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http://www.ncbi.nlm.nih.gov/pubmed/25417706 | 1. Oncogene. 2015 Aug 13;34(33):4403-11. doi: 10.1038/onc.2014.371. Epub 2014 Nov
24.
Rad18 and Rnf8 facilitate homologous recombination by two distinct mechanisms,
promoting Rad51 focus formation and suppressing the toxic effect of
nonhomologous end joining.
Kobayashi S(1), Kasaishi Y(1), Nakada S(2), Takagi T(3), Era S(1), Motegi A(1),
Chiu RK(4), Takeda S(1), Hirota K(5).
Author information:
(1)Department of Radiation Genetics, Kyoto University Graduate School of
Medicine, Kyoto, Japan.
(2)Center of Integrated Medical Research, School of Medicine, Keio University,
Tokyo, Japan.
(3)Department of Chemistry, Graduate School of Science and Engineering, Tokyo
Metropolitan University, Tokyo, Japan.
(4)Department of Radiation Oncology, University Medical Center Groningen,
University of Groningen, Groningen, The Netherlands.
(5)1] Department of Radiation Genetics, Kyoto University Graduate School of
Medicine, Kyoto, Japan [2] Department of Chemistry, Graduate School of Science
and Engineering, Tokyo Metropolitan University, Tokyo, Japan.
The E2 ubiquitin conjugating enzyme Ubc13 and the E3 ubiquitin ligases Rad18 and
Rnf8 promote homologous recombination (HR)-mediated double-strand break (DSB)
repair by enhancing polymerization of the Rad51 recombinase at γ-ray-induced DSB
sites. To analyze functional interactions between the three enzymes, we created
RAD18(-/-), RNF8(-/-), RAD18(-/-)/RNF8(-/-) and UBC13(-/-)clones in chicken DT40
cells. To assess the capability of HR, we measured the cellular sensitivity to
camptothecin (topoisomerase I poison) and olaparib (poly(ADP ribose)polymerase
inhibitor) because these chemotherapeutic agents induce DSBs during DNA
replication, which are repaired exclusively by HR. RAD18(-/-), RNF8(-/-) and
RAD18(-/-)/RNF8(-/-) clones showed very similar levels of hypersensitivity,
indicating that Rad18 and Rnf8 operate in the same pathway in the promotion of
HR. Although these three mutants show less prominent defects in the formation of
Rad51 foci than UBC13(-/-)cells, they are more sensitive to camptothecin and
olaparib than UBC13(-/-)cells. Thus, Rad18 and Rnf8 promote HR-dependent repair
in a manner distinct from Ubc13. Remarkably, deletion of Ku70, a protein
essential for nonhomologous end joining (NHEJ) significantly restored tolerance
of RAD18(-/-) and RNF8(-/-) cells to camptothecin and olaparib without affecting
Rad51 focus formation. Thus, in cellular tolerance to the chemotherapeutic
agents, the two enzymes collaboratively promote DSB repair by HR by suppressing
the toxic effect of NHEJ on HR rather than enhancing Rad51 focus formation. In
contrast, following exposure to γ-rays, RAD18(-/-), RNF8(-/-),
RAD18(-/-)/RNF8(-/-) and UBC13(-/-)cells showed close correlation between
cellular survival and Rad51 focus formation at DSB sites. In summary, the
current study reveals that Rad18 and Rnf8 facilitate HR by two distinct
mechanisms: suppression of the toxic effect of NHEJ on HR during DNA replication
and the promotion of Rad51 focus formation at radiotherapy-induced DSB sites.
DOI: 10.1038/onc.2014.371
PMID: 25417706 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25144364 | 1. PLoS One. 2014 Aug 21;9(8):e104302. doi: 10.1371/journal.pone.0104302.
eCollection 2014.
Poly(ADP-ribose) polymerase 1 (PARP1) overexpression in human breast cancer stem
cells and resistance to olaparib.
Gilabert M(1), Launay S(2), Ginestier C(3), Bertucci F(4), Audebert S(5),
Pophillat M(5), Toiron Y(5), Baudelet E(5), Finetti P(3), Noguchi T(6), Sobol
H(7), Birnbaum D(3), Borg JP(8), Charafe-Jauffret E(9), Gonçalves A(1).
Author information:
(1)Institut Paoli-Calmettes, Department of Molecular Pharmacology, Marseille,
France; Institut Paoli-Calmettes, Department of Medical Oncology, Marseille,
France; Aix-Marseille University, Marseille, France; Centre de Recherche en
Cancérologie de Marseille, U1068 INSERM, U7258 CNRS, Marseille, France.
(2)Institut Paoli-Calmettes, Department of Medical Oncology, Marseille, France;
Institut Paoli-Calmettes, Department of Molecular Oncology, Marseille, France.
(3)Institut Paoli-Calmettes, Department of Molecular Oncology, Marseille,
France; Centre de Recherche en Cancérologie de Marseille, U1068 INSERM, U7258
CNRS, Marseille, France.
(4)Institut Paoli-Calmettes, Department of Medical Oncology, Marseille, France;
Institut Paoli-Calmettes, Department of Molecular Oncology, Marseille, France;
Aix-Marseille University, Marseille, France; Centre de Recherche en Cancérologie
de Marseille, U1068 INSERM, U7258 CNRS, Marseille, France.
(5)Institut Paoli-Calmettes, Department of Molecular Pharmacology, Marseille,
France; Centre de Recherche en Cancérologie de Marseille, U1068 INSERM, U7258
CNRS, Marseille, France.
(6)Institut Paoli-Calmettes, Department of Cancer Genetics, Marseille, France.
(7)Institut Paoli-Calmettes, Department of Cancer Genetics, Marseille, France;
Aix-Marseille University, Marseille, France.
(8)Institut Paoli-Calmettes, Department of Molecular Pharmacology, Marseille,
France; Aix-Marseille University, Marseille, France; Centre de Recherche en
Cancérologie de Marseille, U1068 INSERM, U7258 CNRS, Marseille, France.
(9)Institut Paoli-Calmettes, Department of Biopathology, Marseille, France;
Institut Paoli-Calmettes, Department of Molecular Oncology, Marseille, France;
Aix-Marseille University, Marseille, France; Centre de Recherche en Cancérologie
de Marseille, U1068 INSERM, U7258 CNRS, Marseille, France.
BACKGROUND: Breast cancer stem cells (BCSCs) have been recognized as playing a
major role in various aspects of breast cancer biology. To identify specific
biomarkers of BCSCs, we have performed comparative proteomics of BCSC-enriched
and mature cancer cell populations from the human breast cancer cell line (BCL),
BrCA-MZ-01.
METHODS: ALDEFLUOR assay was used to sort BCSC-enriched (ALDH+) and mature
cancer (ALDH-) cell populations. Total proteins were extracted from both
fractions and subjected to 2-Dimensional Difference In-Gel Electrophoresis (2-D
DIGE). Differentially-expressed spots were excised and proteins were
gel-extracted, digested and identified using MALDI-TOF MS.
RESULTS: 2-D DIGE identified poly(ADP-ribose) polymerase 1 (PARP1) as
overexpressed in ALDH+ cells from BrCA-MZ-01. This observation was confirmed by
western blot and extended to four additional human BCLs. ALDH+ cells from
BRCA1-mutated HCC1937, which had the highest level of PARP1 overexpression,
displayed resistance to olaparib, a specific PARP1 inhibitor.
CONCLUSION: An unbiased proteomic approach identified PARP1 as upregulated in
ALDH+, BCSC-enriched cells from various human BCLs, which may contribute to
clinical resistance to PARP inhibitors.
DOI: 10.1371/journal.pone.0104302
PMCID: PMC4140711
PMID: 25144364 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have read the
journal’s policy and have the following conflicts: This work was supported by a
grant from Sanofi-Aventis. The authors declare that they have no other conflict
of interest. The authors confirm that this does not alter their adherence to
PLOS ONE policies on sharing data and materials. |
http://www.ncbi.nlm.nih.gov/pubmed/21729286 | 1. BMC Evol Biol. 2011 Jul 5;11:193. doi: 10.1186/1471-2148-11-193.
Protein functional links in Trypanosoma brucei, identified by gene fusion
analysis.
Dimitriadis D(1), Koumandou VL, Trimpalis P, Kossida S.
Author information:
(1)Biomedical Research Foundation, Academy of Athens, Athens, Greece.
BACKGROUND: Domain or gene fusion analysis is a bioinformatics method for
detecting gene fusions in one organism by comparing its genome to that of other
organisms. The occurrence of gene fusions suggests that the two original genes
that participated in the fusion are functionally linked, i.e. their gene
products interact either as part of a multi-subunit protein complex, or in a
metabolic pathway. Gene fusion analysis has been used to identify protein
functional links in prokaryotes as well as in eukaryotic model organisms, such
as yeast and Drosophila.
RESULTS: In this study we have extended this approach to include a number of
recently sequenced protists, four of which are pathogenic, to identify fusion
linked proteins in Trypanosoma brucei, the causative agent of African sleeping
sickness. We have also examined the evolution of the gene fusion events
identified, to determine whether they can be attributed to fusion or fission, by
looking at the conservation of the fused genes and of the individual component
genes across the major eukaryotic and prokaryotic lineages. We find relatively
limited occurrence of gene fusions/fissions within the protist lineages
examined. Our results point to two trypanosome-specific gene fissions, which
have recently been experimentally confirmed, one fusion involving proteins
involved in the same metabolic pathway, as well as two novel putative functional
links between fusion-linked protein pairs.
CONCLUSIONS: This is the first study of protein functional links in T. brucei
identified by gene fusion analysis. We have used strict thresholds and only
discuss results which are highly likely to be genuine and which either have
already been or can be experimentally verified. We discuss the possible impact
of the identification of these novel putative protein-protein interactions, to
the development of new trypanosome therapeutic drugs.
DOI: 10.1186/1471-2148-11-193
PMCID: PMC3155505
PMID: 21729286 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12171876 | 1. Clin Cancer Res. 2002 Aug;8(8):2505-11.
A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor
malignancies.
Aghajanian C(1), Soignet S, Dizon DS, Pien CS, Adams J, Elliott PJ, Sabbatini P,
Miller V, Hensley ML, Pezzulli S, Canales C, Daud A, Spriggs DR.
Author information:
(1)The Developmental Chemotherapy Service, Memorial Sloan-Kettering Cancer
Center, New York, New York 10021, USA. [email protected]
PURPOSE: The purpose of this study was to evaluate the toxicity and
pharmacodynamic behavior of the novel proteasome inhibitor PS341 administered as
a twice weekly i.v. bolus for 2 weeks, followed by a 1-week recovery period in
patients with advanced solid tumor malignancies.
EXPERIMENTAL DESIGN: In this Phase I trial, 43 patients were treated with PS341
in doses ranging from 0.13 to 1.56 mg/m2/dose. A standard Phase I design was
used. Pharmacodynamic studies were performed to access 20S proteasome activity.
RESULTS: Forty-three patients were treated with 89 cycles of PS341. Patients
were heavily pretreated. Dose-limiting toxicities on this schedule were diarrhea
and sensory neurotoxicity. Other side effects seen were fatigue, fever,
anorexia, nausea, vomiting, rash, pruritus, and headache. There was no
dose-limiting hematological toxicity. A dose-related inhibition of 20S
proteasome activity with increasing dose of PS341 was seen. There was one major
response in a patient with refractory non-small cell lung carcinoma.
CONCLUSIONS: Given the results of this trial, it is safe and reasonable to
recommend treatment with PS341 on the schedule used in this trial at 1.56
mg/m2/dose in Phase II trials. Particular care should be taken with patients
with preexisting neuropathy. Further testing in Phase II trials is warranted.
PMID: 12171876 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12429063 | 1. Genome Biol. 2002 Oct 25;3(11):research0064. doi:
10.1186/gb-2002-3-11-research0064. Epub 2002 Oct 25.
The society of genes: networks of functional links between genes from
comparative genomics.
Yanai I(1), DeLisi C.
Author information:
(1)Bioinformatics Graduate Program and Department of Biomedical Engineering,
Boston University, Boston, MA 02215, USA. [email protected]
BACKGROUND: Comparative genomics provides at least three methods beyond
traditional sequence similarity for identifying functional links between genes:
the examination of common phylogenetic distributions, the analysis of conserved
proximity along the chromosomes of multiple genomes, and observations of fusions
of genes into a multidomain gene in another organism. We have previously
generated the links according to each of these methods individually for 43 known
microbial genomes. Here we combine these results to construct networks of
functional associations.
RESULTS: We show that the functional networks obtained by applying these methods
have different topologies and that the information they provide is largely
additive. In particular, the combined networks of functional links contain an
average of 57% of an organism's complete genetic complement, uncover substantial
portions of known pathways, and suggest the function of previously unannotated
genes. In addition, the combined networks are qualitatively different from the
networks obtained using individual methods. They have a dominant cluster that
contains approximately 80%-90% of the genes, independent of genome size, and the
dominant clusters show the small world behavior expected of a biological system,
with global connectivity that is nearly random, and local properties that are
highly ordered.
CONCLUSIONS: When the information on functional linkage provided by three
emerging computational methods is combined, the integrated network uncovers
large numbers of conserved pathways and identifies clusters of functionally
related genes. It therefore shows considerable utility and promise as a tool for
understanding genomic structure, and for guiding high throughput experimental
investigations.
DOI: 10.1186/gb-2002-3-11-research0064
PMCID: PMC133448
PMID: 12429063 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25275045 | 1. Anticancer Res. 2014 Oct;34(10):5487-94.
Gemtuzumab ozogamicin and olaparib exert synergistic cytotoxicity in
CD33-positive HL-60 myeloid leukemia cells.
Yamauchi T(1), Uzui K(2), Nishi R(2), Shigemi H(2), Ueda T(2).
Author information:
(1)Department of Hematology and Oncology, University of Fukui, Eiheiji, Fukui,
Japan [email protected].
(2)Department of Hematology and Oncology, University of Fukui, Eiheiji, Fukui,
Japan.
BACKGROUND/AIM: Gemtuzumab ozogamicin (GO) consists of the cluster of
differentiation 33 (CD33) antibody linked to calicheamicin. The binding of GO to
the CD33 antigen on leukemic cells results in internalization and subsequent
release of calicheamicin, thereby inducing DNA strand breaks. We hypothesized
that the poly (ADP-ribose) polymerase inhibitor olaparib might inhibit DNA
repair initiated by GO-induced DNA strand breaks, thereby increasing
cytotoxicity.
MATERIALS AND METHODS: The human myeloid leukemia cell line HL-60 and a
GO-resistant variant (HL/GO20) were used.
RESULTS: The 50% growth-inhibitory concentrations (IC50) were 24 ng/ml for HL-60
cells and 550 ng/ml for GO-resistant variant HL/GO20 cells. HL/GO20 cells were
also refractory to GO-induced apoptosis. CD33 positivity was reduced in HL/GO20
cells. Olaparib-alone did not inhibit the cell growth and did not induce
apoptosis in either HL-60 cells or HL/GO20 cells at concentrations of up to 10
μM. When cells were treated with different concentrations of GO in the presence
of 10 μM olaparib, the IC50 of GO for HL-60 cells was 13 ng/ml. The combination
index was 0.86, indicating synergistic cytotoxicity of GO and olaparib in
combination. Such a combination was ineffective for HL/GO20 cells.
CONCLUSION: GO and olaparib exerted synergistic cytotoxicity in CD33-positive
myeloid leukemia cells in vitro.
Copyright© 2014 International Institute of Anticancer Research (Dr. John G.
Delinassios), All rights reserved.
PMID: 25275045 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25374341 | 1. BMC Cancer. 2014 Nov 5;14:813. doi: 10.1186/1471-2407-14-813.
Phase II study of olaparib in patients with refractory Ewing sarcoma following
failure of standard chemotherapy.
Choy E(1), Butrynski JE, Harmon DC, Morgan JA, George S, Wagner AJ, D'Adamo D,
Cote GM, Flamand Y, Benes CH, Haber DA, Baselga JM, Demetri GD.
Author information:
(1)Division of Hematology Oncology, Massachusetts General Hospital, Boston, MA,
USA. [email protected].
BACKGROUND: Preclinical studies have documented antitumor activity of PARP
inhibition both in vitro and in vivo, against Ewing sarcoma cells. This study
aimed to translate that observation into a clinical trial to assess the efficacy
and tolerability of olaparib, a PARP inhibitor, in patients with advanced Ewing
sarcoma (EWS) progressing after prior chemotherapy.
METHODS: In this nonrandomized phase II trial, adult participants with
radiographically measureable metastatic EWS received olaparib tablets, 400 mg
orally twice daily, until disease progression or drug intolerance. Tumor
measurements were determined by CT or MRI at 6 and 12 weeks after starting
olaparib administration, and then every 8 weeks thereafter. Tumor response
determinations were made according to RECIST 1.1, and adverse event
determinations were made according to CTCAE, version 4.0. A total of 22
participants were planned to be enrolled using a conventional 2-step phase II
study design. If no objective responses were observed after 12 participants had
been followed for at least 3 months, further accrual would be stopped.
RESULTS: 12 participants were enrolled, and all were evaluable. There were no
objective responses (PR/CR), 4 SD (duration 10.9, 11.4, 11.9, and 17.9 wks), and
8 PD as best response. Of the SD, 2 had minor responses (-9% and -11.7% by
RECIST 1.1). The median time to disease progression was 5.7 weeks. Further
enrollment was therefore discontinued. No significant or unexpected toxicities
were observed with olaparib, with only a single case each of grade 3 anemia and
grade 3 thrombocytopenia observed.
CONCLUSIONS: This study is the first report of a prospective phase II trial to
evaluate the safety and efficacy of a PARP inhibitor in patients with advanced
Ewing sarcoma after failure of standard chemotherapy. Olaparib administration
was safe and well tolerated when administered to this small heavily pre-treated
cohort at the 400 mg BID dose, although the median duration of dosing was for
only 5.7 weeks. No significant responses or durable disease control was seen,
and the short average interval to disease progression underscores the
aggressiveness of this disease. Other studies to combine cytotoxic chemotherapy
with PARP inhibition in EWS are actively ongoing.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01583543.
DOI: 10.1186/1471-2407-14-813
PMCID: PMC4230717
PMID: 25374341 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17966446 | 1. Rom J Intern Med. 2007;45(1):77-83.
Heart failure and dilated cardiomyopathy associated with severe longstanding
untreated hypothyroidism.
Stănescu C(1), Branidou K, Ranetti EA.
Author information:
(1)Department of Cardiology, Colentina Hospital, Bucharest, Romania.
[email protected]
Thyroid hormones have many effects on the heart and vascular system. Although
cardiac output is reduced in hypothyroidism, heart failure is relatively rare
because there is a lower demand for peripheral oxygen delivery. Hypothyroidism
may also result in accelerated atherosclerosis and coronary artery disease. We
report the case of a 55-year-old man with severe heart failure associated with
severe longstanding untreated hypothyroidism. The patient was admitted for
shortness of breath and chest pain. On presentation, signs and symptoms of
severe hypothyroidism and heart failure were noticed. The electrocardiogram
showed sinus bradycardia and ischemia. Thyroid stimulating hormone was extremely
elevated and thyroid hormone levels were undetectable. A cardiac ultrasonography
exam revealed abnormalities of the left ventricular dimensions and function
consistent with dilated cardiomyopathy. Coronary angiography showed severe
multivessel disease. Coronary by-pass was deemed necessary, but surgery was
postponed because of severe heart failure. After an increasingly downhill
clinical course, the patient died, eight month after his initial presentation,
owing to severe heart failure. This patient represents an example of an
overlooked diagnosis of severe hypothyroidism, rarely encountered nowadays,
leading to dramatic consequences.
PMID: 17966446 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25127709 | 1. Mol Cancer Res. 2014 Dec;12(12):1755-66. doi: 10.1158/1541-7786.MCR-14-0173.
Epub 2014 Aug 15.
Synergistic loss of prostate cancer cell viability by coinhibition of HDAC and
PARP.
Chao OS(1), Goodman OB Jr(2).
Author information:
(1)Cancer Research Center, College of Medicine, Roseman University of Health
Sciences, Las Vegas, Nevada.
(2)Cancer Research Center, College of Medicine, Roseman University of Health
Sciences, Las Vegas, Nevada. Comprehensive Cancer Centers of Nevada, Las Vegas,
Nevada. [email protected].
Tumors with BRCA germline mutations are defective in repairing DNA double-strand
breaks (DSB) through homologous recombination (HR) pathways, making them
sensitive to PARP inhibitors (PARPi). However, BRCA germline mutations are rare
in prostate cancer limiting the ability to therapeutically target these
pathways. This study investigates whether histone deacetylase (HDAC) inhibitors
(HDACi), reported to modulate DSB repair pathways in sporadic cancers, can
downregulate DSB repair pathways and sensitize prostate cancer cells to PARPi.
Prostate cancer cells cotreated with the HDAC inhibitor, suberoylanilide
hydroxamic acid (SAHA) and the PARPi, olaparib, demonstrated a synergistic
decrease in cell viability compared with single-agent treatment (combination
index < 0.9), whereas normal prostatic cells did not. Similarly, clonogenicity
was significantly decreased after cotreatment. Flow cytometric cell-cycle
analysis and Annexin-V staining revealed significant apoptosis upon treatment
with SAHA+olaparib. This coincided with increased DNA damage observed by
immunofluorescence microscopy analysis of γH2AX foci, a marker of DSBs. In
addition, immunoblot analysis showed a significant and persistent increase in
nuclear γH2AX levels. Both SAHA and olaparib downregulated the expression of
HR-related proteins, BRCA1 and RAD51, whereas SAHA + olaparib had an additive
effect on RAD51. Silencing RAD51 sensitized prostate cancer cells to SAHA and
olaparib alone. Collectively, cotreatment with HDACi and PARPi downregulated
HR-related protein expression and concomitantly increased DNA damage, resulting
in prostate cancer cell death.
IMPLICATIONS: These findings provide a strong rationale for supporting the use
of combined HDAC and PARP inhibition in treating advanced prostate cancer.
©2014 American Association for Cancer Research.
DOI: 10.1158/1541-7786.MCR-14-0173
PMID: 25127709 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18248532 | 1. Scand J Med Sci Sports. 2008 Dec;18(6):698-705. doi:
10.1111/j.1600-0838.2007.00647.x. Epub 2008 Jan 31.
Myocardial response to a triathlon in male athletes evaluated by Doppler tissue
imaging and biochemical parameters.
Leetmaa TH(1), Dam A, Glintborg D, Markenvard JD.
Author information:
(1)Department of Internal Medicine, Fredericia Hospital, Fredericia, Denmark.
[email protected]
The aim of this study was to examine cardiac dysfunction following
ultra-endurance exercise in male athletes. Fourteen athletes (mean+/-SD, age
39+/-8 years) were evaluated before and after the European Championship in
Triathlon 2003 using echocardiogram (ECG), cardiac markers [cardiac troponin T
(cTnT) and pro-brain natriuretic peptide (pro-BNP)] and echocardiography.
Conventional echocardiography techniques and new Doppler tissue imaging (DTI)
modalities were applied before and immediately after the competition. Blood
samples were drawn 1 week before, immediately after and 12-24 h
post-competition. CTnT significantly increased immediately, but decreased to
within normal limits 12-24 h post-competition. Pro-BNP was significantly
increased immediately post-race (27+/-21 vs 7+/-2 pmol/L pre-race, P < or =
0.007), which 12-24 h later, decreased to 19+/-14 pmol/L (P = 0.07 vs pre-race).
During echocardiography, no significant differences were found in regional or
global systolic parameters. Early diastolic peak flow velocity (9+/-2, P = 0.04)
and E/A ratio (2+/-1, P = 0.004) were increased pre-race and decreased
significantly toward normal values. In one athlete, cTnT levels increased
significantly and systolic velocities decreased, thus suggesting reversible
cardiac fatigue. When using cardiac markers and echocardiographic findings, a
triathlon was found to have no significant negative effects on left ventricular
function or myocardial tissue in male athletes.
DOI: 10.1111/j.1600-0838.2007.00647.x
PMID: 18248532 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24928708 | 1. J Am Acad Dermatol. 2014 Oct;71(4):725-30. doi: 10.1016/j.jaad.2014.04.007.
Epub 2014 Jun 11.
Noninvasive monitoring of basal cell carcinomas treated with systemic hedgehog
inhibitors: pseudocysts as a sign of tumor regression.
Maier T(1), Kulichova D(2), Ruzicka T(2), Berking C(2).
Author information:
(1)Department of Dermatology and Allergology, Ludwig-Maximilian University of
Munich, Munich, Germany. Electronic address: [email protected].
(2)Department of Dermatology and Allergology, Ludwig-Maximilian University of
Munich, Munich, Germany.
BACKGROUND: Oral hedgehog inhibitors (HHIs) have shown significant efficacy in
the treatment of basal cell carcinoma (BCC). The evaluation of tumor regression
has been performed using clinical photography and radiographic scans.
Noninvasive imaging techniques, such as reflectance confocal microscopy (RCM)
and high-definition optical coherence tomography (HD-OCT), have been shown to be
valuable in detecting BCC in the skin.
OBJECTIVE: We monitored HHI-treated BCC using RCM and HD-OCT in vivo and
correlated morphologic changes seen on imaging to changes in traditional
histopathology.
METHODS: Six BCCs in 5 patients receiving HHIs (vismodegib or sonidegib) were
examined by RCM and HD-OCT before and during treatment. Characteristic features
were compared to histopathologic findings, including immunohistochemical
analysis.
RESULTS: Characteristic features of BCC in RCM and HD-OCT decreased or
disappeared completely during HHI treatment. Half of the clinically complete
responding tumors still featured tumor residue. Pseudocystic structures ("empty"
tumor nests in imaging) and widespread fibrosis (coarse bright fibers) were new
findings and could be confirmed by histopathology.
LIMITATIONS: Our study was limited by the number of tumor samples and imaging
timepoints.
CONCLUSION: Using RCM and HD-OCT, HHI-induced regression of BCC can be
visualized noninvasively in the skin. The formation of pseudocysts and fibrosis
were characteristic signs of BCC response to HHIs.
Copyright © 2014 American Academy of Dermatology, Inc. Published by Elsevier
Inc. All rights reserved.
DOI: 10.1016/j.jaad.2014.04.007
PMID: 24928708 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8333797 | 1. Ann Thorac Surg. 1993 Jul;56(1 Suppl):S48-52; discussion S52-3. doi:
10.1016/0003-4975(93)90554-u.
Prevalence and clinical implications of abnormal thyroid hormone metabolism in
advanced heart failure.
Hamilton MA(1).
Author information:
(1)Division of Cardiology, University of California, Los Angeles School of
Medicine 90024-1679.
Patients with advanced congestive heart failure are often severely ill and may
experience substantial abnormalities in thyroid hormone metabolism. Thus, we
examined this patient population to determine the prevalence and prognostic
significance of altered thyroid hormone concentrations, the course of thyroid
abnormalities in congestive heart failure survivors, and the potential
relationship of thyroid abnormalities to overall metabolic rate. Our results
indicate that thyroid hormone metabolism (ie, the triiodothyronine to reverse
triiodothyronine ratio) is altered in a majority of patients with advanced
congestive heart failure and is an independent predictor of mortality. Currently
a study is underway that will provide further evidence for the mechanisms
involved in congestive heart failure and abnormal thyroid hormone metabolism.
DOI: 10.1016/0003-4975(93)90554-u
PMID: 8333797 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15689398 | 1. Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2832-7. doi:
10.1073/pnas.0409853102. Epub 2005 Feb 2.
Positive selection of primate TRIM5alpha identifies a critical species-specific
retroviral restriction domain.
Sawyer SL(1), Wu LI, Emerman M, Malik HS.
Author information:
(1)Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle,
WA 98109, USA.
Comment in
Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3179-80. doi:
10.1073/pnas.0500371102.
Primate genomes encode a variety of innate immune strategies to defend
themselves against retroviruses. One of these, TRIM5alpha, can restrict diverse
retroviruses in a species-specific manner. Thus, whereas rhesus TRIM5alpha can
strongly restrict HIV-1, human TRIM5alpha only has weak HIV-1 restriction. The
biology of TRIM5alpha restriction suggests that it is locked in an antagonistic
conflict with the proteins encoding the viral capsid. Such antagonistic
interactions frequently result in rapid amino acid replacements at the
protein-protein interface, as each genetic entity vies for evolutionary
dominance. By analyzing its evolutionary history, we find strong evidence for
ancient positive selection in the primate TRIM5alpha gene. This selection is
strikingly variable with some of the strongest selection occurring in the human
lineage. This history suggests that TRIM5alpha evolution has been driven by
antagonistic interactions with a wide variety of viruses and endogenous
retroviruses that predate the origin of primate lentiviruses. A 13-aa "patch" in
the SPRY protein domain bears a dense concentration of positively selected
residues, potentially implicating it as an antiviral interface. By using
functional studies of chimeric TRIM5alpha genes, we show that this patch is
generally essential for retroviral restriction and is responsible for most of
the species-specific antiretroviral restriction activity. Our study highlights
the power of evolutionary analyses, in which positive selection identifies not
only the age of genetic conflict but also the interaction interface where this
conflict plays out.
DOI: 10.1073/pnas.0409853102
PMCID: PMC549489
PMID: 15689398 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25817016 | 1. Am J Hum Genet. 2015 Apr 2;96(4):612-22. doi: 10.1016/j.ajhg.2015.02.015. Epub
2015 Mar 26.
DVL1 frameshift mutations clustering in the penultimate exon cause
autosomal-dominant Robinow syndrome.
White J(1), Mazzeu JF(2), Hoischen A(3), Jhangiani SN(4), Gambin T(5), Alcino
MC(6), Penney S(1), Saraiva JM(7), Hove H(8), Skovby F(8), Kayserili H(9),
Estrella E(10), Vulto-van Silfhout AT(3), Steehouwer M(3), Muzny DM(4), Sutton
VR(11), Gibbs RA(12); Baylor-Hopkins Center for Mendelian Genomics; Lupski
JR(13), Brunner HG(14), van Bon BW(3), Carvalho CM(15).
Author information:
(1)Department of Molecular and Human Genetics, Baylor College of Medicine,
Houston, TX 77030, USA.
(2)Programa de Pós-graduação em Ciências Genômicas e Biotecnologia, Universidade
Católica de Brasília, Brasília, DF 70790-160, Brazil; Robinow Syndrome
Foundation, Anoka, MN 55303, USA.
(3)Department of Human Genetics, Radboud Institute for Molecular Life Sciences,
Radboud University Medical Center, 6500HB Nijmegen, the Netherlands.
(4)Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX
77030, USA.
(5)Department of Molecular and Human Genetics, Baylor College of Medicine,
Houston, TX 77030, USA; Institute of Computer Science, Warsaw University of
Technology, 00-661 Warsaw, Poland.
(6)Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte MG
30190-002, Brazil.
(7)Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário
de Coimbra, Coimbra 3000-075 Portugal; University Clinic of Pediatrics, Faculty
of Medicine, University of Coimbra, Coimbra 3000-354, Portugal.
(8)Department of Clinical Genetics, Rigshospitalet, University of Copenhagen,
Copenhagen 2100, Denmark.
(9)Medical Genetics Department, Istanbul Medical Faculty, Istanbul University,
Istanbul 34093, Turkey; Medical Genetics Department, School of Medicine, Koc
University, Rumelifeneri Yolu, Sariyer Istanbul 34450 Turkey.
(10)Department of Genetics & Genomics, Boston Children's Hospital and Harvard
Medical School, Boston, MA 02115, USA.
(11)Department of Molecular and Human Genetics, Baylor College of Medicine,
Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
(12)Department of Molecular and Human Genetics, Baylor College of Medicine,
Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of
Medicine, Houston, TX 77030, USA.
(13)Department of Molecular and Human Genetics, Baylor College of Medicine,
Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of
Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030,
USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030,
USA.
(14)Department of Human Genetics, Radboud Institute for Molecular Life Sciences,
Radboud University Medical Center, 6500HB Nijmegen, the Netherlands; Department
of Clinical Genetics, Maastricht University Medical Center, 6200 AZ Maastricht,
the Netherlands.
(15)Department of Molecular and Human Genetics, Baylor College of Medicine,
Houston, TX 77030, USA; Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz,
Belo Horizonte MG 30190-002, Brazil. Electronic address: [email protected].
Robinow syndrome is a genetically heterogeneous disorder characterized by
mesomelic limb shortening, genital hypoplasia, and distinctive facial features
and for which both autosomal-recessive and autosomal-dominant inheritance
patterns have been described. Causative variants in the non-canonical signaling
gene WNT5A underlie a subset of autosomal-dominant Robinow syndrome (DRS) cases,
but most individuals with DRS remain without a molecular diagnosis. We performed
whole-exome sequencing in four unrelated DRS-affected individuals without coding
mutations in WNT5A and found heterozygous DVL1 exon 14 mutations in three of
them. Targeted Sanger sequencing in additional subjects with DRS uncovered DVL1
exon 14 mutations in five individuals, including a pair of monozygotic twins. In
total, six distinct frameshift mutations were found in eight subjects, and all
were heterozygous truncating variants within the penultimate exon of DVL1. In
five families in which samples from unaffected parents were available, the
variants were demonstrated to represent de novo mutations. All variant alleles
are predicted to result in a premature termination codon within the last exon,
escape nonsense-mediated decay (NMD), and most likely generate a C-terminally
truncated protein with a distinct -1 reading-frame terminus. Study of the
transcripts extracted from affected subjects' leukocytes confirmed expression of
both wild-type and variant alleles, supporting the hypothesis that mutant mRNA
escapes NMD. Genomic variants identified in our study suggest that truncation of
the C-terminal domain of DVL1, a protein hypothesized to have a downstream role
in the Wnt-5a non-canonical pathway, is a common cause of DRS.
Copyright © 2015 The American Society of Human Genetics. Published by Elsevier
Inc. All rights reserved.
DOI: 10.1016/j.ajhg.2015.02.015
PMCID: PMC4385180
PMID: 25817016 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11820254 | 1. Genome Biol. 2001;2(9):RESEARCH0034. doi: 10.1186/gb-2001-2-9-research0034.
Functional associations of proteins in entire genomes by means of exhaustive
detection of gene fusions.
Enright AJ(1), Ouzounis CA.
Author information:
(1)Computational Genomics Group, European Bioinformatics Institute, EMBL
Cambridge Outstation, Cambridge CB10 1SD, UK.
Comment in
Genome Biol. 2002;3(2):INTERACTIONS1001. doi:
10.1186/gb-2002-3-2-interactions1001.
BACKGROUND: It has recently been shown that the detection of gene fusion events
across genomes can be used for predicting functional associations of proteins,
including physical interaction or complex formation. To obtain such predictions
we have made an exhaustive search for gene fusion events within 24 available
completely sequenced genomes.
RESULTS: Each genome was used as a query against the remaining 23 complete
genomes to detect gene fusion events. Using an improved, fully automatic
protocol, a total of 7,224 single-domain proteins that are components of gene
fusions in other genomes were detected, many of which were identified for the
first time. The total number of predicted pairwise functional associations is
39,730 for all genomes. Component pairs were identified by virtue of their
similarity to 2,365 multidomain composite proteins. We also show for the first
time that gene fusion is a complex evolutionary process with a number of
contributory factors, including paralogy, genome size and phylogenetic distance.
On average, 9% of genes in a given genome appear to code for single-domain,
component proteins predicted to be functionally associated. These proteins are
detected by an additional 4% of genes that code for fused, composite proteins.
CONCLUSIONS: These results provide an exhaustive set of functionally associated
genes and also delineate the power of fusion analysis for the prediction of
protein interactions.
DOI: 10.1186/gb-2001-2-9-research0034
PMCID: PMC65099
PMID: 11820254 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22617881 | 1. RNA Biol. 2012 Jun;9(6):881-90. doi: 10.4161/rna.19353. Epub 2012 May 23.
CpG island hypermethylation-associated silencing of small nucleolar RNAs in
human cancer.
Ferreira HJ(1), Heyn H, Moutinho C, Esteller M.
Author information:
(1)Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research
Institute (IDIBELL), Barcelona, Catalonia, Spain.
Much effort in cancer research has focused on the tiny part of our genome that
codes for mRNA. However, it has recently been recognized that microRNAs also
contribute decisively to tumorigenesis. Studies have also shown that epigenetic
silencing by CpG island hypermethylation of microRNAs with tumor suppressor
activities is a common feature of human cancer. The importance of other classes
of non-coding RNAs, such as long intergenic ncRNAs (lincRNAs) and transcribed
ultraconserved regions (T-UCRs) as altered elements in neoplasia, is also
gaining recognition. Thus, we wondered whether there were other ncRNAs
undergoing CpG island hypermethylation-associated inactivation in cancer cells.
We focused on the small nucleolar RNAs (snoRNAs), a subset of ncRNA with a wide
variety of cellular functions, such as chemical modification of RNA, pre-RNA
processing and control of alternative splicing. By data mining snoRNA databases
and the scientific literature, we selected 49 snoRNAs that had a CpG island
within ≤ 2 Kb or that were processed from a host gene with a 5'-CpG island.
Bisulfite genomic sequencing of multiple clones in normal colon mucosa and the
colorectal cancer cell line HCT-116 showed that 46 snoRNAs were equally
methylated in the two samples: completely unmethylated (n = 26) or fully
methylated (n = 20). Most interestingly, the host gene-associated 5'-CpG islands
of the snoRNAs SNORD123, U70C and ACA59B were hypermethylated in the cancer
cells but not in the corresponding normal tissue. CpG island hypermethylation
was associated with the transcriptional silencing of the respective snoRNAs.
Results of a DNA methylation microarray platform in a comprehensive collection
of normal tissues, cancer cell lines and primary malignancies demonstrated that
the observed hypermethylation of snoRNAs was a common feature of various tumor
types, particularly in leukemias. Overall, our findings indicate the existence
of a new subclass of ncRNAs, snoRNAs, that are targeted by epigenetic
inactivation in human cancer.
DOI: 10.4161/rna.19353
PMCID: PMC3495749
PMID: 22617881 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8807287 | 1. Genetics. 1996 Jul;143(3):1127-35. doi: 10.1093/genetics/143.3.1127.
Mismatch repair mutants in yeast are not defective in transcription-coupled DNA
repair of UV-induced DNA damage.
Sweder KS(1), Verhage RA, Crowley DJ, Crouse GF, Brouwer J, Hanawalt PC.
Author information:
(1)Department of Biological Sciences, Stanford University, California
94305-5020, USA. [email protected]
Transcription-coupled repair, the targeted repair of the transcribed strands of
active genes, is defective in bacteria, yeast, and human cells carrying
mutations in mfd, RAD26 and ERCC6, respectively. Other factors probably are also
uniquely involved in transcription-repair coupling. Recently, a defect was
described in transcription-coupled repair for Escherichia coli mismatch repair
mutants and human tumor cell lines with mutations in mismatch repair genes. We
examined removal of UV-induced DNA damage in yeast strains mutated in mismatch
repair genes in an effort to confirm a defect in transcription-coupled repair in
this system. In addition, we determined the contribution of the mismatch repair
gene MSH2 to transcription-coupled repair in the absence of global genomic
repair using rad7 delta mutants. We also determined whether the
Rad26-independent transcription-coupled repair observed in rad26 delta and rad7
delta rad26 delta mutants depends on MSH2 by examining repair deficiencies of
rad26 delta msh2 delta and rad7 delta rad26 delta msh2 delta mutants. We found
no defects in transcription-coupled repair caused by mutations in the mismatch
repair genes MSH2, MLH1, PMS1, and MSH3. Yeast appears to differ from bacteria
and human cells in the capacity for transcription-coupled repair in a mismatch
repair mutant background.
DOI: 10.1093/genetics/143.3.1127
PMCID: PMC1207384
PMID: 8807287 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22926237 | 1. Methods. 2012 Oct;58(2):94-105. doi: 10.1016/j.ymeth.2012.08.006. Epub 2012
Aug 19.
Genome-wide identification of miRNA targets by PAR-CLIP.
Hafner M(1), Lianoglou S, Tuschl T, Betel D.
Author information:
(1)Laboratory of RNA Molecular Biology, Howard Hughes Medical Institute, The
Rockefeller University, New York, NY, USA.
miRNAs are short (20-23 nt) RNAs that are loaded into proteins of the Argonaute
(AGO) family and guide them to partially complementary target sites on mRNAs,
resulting in mRNA destabilization and/or translational repression. It is
estimated that about 60% of the mammalian genes are potentially regulated by
miRNAs, and therefore methods for experimental miRNA target determination have
become valuable tools for the characterization of posttranscriptional gene
regulation. Here we present a step-by-step protocol and guidelines for the
computational analysis for the large-scale identification of miRNA target sites
in cultured cells by photoactivatable ribonucleoside enhanced crosslinking and
immunoprecipitation (PAR-CLIP) of AGO proteins.
Copyright © 2012 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ymeth.2012.08.006
PMCID: PMC3508682
PMID: 22926237 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23612755 | 1. Int J Oncol. 2013 Jul;43(1):219-27. doi: 10.3892/ijo.2013.1916. Epub 2013 Apr
23.
Effect of the STAT3 inhibitor STX-0119 on the proliferation of cancer stem-like
cells derived from recurrent glioblastoma.
Ashizawa T(1), Miyata H, Iizuka A, Komiyama M, Oshita C, Kume A, Nogami M,
Yagoto M, Ito I, Oishi T, Watanabe R, Mitsuya K, Matsuno K, Furuya T, Okawara T,
Otsuka M, Ogo N, Asai A, Nakasu Y, Yamaguchi K, Akiyama Y.
Author information:
(1)Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shizuoka
Cancer Center Hospital, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan.
Signal transducer and activator of transcription (STAT) 3, a member of a family
of DNA-binding molecules, is a potential target in the treatment of cancer. The
highly phosphorylated STAT3 in cancer cells contributes to numerous
physiological and oncogenic signaling pathways. Furthermore, a significant
association between STAT3 signaling and glioblastoma multiforme stem-like cell
(GBM-SC) development and maintenance has been demonstrated in recent studies.
Previously, we reported a novel small molecule inhibitor of STAT3 dimerization,
STX-0119, as a cancer therapeutic. In the present study, we focused on cancer
stem-like cells derived from recurrent GBM patients and investigated the
efficacy of STX-0119. Three GBM stem cell lines showed many stem cell markers
such as CD133, EGFR, Nanog, Olig2, nestin and Yamanaka factors (c-myc, KLF4,
Oct3/4 and SOX2) compared with parental cell lines. These cell lines also formed
tumors in vivo and had similar histological to surgically resected tumors. STAT3
phosphorylation was activated more in the GBM-SC lines than serum-derived GB
cell lines. The growth inhibitory effect of STX-0119 on GBM-SCs was moderate
(IC50 15-44 µM) and stronger compared to that of WP1066 in two cell lines. On
the other hand, the effect of temozolomide was weak in all the cell lines (IC50
53-226 µM). Notably, STX-0119 demonstrated strong inhibition of the expression
of STAT3 target genes (c-myc, survivin, cyclin D1, HIF-1α and VEGF) and stem
cell-associated genes (CD44, Nanog, nestin and CD133) as well as the induction
of apoptosis in one stem-like cell line. Interestingly, VEGFR2 mRNA was also
remarkably inhibited by STX-0119. In a model using transplantable stem-like cell
lines in vivo GB-SCC010 and 026, STX-0119 inhibited the growth of GBM-SCs at 80
mg/kg. STX-0119, an inhibitor of STAT3, may serve as a novel therapeutic
compound against GBM-SCs even in temozolomide-resistant GBM patients and has the
potential for GBM-SC-specific therapeutics in combination with temozolomide plus
radiation therapy.
DOI: 10.3892/ijo.2013.1916
PMID: 23612755 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16978026 | 1. Chem Res Toxicol. 2006 Sep;19(9):1215-20. doi: 10.1021/tx060103g.
Transcription arrest at an abasic site in the transcribed strand of template
DNA.
Tornaletti S(1), Maeda LS, Hanawalt PC.
Author information:
(1)Department of Biological Sciences, Stanford University, Stanford, California
94305-5020, USA.
A dedicated excision repair pathway, termed transcription-coupled repair (TCR),
targets the removal of DNA lesions from transcribed strands of expressed genes.
Transcription arrest at the site of the lesion has been proposed as the first
step for initiation of TCR. In support of this model, a strong correlation
between arrest of transcription by a lesion in vitro and TCR of that lesion in
vivo has been found in most cases analyzed. TCR has been reported for oxidative
DNA damage; however, very little is known about how frequently occurring and
spontaneous DNA damage, such as depurination and base deamination, affects
progression of the transcription complex. We have previously determined that the
oxidative lesion, thymine glycol, is a significant block to transcription by T7
RNA polymerase (T7 RNAP) but has no detectable effect on transcription by RNA
polymerase II (RNAP II) in a reconstituted system with all of the required
factors. Another oxidative lesion, 8-oxoguanine, only slightly blocked T7 RNAP
and caused RNAP II to briefly pause at the lesion before bypassing it. Because
an abasic site is an intermediate in the repair of oxidative damage, it was of
interest to learn whether it arrested transcription. Using in vitro
transcription assays and substrates containing a specifically positioned lesion,
we found that an abasic site in the transcribed strand is a 60% block to
transcription by T7 RNAP but nearly a complete block to transcription by
mammalian RNAP II. An abasic site in the nontranscribed strand did not block
either polymerase. Our results clearly indicate that an abasic site is a much
stronger block to transcription than either a thymine glycol or an 8-oxoguanine.
Because the predominant model for TCR postulates that only lesions that block
RNAP will be subject to TCR, our findings suggest that the abasic site may be
sufficient to initiate TCR in vivo.
DOI: 10.1021/tx060103g
PMID: 16978026 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7607467 | 1. Gene. 1995 May 19;157(1-2):105. doi: 10.1016/0378-1119(94)00635-6.
Self-methylation of the M.BspRI methyltransferase.
Szilák L(1), Finta C, Patthy A, Venetianer P, Kiss A.
Author information:
(1)Institute of Biochemistry, Hungarian Academy of Sciences, Szeged.
In the absence of DNA substrate, the DNA methyltransferase (MTase) M.BspRI can
methylate itself using the methyl donor S-adenosyl-L-methionine (AdoMet). The
methyl group is transferred to two Cys residues of the MTase.
DOI: 10.1016/0378-1119(94)00635-6
PMID: 7607467 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11208790 | 1. J Bacteriol. 2001 Feb;183(3):921-7. doi: 10.1128/JB.183.3.921-927.2001.
Lowering S-adenosylmethionine levels in Escherichia coli modulates C-to-T
transition mutations.
Macintyre G(1), Atwood CV, Cupples CG.
Author information:
(1)Biology Department, Concordia University, Montreal, Quebec H3G 1M8, Canada.
[email protected]
Deoxycytosine methylase (Dcm) enzyme activity causes mutagenesis in vitro either
directly by enzyme-induced deamination of cytosine to uracil in the absence of
the methyl donor, S-adenosylmethionine (SAM), or indirectly through spontaneous
deamination of [5-methyl]cytosine to thymine. Using a Lac reversion assay, we
investigated the contribution of the first mechanism to Dcm mutagenesis in vivo
by lowering the levels of SAM. Escherichia coli SAM levels were lowered by
reducing SAM synthetase activity via the introduction of a metK84 allele or by
hydrolyzing SAM using the bacteriophage T3 SAM hydrolase. The metK84 strains
exhibited increased C-to-T mutagenesis. Expression of the T3 SAM hydrolase gene,
under the control of the arabinose-inducible P(BAD) promoter, effectively
reduced Dcm-mediated genomic DNA methylation. However, increased mutagenesis was
not observed until extremely high arabinose concentrations were used, and genome
methylation at Dcm sites was negligible.
DOI: 10.1128/JB.183.3.921-927.2001
PMCID: PMC94959
PMID: 11208790 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11821423 | 1. J Biol Chem. 2002 Apr 12;277(15):12777-83. doi: 10.1074/jbc.M112297200. Epub
2002 Jan 30.
Transcription-coupled DNA repair is genomic context-dependent.
Feng Z(1), Hu W, Komissarova E, Pao A, Hung MC, Adair GM, Tang MS.
Author information:
(1)Department of Environmental Medicine, Pathology and Medicine, New York
University School of Medicine, Tuxedo, NY 10987, USA.
DNA damage is preferentially repaired in the transcribed strand of many active
genes. Although the concept of DNA repair coupled with transcription has been
widely accepted, its mechanisms remain elusive. We recently reported that in
Chinese hamster ovary cells while ultraviolet light-induced cyclobutane
pyrimidine dimers (CPDs) are preferentially repaired in the transcribed strand
of dihydrofolate reductase gene, CPDs are efficiently repaired in both strands
of adenine phosphoribosyltransferase (APRT) locus, in either a transcribed or
nontranscribed APRT gene (1). These results suggested that the transcription
dependence of repair may depend on genomic context. To test this hypothesis, we
constructed transfectant cell lines containing a single, actively transcribed
APRT gene, integrated at different genomic sites. Mapping of CPD repair in the
integrated APRT genes in three transfectant cell lines revealed two distinct
repair patterns, either preferential repair of CPDs in the transcribed strand or
very poor repair in both strands. Similar kinetics of micrococcal nuclease
digestion were seen for all three transfectant APRT gene domains and endogenous
APRT locus. Our results suggest that both the efficiency and strand-specificity
of repair of an actively transcribed gene are profoundly affected by genomic
context but do not reflect changes in first order nucleosomal structure.
DOI: 10.1074/jbc.M112297200
PMID: 11821423 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25526472 | 1. Medicine (Baltimore). 2014 Dec;93(28):e294. doi: 10.1097/MD.0000000000000294.
XRCC2 promotes colorectal cancer cell growth, regulates cell cycle progression,
and apoptosis.
Xu K(1), Song X, Chen Z, Qin C, He Y, Zhan W.
Author information:
(1)From the Gastrointestinal and Pancreatic Surgery Department, The First
Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province,
People's Republic of China.
X-ray repair complementing defective repair in Chinese hamster cells 2 (XRCC2)
and poly(ADP-ribose) polymerase 1 (PARP1) both play important roles in
homologous recombination DNA repair. According to the theory of synthetic
lethality, XRCC2-deficient cells are more sensitive to PARP1 inhibitors compared
to XRCC2-expressing cells. We investigated XRCC2 expression and function in
colorectal cancer (CRC), and the characteristics of sensitivity to PARP1
inhibitor in CRC cells with different XRCC2 levels. We enrolled 153 patients
with CRC who had undergone surgery in this study. XRCC2 expression was assessed
using immunohistochemistry. Stable CRC SW480 cell lines with low or high XRCC2
expression were constructed. Following treatment with the PARP1 inhibitor
olaparib, the viability of cells with different XRCC2 levels was determined;
cell cycle distribution and apoptosis were analyzed using flow cytometry. B-cell
lymphoma-2 (Bcl-2) protein expression was measured by Western blotting. The
positive rates of XRCC2 in primary CRC tissue were significantly higher than
that in the matched adjacent noncancerous tissue, and XRCC2 expression status in
primary CRC was related to tumor site, Dukes' stage, and tumor-nodes-metastasis
(TNM) stage. XRCC2 overexpression inhibited CRC cell apoptosis and promoted
proliferation by enriching cells in the G0/G1 phase. Moreover, olaparib
suppressed proliferation, and olaparib sensitivity in CRC cells with high XRCC2
expression was greater. High XRCC2 expression promotes CRC cell proliferation
and enriches cells in the G0/G1 phase but inhibits apoptosis. High XRCC2
expression cells are more sensitive to olaparib, which inhibits their viability.
DOI: 10.1097/MD.0000000000000294
PMCID: PMC4603138
PMID: 25526472 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no conflict
of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/22749141 | 1. Prog Mol Biol Transl Sci. 2012;110:25-40. doi:
10.1016/B978-0-12-387665-2.00002-X.
Transcription-coupled DNA repair in prokaryotes.
Ganesan A(1), Spivak G, Hanawalt PC.
Author information:
(1)Department of Biology, Stanford University, Stanford, California, USA.
Transcription-coupled repair (TCR) is a subpathway of nucleotide excision repair
(NER) that acts specifically on lesions in the transcribed strand of expressed
genes. First reported in mammalian cells, TCR was then documented in Escherichia
coli. In this organism, an RNA polymerase arrested at a lesion is displaced by
the transcription repair coupling factor, Mfd. This protein recruits the NER
lesion-recognition factor UvrA, and then dissociates from the DNA. UvrA binds
UvrB, and the assembled UvrAB* complex initiates repair. In mutants lacking
active Mfd, TCR is absent. A gene transcribed by the bacteriophage T7 RNA
polymerase in E. coli also requires Mfd for TCR. The CSB protein (missing or
defective in cells of patients with Cockayne syndrome, complementation group B)
is essential for TCR in humans. CSB and its homologs in higher eukaryotes are
likely functional equivalents of Mfd.
Copyright © 2012 Elsevier Inc. All rights reserved.
DOI: 10.1016/B978-0-12-387665-2.00002-X
PMID: 22749141 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23770556 | 1. Protein Expr Purif. 2013 Aug;90(2):178-85. doi: 10.1016/j.pep.2013.06.005.
Epub 2013 Jun 13.
High-level expression of Staphylococcal Protein A in Pichia pastoris and
purification and characterization of the recombinant protein.
Hao J(1), Xu L, He H, Du X, Jia L.
Author information:
(1)School of Life Science and Biotechnology, Dalian University of Technology,
Dalian 116024, China.
Staphylococcal Protein A (SPA), a cell wall protein of Staphylococcus aureus, is
in high demand because of its ability to bind immunoglobulins. Much of the SPA
that we use today is recombinant SPA (rSPA), which is produced in Escherichia
coli. As rSPA is obtained by expressing SPA as an intracellular protein, its
purification is tedious and time consuming. In order to obtain a large amount of
highly purified rSPA with relative ease, we expressed SPA as a secretory form in
the yeast Pichia pastoris. To increase the expression level of SPA and repress
its proteolysis during fermentation, the cell density (OD600), temperature and
pH at which SPA expression was induced as well as the induction time were
optimized. The final yield of SPA obtained was about 8.8 g per liter of culture,
which under the optimized fermentation condition, accounted for 80% of the total
protein in the culture supernatant. The expressed SPA was purified from the
culture supernatant by DEAE ion-exchange chromatography (IEC) after the
supernatant was subjected to a desalting step. The purified SPA was resolved as
a single band by SDS-PAGE and as a single peak by HPLC. Its identity was
confirmed by MALDI-TOF MS and western-blot. Moreover, the protein also exhibited
excellent affinity for IgG when tested with human IgG. The production and
purification of SPA described in this study offers a new method for obtaining
high level of SPA in relatively pure form that is suitable for practical
application.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.pep.2013.06.005
PMID: 23770556 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15913669 | 1. Mutat Res. 2005 Sep 4;577(1-2):155-61. doi: 10.1016/j.mrfmmm.2005.03.016.
Transcription-coupled repair: a complex affair.
Mellon I(1).
Author information:
(1)The Graduate Center for Toxicology, Markey Cancer Center, University of
Kentucky, Lexington, KY 40536-0305, USA. [email protected]
Transcription-coupled repair (TCR) is generally observed as more rapid or more
efficient removal of certain types of DNA damage from the transcribed strands of
expressed genes compared with the nontranscribed strands. It has been clearly
demonstrated to be a subpathway of nucleotide excision repair (NER) in E. coli,
yeast and mammalian cells. Genetic and biochemical studies indicate that it is a
highly complex process and requires the participation of the NER pathway, the
RNA polymerase complex and additional factors. An early event in TCR is likely
the blocking of RNA polymerase complex elongation by damage present in the
transcribed strands of expressed genes. Whether TCR is involved in base excision
repair pathways or the repair of common forms of oxidative damage is less clear.
This review is focused on the description of possible mechanisms of TCR in E.
coli and mammalian cells.
DOI: 10.1016/j.mrfmmm.2005.03.016
PMID: 15913669 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16164190 | 1. No Shinkei Geka. 2005 Sep;33(9):925-9.
[An autopsy case of Down's syndrome with moyamoya syndrome].
[Article in Japanese]
Watabe N(1), Nishino A, Arai H, Nishimura S, Suzuki S, Uenohara H, Sakurai Y,
Suzuki H.
Author information:
(1)Department of Neurosurgery, Sendai National Hospital Organization, Sendai
Medical Center, 2-8-8 Miyagino, Miyagino-ku, Sendai 983-8520, Japan.
We reported an autopsy case of Down's syndrome with moyamoya syndrome. A
30-year-old male with Down's syndrome suffered from a cerebral infarction and
died of brain herniation. Cerebral angiography showed vascular abnormalities
that were the same as moyamoya disease. Pathological findings revealed multiple
stenosis of main trunk of the cerebral arteries. Pathologically, the stenosed
vessels showed eccentric intimal thickness with cholesterin deposit, unlike
moyamoya disease. There are only two previous reports of autopsied cases of
Down's syndrome with moyamoya syndrome. We postulate that a protein encoded on
chromosome 21 may be related to the pathogenesis of Down's syndrome with
moyamoya syndrome.
PMID: 16164190 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19929882 | 1. Transpl Infect Dis. 2010 Apr;12(2):138-42. doi:
10.1111/j.1399-3062.2009.00473.x. Epub 2009 Nov 19.
Nontuberculous mycobacterial pulmonary infection in renal transplant recipients.
Ho TA(1), Rommelaere M, Coche E, Yombi JC, Kanaan N.
Author information:
(1)Division of Nephrology, Cliniques Universitaires Saint-Luc, Université
Catholique de Louvain Medical School, Brussels, Belgium.
The most common presentations of nontuberculous mycobacterial infections in
kidney transplant recipients (KTR) are cutaneous and disseminated diseases.
Pleuropulmonary infection not associated with disseminated disease is rare. Its
diagnosis can be difficult, requiring a combination of clinical, radiological,
and bacteriological criteria. We report on a Mycobacterium avium complex
pulmonary infection in a KTR with underlying chronic obstructive pulmonary
disease. Chest computed tomography showed an excavated lesion of the right upper
lobe, similar to a typical lesion of pulmonary tuberculosis. Evolution was
favorable with multiple-drug therapy including rifampicin, ethambutol, and
clarithromycin, along with a slight reduction in immunosuppression. We review
the literature and discuss the epidemiology, diagnosis, management, and
follow-up of this uncommon post-transplant complication.
DOI: 10.1111/j.1399-3062.2009.00473.x
PMID: 19929882 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23671339 | 1. Nucleic Acids Res. 2013 Jul;41(13):e132. doi: 10.1093/nar/gkt373. Epub 2013
May 13.
r3Cseq: an R/Bioconductor package for the discovery of long-range genomic
interactions from chromosome conformation capture and next-generation sequencing
data.
Thongjuea S(1), Stadhouders R, Grosveld FG, Soler E, Lenhard B.
Author information:
(1)Computational Biology Unit, Uni Computing, Uni Research AS, N-5020 Bergen,
Norway.
The coupling of chromosome conformation capture (3C) with next-generation
sequencing technologies enables the high-throughput detection of long-range
genomic interactions, via the generation of ligation products between DNA
sequences, which are closely juxtaposed in vivo. These interactions involve
promoter regions, enhancers and other regulatory and structural elements of
chromosomes and can reveal key details of the regulation of gene expression.
3C-seq is a variant of the method for the detection of interactions between one
chosen genomic element (viewpoint) and the rest of the genome. We present
r3Cseq, an R/Bioconductor package designed to perform 3C-seq data analysis in a
number of different experimental designs. The package reads a common aligned
read input format, provides data normalization, allows the visualization of
candidate interaction regions and detects statistically significant chromatin
interactions, thus greatly facilitating hypothesis generation and the
interpretation of experimental results. We further demonstrate its use on a
series of real-world applications.
DOI: 10.1093/nar/gkt373
PMCID: PMC3711450
PMID: 23671339 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23776704 | 1. PLoS One. 2013 Jun 12;8(6):e66935. doi: 10.1371/journal.pone.0066935. Print
2013.
Molecular basis for the dissociation dynamics of protein A-immunoglobulin G1
complex.
Liu FF(1), Huang B, Dong XY, Sun Y.
Author information:
(1)Key Laboratory of Systems Bioengineering of the Ministry of Education and
Department of Biochemical Engineering, School of Chemical Engineering and
Technology, Tianjin University, Tianjin, China.
Staphylococcus aureus protein A (SpA) is the most popular affinity ligand for
immunoglobulin G1 (IgG1). However, the molecular basis for the dissociation
dynamics of SpA-IgG1 complex is unclear. Herein, coarse-grained (CG) molecular
dynamics (MD) simulations with the Martini force field were used to study the
dissociation dynamics of the complex. The CG-MD simulations were first verified
by the agreement in the structural and interactional properties of SpA and human
IgG1 (hIgG1) in the association process between the CG-MD and all-atom MD at
different NaCl concentrations. Then, the CG-MD simulation studies focused on the
molecular insight into the dissociation dynamics of SpA-hIgG1 complex at pH 3.0.
It is found that there are four steps in the dissociation process of the
complex. First, there is a slight conformational adjustment of helix II in SpA.
This is followed by the phenomena that the electrostatic interactions provided
by the three hot spots (Glu143, Arg146 and Lys154) of helix II of SpA break up,
leading to the dissociation of helix II from the binding site of hIgG1.
Subsequently, breakup of the hydrophobic interactions between helix I (Phe132,
Tyr133 and His137) in SpA and hIgG1 occurs, resulting in the disengagement of
helix I from its binding site of hIgG1. Finally, the non-specific interactions
between SpA and hIgG1 decrease slowly till disappearance, leading to the
complete dissociation of the SpA-hIgG1 complex. This work has revealed that
CG-MD coupled with the Martini force field is an effective method for studying
the dissociation dynamics of protein-protein complex.
DOI: 10.1371/journal.pone.0066935
PMCID: PMC3680412
PMID: 23776704 [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/17647266 | 1. Cancer. 2007 Sep 15;110(6):1195-200. doi: 10.1002/cncr.22895.
Efficacy and safety of neoadjuvant trastuzumab combined with paclitaxel and
epirubicin: a retrospective review of the M. D. Anderson experience.
Dawood S(1), Gonzalez-Angulo AM, Peintinger F, Broglio K, Symmans WF, Kau SW,
Islam R, Hortobagyi GN, Buzdar AU.
Author information:
(1)Department of Breast Medical Oncology, The University of Texas M. D. Anderson
Cancer Center, Houston, Texas 77030, USA.
BACKGROUND: A previously published prospective randomized phase 3 trial showed
that administration of 24 weeks of primary systemic chemotherapy (PST) with
paclitaxel and FEC(75) (fluorouracil, epirubicin, cyclophosphamide) concurrently
with trastuzumab in patients with HER2-positive primary breast cancer resulted
in a 60% pathologic complete response rate (PCR) with no associated severe
cardiac toxicity. The purpose of this study was to review the efficacy and
safety of a similar regimen outside the setting of a clinical trial.
METHODS: Patients with HER2-positive breast cancer (defined as either
immunohistochemical 3+ or fluorescence in situ hybridization-positive) that had
received 24 weeks of neoadjuvant trastuzumab concurrently with taxane and
anthracycline-based chemotherapy between 2004 and 2006 were included in the
analysis. PST chemotherapy consisted of paclitaxel (80 mg/m(2)) weekly for 12
weeks followed by 4 cycles of FEC(75) (500 mg/m(2), 75 mg/m(2), and 500 mg/m(2),
respectively).
RESULTS: Forty patients were identified. The median age was 48 years (range,
29-81). In all, 60% of patients had stage III disease and 4 had inflammatory
breast cancer. The PCR rate was 55% (95% confidence interval [CI], 38.5%-70.7%).
At a median follow-up of 19 months. 5 patients had a recurrence, of which 4 did
not achieve a PCR. No severe cardiac events were observed.
CONCLUSIONS: Stage II and III HER2-positive breast cancer patients achieved a
high rate of PCR with trastuzumab given concurrently with paclitaxel and FEC(75)
chemotherapy. No severe cardiac events were observed with the regimen. The data
concur with the results of a previously published trial.
(c) 2007 American Cancer Society.
DOI: 10.1002/cncr.22895
PMID: 17647266 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23652674 | 1. Front Horm Res. 2013;41:111-40. doi: 10.1159/000345673. Epub 2013 Mar 19.
Genetics of pituitary adenomas.
Gadelha MR(1), Trivellin G, Hernández Ramírez LC, Korbonits M.
Author information:
(1)Division of Endocrinology, Clementino Fraga Filho University Hospital,
Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Pituitary adenomas are common tumors of the adenohypophysis which can cause
considerable morbidity, due to excessive hormonal secretion or compression and
local invasion of surrounding structures. The vast majority of pituitary
adenomas occur sporadically. Altered gene expression is commonly detected but
somatic mutations, epigenetic changes and abnormal microRNAs have also been
described. Occurrence of GNAS mutations at a postzygotic stage lead to
McCune-Albright syndrome (MAS), a disease causing endocrine hyperfunction and
tumors in several organs, including the pituitary. Familial pituitary adenomas
occur as part of a syndrome affecting other organs, such as in MEN1 or Carney
complex, or occur with pituitary adenomas only as in familial isolated pituitary
adenoma (FIPA). FIPA, an autosomal-dominant disease with variable penetrance, is
explained in 20% of patients by germline mutations in the tumor suppressor aryl
hydrocarbon receptor interacting protein(AIP), while no gene abnormality has
been identified to date in the majority of the FIPA families. AIP
mutation-positive patients have a characteristic clinical phenotype with usually
young- or childhood-onset growth hormone (GH) and/or prolactin (PRL)-secreting
adenomas and can be seen in cases with no apparent family history as well.
Understanding the tumorigenic process in AIP-positive and AIP-negative FIPA
patients could result in better diagnostic and treatment options for both
familial and sporadic cases.
Copyright © 2013 S. Karger AG, Basel.
DOI: 10.1159/000345673
PMID: 23652674 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20024637 | 1. Herz. 2009 Dec;34(8):589-93. doi: 10.1007/s00059-009-3316-4.
Biomarkers for chronic heart failure : diagnostic, prognostic, and therapeutic
challenges.
Lainscak M(1), Anker MS, von Haehling S, Anker SD.
Author information:
(1)Division of Applied Cachexia Research, Department of Cardiology, Campus
Virchow Clinic, Charité - Universitätsmedizin, Berlin, Germany.
[email protected]
Cardiac biomarkers are very important in diagnosis, risk stratification, and
management of patients with heart failure. Although not meeting all criteria for
an ideal biomarker, natriuretic peptides primarily have a diagnostic and
prognostic role. Other routinely available and newly emerging biomarkers have a
complementary role in patient management; thus multimarker strategy might be
warranted in future. The quest for a single marker or a combination is ongoing
and several established, widely available biomarkers might have been overlooked
in the field of heart failure. The authors review some of those biomarkers and
speculate on the possible roles of combining two or more of them.
DOI: 10.1007/s00059-009-3316-4
PMID: 20024637 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17015469 | 1. Mol Cell Biol. 2006 Dec;26(23):8722-30. doi: 10.1128/MCB.01263-06. Epub 2006
Oct 2.
Transcription domain-associated repair in human cells.
Nouspikel TP(1), Hyka-Nouspikel N, Hanawalt PC.
Author information:
(1)Institute for Cancer Studies, University of Sheffield Medical School, Beech
Hill Road, Sheffield S10 2RX, United Kingdom. [email protected]
Nucleotide excision repair (NER), which is arguably the most versatile DNA
repair system, is strongly attenuated in human cells of the monocytic lineage
when they differentiate into macrophages. Within active genes, however, both DNA
strands continue to be proficiently repaired. The proficient repair of the
nontranscribed strand cannot be explained by the dedicated subpathway of
transcription-coupled repair (TCR), which is targeted to the transcribed strand
in expressed genes. We now report that the previously termed
differentiation-associated repair (DAR) depends upon transcription, but not
simply upon RNA polymerase II (RNAPII) encountering a lesion: proficient repair
of both DNA strands can occur in a part of a gene that the polymerase never
reaches, and even if the translocation of RNAPII is blocked with transcription
inhibitors. This suggests that DAR may be a subset of global NER, restricted to
the subnuclear compartments or chromatin domains within which transcription
occurs. Downregulation of selected NER genes with small interfering RNA has
confirmed that DAR relies upon the same genes as global genome repair, rather
than upon TCR-specific genes. Our findings support the general view that the
genomic domains within which transcription is active are more accessible than
the bulk of the genome to the recognition and repair of lesions through the
global pathway and that TCR is superimposed upon that pathway of NER.
DOI: 10.1128/MCB.01263-06
PMCID: PMC1636821
PMID: 17015469 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23001356 | 1. Aging (Albany NY). 2012 Sep;4(9):590-605. doi: 10.18632/aging.100486.
Plasma microRNA biomarkers for detection of mild cognitive impairment.
Sheinerman KS(1), Tsivinsky VG, Crawford F, Mullan MJ, Abdullah L, Umansky SR.
Author information:
(1)DiamiR, LLC, Princeton, NJ 08540, USA.
Comment in
Cell Cycle. 2013 Jan 1;12(1):1-2. doi: 10.4161/cc.23067.
Early stages of many neurodegenerative diseases, such as Alzheimer's disease,
vascular and frontotemporal dementia, and Parkinson's disease, are frequently
associated with Mild Cognitive Impairment (MCI). A minimally invasive screening
test for early detection of MCI may be used to select optimal patient groups in
clinical trials, to monitor disease progression and response to treatment, and
to better plan patient clinical care. Here, we examined the feasibility of using
pairs of brain-enriched plasma microRNA (miRNA), at least one of which is
enriched in synapses and neurites, as biomarkers that could differentiate
patients with MCI from age-matched controls. The identified biomarker pairs fall
into two sets: the "miR-132 family" (miR-128/miR-491-5p, miR-132/miR-491-5p and
mir-874/miR-491-5p) and the "miR-134 family" (miR-134/miR-370,
miR-323-3p/miR-370 and miR-382/miR-370). The area under the Receiver-Operating
Characteristic curve for the differentiation of MCI from controls using these
biomarker pairs is 0.91-0.95, with sensitivity and specificity at 79%-100%
(miR-132 family) and 79%-95% (miR-134 family), and p〈0.001. In a separate
longitudinal study, the identified miRNA biomarker pairs successfully detected
MCI in majority of patients at asymptomatic stage 1-5 years prior to clinical
diagnosis. The reported biomarker pairs also appear useful for detecting
age-related brain changes. Further testing in a larger study is necessary for
validation of these results.
DOI: 10.18632/aging.100486
PMCID: PMC3492224
PMID: 23001356 [Indexed for MEDLINE]
Conflict of interest statement: Kira S. Sheinerman, Vladimir G. Tsivinsky, and
Samuil R. Umansky are shareholders of DiamiR, LLC. |
http://www.ncbi.nlm.nih.gov/pubmed/11125105 | 1. Nucleic Acids Res. 2001 Jan 1;29(1):255-9. doi: 10.1093/nar/29.1.255.
SpliceDB: database of canonical and non-canonical mammalian splice sites.
Burset M(1), Seledtsov IA, Solovyev VV.
Author information:
(1)The Sanger Centre, Hinxton, Cambridge CB10 1SA, UK and Softberry Inc., 108
Corporate Park Drive, Suite 120, White Plains, NY 10604, USA.
A database (SpliceDB) of known mammalian splice site sequences has been
developed. We extracted 43 337 splice pairs from mammalian divisions of the
gene-centered Infogene database, including sites from incomplete or
alternatively spliced genes. Known EST sequences supported 22 815 of them. After
discarding sequences with putative errors and ambiguous location of splice
junctions the verified dataset includes 22 489 entries. Of these, 98.71% contain
canonical GT-AG junctions (22 199 entries) and 0.56% have non-canonical GC-AG
splice site pairs. The remainder (0.73%) occurs in a lot of small groups (with a
maximum size of 0.05%). We especially studied non-canonical splice sites, which
comprise 3.73% of GenBank annotated splice pairs. EST alignments allowed us to
verify only the exonic part of splice sites. To check the conservative
dinucleotides we compared sequences of human non-canonical splice sites with
sequences from the high throughput genome sequencing project (HTG). Out of 171
human non-canonical and EST-supported splice pairs, 156 (91.23%) had a clear
match in the human HTG. They can be classified after sequence analysis as: 79
GC-AG pairs (of which one was an error that corrected to GC-AG), 61 errors
corrected to GT-AG canonical pairs, six AT-AC pairs (of which two were errors
corrected to AT-AC), one case was produced from a non-existent intron, seven
cases were found in HTG that were deposited to GenBank and finally there were
only two other cases left of supported non-canonical splice pairs. The
information about verified splice site sequences for canonical and non-canonical
sites is presented in SpliceDB with the supporting evidence. We also built
weight matrices for the major splice groups, which can be incorporated into gene
prediction programs. SpliceDB is available at the computational genomic Web
server of the Sanger Centre: http://genomic.sanger.ac. uk/spldb/SpliceDB.html
and at http://www.softberry. com/spldb/SpliceDB.html.
DOI: 10.1093/nar/29.1.255
PMCID: PMC29840
PMID: 11125105 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15461575 | 1. Expert Opin Biol Ther. 2004 Oct;4(10):1641-7. doi: 10.1517/14712598.4.10.1641.
Regulatable aptamers in medicine: focus on antithrombotic strategies.
Potti A(1), Rusconi CP, Sullenger BA, Ortel TL.
Author information:
(1)Duke University Medical Center, Department of Medicine, Division of
Haematology, Durham, NC 27710, USA.
Proteins generally execute the key physiological activities required for normal
growth and homeostasis. As such, many different classes of proteins, including
proteases, kinases, cellular receptors and signalling proteins, represent
attractive targets for diagnosis or therapy. Aptamers are small nucleic acid
molecules that function as direct protein inhibitors, much like monoclonal
antibodies. After a decade of intensive research, technology development and
initial clinical evaluation, aptamers have now demonstrated broad potential as
direct protein ligands and inhibitors, and thus represent an exciting class of
compounds for the development of new therapeutic and diagnostic agents. This
review will discuss the basic properties and isolation of aptamers, their use in
animals and the clinic, and describe an exciting recent advance in the
development of antidotes to certain aptamers, which will add a repertoire of new
agents with regulatable activity for clinical use.
DOI: 10.1517/14712598.4.10.1641
PMID: 15461575 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10920507 | 1. Ann Ital Med Int. 2000 Apr-Jun;15(2):166-8.
[A case of acute recurrent benign pericarditis in a patient with
glucose-6-phosphate dehydrogenase deficiency, treated with sodium salicylate].
[Article in Italian]
Tedeschini RC(1), Ruggiano G, Sofo D, Poggesi L.
Author information:
(1)Istituto di Clinica Medica Generale e Cardiologia, Università degli Studi di
Firenze.
Glucose 6-phosphate dehydrogenase deficiency is an important cause of hemolysis.
People with this disease are prone to hemolytic crisis induced by drugs,
including acetylsalicylic acid. Sodium salicylate is the main therapeutic choice
for acute idiopathic pericarditis. In vitro studies have demonstrated the role
played by sodium salicylate in the inhibition of glucose 6-phosphate
dehydrogenase, but, at therapeutic doses, this inhibition is not enough to
explain acetylsalicylic acid-induced hemolysis observed in vivo. We thus treated
a patient affected by acute idiopathic pericarditis and glucose 6-phosphate
dehydrogenase deficiency with sodium salicylate, obtaining complete resolution
of fever and symptoms, without any hemolytic complication. Therapy with sodium
salicylate could thus be a safe and effective alternative for patients with
glucose 6-phosphate dehydrogenase who require anti-inflammatory therapy.
PMID: 10920507 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22518321 | 1. Int J Hepatol. 2012;2012:498232. doi: 10.1155/2012/498232. Epub 2012 Jan 30.
MicroRNA Signature in Alcoholic Liver Disease.
Bala S(1), Szabo G.
Author information:
(1)Department of Medicine, University of Massachusetts Medical School,
Worcester, MA 01605, USA.
Alcoholic liver disease (ALD) is a major global health problem. Chronic alcohol
use results in inflammation and fatty liver, and in some cases, it leads to
fibrosis and cirrhosis or hepatocellular carcinoma. Increased proinflammatory
cytokines, particularly TNF alpha, play a central role in the pathogenesis of
ALD. TNF alpha is tightly regulated at transcriptional and posttranscriptional
levels. Recently, microRNAs (miRNAs) have been shown to modulate gene functions.
The role of miRNAs in ALD is getting attention, and recent studies suggest that
alcohol modulates miRNAs. Recently, we showed that alcohol induces miR-155
expression both in vitro (RAW 264.7 macrophage) and in vivo (Kupffer cells, KCs
of alcohol-fed mice). Induction of miR-155 contributed to increased TNF alpha
production and to the sensitization of KCs to produce more TNF alpha in response
to LPS. In this paper, we summarize the current knowledge of miRNAs in ALD and
also report increased expression of miR-155 and miR-132 in the total liver as
well as in isolated hepatocytes and KCs of alcohol-fed mice. Our novel finding
of the alcohol-induced increase of miRNAs in hepatocytes and KCs after alcohol
feeding provides further insight into the evolving knowledge regarding the role
of miRNAs in ALD.
DOI: 10.1155/2012/498232
PMCID: PMC3296165
PMID: 22518321 |
http://www.ncbi.nlm.nih.gov/pubmed/23345546 | 1. Oncologist. 2013;18(2):115-22. doi: 10.1634/theoncologist.2012-0262. Epub 2013
Jan 23.
The role of MET receptor tyrosine kinase in non-small cell lung cancer and
clinical development of targeted anti-MET agents.
Robinson KW(1), Sandler AB.
Author information:
(1)Oregon Health & Science Center, 3181 SW Sam Jackson Park Road, MC: L586,
Portland, Oregon 97239, USA.
A better understanding of the pathophysiology and evolution of non-small cell
lung cancer (NSCLC) has identified a number of molecular targets and spurred
development of novel targeted therapeutic agents. The MET receptor tyrosine
kinase and its ligand hepatocyte growth factor (HGF) are implicated in tumor
cell proliferation, migration, invasion, and angiogenesis in a broad spectrum of
human cancers, including NSCLC. Amplification of MET has been reported in
approximately 5%-22% of lung tumors with acquired resistance to small-molecule
inhibitors of the epidermal growth factor receptor (EGFR). Resistance to EGFR
inhibitors is likely mediated through downstream activation of the
phosphoinositide 3-kinase /AKT pathway. Simultaneous treatment of resistant
tumors with a MET inhibitor plus an EGFR inhibitor can abrogate activation of
downstream effectors of cell growth, proliferation, and survival, thereby
overcoming acquired resistance to EGFR inhibitors. Development and preclinical
testing of multiple agents targeting the HGF-MET pathway, including monoclonal
antibodies targeting HGF or the MET receptor and small-molecule inhibitors of
the MET tyrosine kinase, have confirmed the crucial role of this pathway in
NSCLC. Several agents are now in phase III clinical development for the
treatment of NSCLC. This review summarizes the role of MET in the
pathophysiology of NSCLC and in acquired resistance to EGFR inhibitors and
provides an update on progress in the clinical development of inhibitors of MET
for treatment of NSCLC.
DOI: 10.1634/theoncologist.2012-0262
PMCID: PMC3579594
PMID: 23345546 [Indexed for MEDLINE]
Conflict of interest statement: Disclosures of potential conflicts of interest
may be found at the end of this article. |
http://www.ncbi.nlm.nih.gov/pubmed/22136061 | 1. J Phys Chem B. 2012 Jan 12;116(1):424-33. doi: 10.1021/jp205770p. Epub 2011
Dec 19.
Molecular mechanism of the effects of salt and pH on the affinity between
protein A and human immunoglobulin G1 revealed by molecular simulations.
Huang B(1), Liu FF, Dong XY, Sun Y.
Author information:
(1)Department of Biological Engineering and Key Laboratory of Systems
Bioengineering of the Ministry of Education, School of Chemical Engineering and
Technology, Tianjin University, Tianjin, China.
Protein A from the bacterium Staphylococcus aureus (SpA) has been widely used as
an affinity ligand for purification of immunoglobulin G (IgG). The affinity
between SpA and IgG is affected differently by salt and pH, but their molecular
mechanisms still remain unclear. In this work, molecular dynamics simulations
and molecular mechanics Poisson-Boltzmann surface area analysis were performed
to investigate the salt (NaCl) and pH effects on the affinity between SpA and
human IgG1 (hIgG1). It is found that salt and pH affect the interactions of the
hot spots of SpA by different mechanisms. In the salt solution, the
compensations between helices I and II of SpA as well as between the nonpolar
and electrostatic energies make the binding free energy independent of salt
concentration. At pH 3.0, the unfavorable electrostatic interactions increase
greatly and become the driving force for dissociation of the SpA-hIgG1 complex.
They mainly come from the strong electrostatic repulsions between positively
charged residues (H137, R146, and K154) of SpA and the positively charged
residues of hIgG1. It is considered to be the molecular basis for hIgG1 elution
from SpA-based affinity adsorbents at pH 3.0. The dissociation mechanism is then
used to refine the binding model of SpA to hIgG1. The model is expected to help
design high-affinity peptide ligands of IgG.
DOI: 10.1021/jp205770p
PMID: 22136061 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23435988 | 1. Intern Emerg Med. 2013 Apr;8 Suppl 1:S71-4. doi: 10.1007/s11739-013-0911-4.
Thyroid hormone and cardiovascular system: from basic concepts to clinical
application.
Iervasi G(1), Nicolini G.
Author information:
(1)CNR Institute of Clinical Physiology, C.N.R.-Tuscany Region G. Monasterio
Foundation, Pisa, Italy. [email protected]
Experimental and clinical findings strongly support the concept that thyroid
hormone (TH) plays a fundamental role in the cardiovascular (CV) homeostasis. CV
diseases represent a major public health care and economic problem being one of
the principal causes of morbidity, mortality and hospitalization. In particular,
chronic heart failure (HF) is one of the most common reasons for general
practitioners consultations in people >65-70 years old. TH derangement may have
a key role in the evolution process of HF. In HF, the main and earlier
alteration of the thyroid function is referred to as "low-T3" syndrome
characterized by the reduction in serum total T3 and free T3 with normal levels
of thyroxine (T4) and thyrotropin (TSH). This syndrome may affect till one-third
of advanced HF patients. The main goal of this mini-review is to examine the
main pathophysiological and clinical links between an altered thyroid metabolism
and CV diseases, namely HF during progression of disease from organ specific to
systemic disorder.
DOI: 10.1007/s11739-013-0911-4
PMID: 23435988 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19747111 | 1. Curr Mol Med. 2009 Dec;9(9):1046-57. doi: 10.2174/156652409789839080.
Medulloblastoma: role of developmental pathways, DNA repair signaling, and other
players.
Saran A(1).
Author information:
(1)Biotechnologies, Agro-Industry and Health Protection Department, Ente per le
Nuove tecnologie, l'Energia e l'Ambiente, Centro Ricerche Casaccia, 00123 Rome,
Italy. [email protected]
Medulloblastoma is a cerebellar tumor affecting children and young adults, and
accounts for approximately one fifth of all pediatric brain tumors. Despite
multimodal therapy that includes surgery, radiotherapy and chemotherapy,
recurrence is frequent and overall mortality rate remains relatively high.
Moreover, radiation therapy results in severe effects on intellect, and younger
age of treatment correlates with larger deficits. Improvements in therapy of
this childhood tumor will focus increasingly on the clarification of the exact
cellular origin and the genetic mechanisms contributing to tumor formation, and
on new targeted therapeutic options. Aberrant activation of the Hedgehog (Hh)
and Wnt developmental pathways is associated with medulloblastoma, but
deregulation of other molecular pathways, including insulin-like growth factor
(IGF) signaling, has also been implicated in the pathogenesis of the tumor.
Recent observations in mouse models have demonstrated the importance of genome
surveillance, as defects in DNA repair pathways in animals can lead to genomic
instability in neural progenitor cells, resulting in medulloblastoma. The
current review will focus on the most recent findings on the molecular pathology
of medulloblastoma and discuss their potential contribution to treatments
directed by the molecular alterations.
DOI: 10.2174/156652409789839080
PMID: 19747111 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12509290 | 1. DNA Repair (Amst). 2002 Aug 6;1(8):683-96. doi: 10.1016/s1568-7864(02)00075-7.
Base excision repair and nucleotide excision repair contribute to the removal of
N-methylpurines from active genes.
Plosky B(1), Samson L, Engelward BP, Gold B, Schlaen B, Millas T, Magnotti M,
Schor J, Scicchitano DA.
Author information:
(1)Department of Biology, New York University, New York, NY 10003, USA.
Many different cellular pathways have evolved to protect the genome from the
deleterious effects of DNA damage that result from exposure to chemical and
physical agents. Among these is a process called transcription-coupled repair
(TCR) that catalyzes the removal of DNA lesions from the transcribed strand of
expressed genes, often resulting in a preferential bias of damage clearance from
this strand relative to its non-transcribed counterpart. Lesions subject to this
type of repair include cyclobutane pyrimidine dimers that are normally repaired
by nucleotide excision repair (NER) and thymine glycols (TGs) that are removed
primarily by base excision repair (BER). While the mechanism underlying TCR is
not completely clear, it is known that its facilitation requires proteins used
by other repair pathways like NER. It is also believed that the signal for TCR
is the stalled RNA polymerase that results when DNA damage prevents its
translocation during transcription elongation. While there is a clear role for
some NER proteins in TCR, the involvement of BER proteins is less clear. To
explore this further, we studied the removal of 7-methylguanine (7MeG) and
3-methyladenine (3MeA) from the dihydrofolate reductase (dhfr) gene of murine
cell lines that vary in their repair phenotypes. 7MeG and 3MeA constitute the
two principal N-methylpurines formed in DNA following exposure to methylating
agents. In mammalian cells, alkyladenine DNA alkyladenine glycosylase (Aag) is
the major enzyme required for the repair of these lesions via BER, and their
removal from the total genome is quite rapid. There is no observable TCR of
these lesions in specific genes in DNA repair proficient cells; however, it is
possible that the rapid repair of these adducts by BER masks any TCR. The repair
of 3MeA and 7MeG was examined in cells lacking Aag, NER, or both Aag and NER to
determine if rapid overall repair masks TCR. The results show that both 3MeA and
7MeG are removed without strand bias from the dhfr gene of BER deficient (Aag
deficient) and NER deficient murine cell lines. Furthermore, repair of 3MeA in
this region is highly dependent on Aag, but repair of 7MeG is equally efficient
in the repair proficient, BER deficient, and NER deficient cell lines.
Strikingly, in the absence of both BER and NER, neither 7MeG nor 3MeA is
repaired. These results demonstrate that NER, but not TCR, contributes to the
repair of 7MeG, and to a lesser extent 3MeA.
DOI: 10.1016/s1568-7864(02)00075-7
PMID: 12509290 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23093191 | 1. Nat Commun. 2012;3:1154. doi: 10.1038/ncomms2158.
Imaging the post-fusion release and capture of a vesicle membrane protein.
Sochacki KA(1), Larson BT, Sengupta DC, Daniels MP, Shtengel G, Hess HF, Taraska
JW.
Author information:
(1)Laboratory of Molecular Biophysics, National Heart Lung and Blood Institute,
National Institutes of Health, 50 South Drive, Bethesda, Maryland 20892, USA.
The molecular mechanism responsible for capturing, sorting and retrieving
vesicle membrane proteins following triggered exocytosis is not understood. Here
we image the post-fusion release and then capture of a vesicle membrane protein,
the vesicular acetylcholine transporter, from single vesicles in living
neuroendocrine cells. We combine these measurements with super-resolution
interferometric photo-activation localization microscopy and electron
microscopy, and modelling to map the nanometer-scale topography and architecture
of the structures responsible for the transporter's capture following
exocytosis. We show that after exocytosis, the transporter rapidly diffuses into
the plasma membrane, but most travels only a short distance before it is locally
captured over a dense network of membrane-resident clathrin-coated structures.
We propose that the extreme density of these structures acts as a short-range
diffusion trap. They quickly sequester diffusing vesicle material and limit its
spread across the membrane. This system could provide a means for
clathrin-mediated endocytosis to quickly recycle vesicle proteins in highly
excitable cells.
DOI: 10.1038/ncomms2158
PMCID: PMC3521636
PMID: 23093191 [Indexed for MEDLINE]
Conflict of interest statement: COMPETING FINANCIAL INTERESTS The authors
declare no competing financial interests. |
http://www.ncbi.nlm.nih.gov/pubmed/7385804 | 1. Vutr Boles. 1980;19(2):68-75.
[Serum levels of thyroxine (T4), triiodothyronine (T3) and thyrotropic hormone
(TSH) in chronic kidney insufficiency].
[Article in Bulgarian]
Mushmov D, Zakharieva B, Patev E, Kiriakov Z.
The authors studied the serum level of T3, T4 and TTH in 30 euthyroid patients
with chronic renal insufficiency (CRI), distributed in three groups of 10
patients. I group includes patients with CRI II and III stage without dialysis
treatment, patients with CRI are included in the II group, being under
hemodialysis treatment from 5 to 12 months, and in III group--patients dialized
three and more years. Low average values of T3--0.65 mg/ml were established only
in the first group; in 8 patients, out of 10 examined, the values were under the
lower limit of the norm. Though the T4 values in the first group were within the
limits of the norm (5.87 mkg/100 ml), they were under the average normal values
(8.5 mkg/100 ml) and lower, with a statistical significance (pt less than 0.025)
as compared with those of the other two groups. The values of T3 and T4 in both
groups dialyzed patients were within the limits of the norm regardless of the
duration of dialysis. In none of the patients from the three groups examined,
deviations in TTH level were found. The authors drew the conclusion that
biochemical hypothyroidism, manifested with low T3 values, normal TTH level and
a tendency of T4 decrease was observed in nondialyzed patients even with CRI II
stage (creatine 6.8 mg%). Biochemical hypothyroidism abates with the adequate
and effective hemodialysis treatment, suggesting that uremic toxins play and
essential role in its development. It was stressed that abatement could be used
as a criterion of adequate and effective dialysis programme and a reliable
rehabilitation of the patients, under chronodialysis treatment.
PMID: 7385804 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23274284 | 1. Curr Opin Cardiol. 2013 Mar;28(2):187-96. doi: 10.1097/HCO.0b013e32835c5492.
Heart failure with preserved ejection fraction: current understanding and
emerging concepts.
Liu Y(1), Haddad T, Dwivedi G.
Author information:
(1)University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
PURPOSE OF REVIEW: Heart failure is a major health problem with significant
morbidity and mortality. Although impressive advances in treatment and reduction
in mortality have marked heart failure with reduced ejection fraction (HFrEF),
the mortality in patients with heart failure with preserved ejection fraction
(HFpEF), which accounts for nearly half of heart failure cases, has remained
unchanged. This may be because of the lack of consistent diagnostic criteria and
limited understanding of the pathophysiology of HFpEF, and thus appropriate
treatment options.
RECENT FINDINGS: Recent data suggest that HFpEF consists of multiple
abnormalities rather than a distinct entity. Advances in testing have improved
diagnosis, but further validation is required. The discoveries of new
pathological abnormalities have identified potential new drug therapy targets.
Traditional agents with strong evidence in HFrEF have proved unsuccessful in
HFpEF. Newer agents such as angiotensin receptor neprilysin inhibitor,
sildenafil, and ivabradine have demonstrated benefits without improving
mortality. Lastly, as HFpEF patients are older with more comorbidities,
alternate endpoints to survival benefit should be considered.
SUMMARY: Although enormous strides have been made in understanding the
pathophysiology and refining the diagnostic criteria of HFpEF, there is
currently no pharmacological therapy with mortality benefits. Further
characterization and the recruitment of more homogeneous patient populations
will be essential to identify effective treatments.
DOI: 10.1097/HCO.0b013e32835c5492
PMID: 23274284 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22951983 | 1. Cell Death Dis. 2012 Sep 6;3(9):e386. doi: 10.1038/cddis.2012.125.
Targeting Cullin-RING ligases by MLN4924 induces autophagy via modulating the
HIF1-REDD1-TSC1-mTORC1-DEPTOR axis.
Zhao Y(1), Xiong X, Jia L, Sun Y.
Author information:
(1)Division of Radiation and Cancer Biology, Department of Radiation Oncology,
University of Michigan, 4424B MS-1, 1301 Catherine Street, Ann Arbor, MI 48109,
USA.
MLN4924, a newly discovered small molecule inhibitor of NEDD8-activating enzyme
(NAE), inactivates Cullin-RING E3 ubiquitin Ligases (CRLs) by blocking cullin
neddylation. As a result, MLN4924 causes accumulation of several key substrates
of CRLs and effectively suppresses tumor cell growth by inducing apoptosis and
senescence. However, the role of MLN4924 in induction of autophagy and its
biological significance are totally unknown. Here we showed that MLN4924
effectively induces autophagy in both time- and dose-dependent manners in
multiple human cancer lines, indicating a general phenomenon. Mechanistically,
by inactivating CRLs, MLN4924 causes accumulation of DEPTOR and HIF1α. The siRNA
knockdown and gene KO studies showed that DEPTOR and the HIF1-REDD1-TSC1 axis
are responsible for MLN4924-induced autophagy via inhibiting mTORC1.
Biologically, autophagy is a survival signal to tumor cells, and blockage of
autophagy via siRNA knockdown, gene KO and small molecule inhibitor remarkably
enhanced MLN4924-induced apoptosis. Our study reveals an uncharacterized
mechanism of MLN4924 action and provides the proof-of-concept evidence for
strategic drug combination of MLN4924 with an autophagy inhibitor for maximal
killing of tumor cells via enhancing apoptosis.
DOI: 10.1038/cddis.2012.125
PMCID: PMC3461362
PMID: 22951983 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24376590 | 1. PLoS One. 2013 Dec 20;8(12):e82841. doi: 10.1371/journal.pone.0082841.
eCollection 2013.
Development of a real-time fluorescence loop-mediated isothermal amplification
assay for rapid and quantitative detection of Fusarium oxysporum f. sp. cubense
tropical race 4 in soil.
Zhang X(1), Zhang H(1), Pu J(1), Qi Y(1), Yu Q(1), Xie Y(1), Peng J(2).
Author information:
(1)Ministry of Agriculture Key Laboratory of Integrated Pest Management on
Tropical Crops, Environmental and Plant Protection Institute, Chinese Academy of
Tropical Agricultural Sciences, Haikou, China.
(2)Ministry of Agriculture Key Laboratory of Integrated Pest Management on
Tropical Crops, Environmental and Plant Protection Institute, Chinese Academy of
Tropical Agricultural Sciences, Haikou, China ; State Key Laboratory of
Agro-biotechnology and Ministry of Agriculture Key Laboratory for Plant
Pathology, China Agricultural University, Beijing, China.
Erratum in
PLoS One. 2014;9(1).
doi:10.1371/annotation/8a1fd6a3-754f-42e2-a906-9d224167344e.
Fusarium oxysporum f. sp. cubense (Foc), the causal agent of Fusarium wilt
(Panama disease), is one of the most devastating diseases of banana (Musa spp.).
The Foc tropical race 4 (TR4) is currently known as a major concern in global
banana production. No effective resistance is known in Musa to Foc, and no
effective measures for controlling Foc once banana plants have been infected in
place. Early and accurate detection of Foc TR4 is essential to protect banana
industry and guide banana planting. A real-time fluorescence loop-mediated
isothermal amplification assay (RealAmp) was developed for the rapid and
quantitative detection of Foc TR4 in soil. The detection limit of the RealAmp
assay was approximately 0.4 pg/µl plasmid DNA when mixed with extracted soil DNA
or 10(3) spores/g of artificial infested soil, and no cross-reaction with other
relative pathogens were observed. The RealAmp assay for quantifying genomic DNA
of TR4 was confirmed by testing both artificially and naturally infested
samples. Quantification of the soil-borne pathogen DNA of Foc TR4 in naturally
infested samples was no significant difference compared to classic real-time PCR
(P>0.05). Additionally, RealAmp assay was visual with an improved closed-tube
visual detection system by adding SYBR Green I fluorescent dye to the inside of
the lid prior to amplification, which avoided the inhibitory effects of the
stain on DNA amplification and makes the assay more convenient in the field and
could thus become a simple, rapid and effective technique that has potential as
an alternative tool for the detection and monitoring of Foc TR4 in field, which
would be a routine DNA-based testing service for the soil-borne pathogen in
South China.
DOI: 10.1371/journal.pone.0082841
PMCID: PMC3869718
PMID: 24376590 [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/17908160 | 1. J Intern Med. 2007 Dec;262(6):690-701. doi: 10.1111/j.1365-2796.2007.01865.x.
Epub 2007 Oct 1.
Clinical and biochemical implications of low thyroid hormone levels (total and
free forms) in euthyroid patients with chronic kidney disease.
Carrero JJ(1), Qureshi AR, Axelsson J, Yilmaz MI, Rehnmark S, Witt MR, Bárány P,
Heimbürger O, Suliman ME, Alvestrand A, Lindholm B, Stenvinkel P.
Author information:
(1)Division of Renal Medicine and Baxter Novum, Department of Clinical Science,
Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
OBJECTIVES: In this study, we explore the associations of decreased thyroid
hormone levels with inflammation, wasting and survival in biochemically
euthyroid patients with end-stage renal disease (ESRD).
DESIGN: After exclusion of 23 patients with thyroid-stimulating hormone (TSH)
values outside the normal range (0.1-4.5 mIU L(-1)), 187 clinically and
biochemically euthyroid incident ESRD stage 5 patients starting dialysis were
followed for a median of 20 (range 1-60) months. Measurements of total and free
forms of thyroid hormones, s-albumin, hs-CRP, interleukin (IL)-6, vascular
adhesion molecule (VCAM)-1 and insulin-like growth factor 1 (IGF-1) were
performed at baseline.
RESULTS: In this population, 17 out of 210 patients (8%) were defined as
subclinically hypothyroid. Multivariate analysis, according to receiver
operating characteristic (ROC) curves, showed that mortality was best predicted
by total triiodothyronine (T3). When using the cut-off levels derived from ROC,
low T3 levels were associated with increased inflammation (higher hs-CRP, IL-6
and VCAM-1) and lower concentration of both s-albumin and IGF-1. Finally, low T3
but not low free triiodothyronine was associated with worse all-cause
(Likelihood ratio = 45.4; P < 0.0001) and cardiovascular mortality (Likelihood
ratio = 47.8; P < 0.0001) after adjustment for confounding factors.
CONCLUSION: This study showed that low T3 levels are independent predictors of
all-cause and also cardiovascular disease mortality in biochemically euthyroid
patients, perhaps due to an intimate association with inflammation. Based on
these results, the use of T3 levels in studies assessing the relationship
between thyroid dysfunction and mortality risk is recommended.
DOI: 10.1111/j.1365-2796.2007.01865.x
PMID: 17908160 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15013214 | 1. Cancer Lett. 2004 Feb 20;204(2):145-57. doi: 10.1016/S0304-3835(03)00451-8.
Hedgehog--Gli signaling in brain tumors: stem cells and paradevelopmental
programs in cancer.
Ruiz i Altaba A(1), Stecca B, Sánchez P.
Author information:
(1)The Skirball Institute, NYU School of Medicine, 540 First Avenue, New York,
NY 10016, USA. [email protected]
The Hedgehog-Gli signaling pathway is involved in the regulation of the
proliferation of precursors in different organs of the normal vertebrate embryo.
These cells express Gli1 and may be the target of cancer-causing agents. Many
tumor types derived from organs that contain Gli1+ precursors appear to
consistently express Gli1, indicating their origin and/or the presence of an
active pathway. Inappropriate pathway activation in a variety of precursor cells
in model organisms leads to tumor formation while inhibition of the pathway in
human tumor cells leads to a decrease in their proliferation. In the brain we
have documented the expression of Gli1 in germinative zones, and a variety of
brain tumors express GLI1, including medulloblastomas of the cerebellum and a
number of gliomas of the cerebral cortex. The requirement for SHH-Gli signaling
in the growth of the mouse brain, together with the ability of inappropriate
pathway activation in the cerebellum to cause medulloblastomas, and the
inhibition of the growth of a number of brain tumors with cyclopamine, a SHH
signaling inhibitor, underscores the critical role of the SHH-GLI pathway in
brain growth and tumor formation. Moreover, they highlight the components of
this pathway as prime targets for drug development, with special emphasis on the
GLI proteins. Such reagents would allow a rational therapeutic approach to
highly intractable diseases.
DOI: 10.1016/S0304-3835(03)00451-8
PMID: 15013214 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8242865 | 1. Carcinogenesis. 1993 Nov;14(11):2341-51. doi: 10.1093/carcin/14.11.2341.
Various inhibitors of DNA topoisomerases diminish repair-specific DNA incision
in UV-irradiated human fibroblasts.
Thielmann HW(1), Popanda O, Gersbach H, Gilberg F.
Author information:
(1)Division of Interaction of Carcinogens, German Cancer Research Center,
Heidelberg.
A function for topoisomerases I and II in DNA excision repair can be postulated
from the organization of the mammalian chromosome, involving nucleosomal
structures and matrix-attached DNA loops. To analyse this function we determined
UV-induced DNA incision in confluent human fibroblasts in the presence of 16
inhibitors of topoisomerases I and II which belonged to at least five different
drug categories, based on their mechanism of action. Dose-response experiments
were performed, analysed by linear regression and the concentrations at which
DNA-incising activity was reduced to 50% were calculated (K50 values). The
majority of these values represent concentrations for which interfering cell
toxicity could be excluded. K50 concentrations, which were determined by
extrapolating dose-response data, may hit the toxicity range, nevertheless, we
deem our K50 scale useful for making biochemical comparisons. With respect to
topoisomerase I, camptothecin and topotecan diminished repair-specific DNA
incision to a small extent, whereas distamycin, which binds to the minor groove
of DNA, caused a stronger effect. With respect to topoisomerase II the results
were as follows. (i) The DNA intercalator ethidium bromide decreased
DNA-incising activity at rather low concentrations, which indicates marked
inhibitory potency. Quinacrine was less effective. (ii) Inhibitors intercalating
and binding to the 'cleavable' DNA-topoisomerase complex (m-AMSA, mitoxantrone,
doxorubicin and daunorubicin) strongly suppressed reparative DNA incision. (iii)
Only small effects were observed using several drugs which act by trapping the
'cleavable' DNA-enzyme complex, namely nalidixic acid and oxolinic acid. In
contrast, etoposide and teniposide inhibited post-UV DNA cleavage sizeably. (iv)
Merbarone had to be applied at very high concentrations to reduce UV-induced DNA
incision. (v) Novobiocin, an inhibitor of the ATPase subunit of topoisomerase
II, markedly diminished repair-specific DNA cleavage. A comparison of the K50
values for DNA incision with those for DNA repair synthesis (1) shows that the
majority of the investigated drugs inhibited both repair parameters. There were,
however, differences in the concentrations required to achieve the 50%
inhibition level. The results are best explained by assuming that in
UV-irradiated human fibroblasts the 180 kd form of topoisomerase II is a target
enzyme for inhibitors which suppressed repair and that this isozyme is involved
in steps preceding repair-specific DNA incision.
DOI: 10.1093/carcin/14.11.2341
PMID: 8242865 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18025536 | 1. Circulation. 2007 Dec 4;116(23):2678-86. doi:
10.1161/CIRCULATIONAHA.107.724864. Epub 2007 Nov 19.
First-in-human evaluation of anti von Willebrand factor therapeutic aptamer
ARC1779 in healthy volunteers.
Gilbert JC(1), DeFeo-Fraulini T, Hutabarat RM, Horvath CJ, Merlino PG, Marsh HN,
Healy JM, Boufakhreddine S, Holohan TV, Schaub RG.
Author information:
(1)Archemix Corp., 300 Third St, Cambridge, MA 02142, USA. [email protected]
BACKGROUND: ARC1779 is a therapeutic aptamer antagonist of the A1 domain of von
Willebrand Factor (vWF), the ligand for receptor glycoprotein 1b on platelets.
ARC1779 is being developed as a novel antithrombotic agent for use in patients
with acute coronary syndromes.
METHODS AND RESULTS: This was a randomized, double-blind, placebo-controlled
study in 47 healthy volunteers of doses of ARC1779 from 0.05 to 1.0 mg/kg.
Pharmacodynamic effects were measured by an ELISA for free vWF A1 binding sites
and by a platelet function analyzer. In terms of pharmacokinetics, the
concentration-time profile of ARC1779 appeared monophasic. The observed
concentration and area under the curve were dose proportional. The mean apparent
elimination half-life was approximately 2 hours, and mean residence time was
approximately 3 hours. The mean apparent volumes of distribution (at steady
state and during terminal phase) were approximately one half the blood volume,
suggesting that ARC1779 distribution is in the central compartment. The mean
clearance ranged from approximately 10% to approximately 21% of the glomerular
filtration rate, suggesting that renal filtration may not be a major mechanism
of clearance of ARC1779. Inhibition of vWF A1 binding activity was achieved with
an EC(90) value of 2.0 mug/mL (151 nmol/L) and of platelet function with an
EC(90) value of 2.6 mug/mL (196 nmol/L). ARC1779 was generally well tolerated,
and no bleeding was observed. Adverse events tended to be minor and not dose
related.
CONCLUSIONS: This is the first-in-human evaluation of a novel aptamer antagonist
of vWF. ARC1779 produced dose- and concentration-dependent inhibition of vWF
activity and platelet function with duration of effect suitable for the intended
clinical use in acute coronary syndromes.
DOI: 10.1161/CIRCULATIONAHA.107.724864
PMID: 18025536 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19656240 | 1. J Cell Mol Med. 2010 Jun;14(6B):1569-93. doi:
10.1111/j.1582-4934.2009.00868.x. Epub 2009 Jul 28.
Podosome-like structures of non-invasive carcinoma cells are replaced in
epithelial-mesenchymal transition by actin comet-embedded invadopodia.
Takkunen M(1), Hukkanen M, Liljeström M, Grenman R, Virtanen I.
Author information:
(1)Institute of Biomedicine/Anatomy, University of Helsinki, Helsinki, Finland.
[email protected]
Erratum in
J Cell Mol Med. 2010 Aug;14(8):2185.
Podosomes and invadopodia are actin-based structures at the ventral cell
membrane, which have a role in cell adhesion, migration and invasion. Little is
known about the differences and dynamics underlying these structures. We studied
podosome-like structures of oral squamous carcinoma cells and invadopodia of
their invasive variant that has undergone a spontaneous epithelial-mesenchymal
transition (EMT). In 3D imaging, podosomes were relatively large structures that
enlarged in time, whereas invadopodia of invasive cells remained small, but were
more numerous, degraded more extracellular matrix (ECM) and were morphologically
strikingly different from podosomes. In live-cell imaging, highly dynamic,
invadopodia-embedded actin tails were frequently released and rocketed through
the cytoplasm. Resembling invadopodia, we found new club-ended cell extensions
in EMT-experienced cells, which contained actin, cortactin, vinculin and
MT1-matrix metalloproteinase. These dynamic cell extensions degraded ECM and, in
field emission scanning electron microscopy, protruded from the dorsal cell
membrane. Plectin, alphaII-spectrin, talin and focal adhesion kinase
immunoreactivities were detected in podosome rings, whereas they were absent
from invadopodia. Tensin potentially replaced talin in invadopodia. Integrin
alpha(3)beta(1) surrounded both podosomes and invadopodia, whereas integrin
alpha(v)beta(5) localized only to invadopodia heads. Pacsin 2, in conjunction
with filamin A, was detected early in podosomes, whereas pacsin 2 was not found
in invadopodia and filamin A showed delayed accumulation. Fluorescence recovery
after photobleaching indicated faster reorganization of actin, cortactin and
filamin A in podosomes compared to invadopodia. In conclusion, EMT affects the
invasion machinery of oral squamous carcinoma cells. Non-invasive squamous
carcinoma cells constitutively organize podosomes, whereas invasive cells form
invadopodia. The club-ended cell extensions, or externalized invadopodia, are
involved in ECM degradation and maintenance of contact to adhesion substrate and
surrounding cells during invasion.
DOI: 10.1111/j.1582-4934.2009.00868.x
PMCID: PMC3829022
PMID: 19656240 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8111973 | 1. Dev Genet. 1993;14(6):449-59. doi: 10.1002/dvg.1020140606.
Gene regulation in Drosophila spermatogenesis: analysis of protein binding at
the translational control element TCE.
Kempe E(1), Muhs B, Schäfer M.
Author information:
(1)Institut für Genetick, Heinrich-Heine-Universität, Düsseldorf, Germany.
We have previously identified a 12 nucleotide long sequence element, the TCE,
that was demonstrated to be necessary for translational control of expression in
the male germ line of Drosophila melanogaster (Schäfer et al., 1990). It is
conserved among all seven members of the Mst(3)CGP gene family, that encode
structural proteins of the sperm tail. The TCE is invariably located in the 5'
untranslated region (UTR) at position +28 relative to the transcription start
site. In this paper we analyse the mode of action of this element. We show that
protein binding occurs at the TCE after incubation with testis protein extracts
from Drosophila melanogaster. While several proteins are associated with the
translational control element in the RNA, only one of these proteins directly
crosslinks to the sequence element. The binding activity is exclusively observed
with testis protein extracts but can be demonstrated with testis extracts from
other Drosophila species as well, indicating that regulatory proteins involved
in translational regulation in the male germ line are conserved. Although
binding to the TCE can occur independent of its position relative to the
transcription start site of the in vitro transcripts, its function in vivo is
not exerted when shifted further downstream within the 5' UTR of a fusion gene.
In addition to being a translational control element the TCE also functions as a
transcriptional regulator. Consequently, a DNA-protein complex is also formed at
the TCE. In contrast to the RNA-protein complexes we find DNA-protein complexes
with protein extracts of several tissues of Drosophila melanogaster.
DOI: 10.1002/dvg.1020140606
PMID: 8111973 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20583541 | 1. J Pediatr Endocrinol Metab. 2010 Apr;23(4):363-8. doi: 10.1515/jpem.2010.057.
Amiodarone-induced thyrotoxicosis in children and adolescents is a possible
outcome in patients with low iodine intake.
Hacihamdioğlu B(1), Berberoğlu M, Siklar Z, Savaş Erdeve S, Oçal G, Tutar E,
Atalay S.
Author information:
(1)Ankara University School of Medicine, Department of Pediatric Endocrinology,
Cebeci, Ankara, Turkey. [email protected]
BACKGROUND/OBJECTIVE: The identification of the different subtypes of
amiodarone-induced thyrotoxicosis (AIT) may provide a rational basis for the
choice of the appropriate medical treatment. The aim of this study was to
evaluate differential diagnosis and treatment regimens of AIT in children and
adolescent.
PATIENTS: We reported 3 patients: A 6.7 years old boy with type I AIT; a 17.9
years old girl with type II AIT and a 14.6 years old girl with mixed type AIT.
CONCLUSIONS: AIT is not an uncommon complication in countries with low iodine
intake. AIT can be asymptomatic and can occur at any time in patients receiving
amiodarone therapy. It is also very important to distinguish the type of AIT
when planning therapy. Steroid therapy should be started when findings indicate
type II or mixed-type AIT. Beta blockers may prevent heart thyrotoxicosis and
recurrence of primary arrhythmia if amiodarone is discontinued.
DOI: 10.1515/jpem.2010.057
PMID: 20583541 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15863236 | 1. Neurochem Int. 2005 Jun;46(8):585-94. doi: 10.1016/j.neuint.2005.03.001. Epub
2005 Apr 12.
Transport of L-[14C]cystine and L-[14C]cysteine by subtypes of high affinity
glutamate transporters over-expressed in HEK cells.
Hayes D(1), Wiessner M, Rauen T, McBean GJ.
Author information:
(1)Department of Biochemistry, Conway Institute of Biomolecular and Biomedical
Research, University College Dublin, Dublin 4, Ireland.
Transport of L-cystine across the cell membrane is essential for synthesis of
the major cellular antioxidant, glutathione (gamma-glutamylcysteinylglycine). In
this study, uptake of L-[14C]cystine by three of the high affinity
sodium-dependent mammalian glutamate transporters (GLT1, GLAST and EAAC1)
individually expressed in HEK cells has been determined. All three transporters
display saturable uptake of L-[14C]cystine with Michaelis affinity (K(m))
constants in the range of 20-110 microM. L-glutamate and L-homocysteate are
potent inhibitors of sodium-dependent L-[14C]cystine uptake in HEK(GLAST),
HEK(GLT1) and HEK(EAAC1) cells. Reduction of L-[14C]cystine to L-[14C]cysteine
in the presence of 1mM cysteinylglycine increases the uptake rate in HEK(GLT1),
HEK(GLAST) and HEK(EAAC1) cells, but only a small proportion (<10%) of
L-[14C]cysteine uptake in HEK(GLT1) and HEK(GLAST) cells occurs by the high
affinity glutamate transporters. The majority (>90%) of L-[14C]cysteine
transport in these cells is mediated by the ASC transport system. In HEK(EAAC1)
cells, on the other hand, L-[14C]cysteine is transported equally by the ASC and
EAAC1 transporters. L-homocysteine inhibits L-[14C]cysteine transport in both
HEK(GLAST) and HEK(GLT1) cells, but not in HEK(EAAC1) cells. It is concluded
that the quantity of L-[14C]cyst(e)ine taken up by individual high affinity
sodium-dependent glutamate transporters is determined both by the extracellular
concentration of amino acids, such as glutamate and homocysteine, and by the
extracellular redox potential, which will control the oxidation state of
L-cystine.
DOI: 10.1016/j.neuint.2005.03.001
PMID: 15863236 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8106171 | 1. Cell. 1993 Nov 5;75(3):443-50. doi: 10.1016/0092-8674(93)90379-5.
A mutation in the homeodomain of the human MSX2 gene in a family affected with
autosomal dominant craniosynostosis.
Jabs EW(1), Müller U, Li X, Ma L, Luo W, Haworth IS, Klisak I, Sparkes R, Warman
ML, Mulliken JB, et al.
Author information:
(1)Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland
21287.
Craniosynostosis, the premature fusion of calvarial sutures, is a common
developmental anomaly that causes abnormal skull shape. The locus for one
autosomal dominant form of craniosynostosis has been mapped to chromosome 5qter.
The human MSX2 gene localizes to chromosome 5, and a polymorphic marker in the
MSX2 intron segregates in a kindred with the disorder with no recombination.
Moreover, a histidine substitutes for a highly conserved proline at position 7
of the MSX2 homeodomain exclusively in affected members. In the mouse,
transcripts of the Msx2 gene are localized to calvarial sutures. These results
provide compelling evidence that the mutation causes this craniosynostosis
syndrome.
DOI: 10.1016/0092-8674(93)90379-5
PMID: 8106171 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16775599 | 1. Kidney Int. 2006 Aug;70(3):523-8. doi: 10.1038/sj.ki.5001566. Epub 2006 Jun
14.
Low triiodothyronine and survival in end-stage renal disease.
Zoccali C(1), Mallamaci F, Tripepi G, Cutrupi S, Pizzini P.
Author information:
(1)CNR-IBIM, Institute of Biomedicine, Clinical Epidemiology and Pathophysiology
of Renal Diseases and Hypertension and Division of Nephrology, Dialysis and
Transplantation, Reggio Calabria, Italy. [email protected]
Comment in
Nat Clin Pract Nephrol. 2007 Feb;3(2):74-5. doi: 10.1038/ncpneph0379.
Plasma triiodothyronine (fT3) is a strong predictor of adverse clinical outcomes
in various clinical conditions. Since fT3 in patients with end-stage renal
diseases (ESRD) is frequently reduced and is associated with inflammation and
cardiovascular damage, we prospectively tested the hypothesis that it predicts
death in a cohort of 200 hemodialysis patients. Plasma fT3 was lower in ESRD
patients (P<0.001) than in healthy subjects and in clinically euthyroid patients
with normal renal function. During the follow-up 102 patients died. Patients who
died had significantly lower plasma fT3 than those who survived (P<0.001) and in
a Kaplan-Meyer analysis plasma fT3 was associated with death (P<0.001). On
multivariate Cox's regression analyses, adjusting for a series of traditional
and emerging risk factors including inflammation markers, patients with
relatively higher plasma fT3 (hazard ratio (HR) (1 pg/ml increase in fT3)) had a
50% reduction in the risk of death (HR=0.50, 95% CI: 0.35-0.72) as compared to
those having relatively lower fT3 levels. Of note, plasma fT3 captured most of
the predictive power of interleukin-6 (IL-6) because this latter variable
emerged as a significant predictor of death only in a model excluding fT3. Low
fT3 is an independent predictor of death in hemodialysis patients. These data
lend support to the hypothesis that thyroid dysfunction is implicated in the
high risk of the ESRD population.
DOI: 10.1038/sj.ki.5001566
PMID: 16775599 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18410546 | 1. Clin Endocrinol (Oxf). 2008 Nov;69(5):812-8. doi:
10.1111/j.1365-2265.2008.03268.x. Epub 2008 Apr 10.
Diagnosis and management of amiodarone-induced thyrotoxicosis: similarities and
differences between North American and European thyroidologists.
Tanda ML(1), Piantanida E, Lai A, Liparulo L, Sassi L, Bogazzi F, Wiersinga WM,
Braverman LE, Martino E, Bartalena L.
Author information:
(1)Department of Clinical Medicine, University of Insubria, Varese, Italy.
Comment in
Clin Endocrinol (Oxf). 2009 May;70(5):810-1. doi:
10.1111/j.1365-2265.2008.03405.x.
OBJECTIVE: To investigate how North American thyroidologists assess and treat
amiodarone-induced thyrotoxicosis (AIT) and to compare the results with those of
the same questionnaire-based survey previously carried out among European
thyroidologists.
DESIGN: Members of the American Thyroid Association (ATA) with clinical
interests were sent by e-mail a questionnaire on the diagnosis and management of
AIT, 115 responses were received from the United States and Canada, representing
about one-third of ATA members with clinical interests.
RESULTS: The majority of respondents (91%vs. 68% in Europe, P < 0.05) see < 10
new cases of AIT per year, and AIT seems less frequent than amiodarone-induced
hypothyroidism (AIH) in North America (34% and 66% of amiodarone-induced thyroid
dysfunction, respectively, vs. 75% and 25%, respectively, in Europe, P < 0.001).
When AIT is suspected, in North America hormonal assessment is mostly based on
serum free T4 (FT4) and TSH measurements, while serum free T3 (FT3)
determination is requested less frequently than in Europe; thyroid autoimmunity
is included in the initial assessment less than in Europe. Most commonly used
additional diagnostic procedures include, as in Europe, thyroid colour-flow
Doppler sonography, and to a lesser extent, thyroid radioactive iodine uptake
and scan, but Europeans tend to request multiple tests more than North
Americans. Withdrawal of amiodarone is more often considered unnecessary by
North American thyroidologists (21%vs. 10% in Europe in type 1 AIT, P < 0.05,
34%vs. 20% in type 2 AIT, P < 0.05). In type 1 AIT thionamides represent the
treatment of choice for North Americans as well as for Europeans, but the former
use them as monotherapy in 65%vs. 51% of Europeans (P < 0.05) who more often
consider potassium perchlorate as an useful addition (31%vs. 15% of North
Americans, P < 0.01). Glucocorticoids are the selected treatment for type 2 AIT,
alone (62%vs. 46% in Europe, P < 0.05) or in association with thionamides
(16%vs. 25% in Europe, P = NS). After restoration of euthyroidism, thyroid
ablation in the absence of recurrent thyrotoxicosis is recommended in type 1 AIT
less frequently by North Americans. If amiodarone therapy needs to be
reinstituted, prophylactic thyroid ablation is advised by 76% in type 1 AIT,
while a 'wait-and-see' strategy is adopted by 61% in type 2 AIT, similar to
behaviour of European thyroidologists.
CONCLUSION: Similarities and differences exist between expert North American and
European thyroidologists concerning the diagnosis and management of AIT. While
differences reflect the frequent uncertainty of the underlying mechanism leading
to AIT, similarities may represent the basis to refine the diagnostic criteria
and to improve the therapeutic outcomes of this challenging clinical situation.
DOI: 10.1111/j.1365-2265.2008.03268.x
PMID: 18410546 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20161621 | 1. Drugs Future. 2009 Sep;34(9):721. doi: 10.1358/dof.2009.034.09.1413267.
Advances in Systemic siRNA Delivery.
Leng Q(1), Woodle MC, Lu PY, Mixson AJ.
Author information:
(1)Department of Pathology, University of Maryland Baltimore, MSTF Building, 10
South Pine Street, Baltimore, MD 21201, USA.
Sequence-specific gene silencing with small interfering RNA (siRNA) has
transformed basic science research, and the efficacy of siRNA therapeutics
toward a variety of diseases is now being evaluated in pre-clinical and clinical
trials. Despite its potential value, the highly negatively charged siRNA has the
classic delivery problem of requiring transport across cell membranes to the
cytosol. Consequently, carrier development for siRNA delivery is one of the most
important problems to solve before siRNA can achieve widespread clinical use. An
assortment of non-viral carriers including liposomes, peptides, polymers, and
aptamers are being evaluated for their ability to shepherd siRNA to the target
tissue and cross the plasma membrane barrier into the cell. Several promising
carriers with low toxicity and increased specificity for disease targets have
emerged for siRNA-based therapeutics. This review will discuss non-viral
approaches for siRNA therapeutics, with particular focus on synthetic carriers
for in vivo systemic delivery of siRNA.
DOI: 10.1358/dof.2009.034.09.1413267
PMCID: PMC2812054
PMID: 20161621 |
http://www.ncbi.nlm.nih.gov/pubmed/24563587 | 1. J Young Pharm. 2013 Dec;5(4):112-5. doi: 10.1016/j.jyp.2013.12.002. Epub 2013
Dec 30.
Bedaquiline - The first ATP synthase inhibitor against multi drug resistant
tuberculosis.
Lakshmanan M(1), Xavier AS(1).
Author information:
(1)Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical
Education and Research, Pondicherry 605006, India.
Increasing incidence of MDR-TB, long duration of treatment and co-infection with
HIV are the significant problems in achieving the eradication of tuberculosis.
Bedaquiline is an anti-tuberculosis drug with unique mechanism of action. It
selectively inhibits the mycobacterial energy metabolism i.e. ATP synthesis and
found to be effective against all states of Mycobacterium tuberculosis like
active, dormant, replicating, non-replicating, intracellular and extracellular.
Preclinical studies have shown the efficacy of bedaquiline in terms of reduction
in bacterial load and treatment duration. Phase II clinical studies have
established the safety, tolerability and earlier sputum conversion time in
patients with MDR-TB. In 2012 FDA approved bedaquiline for treatment of MDR-TB
and XDR-TB.
DOI: 10.1016/j.jyp.2013.12.002
PMCID: PMC3930122
PMID: 24563587 |
http://www.ncbi.nlm.nih.gov/pubmed/23814607 | 1. Therap Adv Gastroenterol. 2013 Jul;6(4):261-8. doi: 10.1177/1756283X13486311.
LINX(®) Reflux Management System in chronic gastroesophageal reflux: a novel
effective technology for restoring the natural barrier to reflux.
Bonavina L(1), Saino G, Lipham JC, Demeester TR.
Author information:
(1)Division of General Surgery, Department of Biomedical Sciences for Health,
University of Milano School of Medicine, via Morandi 30, 20097 San Donato
Milanese, Milan, Italy.
Gastroesophageal reflux disease (GERD) results from incompetency of the lower
esophageal sphincter that allows the contents of the stomach to reflux into the
esophagus, the airways, and the mouth. The disease affects about 10% of the
western population and has a profound negative impact on quality of life. The
majority of patients are successfully treated with proton-pump inhibitors, but
up to 40% have incomplete relief of symptoms even after dose adjustment. The
laparoscopic Nissen fundoplication represents the surgical gold standard, but is
largely underused because of the level of technical difficulty and the
prevalence of side effects. These factors have contributed to the propensity of
patients to continue with medical therapy despite inadequate symptom control and
complications of the disease. As a consequence, a significant 'therapy gap' in
the treatment of GERD remains evident in current clinical practice. The LINX(®)
Reflux Management System (Torax Medical, St. Paul, MN, USA) is designed to
provide a permanent solution to GERD by augmenting the sphincter barrier with a
standardized, reproducible laparoscopic procedure that does not alter gastric
anatomy and is easily reversible. Two single-group trials confirmed that a
magnetic device designed to augment the lower esophageal sphincter can be safely
and effectively implanted using a standard laparoscopic approach. The device
decreased esophageal acid exposure, improved reflux symptoms and quality of
life, and allowed cessation of proton-pump inhibitors in the majority of
patients.
DOI: 10.1177/1756283X13486311
PMCID: PMC3667475
PMID: 23814607
Conflict of interest statement: Conflict of interest statement: All authors
received consulting fees from Torax® Medical, Inc. |
http://www.ncbi.nlm.nih.gov/pubmed/8997138 | 1. Rinsho Shinkeigaku. 1996 Oct;36(10):1143-9.
[A case of Dyke-Davidoff-Masson syndrome with total hemiatrophy].
[Article in Japanese]
Hozumi A(1), Yamazaki K, Hirata K, Iwai T, Katayama S.
Author information:
(1)Department of Neurology, Dokkyo University School of Medicine.
We reported a 39-year-old man with Dyke-Davidoff-Masson syndrome presenting with
total hemiatrophy. The patient had a muscle defect in the left occipital lesion
at birth and left hemiatrophy including the face in his infancy. The present
illness consists of atrophy of the left face, trunk and extremities, a muscle
defect accompanied with scleroderma of the left dorsal cervical lesion,
bilateral pes cavus, cleft palate, left hemiparesis, including facial palsy and
diminished superficial sensation of the left side of the body. Decrease in right
cranial volume and slight elevation of the right temporal pyramid and the
superior border of the orbit were seen on the X-ray study of the head. Atrophy
of the right cerebrum and cerebral peduncle was seen on magnetic resonance
imaging. These findings suggest that hemiatrophy of the brain was responsible
for total hemiatrophy of the body in this patient. The etiology of cerebral
hemiatrophy is not known. There is only a report of Dyke-Davidoff-Masson
syndrome accompanied with total hemiatrophy.
PMID: 8997138 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16004850 | 1. Curr Treat Options Cardiovasc Med. 2005 Jul;7(3):187-95. doi:
10.1007/s11936-005-0047-6.
Role of anti-infective strategies in the prevention of stroke.
Grau AJ(1).
Author information:
(1)Department of Neurology, Klinikum der Stadt Ludwigshafen a. Rhein,
Bremserstr. 70, Ludwigshafen am Rhein 67063, Germany. [email protected]
Case-control studies and a few prospective studies have indicated that chronic
infections may add to the risk of stroke and that acute infections may act as
trigger factors for stroke. Such chronic infections include periodontal disease,
infection with Chlamydia pneumoniae or Helicobacter pylori, and chronic
bronchitis. A causal role of these infectious diseases has not been proved,
given conflicting study results, possible residual confounding in observational
studies, and the lack of evidence from interventional trials. Therefore, special
treatment regimens for stroke prevention based on serologic or genomic evidence
of infection are not indicated outside of randomized studies at present.
However, the preliminary available evidence suggests that in patients with
previous cerebral ischemia, clinically diagnosed chronic infections should be
taken seriously and should receive the treatment that is indicated according to
current guidelines. This may include appropriate treatment of moderate or severe
periodontitis and of chronic bronchitis. Inflammatory parameters (eg, C-reactive
protein, leukocyte count, fibrinogen) are independently associated with the risk
of first or recurrent stroke. The question of whether these indexes are causally
related to stroke or merely represent risk markers is not sufficiently
clarified. Their use in monitoring individual risk in daily clinical practice is
limited at present by the lack of clearly defined therapeutic strategies to
modify these parameters, although statins and other drugs can influence
inflammatory markers. Observational studies have shown that influenza
vaccination is significantly and independently associated with a reduced risk of
stroke and myocardial infarction. Although interventional studies in stroke are
lacking, it is recommendable that in accordance with current guidelines patients
with previous vascular disease, including stroke, patients with high risk of
stroke, and all subjects above age 60, receive an influenza vaccination
annually.
DOI: 10.1007/s11936-005-0047-6
PMID: 16004850 |
http://www.ncbi.nlm.nih.gov/pubmed/7761171 | 1. Pediatr Radiol. 1995;25(1):64-5. doi: 10.1007/BF02020854.
Growing skull fracture in a patient with cerebral hemiatrophy.
Sener RN(1).
Author information:
(1)Department of Radiology, Ege University Hospital, Bornova, Izmir, Turkey.
A growing skull fracture or leptomeningeal cyst most commonly occurs in children
under the age of 3 years, and is extremely rare in adults. The reason for a
growing skull fracture is usually a dural tear in association with the fracture.
This paper presents an 18-year-old mentally retarded patient with cerebral
hemiatrophy (Dyke-Davidoff-Masson syndrome) associated with a growing skull
fracture in the ipsilateral hemicranium, in whom not only a dural tear but also
the ipsilaterally displaced and dilated lateral ventricle due to the original
disease apparently contributed to the development of growing skull fracture.
DOI: 10.1007/BF02020854
PMID: 7761171 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19169186 | 1. CNS Spectr. 2009 Jan;14(1):36-9. doi: 10.1017/s1092852900020034.
Treatment-refractory schizoaffective disorder in a patient with
dyke-davidoff-masson syndrome.
Amann B(1), García de la Iglesia C, McKenna P, Pomarol-Clotet E, Sanchez-Guerra
M, Orth M.
Author information:
(1)Benito Menni Complex Assistencial en Salut Mental, Barcelona, Spain.
[email protected]
Dyke-Davidoff-Masson syndrome, or cerebral hemiatrophy, is a pre- or perinatally
acquired entity characterized by predominantly neurologic symptoms, such as
seizures, facial asymmetry, contralateral hemiplegia, and mental retardation.
Psychiatric symptoms are rarely reported. We report the first case of left
cerebral hemiatrophy and a late onset of treatment-resistant schizoaffective
disorder after a stressful life event. The patient finally responded well to
clozapine. The clinical history and results from structural neuroimaging are
highlighted to discuss the possible developmental bias for psychotic disorders.
DOI: 10.1017/s1092852900020034
PMID: 19169186 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23694722 | 1. Biol Aujourdhui. 2013;207(1):19-31. doi: 10.1051/jbio/2013002. Epub 2013 May
23.
[Three-dimensional genome organization: a lesson from the Polycomb-Group
proteins].
[Article in French]
Bantignies F(1).
Author information:
(1)Institut de Génétique Humaine, CNRS UPR-1142, 141 rue de la Cardonille, 34396
Montpellier Cedex 5, France. [email protected]
As more and more genomes are being explored and annotated, important features of
three-dimensional (3D) genome organization are just being uncovered. In the
light of what we know about Polycomb group (PcG) proteins, we will present the
latest findings on this topic. The PcG proteins are well-conserved chromatin
factors that repress transcription of numerous target genes. They bind the
genome at specific sites, forming chromatin domains of associated histone
modifications as well as higher-order chromatin structures. These 3D chromatin
structures involve the interactions between PcG-bound regulatory regions at
short- and long-range distances, and may significantly contribute to PcG
function. Recent high throughput "Chromosome Conformation Capture" (3C) analyses
have revealed many other higher order structures along the chromatin fiber,
partitioning the genomes into well demarcated topological domains. This revealed
an unprecedented link between linear epigenetic domains and chromosome
architecture, which might be intimately connected to genome function.
© Société de Biologie, 2013.
DOI: 10.1051/jbio/2013002
PMID: 23694722 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25776009 | 1. Ann Hum Genet. 2015 May;79(3):218-24. doi: 10.1111/ahg.12108. Epub 2015 Mar
16.
A novel TAZ gene mutation and mosaicism in a Polish family with Barth syndrome.
Zapała B(1), Płatek T, Wybrańska I.
Author information:
(1)Department of Clinical Biochemistry, Jagiellonian University, Kraków, Poland.
Barth syndrome (BTHS) is an X-linked recessive disease primarily affecting
males. Clinically, the disease is characterized by hypertrophic or dilated
cardiomyopathy, skeletal myopathy, chronic/cyclic neutropenia,
3-methylglutaconic aciduria, growth retardation and respiratory chain
dysfunction. It is caused by mutations in the TAZ gene coding for the tafazzin
protein which is responsible for cardiolipin remodeling. In this work, we
present a novel pathogenic TAZ mutation c.83T>A, p.Val28Glu, found in mosaic
form in almost all female members of a Polish family. Sanger sequencing of DNA
from peripheral blood and from epithelial cells showed female mosaicism in three
generations. This appears to be a new mechanism of inheritance and further
research is required in order to understand the mechanism of this mosaicism. We
conclude that BTHS genetic testing should include two or more tissues for women
that appear to be noncarriers when blood DNA is initially tested. The results of
our study should not only be applicable to BTHS families, but also to families
with other X-linked diseases.
© 2015 The Authors. Annals of Human Genetics published by University College
London (UCL) and John Wiley & Sons Ltd.
DOI: 10.1111/ahg.12108
PMCID: PMC4654251
PMID: 25776009 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11157171 | 1. Stroke. 2001 Feb;32(2):385-91. doi: 10.1161/01.str.32.2.385.
Detection of Helicobacter pylori in human carotid atherosclerotic plaques.
Ameriso SF(1), Fridman EA, Leiguarda RC, Sevlever GE.
Author information:
(1)Department of Neurology, Institute for Neurological Research (FLENI), Buenos
Aires, Argentina.
BACKGROUND AND PURPOSE: Several lines of evidence point toward a relationship
between infection and atherosclerotic vascular disease. Thus, infection and
inflammation often precede ischemic neurological events. Transient alterations
in coagulation and direct arterial invasion by certain microorganisms have been
reported. Helicobacter pylori infection is the major cause of peptic ulcer
disease and appears to be a risk factor for ischemic cerebrovascular disease.
However, in contrast to other chronic infectious agents, H pylori has not been
consistently isolated from atherosclerotic lesions.
METHODS: We investigated the presence of H pylori in 38 atherosclerotic plaques
obtained at carotid endarterectomy by using morphological and
immunohistochemical techniques and a highly sensitive polymerase chain reaction
method. We performed immunohistochemical detection of intercellular adhesion
molecule-1, a marker related to inflammatory cell response. We also examined 7
carotid arteries obtained at autopsy from subjects without carotid
atherosclerosis.
RESULTS: H pylori DNA was found in 20 of 38 atherosclerotic plaques. Ten of the
H pylori DNA-positive plaques also showed morphological and immunohistochemical
evidence of H pylori infection. None of 7 normal carotid arteries was positive
for H pylori. Intercellular adhesion molecule-1 was expressed in 75% of H
pylori-positive plaques and in 22% of H pylori-negative plaques. The presence of
the microorganism was associated with male sex but was independent of age,
vascular risk factor profile, and prior neurological symptoms.
CONCLUSIONS: H pylori is present in a substantial number of carotid
atherosclerotic lesions and is associated with features of inflammatory cell
response. This study provides additional evidence of the relationship between H
pylori infection and atherosclerotic disease.
DOI: 10.1161/01.str.32.2.385
PMID: 11157171 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2117086 | 1. Jpn J Exp Med. 1990 Apr;60(2):73-9.
A case of GM1-gangliosidosis type I: glycosphingolipid profiles of urine and
transformed lymphocytes and beta-D-galactosidase activities in peripheral
lymphocytes, cultured skin fibroblasts and transformed lymphocytes.
Asano K(1), Shindo N, Nakasuji M, Inamori K, Ohta M, Matsushita T, Yamaguchi M,
Oshima M.
Author information:
(1)Division of Clinical Biochemistry, National Medical Center Hospital, Tokyo,
Japan.
A female infant with early-onset GM1-gangliosidosis type I was investigated. The
lymphocytes, transformed lymphocytes and cultured skin fibroblasts of the
patient were demonstrated to have severe beta-D-galactosidase deficiency. The
beta-D-galactosidase activities of these cells from the patient's father and
mother were at the lower limit of the normal range. The oligosaccharide
accumulation in urine of the patient showed the typical type I
GM1-gangliosidosis pattern, but no GM1 ganglioside was detected in the patient's
urine or transformed lymphocytes. The clinical features were compatible with
infantile GM1-gangliosidosis. The mixture of homogenates from the cultured
fibroblasts or transformed lymphocytes of the patient and controls showed no
complementation of beta-D-galactosidase activity against the controls.
PMID: 2117086 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11253332 | 1. Minerva Cardioangiol. 2000 Dec;48(12):467-73.
[Ischemic cardiovascular diseases. Correlation with Helicobacter pylori
infection].
[Article in Italian]
Pellicano R(1), Oliaro E, Mangiardi L, Orzan F, Bergerone S, Gandolfo N, Aruta
E, Rizzetto M, Ponzetto A.
Author information:
(1)UOADU Gastro-Epatologia Azienda Ospedaliera San Giovanni Battista
(Molinette), Torino. [email protected]
Coronary heart disease is the primary cause of mortality in western countries.
The well-established ("classical") risk factors cannot fully explain
epidemiological variations of this disease. From several years infections have
been linked to ischemic vascular events and recent studies pointed to the role
of Helicobacter pylori (H. pylori), a spiral Gram negative bacterium, that
chronically infects human stomach and is involved in the pathogenesis of
gastritis and peptic ulceration. Systematic reviews of studies have suggested
the existence of a possible weakly positive association between this bacterium
and coronary heart disease, but this could be due to confounding bias and
influenced by the degree of investigations heterogeneity. Experiments from
animal studies demonstrated that H. pylori infection in mice induces the
formation of platelet aggregates and in contrast to Chlamydia pneumoniae it has
not been found in the plaque: therefore, the role of H. pylori, could be even
more important in the acute phase of myocardial infarction. There is the need
for extensive prospective studies to evaluate the incidence of these diseases in
relation to the presence of H. pylori infection. Appropriately randomized
studies employing an antibiotic treatment for patients affected by ischemic
vascular disease will answer the question of whether H. pylori has a causal role
in the pathogenesis of acute myocardial infarction and ischemic stroke.
PMID: 11253332 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20230455 | 1. Pain Pract. 2010 Jul-Aug;10(4):306-11. doi: 10.1111/j.1533-2500.2010.00361.x.
Epub 2010 Mar 2.
Oral burning sensation: prevalence and gender differences in a Japanese
population.
Suzuki N(1), Mashu S, Toyoda M, Nishibori M.
Author information:
(1)Nishibori Dental Office and Toyoda Dental Office, Tokyo, Japan.
[email protected]
BACKGROUND: Burning mouth syndrome (BMS) is characterized by an oral burning
sensation (OBS) in the tongue or other oral mucous membrane in the absence of
any clinical abnormal findings. It frequently affects middle-aged and aged
women. Although there are many oral disorders with OBS besides BMS, the
prevalence of OBS is unclear.
AIM: To investigate the prevalence of OBS and analyze the gender differences in
a Japanese population.
METHODS: The study subjects were 2599 dental patients in two dental offices in
Tokyo, Japan. The prevalence of OBS was investigated using a questionnaire.
RESULTS: The mean ages of the subjects were 42.7 +/- 13.8 (mean +/- SD) years of
age in male and 40.1 +/- 15.4 (mean +/- SD) years of age in female. The
prevalence of OBS "at present" was 2.8% of 1310 male subjects and 3.2% of 1289
female subjects. There was no statistically significant difference between them
for each decade. The prevalence including "at present" and "in the past" were
9.3% in male subjects and 10.8% in female subjects; this difference was not
statistically significant.
CONCLUSION: These findings fail to demonstrate a female predilection for OBS.
DOI: 10.1111/j.1533-2500.2010.00361.x
PMID: 20230455 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21159650 | 1. Cancer Res. 2010 Dec 15;70(24):10310-20. doi: 10.1158/0008-5472.CAN-10-2062.
NEDD8-targeting drug MLN4924 elicits DNA rereplication by stabilizing Cdt1 in S
phase, triggering checkpoint activation, apoptosis, and senescence in cancer
cells.
Lin JJ(1), Milhollen MA, Smith PG, Narayanan U, Dutta A.
Author information:
(1)Department of Biochemistry and Molecular Genetics, University of Virginia,
Charlottesville, Virginia, USA.
MLN4924 is a first-in-class experimental cancer drug that inhibits the
NEDD8-activating enzyme, thereby inhibiting cullin-RING E3 ubiquitin ligases and
stabilizing many cullin substrates. The mechanism by which MLN4924 inhibits
cancer cell proliferation has not been defined, although it is accompanied by
DNA rereplication and attendant DNA damage. Here we show that stabilization of
the DNA replication factor Cdt1, a substrate of cullins 1 and 4, is critical for
MLN4924 to trigger DNA rereplication and inhibit cell proliferation. Even only 1
hour of exposure to MLN4924, which was sufficient to elevate Cdt1 for 4-5 hours,
was found to be sufficient to induce DNA rereplication and to activate apoptosis
and senescence pathways. Cells in S phase were most susceptible, suggesting that
MLN4924 will be most toxic on highly proliferating cancers. Although
MLN4924-induced cell senescence seems to be dependent on induction of p53 and
its downstream effector p21(Waf1), we found that p53(-/-) and p21(-/-) cells
were even more susceptible than wild-type cells to MLN4924. Our results
suggested that apoptosis, not senescence, might be more important for the
antiproliferative effect of MLN4924. Furthermore, our findings show that
transient exposure to this new investigational drug should be useful for
controlling p53-negative cancer cells, which often pose significant clinical
challenge.
©2010 AACR.
DOI: 10.1158/0008-5472.CAN-10-2062
PMCID: PMC3059213
PMID: 21159650 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23787507 | 1. Georgian Med News. 2013 May;(218):49-53.
Management of burning mouth syndrome taking into consideration various etiologic
factors.
Kenchadze RL, Ivereli MB, Geladze NM, Khachapuridze NS, Bakhtadze SZ.
The aim of the research was to detect the stomatologic, endocrine and
psycho-neurologic status in patients with burning mouth syndrome, elaborate
different diagnostic criteria and effective therapy for the patients with
burning mouth syndrome. 92 patients with burning mouth syndrome were studied.
Patients ranged in age from 28 to 72 years. The conducted studies gave the
possibility to make conclusions, the most important of which are: burning mouth
syndrome (BMS) is not only stomatologic problem; this psychosomatic syndrome
belongs to gerontologic disease and tendency of its "rejuvenation" was revealed
as well (in the current study --2 women (28 and 32 year old, and 38 year old
man); degree of revelation of the symptoms of depression, anxiety, obsession and
somatization is closely related with duration of the diseases. These symptoms
are progressing together with aging and reach the peak at 60-70 years old.
Individual scheme of therapy was developed on the background of
clinico-paraclinical study.
PMID: 23787507 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22313427 | 1. Thyroid. 2012 Mar;22(3):325-9. doi: 10.1089/thy.2011.0328. Epub 2012 Feb 7.
Propylthiouracil-induced interstitial pneumonia in a Caucasian woman with
amiodarone-induced thyrotoxicosis.
Diazzi C(1), Brigante G, Rossi G, Rochira V.
Author information:
(1)Department of Medicine, Endocrinology and Metabolism, Geriatrics, University
of Modena and Reggio Emilia, Azienda USL of Modena, Modena, Italy.
BACKGROUND: Propylthiouracil (PTU) therapy is associated with a variety of
adverse reactions, among the most rare being interstitial pneumonia. To date,
this has been reported in four Asian patients with autoimmune hyperthyroidism.
Here we describe a Caucasian woman who developed a bronchiolitis obliterans
organizing pneumonia (BOOP)-like interstitial pneumonia after PTU administration
for amiodarone-induced thyrotoxicosis.
PATIENT FINDINGS: The patient was a 68-year-old woman who had been treated with
amiodarone for chronic atrial fibrillation starting in May 2004. She had been a
heavy smoker with a history of hypertension but no dust exposures. In October
2006, amiodarone was stopped after she developed thyrotoxicosis. In January 2007
serum thyroid-stimulating hormone (TSH) was 0.01 mIU/L (0.35-4.94) and free T4
was 17.5 pg/mL (7 to 15). She was initially started on methimazole and then
changed to PTU after she developed pruritus. She developed severe dyspnea 9
months after starting PTU. At the time she was also taking warfarin, enalapril,
and sotalol. Chest X-ray showed diffuse interstitial peripheral opacities and
transbronchial lung biopsy revealed subacute lung injury with organizing
pneumonia with hyperplasia of the alveolar type 2 pneumocytes, and
characteristics of BOOP-like interstitial pneumonia. Signs and symptoms
progressively improved after PTU discontinuation as confirmed at X-ray and
computed tomography (CT) scan of the chest and by respiratory function tests.
She has been recurrence free for 4 years after stopping PTU.
SUMMARY: This woman of Caucasian ancestral origin developed BOOP-like
interstitial pneumonia after PTU treatment for apparent amiodarone-induced
thyrotoxicosis, with resolution of her lung disease after stopping PTU. Tests
for TSH receptor antibodies, thyroid peroxidase antibodies, and antinuclear
cytoplasmic autoantibody were negative. Thyroid ultrasound was consistent with
thyroiditis without nodules.
CONCLUSIONS: PTU-associated interstitial pneumonia is not limited to patients of
Asian origin or those with autoimmune thyroid disease. PTU must be withdrawn in
the presence of respiratory symptoms and documented interstitial pneumonia.
X-ray films, CT-scan, respiratory function tests, and lung biopsy are needed to
diagnose PTU-induced interstitial pneumonia with certainty and to monitor the
evolution of the disease after PTU discontinuation.
DOI: 10.1089/thy.2011.0328
PMID: 22313427 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24117632 | 1. Ann N Y Acad Sci. 2013 Oct;1300:29-42. doi: 10.1111/nyas.12232.
Outcomes of esophageal surgery, especially of the lower esophageal sphincter.
Bonavina L(1), Siboni S(1), Saino GI(1), Cavadas D(2), Braghetto I(3), Csendes
A(3), Korn O(3), Figueredo EJ(4), Swanstrom LL(5), Wassenaar E(4).
Author information:
(1)General Surgery, IRCCS, University of Milano, Milano, Italy.
(2)Department of Surgery, Hospital Italiano, Buenos Aires, Argentina.
(3)Department of Surgery, University Hospital, Faculty of Medicine, University
of Chile, Santiago, Chile.
(4)Department of Surgery, University of Washington, Seattle, Washington.
(5)GI/MIS, The Oregon Clinic, Portland, Oregon.
This paper includes commentaries on outcomes of esophageal surgery, including
the mechanisms by which fundoduplication improves lower esophageal sphincter
(LES) pressure; the efficacy of the Linx™ management system in improving LES
function; the utility of radiologic characterization of antireflux valves
following surgery; the correlation between endoscopic findings and reported
symptoms following antireflux surgery; the links between laparoscopic sleeve
gastrectomy and decreased LES pressure, endoscopic esophagitis, and
gastroesophageal reflux disease (GERD); the less favorable outcomes following
fundoduplication among obese patients; the application of bioprosthetic meshes
to reinforce hiatal repair and decrease the incidence of paraesophageal hernia;
the efficacy of endoluminal antireflux procedures, and the limited efficacy of
revisional antireflux operations, underscoring the importance of good primary
surgery and diligent work-up to prevent the necessity of revisional procedures.
© 2013 New York Academy of Sciences.
DOI: 10.1111/nyas.12232
PMID: 24117632 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24251273 | 1. N Am J Med Sci. 2013 Sep;5(9):546-53. doi: 10.4103/1947-2714.118920.
Fibromyalgia Symptom Reduction by Online Behavioral Self-monitoring,
Longitudinal Single Subject Analysis and Automated Delivery of Individualized
Guidance.
Collinge W(1), Yarnold P, Soltysik R.
Author information:
(1)Collinge and Associates, Eugene, OR, USA.
BACKGROUND: Fibromyalgia (FM) is a complex chronic pain condition that is
difficult to treat. The prevailing approach is an integration of
pharmacological, psycho-educational, and behavioral strategies. Information
technology offers great potential for FM sufferers to systemically monitor
symptoms as well as potential impacts of various management strategies.
AIMS: This study aimed to evaluate effects of a web-based, self-monitoring and
symptom management system (SMARTLog) that analyzes personal self-monitoring data
and delivers data-based feedback over time.
MATERIALS AND METHODS: Subjects were self-referred, anonymous, and recruited via
publicity on FM advocacy websites. Standardized instruments assessed health
status, self-efficacy, and locus of control at baseline and monthly during
participation. Subjects were encouraged to complete the SMARTLog several times
weekly. Within-subject, univariate, and multivariate analyses were used to
derive classification trees for each user associating specific behavior
variables with symptom levels over time.
RESULTS: Moderate use (3 times weekly x 3 months) increased likelihood of
clinically significant improvements in pain, memory, gastrointestinal problems,
depression, fatigue, and concentration; heavy use (4.5 times weekly x five
months) produced the above plus improvement in stiffness and sleep difficulties.
CONCLUSIONS: Individualized, web-based behavioral self-monitoring with
personally-tailored feedback can enable FM sufferers to significantly reduce
symptom levels over time.
DOI: 10.4103/1947-2714.118920
PMCID: PMC3818828
PMID: 24251273
Conflict of interest statement: Conflict of Interest: None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/2303258 | 1. Genomics. 1990 Jan;6(1):174-7. doi: 10.1016/0888-7543(90)90463-5.
The neuroepithelioma breakpoint on chromosome 22 is proximal to the meningioma
locus.
Zhang FR(1), Delattre O, Rouleau G, Couturier J, Lefrançois, Thomas G, Aurias A.
Author information:
(1)CNRS-URA 620, Institut Curie, Paris, France.
The recurrent translocation breakpoint on chromosome 22 of neuroepithelioma has
been localized between two probes, D22S1 and D22S15, by both in situ
hybridization and somatic cell hybrids. These two probes have further been shown
to be genetically linked at theta = 0.0 and a lod score of 5.3. The two probes
were unaffected by a partial deletion of the chromosome 22 long arm of a
meningioma, showing that the meningioma locus is distal to that of the
neuroepithelioma.
DOI: 10.1016/0888-7543(90)90463-5
PMID: 2303258 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15174138 | 1. Proteomics. 2004 Jun;4(6):1695-702. doi: 10.1002/pmic.200300701.
Functional protein nanoarrays for biomarker profiling.
Lynch M(1), Mosher C, Huff J, Nettikadan S, Johnson J, Henderson E.
Author information:
(1)BioForce Nanosciences, Ames, Iowa 50010, USA. [email protected]
The use of microarrays for parallel screening of nucleic acid profiles has
become an industry standard. Similar efforts for screening protein-protein
interactions are gaining momentum, however, they remain limited by the
requirement for relatively large sample volumes. One strategy for overcoming
this problem is to significantly decrease the size and consequently the sample
volume of the protein interaction assay. We report here on our progress over the
last two years in the construction of ultraminiaturized, functional protein
capture assays. Each one micron spot in these array-based assays covers less
than 1/1000(th) of the surface area of a conventional microarray spot while
still maintaining enough antibodies to provide a useful dynamic range. These
nanoarray assays can be read by conventional optical fluorescence microscopy as
well as by novel label-free methods such as atomic force microscopy. The size
reduction realized by functional protein nanoarrays also creates opportunities
for novel applications including highly multiplexed single cell analysis and
integration with microfluidics and other "lab-on-a-chip" technologies.
DOI: 10.1002/pmic.200300701
PMID: 15174138 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25012804 | 1. Surg Endosc. 2015 Mar;29(3):505-9. doi: 10.1007/s00464-014-3704-6. Epub 2014
Jul 11.
A comparative trial of laparoscopic magnetic sphincter augmentation and Nissen
fundoplication.
Sheu EG(1), Nau P, Nath B, Kuo B, Rattner DW.
Author information:
(1)Department of Surgery, Massachusetts General Hospital, Boston, MA, USA,
[email protected].
BACKGROUND: Laparoscopic magnetic sphincter augmentation (MSA) with the LINX
device is a promising new therapy for the treatment of gastroesophageal reflux
disease (GERD). Initial studies have demonstrated MSA to be safe and effective.
However, no direct comparison between MSA and laparoscopic Nissen fundoplication
(LNF), the gold standard surgical therapy for GERD, has been performed.
METHODS: A single institution, case-control study was conducted of MSA performed
from 2012 to 2013 and a cohort of LNF matched for age, gender, and hiatal hernia
size.
RESULTS: MSA and LNF were both effective treatments for reflux with 75 and 83 %
of patients, respectively, reporting resolution of GERD at short-term follow-up.
Dysphagia was common following both MSA and LNF, but severe dysphagia requiring
endoscopic dilation was more frequent after MSA (50 vs. 0 %, p = 0.01). Need for
dilation did not correlate with size of the LINX device or any other examined
patient factors. A trend toward decreased adverse GI symptoms of bloating,
flatulence, and diarrhea was seen after MSA compared to LNF (0 vs. 33 %). MSA
had a shorter operative time (64 vs. 90 min, p < 0.01) but other peri-operative
outcomes, including pain, morbidity, and re-admissions were equivalent to LNF.
MSA patients were more likely to be self-referred (58 vs. 0 %, p < 0.001).
CONCLUSIONS: MSA and LNF are both effective and safe treatments for GERD;
however, severe dysphagia requiring endoscopic intervention is more common with
MSA. Other adverse GI side effects may be less frequent after MSA. Consideration
should be paid to these distinct post-operative symptom profiles when selecting
a surgical therapy for reflux disease.
DOI: 10.1007/s00464-014-3704-6
PMID: 25012804 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23352688 | 1. J Stroke Cerebrovasc Dis. 2013 Nov;22(8):1317-25. doi:
10.1016/j.jstrokecerebrovasdis.2012.12.010. Epub 2013 Jan 22.
Rivaroxaban versus warfarin in Japanese patients with nonvalvular atrial
fibrillation for the secondary prevention of stroke: a subgroup analysis of
J-ROCKET AF.
Tanahashi N(1), Hori M, Matsumoto M, Momomura S, Uchiyama S, Goto S, Izumi T,
Koretsune Y, Kajikawa M, Kato M, Ueda H, Iwamoto K, Tajiri M; J-ROCKET AF Study
Investigators.
Author information:
(1)Department of Neurology, Saitama Medical University International Medical
Center, Saitama, Japan. Electronic address: [email protected].
BACKGROUND: The overall analysis of the rivaroxaban versus warfarin in Japanese
patients with atrial fibrillation (J-ROCKET AF) trial revealed that rivaroxaban
was not inferior to warfarin with respect to the primary safety outcome. In
addition, there was a strong trend for a reduction in the rate of
stroke/systemic embolism with rivaroxaban compared with warfarin.
METHODS: In this subanalysis of the J-ROCKET AF trial, we investigated the
consistency of safety and efficacy profile of rivaroxaban versus warfarin among
the subgroups of patients with previous stroke, transient ischemic attack, or
non-central nervous system systemic embolism (secondary prevention group) and
those without (primary prevention group).
RESULTS: Patients in the secondary prevention group were 63.6% of the overall
population of J-ROCKET AF. In the secondary prevention group, the rate of the
principal safety outcome (% per year) was 17.02 in rivaroxaban-treated patients
and 18.26 in warfarin-treated patients (hazard ratio [HR] 0.95; 95% confidence
interval [CI] 0.70-1.29), while the rate of the primary efficacy endpoint was
1.66 in rivaroxaban-treated patients and 3.25 in warfarin-treated patients (HR
0.51; 95% CI 0.23-1.14). There were no significant interactions in the principal
safety and the primary efficacy endpoints of rivaroxaban compared to warfarin
between the primary and secondary prevention groups (P=.090 and .776 for both
interactions, respectively).
CONCLUSIONS: The safety and efficacy profile of rivaroxaban compared with
warfarin was consistent among patients in the primary prevention group and those
in the secondary prevention group.
Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All
rights reserved.
DOI: 10.1016/j.jstrokecerebrovasdis.2012.12.010
PMID: 23352688 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20359886 | 1. Eur J Cancer. 2010 May;46(8):1382-91. doi: 10.1016/j.ejca.2010.02.035. Epub
2010 Mar 30.
Cost-effectiveness of the 70-gene signature versus St. Gallen guidelines and
Adjuvant Online for early breast cancer.
Retèl VP(1), Joore MA, Knauer M, Linn SC, Hauptmann M, Harten WH.
Author information:
(1)Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital (NKI-AVL),
Department of Psychosocial Research and Epidemiology, Plesmanlaan 121, 1066 CX
Amsterdam, The Netherlands.
BACKGROUND: The 70-gene signature (MammaPrint) is a prognostic test used to
guide adjuvant treatment decisions in patients with node-negative breast cancer.
In order to decide upon its use, a systematic comparative analysis of the
effects of the 70-gene signature, the Sankt Gallen guidelines and the Adjuvant
Online Software for these patients on survival, quality of life and costs is
warranted.
METHODS: A Markov decision model was used to simulate the 20-year costs and
outcomes (survival and quality-of-life adjusted survival (QALYs)) in a
hypothetical cohort of node-negative, estrogen receptor positive breast cancer
patients. Sensitivity and specificity of the three prognostic tools were based
on 5 and 10 years breast cancer specific survival and distant metastasis as
first event, derived from a pooled analysis consisting of 305 tumour samples
from 3 previously reported validation studies concerning the 70-gene signature.
RESULTS: Small differences in survival, but substantial differences in
quality-adjusted survival between the prognostic tools were observed.
Quality-adjusted survival was highest when using the 70-gene signature. Based on
costs per QALY, the 70-gene has the highest probability of being cost-effective
for a willingness to pay for a QALY higher than euro12.000. Sankt Gallen showed
the highest survival rates compared to the 70-gene signature, but leads to a
substantial larger amount of adjuvant chemotherapy and lower cost-effectiveness,
thus demanding a high willingness to pay to save a life year.
CONCLUSIONS: When deciding upon the cost-effectiveness of the prognostic tests,
the 70-gene signature improves quality-adjusted survival and has the highest
probability of being cost-effective.
Copyright (c) 2010 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ejca.2010.02.035
PMID: 20359886 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16386288 | 1. Thromb Res. 2006;118(6):671-7. doi: 10.1016/j.thromres.2005.11.007. Epub 2005
Dec 28.
Helicobacter pylori infection and the CD14 C(-260)T gene polymorphism in
ischemic stroke.
Park MH(1), Min JY, Koh SB, Kim BJ, Park MK, Park KW, Lee DH.
Author information:
(1)Department of Neurology, Korea University Medical College, 126-1,
Anam-dong-5-ga, Sungbuk-gu, Seoul [136-705], Korea.
INTRODUCTION: There is increasing evidence that infective pathogens such as
Helicobacter pylori is linked to atherosclerosis of cerebral vessels. As an
independent contributing factor, the CD14 receptor-lipopolysaccharide complex
plays an important role in activating inflammatory reactions. In particular, the
C(-260)T polymorphism in the CD14 receptor may be implicated in atherosclerotic
disease. In this study, we investigated a possible association between H. pylori
infection and the polymorphism of CD14, and ischemic stroke.
MATERIALS AND METHODS: A total of 125 patients with ischemic stroke and 125 age-
and sex-matched controls were included in the study. The stroke subtype of each
of the patients was characterized based on the underlying etiology. H. pylori
serologic status and the CD14 genotype were determined in both patients and
controls.
RESULTS: H. pylori seropositivity was more common in the stroke patients than in
the controls (80.0% vs. 60.0%, P=0.001). Moreover, H. pylori seropositivity was
more common in the stroke subtype of large artery disease (87.7%, P<0.001). The
distribution of CD14 genotypes was as follows: patients, T/T 21.6%, C/T 63.2%,
C/C 15.2%; controls, T/T 19.2%, C/T 57.6%, C/C 23.2%. There was no significant
difference between these two CD14 genotype distributions.
CONCLUSIONS: These results suggest that H. pylori infection is a risk factor for
ischemic stroke and that CD14 polymorphism is not.
DOI: 10.1016/j.thromres.2005.11.007
PMID: 16386288 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23227861 | 1. Thyroid. 2013 Mar;23(3):269-72. doi: 10.1089/thy.2012.0459.
Initial treatment with 15 mg of prednisolone daily is sufficient for most
patients with subacute thyroiditis in Japan.
Kubota S(1), Nishihara E, Kudo T, Ito M, Amino N, Miyauchi A.
Author information:
(1)Kuma Hospital, Chuo-Ku, Kobe, Japan. [email protected]
BACKGROUND: Oral glucocorticoids are administered in moderate and severe cases
of subacute thyroiditis (SAT), providing dramatic relief from pain and fever.
However, there have been no reports regarding the optimal dose of prednisolone
(PSL) for treatment of SAT. In this study, we used 15 mg/day of PSL as the
initial dosage and tapered it by 5 mg every 2 weeks. We assessed the
effectiveness of this treatment protocol.
METHODS: We examined 384 consecutive and untreated patients with SAT who visited
our thyroid clinic between February 2005 and December 2008. We excluded patients
who did not fit our protocol, and the final number of subjects was 219. When
patients complained of pain in their neck or C-reactive protein (CRP) was still
high, physicians were able to extend the tapering of the dose of PSL or increase
it at 2-week intervals. The endpoint of the study was the duration of the PSL
medication. We also compared the severity of thyrotoxicosis and rate of
hypothyroidism after SAT between the short medication group (patients who
recovered within 6 weeks) and long medication group (patients who recovered in
12 weeks or more).
RESULTS: The number of patients whose thyroiditis improved within 6 weeks and
did not recur was 113 (51.6%), and 61 (27.9%) improved within 7 to 8 weeks and
did not have a recurrence. The longest duration was 40 weeks. Seven patients
(3.2%) needed increases in the dosage of PSL. Thyroid hormone (free thyroxine
and free triiodothyronine) levels measured at the initial visit in the short
medication group were significantly higher than those in the long medication
group (p<0.05). Serum CRP, male-to-female ratio, body weight, and age showed no
differences between the two groups. There were no differences in the rate of
hypothyroidism after SAT between the two groups (p=0.0632).
CONCLUSIONS: The treatment protocol that we employed had 15 mg/day of PSL as the
initial dosage for the treatment of SAT, with tapering by 5 mg every 2 weeks,
and was effective and safe for Japanese patients. However, 20% of patients with
SAT needed longer than 8 weeks to recover from the inflammation.
DOI: 10.1089/thy.2012.0459
PMID: 23227861 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16957286 | 1. Methods Mol Biol. 2006;346:95-109. doi: 10.1385/1-59745-144-4:95.
Proteomic analysis of Dictyostelium discoideum.
Roth U(1), Müller S, Hanisch FG.
Author information:
(1)Center for Molecular Medicine Cologne, Germany.
The social amoeba Dictyostelium discoideum is already known as a model organism
for a variety of cellular and molecular studies. Now that the genome sequencing
project has been completed and different tools with which to overexpress or
knock out genes are available, this species has also moved into the spotlight of
functional genomics studies. Consequently, this genomic sequence information can
now be exploited to realize D. discoideum proteomics projects. Here, we present
validated protocols adapted for analysis of the D. discoideum proteome. The
workflow described in this chapter comprises two-dimensional polyacrylamide gel
electrophoresis for protein separation and peptide mass fingerprint
(matrix-assisted laser desorption/ionization time-of-flight mass spectrometry)
for protein identification.
DOI: 10.1385/1-59745-144-4:95
PMID: 16957286 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18682362 | 1. J R Soc Interface. 2008 Oct 6;5 Suppl 2(Suppl 2):S139-50. doi:
10.1098/rsif.2008.0233.focus.
Microfluidic single-cell analysis of intracellular compounds.
Chao TC(1), Ros A.
Author information:
(1)Department of Chemistry and Biochemistry, Arizona State University, Box
871604, Tempe, AZ 85287-1604, USA.
Biological analyses traditionally probe cell ensembles in the range of 103-106
cells, thereby completely averaging over relevant individual cell responses,
such as differences in cell proliferation, responses to external stimuli or
disease onset. In past years, this fact has been realized and increasing
interest has evolved for single-cell analytical methods, which could give
exciting new insights into genomics, proteomics, transcriptomics and systems
biology. Microfluidic or lab-on-a-chip devices are the method of choice for
single-cell analytical tools as they allow the integration of a variety of
necessary process steps involved in single-cell analysis, such as selection,
navigation, positioning or lysis of single cells as well as separation and
detection of cellular analytes. Along with this advantageous integration,
microfluidic devices confine single cells in compartments near their intrinsic
volume, thus minimizing dilution effects and increasing detection sensitivity.
This review overviews the developments and achievements of microfluidic
single-cell analysis of intracellular compounds in the past few years, from
proof-of-principle devices to applications demonstrating a high biological
relevance.
DOI: 10.1098/rsif.2008.0233.focus
PMCID: PMC2706030
PMID: 18682362 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23445532 | 1. Anal Chem. 2013 Apr 2;85(7):3592-8. doi: 10.1021/ac303347n. Epub 2013 Mar 11.
Toward single-cell analysis by plume collimation in laser ablation electrospray
ionization mass spectrometry.
Stolee JA(1), Vertes A.
Author information:
(1)Department of Chemistry, W M Keck Institute for Proteomics Technology and
Applications, The George Washington University, Washington, District of Columbia
20052, United States.
Ambient ionization methods for mass spectrometry have enabled the in situ and in
vivo analysis of biological tissues and cells. When an etched optical fiber is
used to deliver laser energy to a sample in laser ablation electrospray
ionization (LAESI) mass spectrometry, the analysis of large single cells becomes
possible. However, because in this arrangement the ablation plume expands in
three dimensions, only a small portion of it is ionized by the electrospray.
Here we show that sample ablation within a capillary helps to confine the radial
expansion of the plume. Plume collimation, due to the altered expansion
dynamics, leads to greater interaction with the electrospray plume resulting in
increased ionization efficiency, reduced limit of detection (by a factor of ~13,
reaching 600 amol for verapamil), and extended dynamic range (6 orders of
magnitude) compared to conventional LAESI. This enhanced sensitivity enables the
analysis of a range of metabolites from small cell populations and single cells
in the ambient environment. This technique has the potential to be integrated
with flow cytometry for high-throughput metabolite analysis of sorted cells.
DOI: 10.1021/ac303347n
PMID: 23445532 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23480756 | 1. Asian Pac J Cancer Prev. 2012;13 Suppl:143-7.
Suppression of PRKAR1A expression enhances anti-proliferative and apoptotic
effects of protein kinase inhibitors and chemotherapeutic drugs on
cholangiocarcinoma cells.
Loilome W(1), Juntana S, Pinitsoontorn C, Namwat N, Tassaneeyakul W, Yongvanit
P.
Author information:
(1)Department of Biochemistry, Khon Kaen University, Khon Kaen, Thailand.
[email protected]
Suppression of protein kinase A regulatory subunit 1 alpha (PRKAR1A) has been
proven to inhibit cholangiocarcinoma (CCA) cell growth and enhance apoptosis. In
the present study, we aimed to determine synergistic and/or additive effects of
chemotherapeutic agents, including protein kinase inhibitors (i.e. sorafenib,
sunitinib, gefitinib, Met inhibitor) and conventional chemotherapeutic drugs
(i.e. 5-fluorouracil, doxorubicin, paclitaxel, gemcitabine), in PRKARIA
knockdown CCA cell lines. The results revealed that PRKAR1A suppressed CCA cell
lines demonstrated enhanced sensitivity to some chemotherapeutic drugs when
compared to control cells. Moreover, PRKAR1A knockdown in combination with
either sorafenib or 5-fluorouracil increased apoptotic effects on CCA cell
lines. Therefore, selective inhibition of PRKAR1A appears to enhance the growth
inhibitory effects of chemotherapeutic drugs as well as induce apoptotic cell
death. Our findings suggest that additional suppression of PRKAR1A expression
may increase the efficacy of conventional CCA chemotherapeutic treatment.
Clinical studies in CCA patients now need to be conducted.
PMID: 23480756 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23521791 | 1. Chem Biol. 2013 Mar 21;20(3):333-40. doi: 10.1016/j.chembiol.2012.12.008.
A yeast chemical genetic screen identifies inhibitors of human telomerase.
Wong LH(1), Unciti-Broceta A, Spitzer M, White R, Tyers M, Harrington L.
Author information:
(1)Wellcome Trust Centre for Cell Biology, King's Buildings, University of
Edinburgh, Mayfield Road, Edinburgh EH9 3JR, UK.
Telomerase comprises a reverse transcriptase and an internal RNA template that
maintains telomeres in many eukaryotes, and it is a well-validated cancer
target. However, there is a dearth of small molecules with efficacy against
human telomerase in vivo. We developed a surrogate yeast high-throughput assay
to identify human telomerase inhibitors. The reversibility of growth arrest
induced by active human telomerase was assessed against a library of 678
compounds preselected for bioactivity in S. cerevisiae. Four of eight compounds
identified reproducibly restored growth to strains expressing active human
telomerase, and three of these four compounds also specifically inhibited
purified human telomerase in vitro. These compounds represent probes for human
telomerase function, and potential entry points for development of lead
compounds against telomerase-positive cancers.
Copyright © 2013 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.chembiol.2012.12.008
PMCID: PMC3650558
PMID: 23521791 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20429673 | 1. Expert Opin Drug Metab Toxicol. 2010 Jun;6(6):773-9. doi:
10.1517/17425255.2010.487483.
Pharmacologic evaluation of ospemifene.
McCall JL(1), DeGregorio MW.
Author information:
(1)Pharmacology and Toxicology, University of California, Davis, Suite 3016,
Sacramento, CA 95817, USA.
IMPORTANCE OF THE FIELD: Millions of women worldwide suffer from vulvovaginal
atrophy (VVA) associated with menopause, and many women report that this
adversely affects their quality of life. Ospemifene is a non-hormonal estrogen
receptor agonist/antagonist effective in the treatment of VVA. Although similar
in structure to other estrogen receptor agonists/antagonists that have
antagonistic effects on the vagina, ospemifene has an estrogen-like effect on
vaginal epithelium. This review focuses on ospemifene including its
pharmacologic properties, clinical efficacy and safety.
AREAS COVERED IN THIS REVIEW: The paper provides information on the
phamacodynamic and pharmacokinetic properties of ospemifene. It also contains an
overview of its preclinical and clinical efficacy as well as its clinical
safety.
WHAT THE READER WILL GAIN: From this paper, the reader will gain an appreciation
for a new non-hormonal estrogen receptor agonist/antagonist, ospemifene.
TAKE HOME MESSAGE: The pharmacologic properties of ospemifene make it a logical
candidate for the treatment of women with moderate to severe symptoms of VVA
associated with menopause. Clinical trials have confirmed that daily doses are
well-tolerated and that it is effective in normalizing vaginal maturation index
and pH as well as improving the symptoms associated with VVA including
dyspareunia.
DOI: 10.1517/17425255.2010.487483
PMID: 20429673 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23256674 | 1. Expert Rev Proteomics. 2012 Dec;9(6):635-48. doi: 10.1586/epr.12.61.
Deciphering the single-cell omic: innovative application for translational
medicine.
Mannello F(1), Ligi D, Magnani M.
Author information:
(1)Department of Biomolecular Sciences, Section of Clinical Biochemistry, Unit
of Cell Biology, University Carlo Bo, Via O Ubaldini 7, 61029 Urbino (PU),
Italy. [email protected]
Traditional technologies to investigate system biology are limited by the
detection of parameters resulting from the averages of large populations of
cells, missing cells produced in small numbers, and attempting to uniform the
heterogeneity. The advent of proteomics and genomics at a single-cell level has
set the basis for an outstanding improvement in analytical technology and data
acquisition. It has been well demonstrated that cellular heterogeneity is
closely related to numerous stochastic transcriptional events leading to
variations in patterns of expression among single genetically identical cells.
The new-generation technology of single-cell analysis is able to better
characterize a cell's population, identifying and differentiating outlier cells,
in order to provide both a single-cell experiment and a corresponding bulk
measurement, through the identification, quantification and characterization of
all system biology aspects (genomics, transcriptomics, proteomics, metabolomics,
degradomics and fluxomics). The movement of omics into single-cell analysis
represents a significant and outstanding shift.
DOI: 10.1586/epr.12.61
PMID: 23256674 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23030284 | 1. Expert Rev Cardiovasc Ther. 2012 Aug;10(8):965-72. doi: 10.1586/erc.12.91.
Rivaroxaban for stroke prevention in atrial fibrillation: a critical review of
the ROCKET AF trial.
Paikin JS(1), Manolakos JJ, Eikelboom JW.
Author information:
(1)Division of Cardiology, Hamilton General Hospital, McMaster University, 237
Barton St E, Hamilton, ON, L8L 2X2, Canada. [email protected]
Oral anticoagulation is the mainstay of therapy for stroke prevention in
patients with atrial fibrillation (AF). Vitamin K antagonists such as warfarin
have many drawbacks that reduce their uptake, safety and effectiveness. The
ROCKET AF trial compared rivaroxaban (20 mg/day; 15 mg/day in patients with
creatinine clearance 30-49 ml/min) with dose-adjusted warfarin (international
normalized ratio 2-3) in 14,264 patients with AF and a prior history of stroke
or at least two other additional risk factors for stroke. The ROCKET AF trial
demonstrated the noninferiority of rivaroxaban compared with warfarin for the
prevention of stroke and systemic embolism, with a similar rate of major
bleeding and a substantial reduction in intracranial hemorrhage. These results,
in conjunction with its convenient once-daily dosing regimen, make rivaroxaban
an attractive alternative to warfarin for stroke prevention in AF.
DOI: 10.1586/erc.12.91
PMID: 23030284 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21514945 | 1. Rev Neurol (Paris). 2011 Nov;167(11):841-6. doi: 10.1016/j.neurol.2011.01.016.
Epub 2011 Apr 22.
[An evaluation of fatigue in patients with glioblastoma relapse treated with the
combination of irinotecan-bevacizumab].
[Article in French]
Dehais C(1), Souvannavong V, Nguyen BK, Jouniaux-Delbez N, Golmard JL, Tadrist
C, Liou A, Delattre JY.
Author information:
(1)Service de Neurologie Mazarin, Groupe Hospitalier Pitié-Salpêtrière, AP-HP,
47-83, Boulevard de l'Hôpital, 75651 Paris cedex 13, France.
[email protected]
OBJECTIVE: The combination of irinotecan-bevacizumab is effective in patients
with glioblastoma relapse but fatigue is a commonly reported side effect. The
objective of this study was to evaluate the level and evolution of fatigue in a
series of patients treated with therapeutic combination.
PATIENTS AND METHODS: We used two self-evaluation tools to quantify the physical
and emotional aspects of this fatigue. The Norris Visual Analog Scale (VAS
Norris) and the Multidimensional Fatigue Inventory-20 (MFI) tools were
undertaken by 39 patients with glioblastoma relapse treated with
irinotecan-bevacizumab, initially before the first cycle and thereafter with
each cycle up until tumor progression.
RESULTS: Analysis of the results of the VAS Norris scale did not demonstrate an
increase in emotional fatigue but did show an increase in physical fatigue that
did not reach statistical significance. With regards to the MFI 20 tool,
analysis of the results demonstrated a significant increase in general
(P=0.0260) as well as physical (P=0.0141) fatigue but there was no difference in
the other indices.
CONCLUSION: This study demonstrated a progressive increase in physical fatigue
in patients with glioblastoma relapse treated with irinotecan-bevacizumab. We
suspect that this is as a direct consequence of the treatment. There are however
other confounding factors: insidious tumour progression not detected on
follow-up imaging or delayed side effects of the initial
radiotherapy-chemotherapy.
Copyright © 2011 Elsevier Masson SAS. All rights reserved.
DOI: 10.1016/j.neurol.2011.01.016
PMID: 21514945 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19534676 | 1. Med Chem. 2009 Nov;5(6):507-16. doi: 10.2174/157340609790170542.
2-Arylbenzimidazoles as antiviral and antiproliferative agents--Part 2.
Vitale G(1), Corona P, Loriga M, Carta A, Paglietti G, La Colla P, Busonera B,
Marongiu E, Collu D, Loddo R.
Author information:
(1)Dipartimento Farmaco Chimico Tossicologico, University of Sassari, Via
Muroni, 23-07100 Sassari, Italy.
In prosecution of an anti-Flaviviridae project a new series of variously
substituted 2-diphenyl-benzimidazoles were synthesized and tested in vitro for
antiviral and antiproliferative activities. Compounds were tested in cell-based
assays against viruses representative of: i) two of the three genera of the
Flaviviridae family, i.e. Flaviviruses and Pestiviruses; ii) other RNA virus
families, such as Retroviridae, Picornaviridae, Paramyxoviridae, Rhabdoviridae
and Reoviridae; iii) two DNA virus families (Herpesviridae and Poxviridae). The
5-Acetyl-2-(4'-nitrobiphenyl-4-yl)-1H-benzimidazole (24) emerged as potent
active lead compound against Yellow Fever Virus (a Flavivirus) (EC(50) = 0.5
microM) and CVB-2 at 1 microM and was not cytotoxic, whereas the other title
benzimidazoles showed no antiviral activity at concentrations not cytotoxic for
the resting cell monolayers. Among the examined series, the most cytotoxic
derivatives (11,12,14,16,18,19,20,21,23,25-30) against mock-infected MT-4 cells
(CC50 < 8.0 microM) were evaluated against a panel of human cell lines derived
from haematological and solid tumours,using 6-mercaptopurine (6-MP) and
etoposide as reference drugs. In particular, compounds 26 and 28 showed a
similar potency of 6-MP and etoposide.
DOI: 10.2174/157340609790170542
PMID: 19534676 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23361170 | 1. Menopause. 2013 Jun;20(6):623-30. doi: 10.1097/gme.0b013e318279ba64.
Ospemifene, a novel selective estrogen receptor modulator for treating
dyspareunia associated with postmenopausal vulvar and vaginal atrophy.
Portman DJ(1), Bachmann GA, Simon JA; Ospemifene Study Group.
Collaborators: Williams J, Kirstein J, Patton W, Eder S, Pack E, Abdelsayed N,
Mabey RG Jr, Lederman S, Beavins J, Schnecker JR, Stavoy T, Donovan A, Eubank C,
Luciano A, Rosen J, Johnson B, Moyer G, Hrozenzik D, Portman DJ, Ackerman R,
Michelson J, Walland D, Samuel D, Strafford J, Cooper T, Hammond S, Parker R Jr,
Koltun W, Elliott S, Lefebvre G, Blank S, Burigo J, Seidman L, Levine B,
Nattrass S, Funk S, Marx P, Noss M, Jennings W, Roller R, Smith R, Morgan F Jr,
Rice J, Zedler P, Aqua K, Bhiwandi P, Portnoy E, Lowder KB, Swanson S,
Goldfischer E, Beyerlein R, Clary BB 3rd, Hedrick R Jr, Sager N, Corder C, Young
P, Seid M, Yankaskas M, Waldbaum A, Redrick S, Hardy R.
Author information:
(1)Columbus Center for Women's Health Research, Columbus, OH 43213, USA.
[email protected]
Comment in
Menopause. 2013 Jun;20(6):596-7. doi: 10.1097/GME.0b013e318291ef83.
OBJECTIVE: The aim of this work was to study the role of ospemifene, a novel
selective estrogen receptor modulator, in the treatment of vulvar and vaginal
atrophy in postmenopausal women with moderate to severe dyspareunia and
physiological vaginal changes.
METHODS: This multicenter phase 3 study used a randomized, double-blind,
parallel-group design to compare the efficacy, safety, and tolerability of oral
ospemifene 60 mg/day versus placebo. A total of 605 women aged 40 to 80 years
who self-reported a most bothersome symptom of dyspareunia and had a diagnosis
of vulvar and vaginal atrophy were randomized to take a once-daily dose of
ospemifene (n = 303) or placebo (n = 302) for 12 weeks.
RESULTS: Analysis of the intent-to-treat (n = 605) population found the efficacy
of ospemifene to be significantly greater than that of placebo for each of the
following coprimary endpoints: percentages of parabasal and superficial cells,
vaginal pH, and severity of dyspareunia. With ospemifene, the percentage of
parabasal cells and vaginal pH significantly decreased; the percentage of
superficial cells significantly increased; and dyspareunia was significantly
reduced versus placebo (all P < 0.0001, except for dyspareunia: P = 0.0001).
Among the randomized women, 186 (61.4%) in the ospemifene group and 154 (51.0%)
in the placebo group reported at least one treatment-emergent adverse event. Hot
flushes were the most frequently reported treatment-related adverse event
(ospemifene 6.6% vs placebo 3.6%); only one participant discontinued in each
group. As determined by the investigators, no serious adverse events related to
the study drug were reported.
CONCLUSIONS: In this study, once-daily oral ospemifene 60 mg was effective for
the treatment of vulvar and vaginal atrophy in postmenopausal women with
dyspareunia.
DOI: 10.1097/gme.0b013e318279ba64
PMID: 23361170 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20013782 | 1. Proteomics. 2010 Jan;10(1):6-22. doi: 10.1002/pmic.200900352.
Dynamics of the Dictyostelium discoideum mitochondrial proteome during
vegetative growth, starvation and early stages of development.
Czarna M(1), Mathy G, Mac'Cord A, Dobson R, Jarmuszkiewicz W, Sluse-Goffart CM,
Leprince P, De Pauw E, Sluse FE.
Author information:
(1)Laboratory of Bioenergetics and Cellular Physiology, University of Liege,
Belgium.
In this study, a quantitative comparative proteomics approach has been used to
analyze the Dictyostelium discoideum mitochondrial proteome variations during
vegetative growth, starvation and the early stages of development. Application
of 2-D DIGE technology allowed the detection of around 2000 protein spots on
each 2-D gel with 180 proteins exhibiting significant changes in their
expression level. In total, 96 proteins (51 unique and 45 redundant) were
unambiguously identified. We show that the D. discoideum mitochondrial proteome
adaptations mainly affect energy metabolism enzymes (the Krebs cycle,
anaplerotic pathways, the oxidative phosphorylation system and energy
dissipation), proteins involved in developmental and signaling processes as well
as in protein biosynthesis and fate. The most striking observations were the
opposite regulation of expression of citrate synthase and aconitase and the very
large variation in the expression of the alternative oxidase that highlighted
the importance of citrate and alternative oxidase in the physiology of the
development of D. discoideum. Mitochondrial energy states measured in vivo with
MitoTracker Orange CM Ros showed an increase in mitochondrial membrane
polarization during D. discoideum starvation and starvation-induced development.
DOI: 10.1002/pmic.200900352
PMID: 20013782 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23385700 | 1. Continuum (Minneap Minn). 2013 Feb;19(1 Sleep Disorders):170-84. doi:
10.1212/01.CON.0000427207.13553.68.
Sleep-related movement disorders.
Silber MH(1).
Author information:
(1)Mayo Clinic, Department of Neurology, 200 1st Street SW, Rochester, MN 55905,
USA. [email protected]
PURPOSE OF REVIEW: This article reviews the sleep-related movement disorders,
including restless legs syndrome (RLS; Willis-Ekbom disease), periodic limb
movement disorder, rhythmic movement disorders, sleep-related bruxism, and
sleep-related leg cramps.
RECENT FINDINGS: The prevalence of clinically significant RLS is 1.5% to 3.0%.
The pathophysiology of RLS may involve abnormal iron transport across the
blood-brain barrier and down-regulation of putaminal D2 receptors. The
availability of the rotigotine patch provides an additional form of dopaminergic
therapy for RLS. Calcium channel alpha-2-delta ligands (gabapentin, gabapentin
enacarbil, and pregabalin) provide alternative therapies for RLS especially in
patients with augmentation, impulse control disorders, or hypersomnia induced by
dopamine agonists. Long-term use of opioid medication is safe and effective for
refractory cases of RLS.
SUMMARY: RLS is a common disorder causing considerable morbidity. Accurate
diagnosis and appropriate investigations are essential. Many effective therapies
are available, but the side effects of each class of medication should be
considered in determining optimal treatment. Periodic limb movements of sleep,
bruxism, and rhythmic movement disorders are sleep-related phenomena often
accompanying other sleep disorders and only sometimes requiring primary therapy.
Sleep-related leg cramps are generally idiopathic. Management is challenging
with few effective therapies.
DOI: 10.1212/01.CON.0000427207.13553.68
PMID: 23385700 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18285831 | 1. Eur J Hum Genet. 2008 Jul;16(7):833-40. doi: 10.1038/ejhg.2008.18. Epub 2008
Feb 20.
Mapping of a Hirschsprung's disease locus in 3p21.
Garcia-Barceló MM(1), Fong PY, Tang CS, Miao XP, So MT, Yuan ZW, Li L, Guo WH,
Liu L, Wang B, Sun XB, Huang LM, Tou JF, Wong KK, Ngan ES, Lui VC, Cherny SS,
Sham PC, Tam PK.
Author information:
(1)Department of Surgery, Queen Mary Hospital, Li Ka Shing Faculty of Medicine,
University of Hong Kong, Hong Kong SAR, China. [email protected]
Hirschsprung's disease (HSCR) is a congenital disorder in which ganglion cells
are absent in variable portions of the lower digestive tract according to which
patients are classified. The RET gene is the major HSCR gene, although reduced
penetrance of RET mutations and variable expression of HSCR phenotype indicates
that more than one gene is required. An unidentified RET-dependent modifier on
3p21 appears to be necessary for transmission of the short HSCR (S-HSCR)
phenotype. We investigated 6 Mb of the 3p21 region on a quest for the
HSCR-susceptibility locus. Fifty-eight S-HSCR case-parent trios were genotyped
using Sequenom technology for 214 tag single nucleotide polymorphisms (SNPs)
distributed along 6 Mb of the 3p21 region. A five-marker haplotype, spanning a
118 kb gene-rich region, was found to be overtransmitted to affected offspring.
The associated haplotype encompasses three genes involved in neurological
phenotypes. Importantly, this association was replicated in an independent
sample of 172 S-HSCR cases and 153 unrelated controls. Ranking markers by
proximity to candidate genes or by expected functional consequences could be
used in follow-up studies to finally pinpoint this HSCR locus.
DOI: 10.1038/ejhg.2008.18
PMID: 18285831 [Indexed for MEDLINE] |