity (LOH) in the adenoma but showed that LOH was not present in the
hyperplastic pituitary tissue from either patient. AIP immunostaining confirmed
normal staining in the hyperplastic tissue and decreased staining in the adenoma
in the tumors from both patients. These results demonstrate that patients with
AIP germline mutation can present with silent somatotrope pituitary adenomas.
The finding of somatotrope hyperplasia unaccompanied by AIP LOH suggests that
LOH at the AIP locus might be a late event in a potential progression from
hyperplastic to adenomatous tissue.
DOI: 10.1530/ERC-11-0059
PMID: 21450940 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/26100513
|
1. Cell Mol Life Sci. 2015 Aug;72(15):2793-808. doi: 10.1007/s00018-015-1960-9.
Epub 2015 Jun 23.
The lung communication network.
Losa D(1), Chanson M.
Author information:
(1)Geneva University Hospitals and University of Geneva, 1211 Geneva,
Switzerland.
The different types of cells in the lung, from the conducting airway epithelium
to the alveolar epithelium and the pulmonary vasculature, are interconnected by
gap junctions. The specific profile of gap junction proteins, the connexins,
expressed in these different cell types forms compartments of intercellular
communication that can be further shaped by the release of extracellular
nucleotides via pannexin1 channels. In this review, we focus on the physiology
of connexins and pannexins and describe how this lung communication network
modulates lung function and host defenses in conductive and respiratory airways.
DOI: 10.1007/s00018-015-1960-9
PMCID: PMC11113880
PMID: 26100513 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationship that could
be construed as a potential conflict of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/22815480
|
1. J Biol Chem. 2012 Sep 14;287(38):31845-55. doi: 10.1074/jbc.M112.377713. Epub
2012 Jul 18.
A mutation in TNNC1-encoded cardiac troponin C, TNNC1-A31S, predisposes to
hypertrophic cardiomyopathy and ventricular fibrillation.
Parvatiyar MS(1), Landstrom AP, Figueiredo-Freitas C, Potter JD, Ackerman MJ,
Pinto JR.
Author information:
(1)Department of Molecular and Cellular Pharmacology, Miller School of Medicine,
University of Miami, Miami, Florida 33136, USA.
Defined as clinically unexplained hypertrophy of the left ventricle,
hypertrophic cardiomyopathy (HCM) is traditionally understood as a disease of
the cardiac sarcomere. Mutations in TNNC1-encoded cardiac troponin C (cTnC) are
a relatively rare cause of HCM. Here, we report clinical and functional
characterization of a novel TNNC1 mutation, A31S, identified in a pediatric HCM
proband with multiple episodes of ventricular fibrillation and aborted sudden
cardiac death. Diagnosed at age 5, the proband is family history-negative for
HCM or sudden cardiac death, suggesting a de novo mutation. TnC-extracted
cardiac skinned fibers were reconstituted with the cTnC-A31S mutant, which
increased Ca(2+) sensitivity with no effect on the maximal contractile force
generation. Reconstituted actomyosin ATPase assays with 50% cTnC-A31S:50%
cTnC-WT demonstrated Ca(2+) sensitivity that was intermediate between 100%
cTnC-A31S and 100% cTnC-WT, whereas the mutant increased the activation of the
actomyosin ATPase without affecting the inhibitory qualities of the ATPase. The
secondary structure of the cTnC mutant was evaluated by circular dichroism,
which did not indicate global changes in structure. Fluorescence studies
demonstrated increased Ca(2+) affinity in isolated cTnC, the troponin complex,
thin filament, and to a lesser degree, thin filament with myosin subfragment 1.
These results suggest that this mutation has a direct effect on the Ca(2+)
sensitivity of the myofilament, which may alter Ca(2+) handling and contribute
to the arrhythmogenesis observed in the proband. In summary, we report a novel
mutation in the TNNC1 gene that is associated with HCM pathogenesis and may
predispose to the pathogenesis of a fatal arrhythmogenic subtype of HCM.
DOI: 10.1074/jbc.M112.377713
PMCID: PMC3442518
PMID: 22815480 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21498161
|
1. Orv Hetil. 2011 May 1;152(18):722-30. doi: 10.1556/OH.2011.29093.
[Familial isolated pituitary adenoma syndrome].
[Article in Hungarian]
Dénes J(1), Korbonits M, Hubina E, Kovács GL, Kovács L, Görömbey Z, Czirják S,
Góth M.
Author information:
(1)Honvédkórház-Állami Egészségügyi Központ II. Belgyógyászati Osztály,
Endokrinológiai Szakprofil Budapest.
Familial pituitary adenomas occur in multiple endocrine neoplasia type 1, Carney
complex, as well as in familial isolated pituitary adenoma syndrome. Familial
isolated pituitary adenoma syndrome is an autosomal dominant disease with
incomplete penetrance. Pituitary adenomas occur in familial setting but without
any other specific tumors. In 20-40% of families with this syndrome, mutations
have been identified in the aryl hydrocarbon receptor interacting protein gene
while in the rest of the families the causative gene or genes have not been
identified. Families carrying aryl hydrocarbon receptor interacting protein gene
mutations have a distinct phenotype with younger age at diagnosis and a
predominance of somatotroph and lactotroph adenomas. Germline mutations of the
aryl hydrocarbon receptor interacting protein gene can be occasionally
identified in usually young-onset seemingly sporadic cases. Genetic and clinical
testing of relatives of patients with aryl hydrocarbon receptor interacting
protein gene mutations can lead to earlier diagnosis and treatment at an earlier
stage of the pituitary tumor.
DOI: 10.1556/OH.2011.29093
PMID: 21498161 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24996936
|
1. J Endocrinol Invest. 2014 Oct;37(10):949-55. doi: 10.1007/s40618-014-0123-4.
Epub 2014 Jul 5.
A novel germline mutation in the aryl hydrocarbon receptor-interacting protein
(AIP) gene in an Italian family with gigantism.
Urbani C(1), Russo D, Raggi F, Lombardi M, Sardella C, Scattina I, Lupi I,
Manetti L, Tomisti L, Marcocci C, Martino E, Bogazzi F.
Author information:
(1)Section of Endocrinology, Department of Clinical and Experimental Medicine,
University of Pisa, Ospedale Cisanello, Via Paradisa 2, 56124, Pisa, Italy,
[email protected].
PURPOSE: Acromegaly usually occurs as a sporadic disease, but it may be a part
of familial pituitary tumor syndromes in rare cases. Germline mutations in the
aryl hydrocarbon receptor-interacting protein (AIP) gene have been associated
with a predisposition to familial isolated pituitary adenoma. The aim of the
present study was to evaluate the AIP gene in a patient with gigantism and in
her relatives.
METHODS: Direct sequencing of AIP gene was performed in fourteen members of the
family, spanning among three generations.
RESULTS: The index case was an 18-year-old woman with gigantism due to an
invasive GH-secreting pituitary adenoma and a concomitant tall-cell variant of
papillary thyroid carcinoma. A novel germline mutation in the AIP gene
(c.685C>T, p.Q229X) was identified in the proband and in two members of her
family, who did not present clinical features of acromegaly or other pituitary
disorders. Eleven subjects had no mutation in the AIP gene. Two members of the
family with clinical features of acromegaly refused either the genetic or the
biochemical evaluation. The Q229X mutation was predicted to generate a truncated
AIP protein, lacking the last two tetratricopeptide repeat domains and the final
C-terminal α-7 helix.
CONCLUSIONS: We identified a new AIP germline mutation predicted to produce a
truncated AIP protein, lacking its biological properties due to the disruption
of the C-terminus binding sites for both the chaperones and the client proteins
of AIP.
DOI: 10.1007/s40618-014-0123-4
PMID: 24996936 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24366639
|
1. Endocrine. 2014 Aug;46(3):387-96. doi: 10.1007/s12020-013-0125-6. Epub 2013
Dec 24.
The AIP (aryl hydrocarbon receptor-interacting protein) gene and its relation to
the pathogenesis of pituitary adenomas.
Lloyd C(1), Grossman A.
Author information:
(1)Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital,
University of Oxford, Oxford, OX3 7LE, UK.
Pituitary adenomas are monoclonal neoplasms that may secrete excessive
quantities of their endogenous hormones, or may not be associated with any
obvious syndrome, in which case they are known as non-functioning pituitary
adenomas. Around 2 % have been said to occur in a familial setting, in the
absence of any other tumor, now described as familial isolated pituitary
adenomas (FIPA). Some 15-30 % of such families harbor inactivating germ-line
mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene, along
with 20 % of pediatric seemingly sporadic cases. AIP mutants are referred to as
having pituitary adenoma predisposition, and present with early onset,
aggressive macroadenomas, most of which secrete somatotropin. Evidence from
transfection studies implies that AIP acts as a tumor suppressor; although
whether this is mediated through an interaction with the aryl hydrocarbon
receptor, phosphodiesterases, or with cell cycle regulators such as survivin or
RET remains controversial. However, at present an interaction with the cyclic
AMP pathway seems most plausible. Recently, evidence has shown that AIP may act
at the cell surface, causing changes in integrin function. The presence of AIP
mutations in a significant proportion of FIPA families as well as in apparently
sporadic cases, particularly in young patients, suggests a need to screen such
patients for AIP mutations to enable better clinical management. However, the
absence of AIP mutations in over half of such cases highlights the need to
search for further gene mutations.
DOI: 10.1007/s12020-013-0125-6
PMID: 24366639 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21364123
|
1. Am J Physiol Endocrinol Metab. 2011 May;300(5):E902-8. doi:
10.1152/ajpendo.00610.2010. Epub 2011 Mar 1.
The significance of Her2 on androgen receptor protein stability in the
transition of androgen requirement in prostate cancer cells.
Hsu FN(1), Yang MS, Lin E, Tseng CF, Lin H.
Author information:
(1)Dept. of Life Sciences, National Chung Hsing University, 250 Kuo Kuang Rd.,
Taichung 40227, Taiwan.
Androgen ablation therapy is the most common strategy for suppressing prostate
cancer progression; however, tumor cells eventually escape androgen dependence
and progress to an androgen-independent phase. The androgen receptor (AR) plays
a pivotal role in this transition. To address this transition mystery in
prostate cancer, we established an androgen-independent prostate cancer cell
line (LNCaPdcc), by long-term screening of LNCaP cells in androgen-deprived
conditions, to investigate changes of molecular mechanisms before and after
androgen withdrawal. We found that LNCaPdcc cells displayed a neuroendocrine
morphology, less aggressive growth, and lower expression levels of cell
cycle-related factors, although the cell cycle distribution was similar to
parental LNCaP cells. Notably, higher protein expression of AR,
phospho-Ser(81)-AR, and PSA in LNCaPdcc cells were observed. The nuclear
distribution and protein stability of AR increased in LNCaPdcc cells. In
addition, cell proliferation results exhibited the biphasic nature of the
androgen (R1881) effect in two cell lines. On the other hand, LNCaPdcc cells
expressed higher levels of Her2, phospho-Tyr(1221/1222)-Her2, ErbB3, and ErbB4
proteins than parental LNCaP cells. These two cell lines exhibited distinct
responses to Her2 activation (by heregulin treatment) on Her2 phosphorylation
and Her2 inhibition (by AG825 or Herceptin treatments) on proliferation. In
addition, the Her2 inhibitor more effectively caused AR degradation and
diminished AR Ser(81) phosphorylation in LNCaPdcc cells. Taken together, our
data demonstrate that Her2 plays an important role in the support of AR protein
stability in the transition of androgen requirement in prostate cancer cells. We
hope these findings will provide novel insight into the treatment of
hormone-refractory prostate cancer.
DOI: 10.1152/ajpendo.00610.2010
PMID: 21364123 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17264832
|
1. Acupunct Med. 2006 Dec;24(4):149-56. doi: 10.1136/aim.24.4.149.
The effects of auricular acupuncture on smoking cessation may not depend on the
point chosen--an exploratory meta-analysis.
White A(1), Moody R.
Author information:
(1)Primary Care Research Group, Peninsula Medical School, Universities of Exeter
and Plymouth, UK. [email protected]
INTRODUCTION: Auricular acupuncture is given as a treatment for drug dependence.
Points are usually chosen on the assumption that the body is represented
somatotopically in the ear, although there is no anatomical basis for this. In
clinical trials, sham treatment is often given at points that are supposedly
'incorrect' for the condition, in the belief that they are inactive. The aim of
this study was to explore whether there is any difference in the effectiveness
of auricular acupuncture at 'correct' and 'incorrect' points.
METHODS: Controlled trials of semi-permanent auricular acupuncture or
acupressure for smoking cessation were systematically located, and the results
combined in exploratory meta-analyses which took into account the study quality.
RESULTS: Thirteen studies were included. Combining ten studies showed auricular
acupuncture at 'correct' points to be more effective than control interventions,
odds ratio 2.24 (95% CI 1.61, 3.10), a result which is confirmed in the four
high validity studies. Other analyses showed inconsistent results between all
studies and higher quality studies. Comparisons of three higher quality studies
suggest that 'correct' and 'incorrect' point acupuncture is no different (odds
ratio 1.22, CI 0.72, 2.07); and two studies showed that 'incorrect' point
acupuncture may be more effective than other interventions (odds ratio 1.96, CI
1.00, 3.86).
CONCLUSION: Auricular acupuncture appears to be effective for smoking cessation,
but the effect may not depend on point location. This calls into question the
somatotopic model underlying auricular acupuncture and suggests a need to
re-evaluate sham controlled studies which have used 'incorrect' points. Further
experiments are necessary to confirm or refute these observational conclusions.
DOI: 10.1136/aim.24.4.149
PMID: 17264832 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20506337
|
1. Hum Mutat. 2010 Aug;31(8):950-60. doi: 10.1002/humu.21292.
Characterization of aryl hydrocarbon receptor interacting protein (AIP)
mutations in familial isolated pituitary adenoma families.
Igreja S(1), Chahal HS, King P, Bolger GB, Srirangalingam U, Guasti L, Chapple
JP, Trivellin G, Gueorguiev M, Guegan K, Stals K, Khoo B, Kumar AV, Ellard S,
Grossman AB, Korbonits M; International FIPA Consortium.
Collaborators: Akker S, Atkinson B, Aylwin S, Baldeweg S, Bevan J, Cheetham T,
Chew S, Choudry K, Clayton R, Damjanovic S, Darzy K, Dattani M, Davis J, Drake
W, Dzeranova L, Eden B, Eguchi K, Fica S, Flanagan D, Frohman L, Gadelha M,
Gallego P, Gla E, Goldman J, Goldstone T, Howlett T, Inder W, Iwata T, Kaplan F,
Karavitaki N, Laws E, Lechan R, Levy M, Matsuno A, Miljic D, Modenesi S, Molitch
M, Musat M, Orme S, Patocs A, Popovic V, Powell M, Quinton R, Randeva H, Ribeiro
de Oliveira J R A, Schofl C, Soares B, Spada A, Strasburger C, Swords F,
Tsagarakis S, Vaks V, Wass JA, Widell H, Yarman S, Yoshimoto K.
Author information:
(1)Department of Endocrinology, Barts and the London School of Medicine, Queen
Mary University of London, London, United Kingdom EC1M 6BQ.
Familial isolated pituitary adenoma (FIPA) is an autosomal dominant condition
with variable genetic background and incomplete penetrance. Germline mutations
of the aryl hydrocarbon receptor interacting protein (AIP) gene have been
reported in 15-40% of FIPA patients. Limited data are available on the
functional consequences of the mutations or regarding the regulation of the AIP
gene. We describe a large cohort of FIPA families and characterize missense and
silent mutations using minigene constructs, luciferase and beta-galactosidase
assays, as well as in silico predictions. Patients with AIP mutations had a
lower mean age at diagnosis (23.6+/-11.2 years) than AIP mutation-negative
patients (40.4+/-14.5 years). A promoter mutation showed reduced in vitro
activity corresponding to lower mRNA expression in patient samples. Stimulation
of the protein kinase A-pathway positively regulates the AIP promoter. Silent
mutations led to abnormal splicing resulting in truncated protein or reduced AIP
expression. A two-hybrid assay of protein-protein interaction of all missense
variants showed variable disruption of AIP-phosphodiesterase-4A5 binding. In
summary, exonic, promoter, splice-site, and large deletion mutations in AIP are
implicated in 31% of families in our FIPA cohort. Functional characterization of
AIP changes is important to identify the functional impact of gene sequence
variants.
DOI: 10.1002/humu.21292
PMCID: PMC3065644
PMID: 20506337 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/12356614
|
1. Am J Public Health. 2002 Oct;92(10):1642-7. doi: 10.2105/ajph.92.10.1642.
Auricular acupuncture, education, and smoking cessation: a randomized,
sham-controlled trial.
Bier ID(1), Wilson J, Studt P, Shakleton M.
Author information:
(1)I. B. Scientific, LLC, 1 Griffith Drive, Durham, NH 03824, USA.
[email protected]
Comment in
Am J Public Health. 2003 Feb;93(2):187. doi: 10.2105/ajph.93.2.187.
OBJECTIVES: This study examined the effect of acupuncture alone and in
combination with education on smoking cessation and cigarette consumption.
METHODS: We prospectively studied 141 adults in a quasi-factorial design using
acupuncture, sham acupuncture, and education.
RESULTS: All groups showed significant reductions in smoking and posttreatment
cigarette consumption, with the combined acupuncture-education group showing the
greatest effect from treatment. The trend continued in follow-up; however,
significant differences were not maintained. Greater pack-year history (i.e. the
number of years smoking multiplied by baseline number of cigarettes smoked per
year, divided by 20 cigarettes per pack) negatively correlated with treatment
effect. Trend analysis suggested 20 pack-years as the cutoff point for this
correlation.
CONCLUSIONS: Acupuncture and education, alone and in combination, significantly
reduce smoking; however, combined they show a significantly greater effect, as
seen in subjects with a greater pack-year history.
DOI: 10.2105/ajph.92.10.1642
PMCID: PMC1447300
PMID: 12356614 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23255921
|
1. Oncol Lett. 2013 Jan;5(1):208-214. doi: 10.3892/ol.2012.996. Epub 2012 Oct 25.
Tendencies for higher co-expression of EGFR and HER2 and downregulation of HER3
in prostate cancer lymph node metastases compared with corresponding primary
tumors.
Carlsson J(1), Shen L, Xiang J, Xu J, Wei Q.
Author information:
(1)Unit of Biomedical Radiation Science, Department of Radiology, Oncology and
Radiation Science, Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala,
Sweden ;
The epidermal growth factor receptor (EGFR) family members are potential targets
for therapy using extra-cellular domain receptor binding agents, such as the
antibodies trastuzumab and cetuximab, or antibodies labeled with therapeutically
useful radionuclides or toxins. This is especially the case when the tumor cells
are resistant to chemotherapy and tyrosine kinase inhibitors. Studies concerning
the expression of these receptors in prostate cancer vary in the literature,
possibly due to differences in patient inclusion, sample preparations and
scoring criteria. In our study, EGFR, HER2 and HER3 expression was analyzed in
prostate cancer samples from primary tumors and corresponding lymph node
metastases from 12 patients. The expression of HER2 and EGFR was scored from
immunohistochemical preparations and the HercepTest criteria (0, 1+, 2+ or 3+),
while HER3 expression was scored as no, weak or strong staining. There were 5
EGFR-positive (2+ or 3+) primary tumors and 6 EGFR-positive lymph node
metastases, and there was EGFR upregulation in one metastasis. Only 4 of the 12
patients had marked HER2 expression (2+ or 3+) in their primary tumors and there
was one downregulation and 5 cases of upregulation in the metastases. Thus, a
total of 8 out of 12 analyzed metastases were HER2-positive. Of the 12 primary
tumors, 9 expressed HER3 while only 2 of the lymph node metastases expressed
recognizable HER3 staining, so 7 metastases appeared to have downregulated HER3
expression. In one of the primary tumors there was positive co-expression of
EGFR and HER2, while this co-expression was observed in 4 of the metastases.
Thus, there were tendencies for upregulation of HER2, increased co-expression of
EGFR and HER2 and downregulation of HER3 in the prostate cancer lymph node
metastases in comparison to the primary tumors. The results are encouraging for
studies involving more patients. Possible strategies for EGFR- and HER2-targeted
therapy are briefly discussed in the present study, especially with regard to
the expression and co-expression of EGFR and HER2 in metastases.
DOI: 10.3892/ol.2012.996
PMCID: PMC3525498
PMID: 23255921
|
http://www.ncbi.nlm.nih.gov/pubmed/12677892
|
1. Cesk Patol. 2002;38 Suppl 1:15-9.
[What is the real importance of evaluating the expression of c-erbB-2
(HER-2/neu) in carcinoma of the breast and prostate? (A short review)].
[Article in Czech]
Kolár Z(1), Dvorácková J, Plevová P, Student V, Hajdúch M, Trojanec R, Spacková
K.
Author information:
(1)Ustav patologie LF UP a FN Olomouc & Laborator molekulární patologie LF UP,
Univerzita Palackého, Olomouc. [email protected]
This minireview covers the key data on biology and clinical implications of the
c-erbB-2 oncogene in breast and prostate cancer. The aim was to provide basic
information to practically oriented pathologists in order to make a reasonable
application of methods for c-erbB-2 overexpression or amplification analysis.
The clinical interpretation of c-erbB-2 abnormalities should reflect the
complexity of c-erbB-2 mediated regulatory pathway and explain why tumours with
overexpression/amplification of c-erbB-2 very often do not respond to therapy
using Herceptin.
PMID: 12677892 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/11154059
|
1. Am J Chin Med. 2000;28(3-4):443-9. doi: 10.1142/S0192415X00000520.
Laser acupuncture for adolescent smokers--a randomized double-blind controlled
trial.
Yiming C(1), Changxin Z, Ung WS, Lei Z, Kean LS.
Author information:
(1)Department of Child and Adolescent Psychiatry, Woodbridge Hospital/Institute
of Mental Health, Singapore.
A double blind, randomized, placebo-controlled clinical study was conducted to
evaluate the efficacy of laser acupuncture treatment in adolescent smokers.
Three hundred and thirty adolescent smokers at the Smoking Cessation Clinic of
Child Guidance Clinic, Institute of Health, Singapore, were randomly assigned in
equal numbers to laser acupuncture treatment and sham acupuncture (control)
groups. The proportions of patients with complete smoking cessation after
completing treatment for four weeks were 21.9% in the treatment group and 21.4%
in the control group. At three months post-treatment, the rates for complete
cessation were 24.8% and 26.2%, respectively. Thus, there was no significant
difference in the rates of smoking cessation in the treatment and control
groups.
DOI: 10.1142/S0192415X00000520
PMID: 11154059 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/10024707
|
1. Br J Gen Pract. 1998 Aug;48(433):1487-90.
A single-blind, placebo-controlled trial of a simple acupuncture treatment in
the cessation of smoking.
Waite NR(1), Clough JB.
Author information:
(1)Child Health, Southampton Hospital.
Comment in
Br J Gen Pract. 1998 Nov;48(436):1789.
BACKGROUND: Tobacco smoking is a major cause of preventable disease and
premature death. Physicians should play an active role in the control of smoking
by encouraging cessation and helping the smoker to choose the most suitable aid
to cessation.
AIM: To evaluate a simple, ear acupuncture treatment for the cessation of
smoking.
METHOD: Randomized, single-blind, placebo-controlled trial of 78 currently
smoking volunteers from the general public. Volunteers attended an acupuncture
clinic in a general practice setting and were given a single treatment of
electroacupuncture using two needles at either an active or a placebo site plus
self-retained ear seeds for two weeks. The major outcome measure was
biochemically validated total cessation of smoking at six months.
RESULTS: A total of 12.5% of the active treatment group compared with 0% of the
placebo group ceased smoking at six months (P = 0.055, 95% confidence interval
-0.033 to 0.323).
CONCLUSION: This simple ear electroacupuncture treatment was significantly more
effective in helping volunteers to quit smoking than placebo treatment.
PMCID: PMC1313196
PMID: 10024707 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20566645
|
1. J Biol Chem. 2010 Sep 3;285(36):27785-97. doi: 10.1074/jbc.M110.112326. Epub
2010 Jun 21.
Predicting cardiomyopathic phenotypes by altering Ca2+ affinity of cardiac
troponin C.
Parvatiyar MS(1), Pinto JR, Liang J, Potter JD.
Author information:
(1)Department of Molecular and Cellular Pharmacology, University of Miami Miller
School of Medicine, Miami, Florida 33136, USA.
Cardiac diseases associated with mutations in troponin subunits include
hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and restrictive
cardiomyopathy (RCM). Altered calcium handling in these diseases is evidenced by
changes in the Ca(2+) sensitivity of contraction. Mutations in the Ca(2+)
sensor, troponin C (TnC), were generated to increase/decrease the Ca(2+)
sensitivity of cardiac skinned fibers to create the characteristic effects of
DCM, HCM, and RCM. We also used a reconstituted assay to determine the mutation
effects on ATPase activation and inhibition. One mutant (A23Q) was found with
HCM-like properties (increased Ca(2+) sensitivity of force and normal levels of
ATPase inhibition). Three mutants (S37G, V44Q, and L48Q) were identified with
RCM-like properties (a large increase in Ca(2+) sensitivity, partial loss of
ATPase inhibition, and increased basal force). Two mutations were identified
(E40A and I61Q) with DCM properties (decreased Ca(2+) sensitivity, maximal force
recovery, and activation of the ATPase at high [Ca(2+)]). Steady-state
fluorescence was utilized to assess Ca(2+) affinity in isolated cardiac (c)TnCs
containing F27W and did not necessarily mirror the fiber Ca(2+) sensitivity.
Circular dichroism of mutant cTnCs revealed a trend where increased
alpha-helical content correlated with increased Ca(2+) sensitivity in skinned
fibers and vice versa. The main findings from this study were as follows: 1)
cTnC mutants demonstrated distinct functional phenotypes reminiscent of bona
fide HCM, RCM, and DCM mutations; 2) a region in cTnC associated with increased
Ca(2+) sensitivity in skinned fibers was identified; and 3) the F27W reporter
mutation affected Ca(2+) sensitivity, maximal force, and ATPase activation of
some mutants.
DOI: 10.1074/jbc.M110.112326
PMCID: PMC2934646
PMID: 20566645 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20669561
|
1. Bull Acad Natl Med. 2010 Jan;194(1):81-95; discussion 95-6.
[Multiple endocrine neoplasia: genetic aspects].
[Article in French]
Calender A(1); Groupe d'étude des Tumeurs Endocrines.
Author information:
(1)Génétique Moléculaire et Médicale, Hôpital Edouard Herriot, F-69437 - Lyon
cedex 03. [email protected]
Multiple endocrine neoplasia type 1 (MEN1) and type 2 (MEN2) are major genetic
disorders carrying a high risk of endocrine tumor development. The mutated genes
were identified in 1993 (MEN2-RET) and 1997 (MEN1), enabling genetic testing and
functional studies. Genetic analysis has led to new clinical and therapeutic
strategies for MEN1/2 patients, and has improved our understanding of the
pathways underlying the development of such tumors, which occur in an autosomal
dominant manner and with high penetrance. The MEN1 gene encodes menin, a protein
involved in many cell functions, such as transcription, genome stability, cell
cycling and apoptosis. The MEN1 gene has 10 exons, and its exhaustive analysis
in MEN1 patients helps guide their management. MEN2 is related to activating
missense mutations in the RET protooncogene, which encodes a tyrosine kinase
receptor (TKR). RET activation occurs upon autodimerization induced by the
binding of specific ligands belonging to glial cell-derived neurotrophic
factor-like family (GFL) proteins, regulated by coreceptors. The position of
missense mutations--in the extracellular or intracellular TK domains--influences
the aggressiveness of the most frequent malignancy, medullary thyroid carcinoma,
establishing a genotype-phenotype correlation. We also briefly describe the
genetic basis of three other inherited states predisposing individuals to
endocrine tumors, namely Carney's syndrome, hyperparathyroidism type 2 (HRPT2)
and familial isolated pituitary adenoma (FIPA), which are related to
inactivating mutations in the PRKAR1-alpha, HRPT2 and AIP genes, respectively.
PMID: 20669561 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/12581305
|
1. Plant J. 2003 Feb;33(3):471-80. doi: 10.1046/j.1365-313x.2003.01638.x.
Histone modifications in Arabidopsis- high methylation of H3 lysine 9 is
dispensable for constitutive heterochromatin.
Jasencakova Z(1), Soppe WJ, Meister A, Gernand D, Turner BM, Schubert I.
Author information:
(1)Institut für Pflanzengenetik und Kulturpflanzenforschung (IPK), D-06466
Gatersleben, Germany.
N-terminal modifications of nucleosomal core histones are involved in gene
regulation, DNA repair and recombination as well as in chromatin modeling. The
degree of individual histone modifications may vary between specific chromatin
domains and throughout the cell cycle. We have studied the nuclear patterns of
histone H3 and H4 acetylation and of H3 methylation in Arabidopsis. A
replication-linked increase of acetylation only occurred at H4 lysine 16 (not
for lysines 5 and 12) and at H3 lysine 18. The last was not observed in other
plants. Strong methylation at H3 lysine 4 was restricted to euchromatin, while
strong methylation at H3 lysine 9 occurred preferentially in heterochromatic
chromocenters of Arabidopsis nuclei. Chromocenter appearance, DNA methylation
and histone modification patterns were similar in nuclei of wild-type and
kryptonite mutant (which lacks H3 lysine 9-specific histone methyltransferase),
except that methylation at H3 lysine 9 in heterochromatic chromocenters was
reduced to the same low level as in euchromatin. Thus, a high level of
H3methylK9 is apparently not necessary to maintain chromocenter structure and
does not prevent methylation of H3 lysine 4 within Arabidopsis chromocenters.
DOI: 10.1046/j.1365-313x.2003.01638.x
PMID: 12581305 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15861492
|
1. Yonsei Med J. 2005 Apr 30;46(2):206-12. doi: 10.3349/ymj.2005.46.2.206.
The effects of the acupuncture treatment for smoking cessation in high school
student smokers.
Kang HC(1), Shin KK, Kim KK, Youn BB.
Author information:
(1)Department of Family Medicine, Yonsei University College of Medicine, 134,
Shinchon-dong, Seodaemun-gu, Seoul 120-752, Korea.
Comment in
Yonsei Med J. 2006 Feb 28;47(1):155; author reply 155-6. doi:
10.3349/ymj.2006.47.1.155.
The use of alternative medicine for smoking cessation have been increasing
steadily in recent years. A series of clinical group studies was performed to
clarify the effect, outcome and success rate of an acupuncture treatment for
smoking cessation. This study was conducted for four weeks using 238 smoking
students at 2 high schools. The subjects were separated into two groups: 159
students were treated with acupuncture on the anti-smoking acupoints of the ear,
which is known to be effective for cessation of smoking (case group), and 79
students were treated at other sites of the ear (control group). The acupuncture
treatment was alternately administered at each side of the ears on a weekly
basis for 4 weeks. The smoking cessation success was only 1 case (0.6%) in the
case group and none in the control group after 4 weeks. The change in the taste
of tobacco and the intensity of the desire to smoke were not significantly
different between the case and control groups, but the case group showed a
tendency of reduction in the taste of tobacco and the intensity of the desire to
smoke. In addition, the reduction in cigarette consumption was not significant,
but the tendency of reduction in the study group was significant. It is believed
that the site of auricular acupuncture for smoking cessation is not important.
However, there was a significant tendency in terms of the reduction in cigarette
consumption, the taste of tobacco and the intensity of the desire to smoke in
the case group, indicating that auricular acupuncture in smoking cessation has
some effect.
DOI: 10.3349/ymj.2005.46.2.206
PMCID: PMC2823015
PMID: 15861492 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19506933
|
1. Basic Res Cardiol. 2009 Nov;104(6):751-60. doi: 10.1007/s00395-009-0038-y.
Epub 2009 Jun 9.
The cardiac troponin C mutation Leu29Gln found in a patient with hypertrophic
cardiomyopathy does not alter contractile parameters in skinned murine
myocardium.
Neulen A(1), Stehle R, Pfitzer G.
Author information:
(1)Institute of Vegetative Physiology, University of Cologne,
Robert-Koch-Strasse 39, 50931 Cologne, Germany. [email protected]
The present study investigates the effects of the first mutation of troponin C
(hcTnC(L29Q)) found in a patient with hypertrophic cardiomyopathy (HCM) on
force-pCa relations and the interplay with phosphorylation of sarcomeric PKA
substrates. In triton-skinned murine cardiac fibers, the endogenous mcTnC was
extracted and the fibers were subsequently reconstituted with recombinant
wild-type and mutant hcTnC. Force-pCa relations of preparations containing
hcTnC(L29Q) or hcTnC(WT) were similar. Incubation of fibers reconstituted with
the recombinant proteins with phosphatase to dephosphorylate sarcomeric PKA
substrates induced an increase in Ca2+ sensitivity, slightly more pronounced
(0.04 pCa units) in hcTnC(L29Q)-containing fibers. Incubation of the
dephosphorylated fibers with PKA induced significant rightward shifts of
force-pCa relations of similar magnitude with both, hcTnC(L29Q) and hcTnC(WT).
No significant effects of hcTnC(L29Q) on the velocity of unloaded shortening
were observed. In conclusion, no major differences in contractile parameters of
preparations containing hcTnC(L29Q) compared to hcTnC(WT) were observed.
Therefore, it appears unlikely that hcTnC(L29Q) induces the development of HCM
by affecting the regulation of Ca2+-activated force and interference with
PKA-mediated modulation of the Ca2+ sensitivity of contraction.
DOI: 10.1007/s00395-009-0038-y
PMCID: PMC2758205
PMID: 19506933 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24030452
|
1. Forsch Komplementmed. 2013;20(4):290-4. doi: 10.1159/000354597. Epub 2013 Aug
15.
Ear acupressure for smoking cessation: study protocol for a randomised
controlled trial.
Zhang AL(1), Di YM, Worsnop C, May BH, Xue CC.
Author information:
(1)School of Health Sciences, and Traditional and Complementary Medicine
Research Program, Health Innovations Research Institute, RMIT University,
Bundoora, Australia.
BACKGROUND: Smoking is the largest preventable cause of death and disease
worldwide but smokers often fail to quit due to nicotine withdrawal symptoms.
Current available pharmaceutical therapies may assist with smoking cessation but
may have side effects. Ear acupressure (EAP) and ear acupuncture have been used
for smoking cessation, and some positive results have been reported. The aim of
the study is to assess the efficacy and safety of EAP in assisting individuals
to quit smoking and/or support them in the management of nicotine withdrawal
symptoms.
METHODS: This study will be a randomised, single-blind, sham-controlled study
conducted at RMIT University in Melbourne, Australia. Adult smokers will be
randomly assigned to receive EAP specifically for smoking cessation or
nonspecific EAP treatments. After a 2-week run-in, participants will be treated
once a week for 8 weeks and followed up for 12 weeks. The primary outcome
measures will be 7 day point-prevalence cessation rate by self-report validated
by expired carbon monoxide and nicotine withdrawal symptoms measured by the Mood
and Physical Symptoms Score questionnaire. Secondary outcomes will be
self-reported usage of nicotine replacement therapies, cigarette consumption,
body weight change and quality of life. The safety end point will be
self-reported adverse events associated with EAP. Intention-to-treat analysis
will be applied.
DISCUSSION: Findings from this study will determine if this EAP intervention
alone can be an effective and safe therapy to assist with smoking cessation and
the management of nicotine withdrawal symptoms.
© 2013 S. Karger GmbH, Freiburg.
DOI: 10.1159/000354597
PMID: 24030452 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15004442
|
1. Forsch Komplementarmed Klass Naturheilkd. 2004 Feb;11(1):8-13. doi:
10.1159/000077190.
[Smoking cessation with ear acupuncture. Descriptive study on patients after a
smoking cessation treatment with ear acupuncture].
[Article in German]
Ausfeld-Hafter B(1), Marti F, Hoffmann S.
Author information:
(1)Kollegiale Instanz für Komplementärmedizin, Universität Bern, Switzerland.
[email protected]
BACKGROUND: In complementary medicine literature studies on long-term
observation of one of its methods are rare.
OBJECTIVE: The present study is an evaluation of the smoking behavior of
patients treated with ear acupuncture for smoking cessation. Additionally we
investigated factors that favor or impede smoking cessation.
PATIENTS AND METHODS: 249 patients who had undergone ear acupuncture for smoking
cessation between 1985 and 1998 in a practice in Aarau (Switzerland) were asked
before the first treatment to fill in a form regarding their smoking behavior
and retrospectively in autumn 1998 a questionnaire regarding the success of
therapy. Ear acupuncture treatment consisted of 2 consultations at an interval
of 10 days. The responder rate was 53.8% (134 questionnaires were returned).
Finally the data of 126 persons could be evaluated.
RESULTS: The Kaplan Meier analysis of the abstinence time yielded a one-year
success rate of 41.1%. Men gave up smoking more easily than women. Start of
smoking as well as start of treatment between the age of 20 and 40 years were
favorable conditions for smoking cessation. People who had smoked 20 cigarettes
or more per day before treatment profited the best. For people who smoked as a
way of passing the time or because of tediousness it was easier to stop smoking
than for people smoking because of nervousness. People living in a non-smoker
household were able to stop smoking significantly easier than persons living in
a smoker household.
CONCLUSIONS: With a one-year success rate of 41.1% ear acupuncture is a
competitive alternative to orthodox medicine withdrawal methods. Acupuncture
treatment can be applied and adapted individually, furthermore it is economical
and without side effects.
Copyright 2004 S. Karger GmbH, Freiburg
DOI: 10.1159/000077190
PMID: 15004442 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/11740497
|
1. Nat Genet. 2002 Jan;30(1):77-80. doi: 10.1038/ng789. Epub 2001 Dec 10.
Histone H3 lysine 9 methylation is an epigenetic imprint of facultative
heterochromatin.
Peters AH(1), Mermoud JE, O'Carroll D, Pagani M, Schweizer D, Brockdorff N,
Jenuwein T.
Author information:
(1)Research Institute of Molecular Pathology, The Vienna Biocenter, Dr.
Bohrgasse 7, A-1030 Vienna, Austria.
Post-translational modifications of histone amino termini are an important
regulatory mechanism that induce transitions in chromatin structure, thereby
contributing to epigenetic gene control and the assembly of specialized
chromosomal subdomains. Methylation of histone H3 at lysine 9 (H3-Lys9) by
site-specific histone methyltransferases (Suv39h HMTases) marks constitutive
heterochromatin. Here, we show that H3-Lys9 methylation also occurs in
facultative heterochromatin of the inactive X chromosome (Xi) in female mammals.
H3-Lys9 methylation is retained through mitosis, indicating that it might
provide an epigenetic imprint for the maintenance of the inactive state.
Disruption of the two mouse Suv39h HMTases abolishes H3-Lys9 methylation of
constitutive heterochromatin but not that of the Xi. In addition, HP1 proteins,
which normally associate with heterochromatin, do not accumulate with the Xi.
These observations suggest the existence of an Suv39h-HP1-independent pathway
regulating H3-Lys9 methylation of facultative heterochromatin.
DOI: 10.1038/ng789
PMID: 11740497 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/12416359
|
1. Tunis Med. 2002 Apr;80(4):217-9.
[Role of auriculotherapy in smoking cessation. Personal experience].
[Article in French]
Sakka F.
Smoking is one of the main causes of poor health and early death. In line with
the 1999 law which aims at reducing smoking, we have tested auriculotherapy as
an aid for giving up smoking. We tried this treatment on 39 people who wanted to
give up smoking. After two months of treatment, 15 people (38.5%) had given up
completely and 24 people had reduced their smoking by more than half.
Auriculotherapy is an useful aid for giving up smoking. It is easy and painless,
has no secondary effects and it is economic.
PMID: 12416359 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23827187
|
1. Biomaterials. 2013 Oct;34(30):7495-505. doi:
10.1016/j.biomaterials.2013.06.015. Epub 2013 Jul 1.
Heat shock protein-mediated cell penetration and cytosolic delivery of
macromolecules by a telomerase-derived peptide vaccine.
Lee SA(1), Kim BR, Kim BK, Kim DW, Shon WJ, Lee NR, Inn KS, Kim BJ.
Author information:
(1)Department of Microbiology and Immunology, Liver Research Institute, Cancer
Research Institute and SNUMRC, College of Medicine, Seoul National University,
Seoul, Republic of Korea.
A reverse-transcriptase-subunit of telomerase (hTERT) derived peptide, GV1001,
has been developed as a vaccine against various cancers. Here, we report an
unexpected function of GV1001 as a cell-penetrating peptide (CPP). GV1001 was
delivered into a variety of cells including various cancer cell lines and
primary blood cells. Moreover, the delivered GV1001 was predominantly located in
the cytoplasm of the cells, while a significantly higher proportion of TAT
peptide was localized in the nucleus. Macromolecules such as proteins, DNA and
siRNA, which were linked to GV1001 by direct covalent conjugation or
non-covalent complexation through poly-lysine, were successfully delivered into
cells, indicating that GV1001 can be used as a carrier for macromolecules.
Expression of the delivered DNA, and lowered expression of the target gene by
the delivered siRNA, suggest the potential therapeutic use of GV1001. Pull-down
analysis identified Heat Shock Protein 90 (HSP90) and 70 (HSP70) as GV1001
interacting proteins. Treatment of Anti-HSP90 and HSP70 antibodies lowered the
internalization of GV1001, indicating that the interaction is critical for the
efficient internalization of GV1001. Collectively, the results of this study
suggest the pharmaceutical potential of GV1001, already proven safe in clinical
trials, as a carrier for the delivery of macromolecular therapeutics into cells,
in addition to its own anti-cancer activity.
Copyright © 2013 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.biomaterials.2013.06.015
PMID: 23827187 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24815142
|
1. Transplant Proc. 2014 May;46(4):1117-22. doi:
10.1016/j.transproceed.2013.12.019.
Protective effect of peptide GV1001 against renal ischemia-reperfusion injury in
mice.
Koo TY(1), Yan JJ(2), Yang J(3).
Author information:
(1)Transplantation Research Institute, Seoul National University College of
Medicine, Seoul, Republic of Korea; Transplantation Center, Seoul National
University Hospital, Seoul, Republic of Korea.
(2)Transplantation Research Institute, Seoul National University College of
Medicine, Seoul, Republic of Korea.
(3)Transplantation Research Institute, Seoul National University College of
Medicine, Seoul, Republic of Korea; Transplantation Center, Seoul National
University Hospital, Seoul, Republic of Korea. Electronic address:
[email protected].
BACKGROUND: Ischemia reperfusion injury (IRI) is a common complication after
kidney transplantation. Peptide GV1001 is a peptide vaccine representing a
16-amino acid human telomerase reverse transcriptase sequence, which has been
reported to possess potential antineoplastic and anti-inflammatory activity.
This study aimed to investigate the potential effects of peptide GV1001 on renal
IRI.
METHODS: Peptide GV1001 was subcutaneously administered to C57BL6/J mice 30
minutes before and 12 hours after bilateral IRI. Sham operation and
phosphate-buffered saline (PBS) injection were used as controls. Blood and renal
tissues were harvested at 1 day after IRI.
RESULTS: Peptide GV1001 treatment significantly attenuated renal functional
deterioration after IRI (peptide GV1001 group vs PBS group; blood urea nitrogen,
P < .05; creatinine, P < .05). Peptide GV1001 treatment also attenuated renal
tissue injury (tubular injury score; the peptide GV1001 group vs PBS group; P <
.001). Renal apoptosis was also lower in the peptide GV1001 group.
Immunohistochemical studies showed that IRI increased perirenal infiltration of
both neutrophils and macrophages, and that peptide GV1001 significantly
attenuated this process. Expression of interleukin-6 and monocyte chemotactic
protein-1 was significantly reduced by peptide GV1001 treatment.
CONCLUSIONS: Peptide GV1001 ameliorates acute renal IRI by reducing inflammation
and apoptosis; therefore, it is promising as a potential therapeutic agent for
renal IRI. The mechanisms of protection should be explored in further studies.
Copyright © 2014 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.transproceed.2013.12.019
PMID: 24815142 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24919654
|
1. Int J Oncol. 2014 Sep;45(3):1293-303. doi: 10.3892/ijo.2014.2496. Epub 2014
Jun 11.
Telomerase (GV1001) vaccination together with gemcitabine in advanced pancreatic
cancer patients.
Staff C(1), Mozaffari F(2), Frödin JE(1), Mellstedt H(1), Liljefors M(1).
Author information:
(1)Department of Oncology-Pathology (Radiumhemmet), Karolinska Institutet and
Karolinska University Hospital Solna, SE-17176 Stockholm, Sweden.
(2)Immune and Gene Therapy Laboratory, Cancer Center Karolinska, Karolinska
Institutet and Karolinska University Hospital Solna, SE-17176 Stockholm, Sweden.
Telomerase is expressed in 85-90 % of pancreatic adenocarcinomas and might be a
target for active cancer immunotherapy. A study was conducted to investigate
safety and immunogenicity in non-resectable pancreatic carcinoma patients using
a 16-amino acid telomerase peptide (GV1001) for vaccination in combination with
GM-CSF and gemcitabine as first line treatment. Three different vaccine
treatment schedules were used; [A (n=6), B (n=6) and C (n=5)]. Groups A/B
received GV1001, GM-CSF and gemcitabine concurrently. Group C received initially
GV1001 and GM-CSF while gemcitabine was added at disease progression. Group D
(n=4) was treated with gemcitabine alone. Adverse events (AE) related to
vaccination were mild (grades I-II). Grade III AEs were few and transient. An
induced GV 1001‑specific immune response was defined as an increase ≥2 above the
baseline value in one of the assays (DTH, proliferation, ELISPOT and cytokine
secretion assays, respectively). A telomerase‑specific immune response was noted
in 4/6 patients in group A, 4/6 patients in group B and 2/5 patients in group C.
An induced ras‑specific immune response (antigenic spreading) was seen in 5 of
the 17 patients. The cytokine pattern was that of a Th1-like profile. A
treatment induced telomerase or ras response was also noted in group D. All
responses were weak and transient. A significant decrease in regulatory T-cells
over time was noted in patients in groups A and B (p<0.05). Telomerase
vaccination (GV1001) in combination with chemotherapy appeared to be safe but
the immune responses were weak and transient. Measures have to be taken to
optimize immune responses of GV1001 for it to be considered of clinical
interest.
DOI: 10.3892/ijo.2014.2496
PMID: 24919654 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19388882
|
1. Expert Opin Investig Drugs. 2009 May;18(5):687-94. doi:
10.1517/13543780902897631.
Cancer vaccination with telomerase peptide GV1001.
Kyte JA(1).
Author information:
(1)Department of Clinical Cancer Research, The Norwegian Radium Hospital, Oslo
University Hospital, 0310 Oslo, Norway. jon.amund.kyte@rr research.no
Telomerase is highly expressed in essentially all cancer forms, while the
expression in normal tissues is restricted. Moreover, telomerase activity is
considered indispensable for tumor immortalization and growth. Human telomerase
reverse transcriptase (hTERT), the rate-limiting subunit of the telomerase
complex, is therefore an attractive target for cancer vaccination. The present
review provides an update on the development of GV1001, a peptide vaccine
representing a 16-aa hTERT sequence. GV1001 binds multiple HLA class II
molecules and harbors putative HLA class I epitopes. The peptide may therefore
elicit combined CD4/CD8 T-cell responses, considered important to initiate tumor
eradication and long-term memory. Phase I/II trials in advanced pancreatic and
pulmonary cancer patients have demonstrated GV1001-specific T-cell responses in
> 50% of subjects, without clinically important toxicity. The results indicate a
correlation between development of GV1001-specific responses and prolonged
survival. However, as in most cancer vaccine trials, a large proportion of
immune responders experience no clinical benefit. Long-term survivors harbor
durable GV1001-specific T-cell responses with high IFN-gamma/IL-10 ratios and
polyfunctional cytokine patterns. Interestingly, the cytokine profiles do not
follow a T(H)1/T(H)2 delineation. Here, the author discusses how
immunomonitoring may be improved to discriminate between efficient and pointless
immune responses, and which questions to address in the further development of
GV1001.
DOI: 10.1517/13543780902897631
PMID: 19388882 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20532208
|
1. PLoS Pathog. 2010 Jun 3;6(6):e1000935. doi: 10.1371/journal.ppat.1000935.
The epigenetic landscape of latent Kaposi sarcoma-associated herpesvirus
genomes.
Günther T(1), Grundhoff A.
Author information:
(1)Heinrich-Pette-Institute for Experimental Virology and Immunology, Hamburg,
Germany.
Herpesvirus latency is generally thought to be governed by epigenetic
modifications, but the dynamics of viral chromatin at early timepoints of latent
infection are poorly understood. Here, we report a comprehensive spatial and
temporal analysis of DNA methylation and histone modifications during latent
infection with Kaposi Sarcoma-associated herpesvirus (KSHV), the etiologic agent
of Kaposi Sarcoma and primary effusion lymphoma (PEL). By use of high resolution
tiling microarrays in conjunction with immunoprecipitation of methylated DNA
(MeDIP) or modified histones (chromatin IP, ChIP), our study revealed highly
distinct landscapes of epigenetic modifications associated with latent KSHV
infection in several tumor-derived cell lines as well as de novo infected
endothelial cells. We find that KSHV genomes are subject to profound methylation
at CpG dinucleotides, leading to the establishment of characteristic global DNA
methylation patterns. However, such patterns evolve slowly and thus are unlikely
to control early latency. In contrast, we observed that latency-specific histone
modification patterns were rapidly established upon a de novo infection. Our
analysis furthermore demonstrates that such patterns are not characterized by
the absence of activating histone modifications, as H3K9/K14-ac and H3K4-me3
marks were prominently detected at several loci, including the promoter of the
lytic cycle transactivator Rta. While these regions were furthermore largely
devoid of the constitutive heterochromatin marker H3K9-me3, we observed rapid
and widespread deposition of H3K27-me3 across latent KSHV genomes, a bivalent
modification which is able to repress transcription in spite of the simultaneous
presence of activating marks. Our findings suggest that the modification
patterns identified here induce a poised state of repression during viral
latency, which can be rapidly reversed once the lytic cycle is induced.
DOI: 10.1371/journal.ppat.1000935
PMCID: PMC2880564
PMID: 20532208 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/11821397
|
1. J Biol Chem. 2002 Apr 19;277(16):14146-52. doi: 10.1074/jbc.M110687200. Epub
2002 Jan 30.
Hepatocyte growth factor/scatter factor inhibits UVB-induced apoptosis of human
keratinocytes but not of keratinocyte-derived cell lines via the
phosphatidylinositol 3-kinase/AKT pathway.
Mildner M(1), Eckhart L, Lengauer B, Tschachler E.
Author information:
(1)Division of Immunology, Allergy and Infectious Diseases, Department of
Dermatology, Vienna Medical School, Währinger Gürtel 18-20, A-1090 Vienna,
Austria.
Acute irreparable UV-induced DNA damage leads to apoptosis of epidermal
keratinocytes (KC) and the formation of sunburn cells, whereas less severely
damaged cells survive but harbor the potential of tumor formation. Here we
report that hepatocyte growth factor/scatter factor (HGF/SF) prevents
UVB-induced apoptosis in primary KC cultured in vitro. When we analyzed the
signaling pathways initiated by the HGF/SF receptor c-met, we found that the
phosphatidylinositol (PI) 3-kinase and its downstream-element AKT and the
mitogen-activated protein (MAP) kinase were activated. Inhibition of PI 3-kinase
led to a complete abrogation of the anti-apoptotic effect of HGF/SF, whereas
blockade of the MAP kinase pathway had no effect. In contrast to the observation
with primary KC, HGF/SF could not enhance survival after UVB irradiation of
HaCaT and A431 cell lines, despite the fact that in these cells the PI 3-kinase
and MAP kinase pathways were also activated by HGF/SF. Cell cycle analysis of KC
revealed a G(2)/M arrest after UVB irradiation and a complete loss of
proliferating cells. Because HGF/SF in the skin is produced by dermal
fibroblasts, our findings suggest that the HGF/SF-mediated rescue of KC from
apoptosis represents an important paracrine loop by which UVB-damaged KC can be
kept alive to maintain the epidermal barrier function but cannot further
proliferate, thereby preventing the induction of epithelial skin tumors.
DOI: 10.1074/jbc.M110687200
PMID: 11821397 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18262389
|
1. Cell Signal. 2008 May;20(5):825-35. doi: 10.1016/j.cellsig.2007.12.013. Epub
2007 Dec 27.
Hepatocyte growth factor and c-Met promote dendritic maturation during
hippocampal neuron differentiation via the Akt pathway.
Lim CS(1), Walikonis RS.
Author information:
(1)Department of Physiology and Neurobiology, University of Connecticut, Storrs,
CT 06269, USA.
During central nervous system development, growth factors and their associated
receptor protein tyrosine kinases regulate many neuronal functions such as
neurite extension and dendrite maturation. Hepatocyte growth factor (HGF) and
its receptor, c-Met, can promote formation of neurites and enhance elaboration
of dendrites in mature neurons, but their effects on the early stages of
dendrite maturation in hippocampal neurons and the signaling pathways by which
they promote dendrite formation have not been studied. Exogenous HGF treatment
effectively enhanced the phosphorylation and activation of c-Met in cultured
hippocampal neurons at 4 days in vitro. HGF treatment increased the number of
dendrites and promoted dendrite elongation in these neurons. Consistent with
these results, HGF activated Akt, which phosphorylates glycogen synthase
kinase-3beta (GSK-3beta) to inactivate it, and reduced phosphorylation of
microtubule-associated protein 2 (MAP2), which can promote microtubule
polymerization and dendrite elongation when dephosphorylated. Conversely,
pharmacological inhibition of c-Met with its specific inhibitor, PHA-665752, or
genetic knock-down of c-Met with short hairpin RNAs (shRNAs) suppressed
HGF-induced phosphorylation of Akt and GSK-3beta, increased phosphorylation of
MAP2, and reduced dendrite number and length in cultured hippocampal neurons.
Moreover, suppressing c-Met with PHA-665752 or by shRNA decreased MAP2
expression. Inhibiting Akt activity with the phosphoinositide-3-kinase inhibitor
LY294002 or Akt inhibitor X suppressed HGF-induced phosphorylation of GSK-3beta,
increased MAP2 phosphorylation, and blocked the ability of HGF to enhance
dendritic length. These observations indicate that HGF and c-Met can regulate
the early stages of dendrite maturation via activation of the Akt/GSK-3beta
pathway.
DOI: 10.1016/j.cellsig.2007.12.013
PMCID: PMC2302788
PMID: 18262389 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17710556
|
1. Genetica. 2008 May;133(1):93-106. doi: 10.1007/s10709-007-9184-z. Epub 2007
Aug 21.
Glimpses of evolution: heterochromatic histone H3K9 methyltransferases left its
marks behind.
Krauss V(1).
Author information:
(1)Department of Genetics, Institute for Biology II, University of Leipzig,
Johannisallee 21-23, 04103 Leipzig, Germany. [email protected]
In eukaryotes, histone methylation is an epigenetic mechanism associated with a
variety of functions related to gene regulation or genomic stability. Recently
analyzed H3K9 methyltransferases (HMTases) as SUV39H1, Clr4p, DIM-5, Su(var)3-9
or SUVH2 are responsible for the establishment of histone H3 lysine 9
methylation (H3K9me), which is intimately connected with heterochromatinization.
In this review, available data will be evaluated concerning (1) the phylogenetic
distribution of H3K9me as heterochromatin-specific histone modification and its
evolutionary stability in relation to other epigenetic marks, (2) known families
of H3K9 methyltransferases, (3) their responsibility for the formation of
constitutive heterochromatin and (4) the evolution of Su(var)3-9-like and
SUVH-like H3K9 methyltransferases. Compilation and parsimony analysis reveal
that histone H3K9 methylation is, next to histone deacetylation, the
evolutionary most stable heterochromatic mark, which is established by at least
two subfamilies of specialized heterochromatic HMTases in almost all studied
eukaryotes.
DOI: 10.1007/s10709-007-9184-z
PMID: 17710556 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21687953
|
1. Oncol Rep. 2011 Oct;26(4):957-64. doi: 10.3892/or.2011.1348. Epub 2011 Jun 15.
Signaling pathway involved in cyclooxygenase-2 up-regulation by hepatocyte
growth factor in endometrial cancer cells.
Yoshizawa Y(1), Yamada Y, Kanayama S, Shigetomi H, Kawaguchi R, Yoshida S, Nagai
A, Furukawa N, Oi H, Kobayashi H.
Author information:
(1)Department of Obstetrics and Gynecology, Nara Medical University, Kashihara,
Nara 634-8522, Japan.
Hepatocyte growth factor (HGF) is up-regulated in tissue repair and has been
implicated in playing a role in this process through its anti-apoptotic and
proliferative activities. Cyclooxygenase-2 (COX-2) is an inducible enzyme in the
biosynthetic pathway of prostaglandins, and its activation has been shown to
play an important role in cell growth. We previously reported that HGF
significantly inhibited anoikis, possibly through the up-regulation of COX-2
expression in the endometrial RL95-2 cancer cell line. Here, we report that i)
treatment of RL95-2 cells with HGF resulted in phosphorylation of the HGF
receptor c-Met, activation of Akt and IκB, translocation of NF-κB into the
nucleus, and up-regulation of COX-2 mRNA; ii) the IκB-α phosphorylation
inhibitor BAY11-7082 and the selective COX-2 inhibitor CAY10452 blocked
HGF-mediated anoikis resistance in RL95-2 cells; and iii) HGF induced migration
and invasion in RL95-2 cells, while the phosphatidylinositol 3-kinase (PI3K)
inhibitor LY294002 and CAY10452 blocked these effects of HGF stimulation. Our
data suggest that HGF possesses chemotactic ability, has anti-apoptosis action,
and induces cellular infiltration via the PI3K/Akt pathway; it also triggers
NF-κB activation and up-regulates COX-2 gene expression in endometrial cancer
cells.
DOI: 10.3892/or.2011.1348
PMID: 21687953 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20822343
|
1. Expert Rev Vaccines. 2010 Sep;9(9):1007-16. doi: 10.1586/erv.10.92.
Current status of GV1001 and other telomerase vaccination strategies in the
treatment of cancer.
Shaw VE(1), Naisbitt DJ, Costello E, Greenhalf W, Park BK, Neoptolemos JP,
Middleton GW.
Author information:
(1)Liverpool CR-UK Centre, NIHR Pancreas Biomedical Research Unit, Liverpool
Experimental Cancer Medicine Centre, School of Cancer Studies, The Duncan
Building, Daulby Street, Liverpool, L69 3GA, UK.
GV1001 is a telomerase-specific, promiscuous class II peptide vaccine which is
currently in an advanced stage of clinical development. This article reviews the
biological rationale underpinning the design of ongoing studies with the vaccine
as well as its immunogenicity and clinical activity. It places GV1001 in the
context of other immunotherapeutic approaches targeting telomerase and assesses
the chances of the vaccine becoming a future standard of care in the treatment
of cancer.
DOI: 10.1586/erv.10.92
PMID: 20822343 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18405159
|
1. Zhongguo Zhen Jiu. 2008 Feb;28(2):133-4.
[Acupuncture combined with auricular point sticking and pressing for smoking
cessation of 53 cases in Russia].
[Article in Chinese]
Song LZ(1).
Author information:
(1)Section of Community Medicine, The Fourth People's Hospital of Jinan,
Shandong 250014, China). [email protected]
OBJECTIVE: To observe therapeutic effect of acupuncture combined with auricular
point sticking and pressing for smoking cessation.
METHODS: Body acupoints for acupuncture, Jieyan (two horizontal fingers above
styloid process of radius), Shenmen (HT 7), Zhongwan (CV 12), Zusanli (ST 36),
Sanyingjiao (SP 6). Main ear acupoints: Kou (mouth), Fei (lung), Shenmen, and
adjuvant ear points: Shenshangxian (adrenal gland), Wei (stomach), Xin (heart),
Neifenmi (endocrine), Qiguan (trachea), Gan (liver). The treatment was given
once daily, 6 sessions constituting one course, and the therapeutic effects were
observed after 4 courses.
RESULTS: Thirty-six were cured, 12 cases were effective, 5 cases were
ineffective.
CONCLUSION: Acupuncture combined with auricular point sticking and pressing has
reliable therapeutic effect for smoking cessation, but it is needed that the
patient cooperates actively and has the will of smoking cessation, so as to
avoid re-taking smoking.
PMID: 18405159 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21541345
|
1. PLoS One. 2011 Apr 25;6(4):e19040. doi: 10.1371/journal.pone.0019040.
Evolution from XIST-independent to XIST-controlled X-chromosome inactivation:
epigenetic modifications in distantly related mammals.
Chaumeil J(1), Waters PD, Koina E, Gilbert C, Robinson TJ, Graves JA.
Author information:
(1)Comparative Genomics Group, Evolution Ecology and Genetics, Research School
of Biology, The Australian National University, Canberra, Australian Capital
Territory, Australia. [email protected]
X chromosome inactivation (XCI) is the transcriptional silencing of one X in
female mammals, balancing expression of X genes between females (XX) and males
(XY). In placental mammals non-coding XIST RNA triggers silencing of one X (Xi)
and recruits a characteristic suite of epigenetic modifications, including the
histone mark H3K27me3. In marsupials, where XIST is missing, H3K27me3
association seems to have different degrees of stability, depending on
cell-types and species. However, the complete suite of histone marks associated
with the Xi and their stability throughout cell cycle remain a mystery, as does
the evolution of an ancient mammal XCI system. Our extensive immunofluorescence
analysis (using antibodies against specific histone modifications) in nuclei of
mammals distantly related to human and mouse, revealed a general absence from
the mammalian Xi territory of transcription machinery and histone modifications
associated with active chromatin. Specific repressive modifications associated
with XCI in human and mouse were also observed in elephant (a distantly related
placental mammal), as was accumulation of XIST RNA. However, in two marsupial
species the Xi either lacked these modifications (H4K20me1), or they were
restricted to specific windows of the cell cycle (H3K27me3, H3K9me2).
Surprisingly, the marsupial Xi was stably enriched for modifications associated
with constitutive heterochromatin in all eukaryotes (H4K20me3, H3K9me3). We
propose that marsupial XCI is comparable to a system that evolved in the common
therian (marsupial and placental) ancestor. Silent chromatin of the early
inactive X was exapted from neighbouring constitutive heterochromatin and, in
early placental evolution, was augmented by the rise of XIST and the stable
recruitment of specific histone modifications now classically associated with
XCI.
DOI: 10.1371/journal.pone.0019040
PMCID: PMC3081832
PMID: 21541345 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/24439482
|
1. Neurobiol Aging. 2014 Jun;35(6):1255-74. doi:
10.1016/j.neurobiolaging.2013.12.015. Epub 2013 Dec 26.
Novel vaccine peptide GV1001 effectively blocks β-amyloid toxicity by mimicking
the extra-telomeric functions of human telomerase reverse transcriptase.
Park HH(1), Lee KY(1), Kim S(2), Lee JW(2), Choi NY(3), Lee EH(3), Lee YJ(1),
Lee SH(4), Koh SH(5).
Author information:
(1)Department of Neurology, Hanyang University College of Medicine, Guri,
Gyeonggi, Korea.
(2)Department of Neuroscience, KAEL-Gemvax Co, Ltd, Seoul, Korea.
(3)Department of Translational Medicine, Hanyang University Graduate School of
Biomedical Science & Engineering, Seoul, Korea.
(4)Department of Biochemistry and Molecular Biology, Hanyang University College
of Medicine, Seoul, Korea.
(5)Department of Neurology, Hanyang University College of Medicine, Guri,
Gyeonggi, Korea; Department of Translational Medicine, Hanyang University
Graduate School of Biomedical Science & Engineering, Seoul, Korea. Electronic
address: [email protected].
GV1001 is a 16-amino-acid vaccine peptide derived from the human telomerase
reverse transcriptase sequence. We investigated the effects of GV1001 against
β-amyloid (Aβ) oligomer-induced neurotoxicity in rat neural stem cells (NSCs).
Primary culture NSCs were treated with several concentrations of GV1001 and/or
Aβ₂₅₋₃₅ oligomer for 48 hours. GV1001 protected NSCs against the Aβ₂₅₋₃₅
oligomer in a concentration-dependent manner. Aβ₂₅₋₃₅ concentration dependently
decreased viability, proliferation, and mobilization of NSCs and GV1001
treatment restored the cells to wild-type levels. Aβ₂₅₋₃₅ increased free radical
levels in rat NSCs while combined treatment with GV1001 significantly reduced
these levels. In addition, GV1001 treatment of Aβ₂₅₋₃₅-injured NSCs increased
the expression level of survival-related proteins, including
mitochondria-associated survival proteins, and decreased the levels of death and
inflammation-related proteins, including mitochondria-associated death proteins.
Together, these results suggest that GV1001 possesses neuroprotective effects
against Aβ₂₅₋₃₅ oligomer in NSCs and that these effects are mediated through
mimicking the extra-telomeric functions of human telomerase reverse
transcriptase, including the induction of cellular proliferation, anti-apoptotic
effects, mitochondrial stabilization, and anti-aging and anti-oxidant effects.
Copyright © 2014 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.neurobiolaging.2013.12.015
PMID: 24439482 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19072345
|
1. Expert Rev Gastroenterol Hepatol. 2008 Oct;2(5):673-96. doi:
10.1586/17474124.2.5.673.
New treatment options for advanced pancreatic cancer.
Middleton G(1), Ghaneh P, Costello E, Greenhalf W, Neoptolemos JP.
Author information:
(1)Royal Surrey County Hospital NHS Trust, Egerton Road, Guildford, GU2 7XX, UK.
[email protected]
Pancreatic cancer has a very high mortality rate and affects approximately
230,000 individuals worldwide. Gemcitabine has become established as the
standard therapy for advanced pancreatic cancer; however, the survival advantage
is small. Adjuvant chemotherapy using either 5-fluorouracil or gemcitabine is
now established in pancreatic cancer as an alternative therapy. Combinations of
gemcitabine with either platin agents or capecitabine may be advantageous.
Anti-EGFR and anti-VEGF agents have been unsuccessful but multiple tyrosine
kinase inhibitors are under investigation. Of the increasing number of
immunological agents, the GV1001 antitelomerase vaccine holds some interest.
Targeted agents against important mitogenic pathways, including MEK/ERK, Src,
PI3K/Akt, mTOR, Hedgehog and NF-kappaB, as well as agents targeting histone
deacetylase, poly(ADP-ribose) polymerase, heat shock protein 90 and other agents
such as beta-lapachone, hold considerable interest for further development.
However, the probability of individual success is low.
DOI: 10.1586/17474124.2.5.673
PMID: 19072345 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22435548
|
1. Immunol Rev. 2012 Mar;246(1):77-94. doi: 10.1111/j.1600-065X.2012.01098.x.
Regulation of NF-κB by ubiquitination and degradation of the IκBs.
Kanarek N(1), Ben-Neriah Y.
Author information:
(1)Lautenberg Centre for Immunology and Cancer Research, Institute for Medical
Research Israel-Canada, The Hebrew University, Hadassah Medical School,
Jerusalem, Israel.
The nuclear factor-κB (NF-κB) signaling pathway is a busy ground for the action
of the ubiquitin-proteasome system; many of the signaling steps are coordinated
by protein ubiquitination. The end point of this pathway is to induce
transcription, and to this end, there is a need to overcome a major obstacle, a
set of inhibitors (IκBs) that bind NF-κB and prohibit either the nuclear entry
or the DNA binding of the transcription factor. Two major signaling steps are
required for the elimination of the inhibitors: activation of the IκB kinase
(IKK) and degradation of the phosphorylated inhibitors. IKK activation and IκB
degradation involve different ubiquitination modes; the latter is mediated by a
specific E3 ubiquitin ligase SCF(β-TrCP) . The F-box component of this E3,
β-TrCP, recognizes the IκB degron formed following phosphorylation by IKK and
thus couples IκB phosphorylation to ubiquitination. SCF(β-TrCP) -mediated IκB
ubiquitination and degradation is a very efficient process, often resulting in
complete degradation of the key inhibitor IκBα within a few minutes of cell
stimulation. In vivo ablation of β-TrCP results in accumulation of all the IκBs
and complete NF-κB inhibition. As many details of IκB-β-TrCP interaction have
been worked out, the development of β-TrCP inhibitors might be a feasible
therapeutic approach for NF-κB-associated human disease. However, we may still
need to advance our understanding of the mechanism of IκB degradation as well as
of the diverse functions of β-TrCP in vivo.
© 2012 John Wiley & Sons A/S.
DOI: 10.1111/j.1600-065X.2012.01098.x
PMID: 22435548 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22564554
|
1. Vaccine. 2012 Jun 22;30(30):4445-52. doi: 10.1016/j.vaccine.2012.04.081. Epub
2012 May 5.
A(H1N1)v2009: a controlled observational prospective cohort study on vaccine
safety in pregnancy.
Oppermann M(1), Fritzsche J, Weber-Schoendorfer C, Keller-Stanislawski B,
Allignol A, Meister R, Schaefer C.
Author information:
(1)Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy,
Charité - Universitätsmedizin Berlin, Germany.
BACKGROUND: A(H1N1)v2009 influenza vaccination of pregnant women was a challenge
for health care providers, as little safety data were available.
METHODS: We prospectively followed the pregnancies of women who were vaccinated
at any time during pregnancy or ≤ 4 weeks prior to conception and compared these
outcomes to a control cohort matched by the estimated date of birth. Primary
endpoints: rate of spontaneous abortion and major malformations. Secondary
endpoints: preeclampsia, gestational age at birth, and birth weight.
RESULTS: Pregnancy outcome of 323 women immunized with adjuvanted or
non-adjuvanted A(H1N1)v2009 influenza vaccines from 2009-09-28 to 2010-03-31
were compared to 1329 control subjects. The risk for spontaneous abortions (HR
0.89; 95% CI 0.36-2.19) and the rate of major malformations (all trimesters: OR
0.87; 95% CI 0.38-1.77; preconception and first trimester exposure: OR 0.79; 95%
CI 0.13-2.64) did not vary between the two cohorts. Furthermore, there was no
increase in preeclampsia, prematurity, and intrauterine growth retardation in
the vaccinated cohort.
CONCLUSION: The results of our study do not indicate a risk for the pregnant
woman and the developing embryo/fetus after H1N1 vaccination. We provide and
apply methods novel in observational studies on pregnancy outcome, especially if
a single dose exposure is investigated.
Copyright © 2012 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.vaccine.2012.04.081
PMID: 22564554 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21586625
|
1. Clin Cancer Res. 2011 Jul 1;17(13):4568-80. doi:
10.1158/1078-0432.CCR-11-0184. Epub 2011 May 17.
Telomerase peptide vaccination combined with temozolomide: a clinical trial in
stage IV melanoma patients.
Kyte JA(1), Gaudernack G, Dueland S, Trachsel S, Julsrud L, Aamdal S.
Author information:
(1)Section for Clinical Cancer Research, Department of Oncology, Oslo University
Hospital, Oslo, Norway. [email protected]
PURPOSE: The study is a proof-of-principle trial evaluating toxicity, immune
response, and clinical response in melanoma patients after combined therapy with
temozolomide and the telomerase peptide vaccine GV1001. Our previous GV1001
trials showed immune responses in approximately 60% of lung or pancreatic cancer
patients.
EXPERIMENTAL DESIGN: Twenty-five subjects with advanced stage IV melanoma (M1B
or M1C) received concomitant temozolomide and GV1001. Temozolomide was
administered 200 mg/m² orally for 5 days every fourth week, and GV1001 as eight
injections over 11 weeks. Immune response was evaluated by delayed type
hypersensitivity, T-cell proliferation, and cytokine assays. The immunologic
responders continued monthly vaccination.
RESULTS: The treatment was well tolerated. A GV1001-specific immune response was
shown in 18 of 23 evaluated subjects (78%). Patients developing long-term T-cell
memory survived more than those rapidly losing their responses. The immune
response exhibited several characteristics of possible clinical significance
including high IFNγ/IL-10 ratios, polyfunctional cytokine profiles, and
recognition of naturally processed antigens. Survival compared favorably with
matched controls from a benchmark meta-analysis (1 year: 44% vs. 24%, 2 years:
16% vs. 6.6%). The clinical responses developed gradually over years, contrary
to what is expected from chemotherapy. Five patients developed partial tumor
regression and six more recorded stable disease. One patient has no remaining
disease on fluorodeoxyglucose positron emission tomography scans after 5 years.
CONCLUSIONS: The immunologic response rate is considerable compared with
previous GV1001 trials without concomitant chemotherapy, although low toxicity
is retained. The results warrant further studies of GV1001/temozolomide
treatment and support the general concept of combining cancer vaccination with
chemotherapy.
DOI: 10.1158/1078-0432.CCR-11-0184
PMID: 21586625 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22841437
|
1. Cancer Treat Rev. 2013 Aug;39(5):444-56. doi: 10.1016/j.ctrv.2012.06.007. Epub
2012 Jul 26.
Novel anticancer therapeutics targeting telomerase.
Ruden M(1), Puri N.
Author information:
(1)Department of Biomedical Sciences, University of Illinois College of Medicine
at Rockford, Rockford, IL 61107-1822, USA.
Telomeres are protective caps at the ends of human chromosomes. Telomeres
shorten with each successive cell division in normal human cells whereas, in
tumors, they are continuously elongated by human telomerase reverse
transcriptase (hTERT). Telomerase is overexpressed in 80-95% of cancers and is
present in very low levels or is almost undetectable in normal cells. Because
telomerase plays a pivotal role in cancer cell growth it may serve as an ideal
target for anticancer therapeutics. Inhibition of telomerase may lead to a
decrease of telomere length resulting in cell senescence and apoptosis in
telomerase positive tumors. Several strategies of telomerase inhibition are
reviewed, including small molecule inhibitors, antisense oligonucleotides,
immunotherapies and gene therapies, targeting the hTERT or the ribonucleoprotein
subunit hTER. G-quadruplex stabilizers, tankyrase and HSP90 inhibitors targeting
telomere and telomerase assembly, and T-oligo approach are also covered. Based
on this review, the most promising current telomerase targeting therapeutics are
the antisense oligonucleotide inhibitor GRN163L and immunotherapies that use
dendritic cells (GRVAC1), hTERT peptide (GV1001) or cryptic peptides (Vx-001).
Most of these agents have entered phase I and II clinical trials in patients
with various tumors, and have shown good response rates as evidenced by a
reduction in tumor cell growth, increased overall disease survival, disease
stabilization in advanced staged tumors and complete/partial responses. Most
therapeutics have shown to be more effective when used in combination with
standard therapies, resulting in concomitant telomere shortening and tumor mass
shrinkage, as well as preventing tumor relapse and resistance to single agent
therapy.
Copyright © 2012 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ctrv.2012.06.007
PMID: 22841437 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16278380
|
1. Clin Cancer Res. 2005 Nov 1;11(21):7621-8. doi: 10.1158/1078-0432.CCR-05-0479.
X-Linked inhibitor of apoptosis protein expression level in colorectal cancer is
regulated by hepatocyte growth factor/C-met pathway via Akt signaling.
Takeuchi H(1), Kim J, Fujimoto A, Umetani N, Mori T, Bilchik A, Turner R, Tran
A, Kuo C, Hoon DS.
Author information:
(1)Department of Molecular Oncology, Gastrointestinal Section, Santa Monica, CA
90404, USA.
PURPOSE: The inhibitor of the apoptosis protein (IAP) family members, such as
the X-linked IAP (XIAP), survivin, and livin, are essential for cell survival
and antiapoptosis in colorectal cancer cells. We hypothesized that the
hepatocyte growth factor (HGF) activation in colorectal cancer via c-Met
receptor regulates IAP proteins through Akt signaling.
EXPERIMENTAL DESIGN: The level of IAPs and C-Met mRNA expression was assessed
using a quantitative real-time reverse transcriptase-PCR (RT-PCR) assay on
colorectal normal mucosa (n = 13), adenomas (n = 6), and colorectal cancer
tumors (n = 50). The role of HGF/C-Met pathway through Akt and XIAP was
investigated by small interfering RNA (siRNA) and quantitative RT-PCR analysis
of colorectal cancer lines.
RESULTS: Of the IAPs, only XIAP showed significant correlation to tumor
development and progression. XIAP mRNA level in primary colorectal cancer was
significantly higher than that in colorectal normal mucosa (P = 0.01); liver
metastases was significantly higher than primary colorectal cancer tumors (P =
0.04); and primary colorectal cancer N1/N2 cases were significantly higher than
N0 cases (P = 0.008). HGF stimulation of colorectal cancer lines enhanced XIAP
mRNA expression but not other IAPs. Activation of XIAP expression by HGF was
inhibited by siRNA targeting Akt1 and Akt2.
CONCLUSIONS: Activation of C-MET enhances XIAP through the Akt pathway. XIAP
up-regulation was shown to be correlated to colorectal cancer tumor progression.
The Akt-XIAP pathway may be a potential molecular target for regulating
colorectal cancer progression.
DOI: 10.1158/1078-0432.CCR-05-0479
PMID: 16278380 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24954781
|
1. Lancet Oncol. 2014 Jul;15(8):829-40. doi: 10.1016/S1470-2045(14)70236-0. Epub
2014 Jun 19.
Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001
in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an
open-label, randomised, phase 3 trial.
Middleton G(1), Silcocks P(2), Cox T(2), Valle J(3), Wadsley J(4), Propper D(5),
Coxon F(6), Ross P(7), Madhusudan S(8), Roques T(9), Cunningham D(10), Falk
S(11), Wadd N(12), Harrison M(13), Corrie P(14), Iveson T(15), Robinson A(16),
McAdam K(17), Eatock M(18), Evans J(19), Archer C(20), Hickish T(21),
Garcia-Alonso A(22), Nicolson M(23), Steward W(24), Anthoney A(25), Greenhalf
W(2), Shaw V(2), Costello E(2), Naisbitt D(2), Rawcliffe C(2), Nanson G(2),
Neoptolemos J(26).
Author information:
(1)University of Birmingham, Edgbaston, Birmingham, UK.
(2)Liverpool Cancer Research UK Cancer Trials Unit and GCLP Facility, University
of Liverpool, Liverpool, UK.
(3)Manchester Academic Health Sciences Centre, Christie Hospital NHS Foundation
Trust and University of Manchester, Manchester UK.
(4)Weston Park Hospital, Sheffield Teaching Hospital NHS Foundation Trust,
Sheffield, UK.
(5)St Bartholomew's Hospital, Barts Health NHS Trust, West Smithfield, London,
UK.
(6)Northern Centre for Cancer Care, The Newcastle upon Tyne Hospitals NHS
Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK.
(7)Guy's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.
(8)Nottingham City Hospital, Nottingham University Hospitals NHS Trust,
Nottingham, UK.
(9)Norfolk and Norwich University Hospital, Norfolk and Norwich University
Hospital NHS Foundation Trust, Norwich, UK.
(10)The Royal Marsden, The Royal Marsden NHS Foundation Trust, London, UK.
(11)Bristol Haematology And Oncology Centre, University Hospital Bristol NHS
Foundation Trust, Bristol, UK.
(12)The James Cook University Hospital, South Tees Hospitals NHS Foundation
Trust, Middleborough, UK.
(13)Mount Vernon Hospital, The Hillingdon Hospitals NHS Foundation Trust,
Northwood, UK.
(14)Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust,
Cambridge, UK.
(15)Southampton General Hospital, University Hospital Southampton NHS Foundation
Trust, Southampton, Hampshire, UK.
(16)Conquest Hospital, East Sussex Healthcare NHS Trust, The Ridge, St
Leonards-on-Sea, East Sussex, UK.
(17)Peterborough City Hospital, Peterborough and Stamford Hospitals NHS
Foundation Trust, Edith, Cavell Campus, Peterborough, UK.
(18)Belfast City Hospital, Belfast Health and Social Care Trust, Belfast, UK.
(19)University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK.
(20)Queen Alexandra Hospital, Portsmouth Hospitals NHS Trust, Cosham,
Portsmouth, UK.
(21)Royal Bournemouth Hospital, The Royal Bournemouth and Christchurch Hospitals
NHS Foundation Trust, Bournemouth, UK.
(22)Glan Clwyd Hospital, University Health Board, Rhyl, Denbighshire, UK.
(23)Abderdeen Royal Infirmary, NHS Grampian, Aberdeen, UK.
(24)Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust,
Leicester, UK.
(25)St James University Hospital, The Leeds Teaching Hospital Trust, Beckett
Street, Leeds, UK.
(26)Liverpool Cancer Research UK Cancer Trials Unit and GCLP Facility,
University of Liverpool, Liverpool, UK. Electronic address:
[email protected].
Comment in
Lancet Oncol. 2014 Jul;15(8):780-1. doi: 10.1016/S1470-2045(14)70267-0.
BACKGROUND: We aimed to assess the efficacy and safety of sequential or
simultaneous telomerase vaccination (GV1001) in combination with chemotherapy in
patients with locally advanced or metastatic pancreatic cancer.
METHODS: TeloVac was a three-group, open-label, randomised phase 3 trial. We
recruited patients from 51 UK hospitals. Eligible patients were treatment naive,
aged older than 18 years, with locally advanced or metastatic pancreatic ductal
adenocarcinoma, and Eastern Cooperative Oncology Group performance status of
0-2. Patients were randomly assigned (1:1:1) to receive either chemotherapy
alone, chemotherapy with sequential GV1001 (sequential chemoimmunotherapy), or
chemotherapy with concurrent GV1001 (concurrent chemoimmunotherapy). Treatments
were allocated with equal probability by means of computer-generated random
permuted blocks of sizes 3 and 6 in equal proportion. Chemotherapy included six
cycles of gemcitabine (1000 mg/m(2), 30 min intravenous infusion, at days 1, 8,
and 15) and capecitabine (830 mg/m(2) orally twice daily for 21 days, repeated
every 28 days). Sequential chemoimmunotherapy included two cycles of combination
chemotherapy, then an intradermal lower abdominal injection of
granulocyte-macrophage colony-stimulating factor (GM-CSF; 75 μg) and GV1001
(0·56 mg; days 1, 3, and 5, once on weeks 2-4, and six monthly thereafter).
Concurrent chemoimmunotherapy included giving GV1001 from the start of
chemotherapy with GM-CSF as an adjuvant. The primary endpoint was overall
survival; analysis was by intention to treat. This study is registered as an
International Standard Randomised Controlled Trial, number ISRCTN4382138.
FINDINGS: The first patient was randomly assigned to treatment on March 29,
2007, and the trial was terminated on March 27, 2011. Of 1572 patients screened,
1062 were randomly assigned to treatment (358 patients were allocated to the
chemotherapy group, 350 to the sequential chemoimmunotherapy group, and 354 to
the concurrent chemoimmunotherapy group). We recorded 772 deaths; the 290
patients still alive were followed up for a median of 6·0 months (IQR 2·4-12·2).
Median overall survival was not significantly different in the chemotherapy
group than in the sequential chemoimmunotherapy group (7·9 months [95% CI
7·1-8·8] vs 6·9 months [6·4-7·6]; hazard ratio [HR] 1·19, 98·25% CI 0·97-1·48,
p=0·05), or in the concurrent chemoimmunotherapy group (8·4 months [95% CI
7·3-9·7], HR 1·05, 98·25% CI 0·85-1·29, p=0·64; overall log-rank of χ(2)2df=4·3;
p=0·11). The commonest grade 3-4 toxic effects were neutropenia (68 [19%]
patients in the chemotherapy group, 58 [17%] patients in the sequential
chemoimmunotherapy group, and 79 [22%] patients in the concurrent
chemoimmunotherapy group; fatigue (27 [8%] in the chemotherapy group, 35 [10%]
in the sequential chemoimmunotherapy group, and 44 [12%] in the concurrent
chemoimmunotherapy group); and pain (34 [9%] patients in the chemotherapy group,
39 [11%] in the sequential chemoimmunotherapy group, and 41 [12%] in the
concurrent chemoimmunotherapy group).
INTERPRETATION: Adding GV1001 vaccination to chemotherapy did not improve
overall survival. New strategies to enhance the immune response effect of
telomerase vaccination during chemotherapy are required for clinical efficacy.
FUNDING: Cancer Research UK and KAEL-GemVax.
Copyright © 2014 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(14)70236-0
PMID: 24954781 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20233866
|
1. Cancer Res. 2010 Apr 1;70(7):2932-41. doi: 10.1158/0008-5472.CAN-09-3570. Epub
2010 Mar 16.
Cyr61 mediates hepatocyte growth factor-dependent tumor cell growth, migration,
and Akt activation.
Goodwin CR(1), Lal B, Zhou X, Ho S, Xia S, Taeger A, Murray J, Laterra J.
Author information:
(1)Kennedy Krieger Institute, Johns Hopkins School of Medicine, Baltimore, MD,
USA.
Certain tumor cell responses to the growth factor-inducible early response gene
product CCN1/Cyr61 overlap with those induced by the hepatocyte growth factor
(HGF)/c-Met signaling pathway. In this study, we investigate if Cyr61 is a
downstream effector of HGF/c-Met pathway activation in human glioma cells. A
semiquantitative immunohistochemical analysis of 112 human glioma and normal
brain specimens showed that levels of tumor-associated Cyr61 protein correlate
with tumor grade (P < 0.001) and with c-Met protein expression (r(2) = 0.4791, P
< 0.0001). Purified HGF rapidly upregulated Cyr61 mRNA (peak at 30 minutes) and
protein expression (peak at 2 hours) in HGF(-)/c-Met(+) human glioma cell lines
via a transcription- and translation-dependent mechanism. Conversely, HGF/c-Met
pathway inhibitors reduced Cyr61 expression in HGF(+)/c-Met(+) human glioma cell
lines in vitro and in HGF(+)/c-Met(+) glioma xenografts. Targeting Cyr61
expression with small interfering RNA (siRNA) inhibited HGF-induced cell
migration (P < 0.01) and cell growth (P < 0.001) in vitro. The effect of Cyr61
on HGF-induced Akt pathway activation was also examined. Cyr61 siRNA had no
effect on the early phase of HGF-induced Akt phosphorylation (Ser(473)) 30
minutes after stimulation with HGF. Cyr61 siRNA inhibited a second phase of Akt
phosphorylation measured 12 hours after cell stimulation with HGF and also
inhibited HGF-induced phosphorylation of the Akt target glycogen synthase kinase
3alpha. We treated preestablished subcutaneous glioma xenografts with Cyr61
siRNA or control siRNA by direct intratumoral delivery. Cyr61 siRNA inhibited
Cyr61 expression and glioma xenograft growth by up to 40% in a dose-dependent
manner (P < 0.05). These results identify a Cyr61-dependent pathway by which
c-Met activation mediates cell growth, cell migration, and long-lasting
signaling events in glioma cell lines and possibly astroglial malignancies.
DOI: 10.1158/0008-5472.CAN-09-3570
PMCID: PMC2848876
PMID: 20233866 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21596080
|
1. Vaccine. 2011 Aug 26;29(37):6358-65. doi: 10.1016/j.vaccine.2011.04.114. Epub
2011 May 17.
Pregnancy and safety outcomes in women vaccinated with an AS03-adjuvanted split
virion H1N1 (2009) pandemic influenza vaccine during pregnancy: a prospective
cohort study.
Tavares F(1), Nazareth I, Monegal JS, Kolte I, Verstraeten T, Bauchau V.
Author information:
(1)Global Vaccine Development, GlaxoSmithKline (GSK) Biologicals, Parc de la
Noire Epine, Avenue Fleming 20, 1300 Wavre, Belgium. [email protected]
Infection with influenza virus during pregnancy poses a significant risk of
complications for both mother and fetus. During the H1N1 2009 pandemic, pregnant
women constituted one of the priority groups for vaccination in many countries,
creating a need for close monitoring of the safety of the vaccine in pregnant
women. We present findings from an analysis of a cohort of pregnant women
(N=267) from a prospective, observational, post-authorization safety study of
the AS03-adjuvanted split virion H1N1 (2009) pandemic vaccine. There were 265
known pregnancy outcomes with 261 live births, four spontaneous abortions with
no congenital anomalies, and no stillbirths. There were six live births with
congenital anomalies, of which one was diagnosed before vaccination. A total of
247 women (94.6%), of whom four had twin pregnancies, delivered at term, and 14
women (5.4%), of whom two had twin pregnancies, delivered preterm (between Weeks
24 and 36 of gestation), with three of them (1.1%) occurring before 32 weeks
(very preterm). Twenty-one neonates (8.1%) had a low birth weight (<2.5 kg), of
whom nine (3.5%) were term neonates. The prevalence of all outcomes was in line
with the expected rates. The adverse events reported were consistent with the
events anticipated to be reported by this study population. No adverse events of
special interest were reported. The results of this analysis suggest that
exposure to the AS03 adjuvanted H1N1 (2009) vaccine during pregnancy does not
increase the risk of adverse pregnancy outcomes including spontaneous abortion,
congenital anomalies, preterm delivery, low birth weight neonates, or maternal
complications. Although limited in size, the fully prospective nature of the
safety follow-up of these women vaccinated during pregnancy is unique and offers
an important degree of reassurance for the use of the AS03 adjuvanted H1N1
(2009) vaccine in this high risk group for H1N1 infection.
Copyright © 2011 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.vaccine.2011.04.114
PMID: 21596080 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21756329
|
1. J Med Case Rep. 2011 Jul 14;5:314. doi: 10.1186/1752-1947-5-314.
Unusual association of ST-T abnormalities, myocarditis and cardiomyopathy with
H1N1 influenza in pregnancy: two case reports and review of the literature.
Chan K(1), Meek D, Chakravorty I.
Author information:
(1)Department of Respiratory Medicine, Lister Hospital, Corey's Mill Lane,
Stevenage, UK. [email protected].
INTRODUCTION: Myocarditis is rarely reported as an extra-pulmonary manifestation
of influenza while pregnancy is a rare cause of cardiomyopathy. Pregnancy was
identified as a major risk factor for increased mortality and morbidity due to
H1N1 influenza in the pandemic of 2009 to 2010. However, to the best of our
knowledge there are no previous reports in the literature linking H1N1 with
myocarditis in pregnancy.
CASE PRESENTATION: We report the cases of two pregnant Caucasian women (aged 29
and 30), with no pre-existing illness, presenting with respiratory
manifestations of H1N1 influenza virus infection in their third trimester. Both
women developed evidence of myocarditis. One woman developed acute respiratory
distress syndrome, almost reaching the point of requiring extra-corporeal
membrane oxygenation, and subsequently developed persistent cardiomyopathy; the
other recovered without any long-term consequence.
CONCLUSIONS: While it is not possible to ascertain retrospectively if
myocarditis was caused by either infection with H1N1 virus or as a result of
pregnancy (in the absence of endomyocardial biopsies), the significant
association with myocardial involvement in both women demonstrates the increased
risk of exposure to H1N1 influenza virus in pregnant women. This highlights the
need for health care providers to increase awareness amongst caregivers to
target this 'at risk' group aggressively with vaccination and prompt treatment.
DOI: 10.1186/1752-1947-5-314
PMCID: PMC3161951
PMID: 21756329
|
http://www.ncbi.nlm.nih.gov/pubmed/22551713
|
1. BMJ. 2012 May 2;344:e2794. doi: 10.1136/bmj.e2794.
Vaccination against pandemic A/H1N1 2009 influenza in pregnancy and risk of
fetal death: cohort study in Denmark.
Pasternak B(1), Svanström H, Mølgaard-Nielsen D, Krause TG, Emborg HD, Melbye M,
Hviid A.
Author information:
(1)Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5,
2300 Copenhagen, Denmark. [email protected]
Comment in
BMJ. 2012 May 02;344:e3091. doi: 10.1136/bmj.e3091.
OBJECTIVE: To investigate whether an adjuvanted pandemic A/H1N1 2009 influenza
vaccine in pregnancy was associated with an increased risk of fetal death.
DESIGN: Nationwide register based cohort study.
SETTING: Denmark.
PARTICIPANTS: All clinically recognised singleton pregnancies that ended between
November 2009 and September 2010. Individual level data on exposure to an
inactivated AS03 pandemic A/H1N1 2009 influenza vaccine (Pandemrix) and
potential confounders were linked to the study cohort using a unique person
identifier.
MAIN OUTCOME MEASURES: The primary outcome measure was risk of fetal death
(spontaneous abortion and stillbirth combined) in H1N1 vaccinated compared with
unvaccinated pregnancies, adjusting for propensity scores. Secondary outcome
measures were spontaneous abortion (between seven and 22 weeks' gestation) and
stillbirth (after 22 completed weeks' gestation).
RESULTS: The cohort comprised 54,585 pregnancies; 7062 (12.9%) women were
vaccinated against pandemic A/H1N1 2009 influenza during pregnancy. Overall,
1818 fetal deaths occurred (1678 spontaneous abortions and 140 stillbirths).
Exposure to the H1N1 vaccine was not associated with an increased risk of fetal
death (adjusted hazard ratio 0.79, 95% confidence interval 0.53 to 1.16), or the
secondary outcomes of spontaneous abortion (1.11, 0.71 to 1.73) and stillbirth
(0.44, 0.20 to 0.94). Estimates for fetal death were similar in pregnant women
with (0.82, 0.44 to 1.53) and without comorbidities (0.77, 0.47 to 1.25).
CONCLUSION: This large cohort study found no evidence of an increased risk of
fetal death associated with exposure to an adjuvanted pandemic A/H1N1 2009
influenza vaccine during pregnancy.
DOI: 10.1136/bmj.e2794
PMCID: PMC3342154
PMID: 22551713 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: All authors have completed
the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available
on request from the corresponding author) and declare: BP had support from the
Danish Medical Research Council and Lund University for the submitted work; no
financial relationships with any organisations that might have an interest in
the submitted work in the previous three years; and no other relationships or
activities that could appear to have influenced the submitted work.
|
http://www.ncbi.nlm.nih.gov/pubmed/21377838
|
1. J Dermatol Sci. 2011 May;62(2):75-83. doi: 10.1016/j.jdermsci.2011.02.001.
Epub 2011 Feb 15.
Telomerase-specific GV1001 peptide vaccination fails to induce objective tumor
response in patients with cutaneous T cell lymphoma.
Schlapbach C(1), Yerly D, Daubner B, Yawalkar N, Hunger RE.
Author information:
(1)Department of Dermatology, Inselspital, University of Bern, 3010 Bern,
Switzerland. [email protected]
BACKGROUND: There is currently no curative therapy for cutaneous T cell lymphoma
(CTCL). New therapies are therefore needed. Telomerase, the enzyme that allows
for unrestricted cell divisions of cancer cells, is a promising target for
cancer therapy. The telomerase-specific peptide vaccination GV1001 has shown
promising results in previous studies. Since telomerase is expressed in
malignant cells of CTCL, GV1001 vaccination in CTCL is a promising new
therapeutic approach.
OBJECTIVE: We sought to investigate the efficacy of GV1001 vaccination in CTCL
patients and characterize the induced immune response.
METHODS: Six CTCL patients were vaccinated with the GV-peptide using
granulocyte/macrophage colony-stimulating factor as adjuvant. Objective clinical
response and the T cell response were assessed.
RESULTS: None of the patients demonstrated objective clinical response to the
vaccination whereas one patient showed disease progression. 1/6 patients
acquired a GV1001-specifc T cell response with a Th1 cytokine profile and
expression of skin-homing receptors. This hTERT-specific T cell response was not
associated with beneficial modulation of the tumor-infiltrating leukocytes.
Furthermore, removal of regulatory T cells did not enhance responsiveness to
GV1001 in vitro in any of the patients analyzed.
CONCLUSIONS: Our results suggest that the GV1001 vaccination is not effective in
CTCL patients and disease progression in 1/6 patients raises concerns about its
safety. By analyzing skin-homing properties of GV1001-specific T cells and the
involvement of regulatory T cells we nevertheless provide insight into
vaccine-induced immune responses which may help to improve vaccine strategies in
CTCL.
Copyright © 2011. Published by Elsevier Ireland Ltd.
DOI: 10.1016/j.jdermsci.2011.02.001
PMID: 21377838 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21913391
|
1. Zh Mikrobiol Epidemiol Immunobiol. 2011 Jul-Aug;(4):46-50.
[Vaccination against influenza A (H1N1) in pregnancy].
[Article in Russian]
Cherdantsev AP, Kostinov MP, Kuselman AI, Voznesenskaia NV.
AIM: Evaluation of alterations of immune response regulation and possible risk
of antenatal development of fetus in postvaccination period in pregnant women
immunized against influenza A (H1N1).
MATERIALS AND METHODS: Women were vaccinated with MonoGrippol plus vaccine in
the II trimester of physiological pregnancy. At certain intervals ofthe
vaccination period (before the vaccination, 7 and 30 days after the vaccination)
major biochemical markers in blood sera (alanine aminotransferase, aspartate
aminotransferase, lactate dehydrogenase, alkaline phosphatase, creatinine, urea)
and levels of key cytokines in spontaneous and stimulated test (IL-1alpha,
IL-1RA, IL-2, IL-4, IL-10, IFNgamma, TNFalpha) were evaluated. Vaccination
safety for the fetus and trophoblast development was evaluated by using human
chorionic gonadotropin (HCG), alpha-fetoprotein (AFP) and trophoblasitc
beta-1-glycoprotein (TBG) levels.
RESULTS: During vaccination in 13% of cases mild local reactions were noted, in
26.1%--general systemic reactions in the form of weakness, dizziness and
headaches. Levels of major biochemical markers at days 7 and 30 after the
vaccination did not have any significant difference from the initial values (p >
0.05). Cytokine levels in spontaneous and stimulated tests also did not change
significantly. Markers of the course of pregnancy and fetus development (HCG,
AFP and TBG) in the two groups observed had comparable values.
CONCLUSION: Vaccination of pregnant women against influenza A (H1N1) by Russian
subunit formulation (MonoGrippol plus) showed reactogenicity comparable to
control group by the level of influence on general metabolic and immunologic
homeostasis and on the course of pregnancy, which is an evidence of its safety.
PMID: 21913391 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22708672
|
1. BMC Genomics. 2012 Jun 18;13:251. doi: 10.1186/1471-2164-13-251.
Evolution of coding and non-coding genes in HOX clusters of a marsupial.
Yu H(1), Lindsay J, Feng ZP, Frankenberg S, Hu Y, Carone D, Shaw G, Pask AJ,
O'Neill R, Papenfuss AT, Renfree MB.
Author information:
(1)ARC Centre of Excellence in Kangaroo Genomics, The University of Melbourne,
Melbourne, Victoria 3010, Australia.
BACKGROUND: The HOX gene clusters are thought to be highly conserved amongst
mammals and other vertebrates, but the long non-coding RNAs have only been
studied in detail in human and mouse. The sequencing of the kangaroo genome
provides an opportunity to use comparative analyses to compare the HOX clusters
of a mammal with a distinct body plan to those of other mammals.
RESULTS: Here we report a comparative analysis of HOX gene clusters between an
Australian marsupial of the kangaroo family and the eutherians. There was a
strikingly high level of conservation of HOX gene sequence and structure and
non-protein coding genes including the microRNAs miR-196a, miR-196b, miR-10a and
miR-10b and the long non-coding RNAs HOTAIR, HOTAIRM1 and HOXA11AS that play
critical roles in regulating gene expression and controlling development. By
microRNA deep sequencing and comparative genomic analyses, two conserved
microRNAs (miR-10a and miR-10b) were identified and one new candidate microRNA
with typical hairpin precursor structure that is expressed in both fibroblasts
and testes was found. The prediction of microRNA target analysis showed that
several known microRNA targets, such as miR-10, miR-414 and miR-464, were found
in the tammar HOX clusters. In addition, several novel and putative miRNAs were
identified that originated from elsewhere in the tammar genome and that target
the tammar HOXB and HOXD clusters.
CONCLUSIONS: This study confirms that the emergence of known long non-coding
RNAs in the HOX clusters clearly predate the marsupial-eutherian divergence 160
Ma ago. It also identified a new potentially functional microRNA as well as
conserved miRNAs. These non-coding RNAs may participate in the regulation of HOX
genes to influence the body plan of this marsupial.
DOI: 10.1186/1471-2164-13-251
PMCID: PMC3541083
PMID: 22708672 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17464994
|
1. Hepatology. 2007 May;45(5):1210-7. doi: 10.1002/hep.21604.
Met signals hepatocyte survival by preventing Fas-triggered FLIP degradation in
a PI3k-Akt-dependent manner.
Moumen A(1), Ieraci A, Patané S, Solé C, Comella JX, Dono R, Maina F.
Author information:
(1)Developmental Biology Institute of Marseille-Luminy (IBDML) UMR 6216,
CNRS-Univ. de la Mediterranée, Marseille, France.
The FasL-Fas couple is a general death mediator whose activated signals lead to
caspase-8 activation and apoptosis in adult hepatocytes. Suppression of
caspase-8 activation and cell death is a protective mechanism modulated by the
FLICE-Like Inhibitory Protein (FLIP). Although hepatocyte growth factor (HGF)
and its receptor Met are known to mediate cell survival in developing livers,
the molecular mechanisms involved in this process are poorly understood. We show
here that Met activation by HGF impairs Fas-triggered apoptosis of primary
embryonic hepatocytes and cell survival correlates with inhibition of caspase-8
and caspase-3 activities. Furthermore, we found that HGF treatment prevents
degradation of FLIPL triggered by Fas activation. In contrast to this, Met
activation does not modulate FLIPL levels and its stability in untreated cells,
thus showing the specificity of this regulatory mechanism for embryonic
hepatocyte survival. Knocking down FLIP expression abolishes the ability of Met
to inhibit Fas-triggered hepatocyte death, demonstrating the functional
requirement of FLIP in HGF anti-apoptotic signals. By combining genetic and
pharmacological approaches, we also demonstrate that the PI3K-Akt pathway is
required in embryonic hepatocytes to prevent Fas-triggered FLIP degradation and
death. Thus, Met acting on PI3K and Akt ensures high levels of FLIPL, and
disruption of this pathway contributes to hepatic apoptosis and possibly to
Fas-related liver diseases.
DOI: 10.1002/hep.21604
PMID: 17464994 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23463798
|
1. Genetics. 2013 Mar;193(3):651-69. doi: 10.1534/genetics.112.146704.
Long noncoding RNAs: past, present, and future.
Kung JT(1), Colognori D, Lee JT.
Author information:
(1)Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02114,
USA.
Long noncoding RNAs (lncRNAs) have gained widespread attention in recent years
as a potentially new and crucial layer of biological regulation. lncRNAs of all
kinds have been implicated in a range of developmental processes and diseases,
but knowledge of the mechanisms by which they act is still surprisingly limited,
and claims that almost the entirety of the mammalian genome is transcribed into
functional noncoding transcripts remain controversial. At the same time, a small
number of well-studied lncRNAs have given us important clues about the biology
of these molecules, and a few key functional and mechanistic themes have begun
to emerge, although the robustness of these models and classification schemes
remains to be seen. Here, we review the current state of knowledge of the lncRNA
field, discussing what is known about the genomic contexts, biological
functions, and mechanisms of action of lncRNAs. We also reflect on how the
recent interest in lncRNAs is deeply rooted in biology's longstanding concern
with the evolution and function of genomes.
DOI: 10.1534/genetics.112.146704
PMCID: PMC3583990
PMID: 23463798 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20100064
|
1. Clin Infect Dis. 2010 Mar 1;50(5):686-90. doi: 10.1086/650460.
2009 H1N1 influenza A and pregnancy outcomes in Victoria, Australia.
Hewagama S(1), Walker SP, Stuart RL, Gordon C, Johnson PD, Friedman ND, O'Reilly
M, Cheng AC, Giles ML.
Author information:
(1)Monash Medical Centre, Melbourne, Australia.
Comment in
Clin Infect Dis. 2010 Mar 1;50(5):691-2. doi: 10.1086/650461.
BACKGROUND: Pregnant women have been identified as a group at risk of increased
morbidity and mortality associated with the pandemic H1N1 influenza A 2009
(H1N1/09) outbreak.
METHODS: Six hospitals in the state of Victoria, Australia, contributed
retrospective and prospective demographic and clinical data, reason for
admission data, and maternal and fetal outcome data for women with
laboratory-confirmed H1N1/09 admitted to the hospital from 20 May 2009 through
31 July 2009.
RESULTS: Forty-three cases were reported during the study period, including 8
intensive care unit admissions, 1 maternal death, 2 fetal deaths, and 1 neonatal
death. The most common reason for admission was uncomplicated influenza-like
illness. Patients hospitalized for uncomplicated influenza-like illness had a
length of stay significantly less than those with confirmed pneumonia.
Thirty-six percent of women delivered during the hospitalization. Of the women
delivering before 37 weeks' gestation, almost all had pneumonia. Almost half of
our case series had no other comorbidity, a large proportion (77%) of women
received antivirals, and 56% received antibiotics. The incidence of
hospitalization was estimated at 0.46% (95% confidence interval, 0.31%-0.66%) of
all 6094 pregnant women in the third trimester during the 3-month study period.
The incidence of hospitalization in the second trimester was estimated at 0.21%
(95% confidence interval, 0.11%-0.36%).
CONCLUSIONS: This case series confirms a high number of complications in
pregnant women due to pandemic H1N1/09. Many of these women had comorbidities,
although almost 50% of the women in this case series who required
hospitalization did not have an additional risk factor other than being
pregnant.
DOI: 10.1086/650460
PMID: 20100064 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24051575
|
1. J Perinatol. 2013 Dec;33(12):939-43. doi: 10.1038/jp.2013.110. Epub 2013 Sep
19.
A multicenter cohort study of pregnancy outcomes among women with
laboratory-confirmed H1N1 influenza.
Naresh A(1), Fisher BM, Hoppe KK, Catov J, Xu J, Hart J, Lynch AM, Gibbs R,
Eschenbach D, Gravett M, Beigi RH.
Author information:
(1)Department of Obstetrics, Gynecology and Reproductive Sciences, Magee-Womens
Hospital of University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
OBJECTIVE: To evaluate associations between laboratory-confirmed 2009 H1N1
influenza infection and obstetric and neonatal outcomes.
STUDY DESIGN: A multicenter cohort study was performed comparing
laboratory-confirmed cases of 2009 H1N1 infection during pregnancy (N=142) with
matched controls (N=710). Subanalysis was also performed comparing severely
infected (hospitalized) women with controls.
RESULT: No outcome differences were noted in comparing all women with H1N1 with
controls. Women with severe infection had a higher incidence of delivering a
small for gestational age (SGA) infant: 18.8% (6/32) versus 7.4% (52/707),
adjusted odds ratio 2.35 (95% confidence interval 1.03, 5.36, P=0.02). Mean
birth weight was 3013.0 g among severely infected women and 3223.3 g in controls
(P=0.08), and incidence of preterm delivery was 25.0% (8/32) and 11.6% (82/710)
(P=0.08), respectively.
CONCLUSION: Pregnant women with mild clinical illness secondary to 2009 H1N1
were not at a greater risk of adverse pregnancy outcomes. However, severely
infected women were more likely to deliver SGA infants.
DOI: 10.1038/jp.2013.110
PMID: 24051575 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20531946
|
1. PLoS One. 2010 May 28;5(5):e10896. doi: 10.1371/journal.pone.0010896.
Low clinical burden of 2009 pandemic influenza A (H1N1) infection during
pregnancy on the island of La Réunion.
Gérardin P(1), El Amrani R, Cyrille B, Gabrièle M, Guillermin P, Boukerrou M,
Boumahni B, Randrianaivo H, Winer A, Rouanet JF, Bohrer M, Jaffar-Bandjee MC,
Robillard PY, Barau G, Michault A.
Author information:
(1)Neonatal and Pediatric Intensive Care Unit, Centre Hospitalier Régional,
Saint Pierre, La Réunion, France. [email protected]
BACKGROUND: Pregnant women have been identified as a group at risk, both for
respiratory complications than for the admissions to the Intensive Care Unit
(ICU) during the 2009 H1N1 influenza pandemic (pdm). The purpose of this
prospective register-based cohort-study was to characterize the clinical
virulence of the pdm (H1N1/09)v during pregnancy in La Réunion.
METHODS/PRINCIPAL FINDINGS: Over a twelve-week pdm wave (13 July to 3 October
2009), 294 pregnant women presented with an influenza-like illness (ILI) to one
of the three maternity departments of the South Reunion area, Indian Ocean. Out
of these, 278 were checked by RT-PCR for influenza viruses (157 positive and 121
negative, of whom, 141 with pdm flu and 132 with ILIs of non pdm origin, 5
untyped). The median body temperature was higher in women experiencing pdm flu
than in those with non pdm ILI (38.9 degrees C versus 38.3 degrees C, P<0.0001),
without evidence linked to circulating viremia. Oseltamivir was given for 86% of
pdm flu cases in a median time inferior than 48 hrs (range 0-7 days). The
hospitalization rate for pdm flu was of 60% and not associated with underlying
conditions. Six viral pneumonia and fourteen asthma attacks were observed among
84 hospitalized pdm flu cases, of whom, only one led to the ICU for an acute
lung injury. No maternal death occurred during the pdm wave. None adverse
pregnancy outcome was associated with pdm flu. No congenital birth defect, nor
early-onset neonatal influenza infection was attributable to pdm flu exposure.
CONCLUSIONS/SIGNIFICANCE: This report mitigates substantially the presumed
severity of pandemic H1N1/09 influenza infection during pregnancy. The reasons
for which the clinical burden of H1N1/09 influenza virus may differ worldwide
raise questions about a differential local viral-strain effect and public health
preparedness, notably in timely access to special care and antiviral treatments.
DOI: 10.1371/journal.pone.0010896
PMCID: PMC2878351
PMID: 20531946 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/19643469
|
1. Lancet. 2009 Aug 8;374(9688):451-8. doi: 10.1016/S0140-6736(09)61304-0. Epub
2009 Jul 28.
H1N1 2009 influenza virus infection during pregnancy in the USA.
Jamieson DJ(1), Honein MA, Rasmussen SA, Williams JL, Swerdlow DL, Biggerstaff
MS, Lindstrom S, Louie JK, Christ CM, Bohm SR, Fonseca VP, Ritger KA, Kuhles DJ,
Eggers P, Bruce H, Davidson HA, Lutterloh E, Harris ML, Burke C, Cocoros N,
Finelli L, MacFarlane KF, Shu B, Olsen SJ; Novel Influenza A (H1N1) Pregnancy
Working Group.
Collaborators: Chavez G, Harriman K, Winter K, Aragon D, Comstock N, Cosgrove S,
Kenfield J, Sadlowski J, Arnold K, Drenzek CL, Quinlisk P, Von Stein D, Sugg T,
Heisey-Grove D, Soliva S, Lett S, Sharangpani R, Vagasky S, Wells EV, Noyes K,
Anand M, Backenson B, Hunter J, Rice J, McDonald C, Burnsed L, Waller K,
Mersereau P, Goldbaum G, Davis M, Smith B, Walker J, Wing R, Marfin A, Nelson M,
Barnes N, Barzilay EJ, Berman L, Brantley MD, Bridges C, Dharan N, Emery S,
Fiore A, Gross D, Kendrick J, Klimov A, Menon M, O'Reilly CE, Patel M, Uyeki T,
Villanueva J, Wu KH.
Author information:
(1)National Center for Chronic Disease Prevention and Health Promotion, Centers
for Disease Control and Prevention, Atlanta, GA 30341-3717, USA.
[email protected]
Comment in
Lancet. 2009 Aug 8;374(9688):429-30. doi: 10.1016/S0140-6736(09)61431-8.
Lancet. 2009 Oct 24;374(9699):1417; author reply 1417-8. doi:
10.1016/S0140-6736(09)61853-5.
Lancet. 2009 Oct 24;374(9699):1417; author reply 1417-8. doi:
10.1016/S0140-6736(09)61854-7.
J Emerg Med. 2013 Sep;45(3):411-3. doi: 10.1016/j.jemermed.2012.11.082.
BACKGROUND: Pandemic H1N1 2009 influenza virus has been identified as the cause
of a widespread outbreak of febrile respiratory infection in the USA and
worldwide. We summarised cases of infection with pandemic H1N1 virus in pregnant
women identified in the USA during the first month of the present outbreak, and
deaths associated with this virus during the first 2 months of the outbreak.
METHODS: After initial reports of infection in pregnant women, the US Centers
for Disease Control and Prevention (CDC) began systematically collecting
additional information about cases and deaths in pregnant women in the USA with
pandemic H1N1 virus infection as part of enhanced surveillance. A confirmed case
was defined as an acute respiratory illness with laboratory-confirmed pandemic
H1N1 virus infection by real-time reverse-transcriptase PCR or viral culture; a
probable case was defined as a person with an acute febrile respiratory illness
who was positive for influenza A, but negative for H1 and H3. We used population
estimates derived from the 2007 census data to calculate rates of admission to
hospital and illness.
FINDINGS: From April 15 to May 18, 2009, 34 confirmed or probable cases of
pandemic H1N1 in pregnant women were reported to CDC from 13 states. 11 (32%)
women were admitted to hospital. The estimated rate of admission for pandemic
H1N1 influenza virus infection in pregnant women during the first month of the
outbreak was higher than it was in the general population (0.32 per 100 000
pregnant women, 95% CI 0.13-0.52 vs 0.076 per 100 000 population at risk, 95% CI
0.07-0.09). Between April 15 and June 16, 2009, six deaths in pregnant women
were reported to the CDC; all were in women who had developed pneumonia and
subsequent acute respiratory distress syndrome requiring mechanical ventilation.
INTERPRETATION: Pregnant women might be at increased risk for complications from
pandemic H1N1 virus infection. These data lend support to the present
recommendation to promptly treat pregnant women with H1N1 influenza virus
infection with anti-influenza drugs.
FUNDING: US CDC.
DOI: 10.1016/S0140-6736(09)61304-0
PMID: 19643469 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22411229
|
1. Rev Med Virol. 2013 Jan;23(1):3-14. doi: 10.1002/rmv.1712. Epub 2012 Mar 13.
Pandemic influenza A(H1N1) 2009 virus in pregnancy.
Liu SL(1), Wang J, Yang XH, Chen J, Huang RJ, Ruan B, He HX, Wang CM, Zhang HM,
Sun Z, Xie L, Zhuang H.
Author information:
(1)Department of Infectious Diseases, Hangzhou Center for Disease Control and
Prevention, Zhejiang Province Center for Disease Control and Prevention,
Hangzhou, Zhejiang province, China.
Two hundred fourteen abstracts and 87 full texts regarding pregnant women
infected with pandemic influenza A(H1N1) 2009 virus were systematically reviewed
by using a PubMed search and assessing pandemic, clinical, laboratory test,
vaccine, and control experiences. Both policy and health education were
excluded. This review counted the total number of pregnant cases from different
countries and analyzed their epidemic features, including trimester
distribution, morbidity, hospitalization, intensive care unit admissions,
maternal mortality, underlying diseases, complications, high-risk factors for
death, pregnancy outcome, and clinical symptoms compared with the previous
pandemic seasonal influenza A/H1N1 as compared with the general population.
Early identification and treatment were the most important factors in different
countries and areas examined. The vaccine and antiviral drugs that have been the
most efficient means to control the novel virus appear to be safe but require
more extensive study. In the future, the focus should be placed on understanding
vertical transmission and the severe mechanisms.
Copyright © 2012 John Wiley & Sons, Ltd.
DOI: 10.1002/rmv.1712
PMID: 22411229 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23116790
|
1. Enferm Infecc Microbiol Clin. 2012 Oct;30 Suppl 4:32-7. doi:
10.1016/S0213-005X(12)70102-7.
Pregnancy, obesity and other risk factors for complications in influenza A(H1N1)
pdm09 infection.
Rodríguez-Baño J(1), Paño-Pardo JR, Múñez Rubio E, Segura Porta F.
Author information:
(1)Infectious Diseases and Clinical Microbiology Unit, Hospital Universitario
Virgen Macarena, Seville, Spain. [email protected]
Although influenza is usually a self-limited disease, patients who develop
complications are at increased risk of hospitalization, intensive care unit
admission and death. Since preventive and early therapeutic measures should be
prioritized in higher risk patients, identification of the risk factors for
severe infection is important from a public health perspective. Risk factors for
complications in pandemics may show some differences with regard to seasonal
influenza. During the influenza A(H1N1)pmd09 pandemic, although many cases
occurred in younger adults, the risk factors identified for severe infections
and complications were similar to those for seasonal influenza, including
chronic respiratory, renal, liver, and heart diseases. Aged patients, although
less frequently affected, were also at higher risk. Obesity, and particularly
morbid obesity (>40 body mass index) has been noted as a significant risk factor
for severe disease in the 2009 influenza pandemic. Some interesting recent
studies provide insights into the biological reasons behind the poor outcomes in
morbidly obese patients. In terms of pregnancy, the studies have shown
contradictory results due to variations in methodology and medical care.
However, it seems that pregnancy, particularly during the third trimester,
increases the risk of complications, and that early antiviral treatment is
associated with improved outcomes.
Copyright © 2012 Elsevier España, S.L. All rights reserved.
DOI: 10.1016/S0213-005X(12)70102-7
PMID: 23116790 [Indexed for MEDLINE]
|
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.