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What is the target of Sotorasib?

Sotorasib is a KRASG12C inhibitor.

Author information: (1)From the Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, University of Texas M.D. Anderson Cancer Center, Houston (D.S.H., F.M.-B.); the Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte (M.G.F.), the University of California, San Francisco, San Francisco (P.N.M.), and Amgen, Thousand Oaks (H.H., J.N., G.N., J.K., B.E.H., J.C., J.R.L., G.F.) - all in California; Duke University Medical Center, Durham, NC (J.H.S.); Royal Melbourne Hospital/Peter MacCallum Cancer Centre, Melbourne, VIC (J.D.), Queen Elizabeth Hospital and University of Adelaide, Woodville South, SA (T.J.P.), and Scientia Clinical Research, Randwick, NSW (J.C. Kuo) - all in Australia; the Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis (G.A.D.); Dana-Farber Cancer Institute, Harvard Medical School, Boston (G.I.S.); the Sarah Cannon Research Institute at HealthONE, Denver (G.S.F.); Princess Margaret Cancer Centre, University Health Network, Toronto (A.S.); Fox Chase Cancer Center, Philadelphia (C.S.D.); the University of Pittsburgh Medical Center Hillman Cancer Center, University of Pittsburgh, Pittsburgh (T.F.B.); Seoul National University College of Medicine (Y.-J.B.), Samsung Medical Center, Sungkyunkwan University School of Medicine (K.P.), and the Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine (T.W.K.) - all in Seoul, South Korea; Roswell Park Cancer Institute, Buffalo (G.K.D.), and Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York (P.L., B.T.L.) - all in New York; the University of Michigan, Ann Arbor (J.C. Krauss); the Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan (Y.K.); the Department of Medicine, Division of Oncology, University of Washington, Seattle (A.L.C.); Aix Marseille University, Centre National de la Recherche Scientifique, INSERM, Centre de Recherche en Cancérologie de Marseille, Assistance Publique-Hôpitaux de Marseille, Marseille, France (F.B.); Winship Cancer Institute of Emory University, Atlanta (S.S.R.); and the Alvin J. Siteman Cancer Center at Washington University School of Medicine, St. Louis (R.G.). Evidence continues to grow that KRAS, once considered an "undruggable" target, can be targeted successfully in non-small cell lung cancer. In a phase I trial, the KRASG12C inhibitor sotorasib elicited responses in about a third of patients with the disease and was generally well tolerated. KRAS is one of the most common human oncogenes, but concerted efforts to produce direct inhibitors have largely failed, earning KRAS the title of "undruggable". Recent efforts to produce subtype specific inhibitors have been more successful, and several KRASG12C inhibitors have reached clinical trials, including adagrasib and sotorasib, which have shown early evidence of efficacy in patients. Lessons from other inhibitors of the RAS pathway suggest that the effect of these drugs will be limited in vivo by the development of drug resistance, and pre-clinical studies of G12C inhibitors have identified evidence of this. In this review we discuss the current evidence for G12C inhibitors, the mechanisms of resistance to G12C inhibitors and potential approaches to overcome them. We discuss possible targets of combination therapy, including SHP2, receptor tyrosine kinases, downstream effectors and PD1/PDL1, and review the ongoing clinical trials investigating these inhibitors. INTRODUCTION: KRAS mutations have been recognized as undruggable for many years. Recently, novel KRAS G12C inhibitors, such as sotorasib and adagrasib, are being developed in clinical trials and have revealed promising results in metastatic NSCLC. Nevertheless, it is strongly anticipated that acquired resistance will limit their clinical use. In this study, we developed in vitro models of the KRAS G12C cancer, derived from resistant clones against sotorasib and adagrasib, and searched for secondary KRAS mutations as on-target resistance mechanisms to develop possible strategies to overcome such resistance. METHODS: We chronically exposed Ba/F3 cells transduced with KRASG12C to sotorasib or adagrasib in the presence of N-ethyl-N-nitrosourea and searched for secondary KRAS mutations. Strategies to overcome resistance were also investigated. RESULTS: We generated 142 Ba/F3 clones resistant to either sotorasib or adagrasib, of which 124 (87%) harbored secondary KRAS mutations. There were 12 different secondary KRAS mutations. Y96D and Y96S were resistant to both inhibitors. A combination of novel SOS1 inhibitor, BI-3406, and trametinib had potent activity against this resistance. Although G13D, R68M, A59S and A59T, which were highly resistant to sotorasib, remained sensitive to adagrasib, Q99L was resistant to adagrasib but sensitive to sotorasib. CONCLUSIONS: We identified many secondary KRAS mutations causing resistance to sotorasib, adagrasib, or both, in vitro. The differential activities of these two inhibitors depending on the secondary mutations suggest sequential use in some cases. In addition, switching to BI-3406 plus trametinib might be a useful strategy to overcome acquired resistance owing to the secondary Y96D and Y96S mutations. Sotorasib is a first-in class KRASG12C covalent inhibitor in clinical development for the treatment of tumors with the KRAS p.G12C mutation. In the nonclinical toxicology studies of sotorasib, the kidney was identified as a target organ of toxicity in the rat but not the dog. Renal toxicity was characterized by degeneration and necrosis of the proximal tubular epithelium localized to the outer stripe of the outer medulla (OSOM), which suggested that renal metabolism was involved. Here, we describe an in vivo mechanistic rat study designed to investigate the time course of the renal toxicity and sotorasib metabolites. Renal toxicity was dose- and time-dependent, restricted to the OSOM, and the morphologic features progressed from vacuolation and necrosis to regeneration of tubular epithelium. The renal toxicity correlated with increases in renal biomarkers of tubular injury. Using mass spectrometry and matrix-assisted laser desorption/ionization, a strong temporal and spatial association between renal toxicity and mercapturate pathway metabolites was observed. The rat is reported to be particularly susceptible to the formation of nephrotoxic metabolites via this pathway. Taken together, the data presented here and the literature support the hypothesis that sotorasib-related renal toxicity is mediated by a toxic metabolite derived from the mercapturate and β-lyase pathway. Our understanding of the etiology of the rat specific renal toxicity informs the translational risk assessment for patients. Sotorasib is a first-in-class KRASG12C covalent inhibitor in clinical development for the treatment of tumors with the KRAS p.G12C mutation. A comprehensive nonclinical safety assessment package, including secondary/safety pharmacology and toxicology studies, was conducted to support the marketing application for sotorasib. Sotorasib was negative in a battery of genotoxicity assays and negative in an in vitro phototoxicity assay. Based on in vitro assays, sotorasib had no off-target effects against various receptors, enzymes (including numerous kinases), ion channels, or transporters. Consistent with the tumor-specific target distribution (ie, KRASG12C), there were no primary pharmacology-related on-target effects identified. The kidney was identified as a target organ in the rat but not the dog. Renal toxicity in the rat was characterized by tubular degeneration and necrosis restricted to a specific region suggesting that the toxicity was attributed to the local formation of a putative toxic reactive metabolite. In the 3-month dog study, adaptive changes of hepatocellular hypertrophy due to drug metabolizing enzyme induction were observed in the liver that was associated with secondary effects in the pituitary and thyroid gland. Sotorasib was not teratogenic and had no direct effect on embryo-fetal development in the rat or rabbit. Human, dog, and rat circulating metabolites, M24, M10, and M18, raised no clinically relevant safety concerns based on the general toxicology studies, primary/secondary pharmacology screening, an in vitro human ether-à-go-go-related gene assay, or mutagenicity assessment. Overall, the results of the nonclinical safety program support a high benefit/risk ratio of sotorasib for the treatment of patients with KRAS p.G12C-mutated tumors. The FDA has approved the first KRAS-targeted therapy, sotorasib, for patients with previously treated non-small cell lung cancer with KRASG12C mutations. In a phase II trial, the drug yielded a median progression-free survival of 6.8 months in patients whose disease had advanced despite treatment with standard therapies, namely platinum-based chemotherapy and PD-1-PD-L1 inhibitors. The HRAS, NRAS, and KRAS genes are collectively mutated in a fifth of all human cancers. These mutations render RAS GTP-bound and active, constitutively binding effector proteins to promote signaling conducive to tumorigenic growth. To further elucidate how RAS oncoproteins signal, we mined RAS interactomes for potential vulnerabilities. Here we identify EFR3A, an adapter protein for the phosphatidylinositol kinase PI4KA, to preferentially bind oncogenic KRAS. Disrupting EFR3A or PI4KA reduces phosphatidylinositol-4-phosphate, phosphatidylserine, and KRAS levels at the plasma membrane, as well as oncogenic signaling and tumorigenesis, phenotypes rescued by tethering PI4KA to the plasma membrane. Finally, we show that a selective PI4KA inhibitor augments the antineoplastic activity of the KRASG12C inhibitor sotorasib, suggesting a clinical path to exploit this pathway. In sum, we have discovered a distinct KRAS signaling axis with actionable therapeutic potential for the treatment of KRAS-mutant cancers. Kirsten rat sarcoma virus oncogene (KRAS) mutation accounts for approximately 85% of RAS-driven cancers, and participates in multiple signaling pathways and mediates cell proliferation, differentiation and metabolism. KRAS has been considered as an "undruggable" target due to the lack of effective direct inhibitors, although high frequency of KRAS mutations have been identified in multiple carcinomas in the past decades. Encouragingly, the KRASG12C inhibitor AMG510 (sotorasib), which has been approved for treating NSCLC and CRC recently, makes directly targeting KRAS the most promising strategy for cancer therapy. To better understand the current state of KRAS inhibitors, this review summarizes the biological functions of KRAS, the structure-activity relationship studies of the small-molecule inhibitors that directly target KRAS, and highlights the therapeutic agents with improved selectivity, bioavailability and physicochemical properties. Furthermore, the combined medication that can enhance efficacy and overcome drug resistance of KRAS covalent inhibitors is also reviewed. Publisher: IMMUNONKOLOGISCHE MONOTHERAPIE DES NICHTKLEINZELLIGEN LUNGENKARZINOMS:  5-Jahres-Überlebensdaten der KEYNOTE-024-Studie bestätigen die anhaltende Wirksamkeit einer immunonkologischen Monotherapie bei Patienten mit nichtkleinzelligem Lungenkarzinom (NSCLC) mit hoher PD-L1-Expression (≥ 50 %). DUALE IMMUNTHERAPIE IN KOMBINATION MIT CHEMOTHERAPIE ALS ERSTLINIENTHERAPIE DES NICHTKLEINZELLIGEN LUNGENKARZINOMS:  Nivolumab plus Impilimumab in Kombination mit 2 Zyklen platinhaltiger Chemotherapie verbessern das Überleben von NSCLC-Patienten. NEUE TARGETS UND THERAPIEOPTIONEN:  Entrectinib und Larotrectinib mit Wirksamkeit bei NTRK-Fusions-positivem NSCLC. Selpercatinib und Pralsetinib mit Wirksamkeit bei RET-Fusions-positivem NSCLC. Mobocertinib mit Wirksamkeit bei EGFRex20ins-Mutation des EGFR-Gens. Sotorasib mit Wirksamkeit bei kRAS-G12C-Mutation des NSCLC. NATIONALES NETZWERK GENOMISCHE MEDIZIN LUNGENKREBS: Das bundesweite Nationale Netzwerk Genomische Medizin Lungenkrebs (nNGM) ermöglicht NSCLC-Patienten den Zugang zu modernster molekularer Diagnostik und neuesten Therapieoptionen. KRAS genes belong to the most frequently mutated family of oncogenes in cancer. The G12C mutation, found in a third of lung, half of colorectal and pancreatic cancer cases, is believed to be responsible for a substantial number of cancer deaths. For 30 years, KRAS has been the subject of extensive drug-targeting efforts aimed at targeting KRAS protein itself, but also its post-translational modifications, membrane localization, protein-protein interactions and downstream signalling pathways. So far, most KRAS targeting strategies have failed, and there are no KRAS-specific drugs available. However, clinical candidates targeting the KRAS G12C protein have recently been developed. MRTX849 and recently approved Sotorasib are covalent binders targeting the mutated cysteine 12, occupying Switch II pocket.Herein, we describe two fragment screening drug discovery campaigns that led to the identification of binding pockets on the KRAS G12C surface that have not previously been described. One screen focused on non-covalent binders to KRAS G12C, the other on covalent binders. Across a broad range of human cancers, gain-of-function mutations in RAS genes (HRAS, NRAS, and KRAS) lead to constitutive activity of oncoproteins responsible for tumorigenesis and cancer progression. The targeting of RAS with drugs is challenging because RAS lacks classic and tractable drug binding sites. Over the past 30 years, this perception has led to the pursuit of indirect routes for targeting RAS expression, processing, upstream regulators, or downstream effectors. After the discovery that the KRAS-G12C variant contains a druggable pocket below the switch-II loop region, it has become possible to design irreversible covalent inhibitors for the variant with improved potency, selectivity and bioavailability. Two such inhibitors, sotorasib (AMG 510) and adagrasib (MRTX849), were recently evaluated in phase I-III trials for the treatment of non-small cell lung cancer with KRAS-G12C mutations, heralding a new era of precision oncology. In this review, we outline the mutations and functions of KRAS in human tumors and then analyze indirect and direct approaches to shut down the oncogenic KRAS network. Specifically, we discuss the mechanistic principles, clinical features, and strategies for overcoming primary or secondary resistance to KRAS-G12C blockade. In phase I/II KRYSTAL-1 trial, the KRASG12C inhibitor adagrasib demonstrated encouraging clinical activity against metastatic colorectal cancer, both as a monotherapy and when combined with the EGFR inhibitor cetuximab. In patients who received adagrasib alone, the disease control rate was 87% and progression-free survival was 5.6 months. Among patients who received the drug combination, the disease control rate was 100%; data on progression-free survival were immature. The findings, along with data on the KRASG12C inhibitor sotorasib, were presented at the 2021 European Society for Medical Oncology Congress. Mutations in codon 12 of KRAS have been identified in 13% of non-small cell lung cancer patients. Developing targeted therapies against KRASG12C mutation has proven to be challenging due to the abundance of GTP in the cytoplasm, rapid hydrolysis of GTP, and difficulty designing small molecules to achieve sufficient concentration for KRAS inhibition. Based on promising results in both preclinical and clinical trials, sotorasib, a novel KRASG12C inhibitor, was given conditional approval by the FDA in May 2021. The Phase I portion of the clinical trial produced 32% confirmed response with 56% of patients with stable disease. About 91.2% of patients who received the highest dose of 960mg daily achieved disease control. The Phase II portion, which used 960mg daily dosing resulted in 37.1% of patients with confirmed response and 80.6% of patients with disease control. Both phase I and phase II had similar progression-free survival, in 6.3 months and 6.8 months, respectively. In both phases, grade 4 adverse events occurred in only one patient. The most common adverse events were elevations in LFTs, which down-trended upon dose reduction and steroid treatment. While the conditional approval of sotorasib was a major breakthrough for those patients harboring KRASG12C mutations, resistance mutations to sotorasib are increasingly common. Many proposals have been made to address this, such as the use of combination therapy for synthetic lethality, which are producing encouraging results. Here, we explore in further detail the development of sotorasib, its efficacy, mechanism of resistance, and strategies to overcome these resistances. Cancer is the leading cause of death worldwide, and its treatment and outcomes have been dramatically revolutionised by targeted therapies. As the most frequently mutated oncogene, Kirsten rat sarcoma viral oncogene homologue (KRAS) has attracted substantial attention. The understanding of KRAS is constantly being updated by numerous studies on KRAS in the initiation and progression of cancer diseases. However, KRAS has been deemed a challenging therapeutic target, even "undruggable", after drug-targeting efforts over the past four decades. Recently, there have been surprising advances in directly targeted drugs for KRAS, especially in KRAS (G12C) inhibitors, such as AMG510 (sotorasib) and MRTX849 (adagrasib), which have obtained encouraging results in clinical trials. Excitingly, AMG510 was the first drug-targeting KRAS (G12C) to be approved for clinical use this year. This review summarises the most recent understanding of fundamental aspects of KRAS, the relationship between the KRAS mutations and tumour immune evasion, and new progress in targeting KRAS, particularly KRAS (G12C). Moreover, the possible mechanisms of resistance to KRAS (G12C) inhibitors and possible combination therapies are summarised, with a view to providing the best regimen for individualised treatment with KRAS (G12C) inhibitors and achieving truly precise treatment. RAS is the most frequently mutated oncogene in human cancer. Scientists attempted for decades to target this protein or its pathways, however, all the attempts failed and RAS was labeled as "undruggable". With KRAS-G12C covalent inhibitors entering clinical trials, the myth of this "undruggable" RAS is fading away. In 2021, the Food and Drug Administration (FDA) approved the use of Sotorasib (Lumakras) for the treatment of adult patients with KRAS-G12C mutated locally advanced or metastatic NSCLC, following at least one prior systemic therapy. However, and as every other drug, KRAS-G12C inhibitors are facing intrinsic and acquired resistances. In order to overcome these resistances, researchers are now working on combination strategies. Furthermore, studies are currently ongoing to better elucidate the status of KRAS-G12C as a predictive and prognostic tool and to strengthen its role in the field of personalized medicine.

Is ASF1 phopshorylated by the Tousled-like kinases?

Yes, Asf1, a key histone H3-H4 chaperone required for this process, is phosphorylated by Tousled-like kinases (TLKs).

BACKGROUND: The Tousled Like Kinases (TLKs) are involved in chromatin dynamics, including DNA replication and repair, transcription, and chromosome segregation. Indeed, the first two TLK1 substrates were identified as the histone H3 and Asf1 (a histone H3/H4 chaperone), which immediately suggested a function in chromatin remodeling. However, despite the straightforward assumption that TLK1 acts simply by phosphorylating its substrates and hence modifying their activity, TLK1 also acts as a chaperone. In fact, a kinase-dead (KD) mutant of TLK1B is functional in stimulating chromatin assembly in vitro. However, subtle effects of Asf1 phosphorylation are more difficult to probe in chromatin assembly assays. Not until very recently was the Asf1 site phosphorylated by TLK1 identified. This has allowed for probing directly the functionality of a site-directed mutant of Asf1 in chromatin assembly assays. FINDINGS: Addition of either wt or non-phosphorylatable mutant Asf1 to nuclear extract stimulates chromatin assembly on a plasmid. Similarly, TLK1B-KD stimulates chromatin assembly and it synergizes in reactions with supplemental Asf1 (wt or non-phosphorylatable mutant). CONCLUSIONS: Although the actual function of TLKs as mediators of Asf1 activity cannot be easily studied in vivo, particularly since in mammalian cells there are two TLK genes and two Asf1 genes, we were able to study specifically the stimulation of chromatin assembly in vitro. In such assays, clearly the TLK1 kinase activity was not critical, as neither a non-phosphorylatable Asf1 nor use of the TLK1B-KD impaired the stimulation of nucleosome formation. The Tousled-like kinases (TLKs) function in processes of chromatin assembly, including replication, transcription, repair, and chromosome segregation. TLKs interact specifically (and phosphorylate) with the chromatin assembly factor Asf1, a histone H3-H4 chaperone, histone H3 itself at Ser10, and also Rad9, a key protein involved in DNA repair and cell cycle signaling following DNA damage. These interactions are believed to be responsible for the action of TLKs in double-stranded break repair and radioprotection and also in the propagation of the DNA damage response. Hence, I propose that TLKs play key roles in maintece of genome integrity in many organisms of both kingdoms. In this paper, I highlight key issues of the known roles of these proteins, particularly in the context of DNA repair (IR and UV), their possible relevance to genome integrity and cancer development, and as possible targets for intervention in cancer management. During DNA replication, nucleosomes are rapidly assembled on newly synthesized DNA to restore chromatin organization. Asf1, a key histone H3-H4 chaperone required for this process, is phosphorylated by Tousled-like kinases (TLKs). Here, we identify TLK phosphorylation sites by mass spectrometry and dissect how phosphorylation has an impact on human Asf1 function. The divergent C-terminal tail of Asf1a is phosphorylated at several sites, and this is required for timely progression through S phase. Consistent with this, biochemical analysis of wild-type and phospho-mimetic Asf1a shows that phosphorylation enhances binding to histones and the downstream chaperones CAF-1 and HIRA. Moreover, we find that TLK phosphorylation of Asf1a is induced in cells experiencing deficiency of new histones and that TLK interaction with Asf1a involves its histone-binding pocket. We thus propose that TLK signalling promotes histone supply in S phase by targeting histone-free Asf1 and stimulating its ability to shuttle histones to sites of chromatin assembly.

What is Luteolin?

Luteolin has been reviewed as a flavonoid possessing potential cardioprotective, anti-inflammatory, anti-cancer activities.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is an important member of the TNF superfamily with great potential in cancer therapy. Luteolin is a dietary flavonoid commonly found in some medicinal plants. Here we found that pretreatment with a noncytotoxic concentration of luteolin significantly sensitized TRAIL-induced apoptosis in both TRAIL-sensitive (HeLa) and TRAIL-resistant cancer cells (CNE1, HT29, and HepG2). Such sensitization is achieved through enhanced caspase-8 activation and caspase-3 maturation. Further, the protein level of X-linked inhibitor of apoptosis protein (XIAP) was markedly reduced in cells treated with luteolin and TRAIL, and ectopic expression of XIAP protected against cell death induced by luteolin and TRAIL, showing that luteolin sensitizes TRAIL-induced apoptosis through down-regulation of XIAP. In search of the molecular mechanism responsible for XIAP down-regulation, we found that luteolin and TRAIL promoted XIAP ubiquitination and proteasomal degradation. Next, we showed that protein kinase C (PKC) activation prevented cell death induced by luteolin and TRAIL via suppression of XIAP down-regulation. Moreover, luteolin inhibited PKC activity, and bisindolylmaleimide I, a general PKC inhibitor, simulated luteolin in sensitizing TRAIL-induced apoptosis. Taken together, these results present a novel anticancer effect of luteolin and support its potential application in cancer therapy in combination with TRAIL. In addition, our data reveal a new function of PKC in cell death: PKC activation stabilizes XIAP and thus suppresses TRAIL-induced apoptosis. Luteolin is a flavone which occurs in medicinal plants as well as in some vegetables and spices. It is a natural anti-oxidant with less pro-oxidant potential than the flavonol quercetin, the best studied flavonoid, but apparently with a better safety profile. It displays excellent radical scavenging and cytoprotective properties, especially when tested in complex biological systems where it can interact with other anti-oxidants like vitamins. Luteolin displays specific anti-inflammatory effects at micromolar concentrations which are only partly explained by its anti-oxidant capacities. The anti-inflammatory activity includes activation of anti-oxidative enzymes, suppression of the NFkappaB pathway and inhibition of pro-inflammatory substances. In vivo, luteolin reduced increased vascular permeability and was effective in animal models of inflammation after parenteral and oral application. Although luteolin is only a minor component in our nutrition (less than 1 mg/day) epidemiological studies indicate that it has the potential to protect from diseases associated with inflammatory processes such as cardiovascular disease. Luteolin often occurs in the form of glycosides in plants, but these are cleaved and the aglycones are conjugated and metabolized after nutritional uptake which has to be considered when evaluating in vitro studies. Some data for oral and topical bioavailability exist, but more quantitative research in this field is needed to evaluate the physiological and therapeutical potential of luteolin. BACKGROUND: Luteolin, a plant derived flavonoid, exerts a variety of pharmacological activities and anti-oxidant properties associated with its capacity to scavenge oxygen and nitrogen species. Luteolin also shows potent anti-inflammatory activities by inhibiting nuclear factor kappa B (NFkB) signaling in immune cells. To better understand the immuno-modulatory effects of this important flavonoid, we performed a genome-wide expression analysis in pro-inflammatory challenged microglia treated with luteolin and conducted a phenotypic and functional characterization. METHODS: Resting and LPS-activated BV-2 microglia were treated with luteolin in various concentrations and mRNA levels of pro-inflammatory markers were determined. DNA microarray experiments and bioinformatic data mining were performed to capture global transcriptomic changes following luteolin stimulation of microglia. Extensive qRT-PCR analyses were carried out for an independent confirmation of newly identified luteolin-regulated transcripts. The activation state of luteolin-treated microglia was assessed by morphological characterization. Microglia-mediated neurotoxicity was assessed by quantifying secreted nitric oxide levels and apoptosis of 661W photoreceptors cultured in microglia-conditioned medium. RESULTS: Luteolin dose-dependently suppressed pro-inflammatory marker expression in LPS-activated microglia and triggered global changes in the microglial transcriptome with more than 50 differentially expressed transcripts. Pro-inflammatory and pro-apoptotic gene expression was effectively blocked by luteolin. In contrast, mRNA levels of genes related to anti-oxidant metabolism, phagocytic uptake, ramification, and chemotaxis were significantly induced. Luteolin treatment had a major effect on microglial morphology leading to ramification of formerly amoeboid cells associated with the formation of long filopodia. When co-incubated with luteolin, LPS-activated microglia showed strongly reduced NO secretion and significantly decreased neurotoxicity on 661W photoreceptor cultures. CONCLUSIONS: Our findings confirm the inhibitory effects of luteolin on pro-inflammatory cytokine expression in microglia. Moreover, our transcriptomic data suggest that this flavonoid is a potent modulator of microglial activation and affects several signaling pathways leading to a unique phenotype with anti-inflammatory, anti-oxidative, and neuroprotective characteristics. With the identification of several novel luteolin-regulated genes, our findings provide a molecular basis to understand the versatile effects of luteolin on microglial homeostasis. The data also suggest that luteolin could be a promising candidate to develop immuno-modulatory and neuroprotective therapies for the treatment of neurodegenerative disorders. Acute lung injury (ALI), instilled by lipopolysaccharide (LPS), is a severe illness with excessive mortality and has no specific treatment strategy. Luteolin is an anti-inflammatory flavonoid and widely distributed in the plants. Pretreatment with luteolin inhibited LPS-induced histological changes of ALI and lung tissue edema. In addition, LPS-induced inflammatory responses, including increased vascular permeability, tumor necrosis factor (TNF)-α and interleukin (IL)-6 production, and expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), were also reduced by luteolin in a concentration-dependent manner. Furthermore, luteolin suppressed activation of NFκB and its upstream molecular factor, Akt. These results suggest that the protection mechanism of luteolin is by inhibition of NFκB activation possibly via Akt. Transthyretin (TTR) is a homotetrameric plasma protein with amyloidogenic properties that has been linked to the development of familial amyloidotic polyneuropathy (FAP), familial amyloidotic cardiomyopathy, and senile systemic amyloidosis. The in vivo role of TTR is associated with transport of thyroxine hormone T4 and retinol-binding protein. Loss of the tetrameric integrity of TTR is a rate-limiting step in the process of TTR amyloid formation, and ligands with the ability to bind within the thyroxin binding site (TBS) can stabilize the tetramer, a feature that is currently used as a therapeutic approach for FAP. Several different flavonoids have recently been identified that impair amyloid formation. The flavonoid luteolin shows therapeutic potential with low incidence of unwanted side effects. In this work, we show that luteolin effectively attenuates the cytotoxic response to TTR in cultured neuronal cells and rescues the phenotype of a Drosophila melanogaster model of FAP. The plant-derived luteolin analogue cynaroside has a glucoside group in position 7 of the flavone A-ring and as opposed to luteolin is unable to stabilize TTR tetramers and thus prevents a cytotoxic effect. We generated high-resolution crystal-structures of both TTR wild type and the amyloidogenic mutant V30M in complex with luteolin. The results show that the A-ring of luteolin, in contrast to what was previously suggested, is buried within the TBS, consequently explaining the lack of activity from cynaroside. The flavonoids represent an interesting group of drug candidates for TTR amyloidosis. The present investigation shows the potential of luteolin as a stabilizer of TTR in vivo. We also show an alternative orientation of luteolin within the TBS which could represent a general mode of binding of flavonoids to TTR and is of importance concerning the future design of tetramer stabilizing drugs. BACKGROUND: Inflammation of adipocytes has been a therapeutic target for treatment of obesity and metabolic disorders which cause insulin resistance and hence lead to type II diabetes. Luteolin is a bioflavonoid with many beneficial properties such as antioxidant, antiproliferative, and anti-cancer. OBJECTIVES: To elucidate the potential anti-inflammatory response and the underlying mechanism of luteolin in 3T3-L1 adipocytes. MATERIALS AND METHODS: We stimulated 3T3-L1 adipocytes with the mixture of tumor necrosis factor-α, lipopolysaccharide, and interferon-γ (TLI) in the presence or absence of luteolin. We performed Griess' method for nitric oxide (NO) production and measure mRNA and protein expressions by real-time polymerase chain reaction and western blotting, respectively. RESULTS: Luteolin opposed the stimulation of inducible nitric oxide synthase and NO production by simultaneous treatment of adipocytes with TLI. Furthermore, it reduced the pro-inflammatory genes such as cyclooxygenase-2, interleukin-6, resistin, and monocyte chemoattractant protein-1. Furthermore, luteolin improved the insulin sensitivity by enhancing the expression of insulin receptor substrates (IRS1/2) and glucose transporter-4 via phosphatidylinositol-3K signaling pathway. This inhibition was associated with suppression of Iκ-B-α degradation and subsequent inhibition of nuclear factor-κB (NF-κB) p65 translocation to the nucleus. In addition, luteolin blocked the phosphorylation of ERK1/2, c-Jun N-terminal Kinases and also p38 mitogen-activated protein kinases (MAPKs). CONCLUSIONS: These results illustrate that luteolin attenuates inflammatory responses in the adipocytes through suppression of NF-κB and MAPKs activation, and also improves insulin sensitivity in 3T3-L1 cells, suggesting that luteolin may represent a therapeutic agent to prevent obesity-associated inflammation and insulin resistance. Luteolin is a common dietary flavonoid present in Chinese herbal medicines that has been reported to have important anti-inflammatory properties. Previous studies have shown that luteolin is an anti-inflammatory and anti-oxidative agent. In this study, the anti-virus inflammatory capacity of luteolin and its molecular mechanisms of action were analyzed. The cytotoxic effects of luteolin were assessed in the presence or absence of pseudorabies virus (PRV) via LDH and MTT assays. The results showed that luteolin (<10μM) had no toxic effects and there were tendencies toward higher cell survival. In PRV-infected RAW264.7 cells, luteolin potently inhibited the production of NO, iNOS, COX-2 and inflammatory cytokine production. Luteolin did not inhibit the phosphorylation of ERK 1/2, p38, and JNK 1/2 either. We found that PRV-induced NF-κB activation is regulated through inhibition of STAT1and STAT3 phosphorylation in response to luteolin. Additionally, luteolin caused the induction of HO-1 via upregulation of Nrf2, both of which are involved in the secretion of proinflammatory mediators. The blockade of HO-1 expression with SnPP, a HO-1 inhibitor, attenuated HO-1 induction by luteolin and thus mitigated its anti-inflammatory effects during PRV-infected RAW264.7 cells. Taken together, our data indicate that luteolin diminishes the proinflammatory mediators NO, inflammatory cytokines and the expression of their regulatory genes, iNOS and COX-2, in PRV-infected RAW264.7 cells by inhibiting STAT1/3 dependent NF-κB activation and inducing Nrf2mediated HO-1 expression. Luteolin is a naturally occurring flavone that reportedly has anti-inflammatory effects. Because most luteolin is conjugated following intestinal absorption, free luteolin is likely present at low levels in the body. Therefore, luteolin metabolites are presumably responsible for luteolin bioactivity. Here we confirmed that luteolin glucuronides, especially luteolin-3'-O-glucuronide, are the major metabolites found in plasma after oral administration of luteolin (aglycone) or luteolin glucoside (luteolin-7-O-glucoside) to rats. Luteolin-4'-O-glucuronide and luteolin-7-O-glucuronide were also detectable together with luteolin-3'-O-glucuronide in the liver, kidney, and small intestine. Next, we prepared these luteolin glucuronides and compared the anti-inflammatory effects of luteolin and luteolin glucuronides on gene expression in lipopolysaccharide-treated RAW264.7 cells. Luteolin glucuronides, especially luteolin-7-O-glucuronide, reduced expression of inflammatory genes in the cells, although their effects were weaker than those of luteolin. These results indicate that the active compound responsible for the anti-inflammatory effect of luteolin in vivo would be luteolin glucuronide and/or residual luteolin. Glutamatergic excitotoxicity is crucial in the pathogenesis of numerous brain disorders. Luteolin, a flavonoid compound, inhibits glutamate release, however, its ability to affect glutamate-induced brain injury is unknown. Therefore, this study evaluated the protective effect of luteolin against brain damage induced by kainic acid (KA), a glutamate analog. Rats were treated with luteolin (10 or 50mg/kg, intraperitoneally) 30min before an intraperitoneal injection of KA (15mg/kg). Luteolin treatment reduced the KA-induced seizure score and elevations of glutamate levels in the hippocampus. A histopathological analysis showed that luteolin attenuated KA-induced neuronal death and microglial activation in the hippocampus. An immunoblotting analysis showed that luteolin restored the KA-induced reduction in Akt phosphorylation in the hippocampus. Furthermore, a Morris water maze test revealed that luteolin effectively prevented KA-induced learning and memory impairments. The results suggest that luteolin protected rat brains from KA-induced excitotoxic damage by reducing glutamate levels, mitigating inflammation, and enhancing Akt activation in the hippocampus. Therefore, luteolin may be beneficial for preventing or treating brain disorders associated with excitotoxic neuronal damage. Metastatic breast cancer is typically an extremely aggressive cancer with poor prognosis. Metastasis requires the orchestration of homeostatic factors and cellular programs, many of which are potential therapeutic targets. Luteolin (2-[3,4-dihydroxyphenyl]-5,7-dihydroxy-4-chromenone), is a naturally occurring flavonoid found in fruits and vegetables that exhibits many anticancer properties. Luteolin obstructs metastasis through both direct and indirect mechanisms. For instance, luteolin may suppress breast cancer invasion by acting as an antiangiogenic therapeutic inhibiting VEGF production and its receptor's activity. Furthermore, luteolin decreases epithelial-mesenchymal transition markers and metastatic proclivity. Luteolin also acts as an antiproliferative by suppressing receptor tyrosine-kinase activity and apoptosis, both of which could prevent incipient colonization of breast cancer. Many of these antimetastatic characteristics accredited to luteolin are likely functionally related. For instance, the PI3K/Akt pathway, which is impeded by luteolin, has several downstream programs involved in increased proliferation, survival, and metastatic potential in breast cancer. In this review, luteolin's ability to ameliorate breast cancer is summarized. The paper also offers insight into the molecular mechanisms by which luteolin may suppress breast cancer metastasis. Luteolin is a flavonoid present in plants in the form of aglycone or glucosides. In this study, luteolin glucosides (i.e., luteolin-7- O-β-d-glucoside, luteolin-7- O-[2-(β-d-apiosyl)-β-d-glucoside], and luteolin-7- O-[2-(β-d-apiosyl)-6-malonyl-β-d-glucoside]) prepared from green pepper leaves as well as luteolin aglycone were orally administered to rats. Regardless of the administered luteolin form, luteolin glucuronides were mainly detected from plasma and organs. Subsequently, luteolin aglycone, the most absorbed form of luteolin in rats, was orally administered to humans. As a result, luteolin-3'- O-sulfate was mainly identified from plasma, suggesting that not only luteolin form but also animal species affect the absorption and metabolism of luteolin. When LPS-treated RAW264.7 cells were treated with luteolin glucuronides and luteolin sulfate (the characteristic metabolites identified from rats and humans, respectively), the different luteolin conjugates were metabolized in different ways, suggesting that such difference in metabolism results in their difference in anti-inflammatory effects. BACKGROUND: Luteolin (3',4',5,7-tetrahydroxyflavone) is a flavone with a yellow crystalline appearance present in numerous plants such as broccoli, green chili, and carrot. Luteolin is considered to be an endocrine disruptor with potent estrogen agonist activity and potent progesterone antagonist activity. Luteolin has effects on smooth muscle. Luteolin relaxed guinea pig trachea smooth muscle as it inhibited both phosphodiesterase and reduced intracellular Ca2+. Luteolin also caused vasorelaxation in rat thoracic aorta smooth muscle by inhibiting intracellular Ca2+ release, inhibition of sarcolemmal Ca2+ channels, and activation of K+ channels. Luteolin or its glycosides from artichoke extracts may have an ameliorating effect on irritable bowel syndrome. The purpose of this study was to determine if luteolin had an effect on gallbladder motility. METHODS: An in vitro pharmacologic technique was utilized. Either cholecystokinin octapeptide (CCK) or KCl were used to induce tension in male guinea pig gallbladder strips maintained in Sawyer-Bartlestone chambers. Luteolin relaxed either the CCK- or KCl-induced tension in a concentration dependent manner. Various blockers were added to the chambers to determine which second messenger system(s) mediated the observed relaxation. Paired t-tests were used for statistical analysis. Differences between mean values of P < 0.05 were considered significant. RESULTS: Treatment of the gallbladder strips with luteolin prior to either KCl or CCK significantly (P < 0.001) decreased the amount of either KCl- or cholecystokinin-induced tension. The 2-aminoethoxydiphenylborane was used to ascertain if the release of intracellular Ca2+ mediated the luteolin-induced relaxation. It significantly (P < 0.001) decreased the amount of luteolin-induced relaxation. To ascertain if PKA mediated the luteolin-induced relaxation, PKA inhibitor 14-22 amide myristolated was used. It significantly (P < 0.01) reduced the amount of luteolin-induced relaxation. Neither KT5823, NG-methyl-L-arginine acetate salt, genistein, tetraethylammonium, nor fulvestrant had a significant effect. To ascertain if PKC mediated the luteolin-induced relaxation, the PKC inhibitors bisindolymaleimide IV and chelerythrine Cl- were used together. They had no significant effect. CONCLUSIONS: Luteolin relaxed cholecystokinin- or KCl-induced tension by blocking extracellular Ca2+ entry as well as intracellular Ca2+ release. In addition, the actions of PKA are also involved in mediating the luteolin effect. Luteolin is a natural flavonoid with strong anti-oxidative properties that is reported to have an anti-cancer effect in several maligcies other than bladder cancer. In this study, we describe the effect of luteolin on a human bladder cancer cell line, T24, in the context of the regulation of p21, thioredoxin-1 (TRX1) and the mechanistic target of rapamycin (mTOR) pathway. Luteolin inhibited cell survival and induced G2/M cell-cycle arrest, p21 upregulation and downregulation of phospho(p)-S6, which is downstream of mTOR signaling. Luteolin also upregulated TRX1 and reduced intracellular reactive oxygen species production. In a subcutaneous xenograft mouse model using the rat bladder cancer cell line, BC31, tumor volumes were significantly decreased in mice orally administered luteolin compared to control. Immunohistochemical analysis revealed that increased p21 and decreased p-S6 expression were induced in the luteolin treatment group. Moreover, in another in vivo N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced rat bladder cancer model, the oral administration of luteolin led to a trend of decreased bladder tumor dimension and significantly decreased the Ki67-labeling index and p-S6 expression. Furthermore, the major findings on the metabolism of luteolin suggest that both plasma and urine luteolin-3'-O-glucuronide concentrations are strongly associated with the inhibition of cell proliferation and mTOR signaling. Moreover, a significant decrease in the squamous differentiation of bladder cancer is attributed to plasma luteolin-3'-glucuronide concentration. In conclusion, luteolin, and in particular its metabolized product, may represent another natural product-derived therapeutic agent that acts against bladder cancer by upregulating p21 and inhibiting mTOR signaling. Endoplasmic reticulum (ER) stress designates a cellular response to the accumulation of misfolded proteins, which is related to disease progression in the liver. Luteolin (3',4',5,7-tetrahydroxyflavone) is a phytochemical found frequently in medicinal herbs. Although luteolin has been reported to possess the therapeutic potential to prevent diverse stage of liver diseases, its role in hepatic ER stress has not been established. Thus, the present study aimed to determine the role of luteolin in tunicamycin (Tm)-induced ER stress, and to identify the relevant mechanisms involved in its hepatoprotective effects. In hepatocyte-derived cells and primary hepatocytes, luteolin significantly decreased Tm- or thapsigargin-mediated C/EBP homologous protein (CHOP) expression. In addition, luteolin reduced the activation of three canonical signaling pathways related to the unfolded protein response, and decreased mRNA levels of glucose-regulated protein 78, ER DNA J domain-containing protein 4, and asparagine synthetase. Luteolin also significantly upregulated sestrin 2 (SESN2), and luteolin-mediated CHOP inhibition was blocked in SESN2 (+/-) cells. Moreover, luteolin resulted in phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf2), as well as increased nuclear Nrf2 expression. Deletion of the antioxidant response element in the human SESN2 promoter inhibited increased luciferase activation by luteolin, suggesting that Nrf2 is a critical transcription factor for luteolin-dependent SESN2 expression. In a Tm-mediated liver injury model, luteolin decreased serum alanine aminotransferase and aspartate aminotransferase activities, prevented degenerative changes and apoptosis of hepatocytes, and inhibited CHOP and glucose-regulated protein 78 expression in hepatic tissues. Therefore, luteolin may be an effective phytochemical to manage ER stress-related liver injury. Neonatal sepsis is a life-threatening inflammatory condition. Extracellular cold-inducible RNA-binding protein (CIRP), a proinflammatory mediator, plays a critical role in the pathogenesis of sepsis-induced lung injury in neonates. Luteolin, a polyphenolic flavonoid, has potent anti-inflammatory properties. However, the effects of luteolin on CIRP production and neonatal sepsis-induced lung injury remained unknown. We therefore hypothesize that treatment with luteolin suppresses CIRP production and attenuates lung injury in neonatal sepsis. To study this, sepsis was induced in C57BL/6J mouse pups (5-7 days) by intraperitoneal cecal slurry injection (CSI). One hour after CSI, luteolin (10 mg/kg body weight) or vehicle (normal saline) was administered through intraperitoneal injection. CIRP mRNA and protein were determined and lung injury was assessed at 10 h after CSI. Our results showed that administration of luteolin decreased CIRP mRNA and protein, improved lung architecture, reduced lung edema, and apoptosis after CSI. To examine the direct effect of luteolin on CIRP production, peritoneal macrophages were isolated from neonatal mice and stimulated with 100 ng/mL LPS with or without the presence of luteolin. The result indicates that luteolin directly inhibited LPS-induced CIRP production in neonatal macrophages. In addition, luteolin also downregulated hypoxia-inducible factor-1α (HIF-1α) and NOD-like receptor 3 (NLRP3) expression in septic neonates and in LPS-stimulated neonatal macrophages. In conclusion, administration of luteolin suppresses CIRP production and attenuates lung injury in neonatal sepsis. The beneficial effect of luteolin may be related to downregulation of HIF-1α and NLRP3 expression in neonatal macrophages. Luteolin may be developed as an adjunctive therapy for neonatal sepsis. Luteolin is a flavonoid with antioxidant properties already demonstrated in studies related to inflammation, tumor, and cardiovascular processes; however, there are no available information regarding its antioxidant effects at the venous endothelial site. We investigated the effects of luteolin (10, 20, and 50 μmol/L) in cultures of rat venous endothelial cells. Nitric oxide (NO) and reactive oxygen species (ROS) were analyzed by fluorimetry; 3-nitrotyrosine (3-NT) residues were evaluated by immunofluorescence, and prostacyclin (PGI2) release was investigated by colorimetry. Intracellular NO levels were significantly enhanced after 10 min of luteolin incubation, with a parallel decrease in ROS generation. These results were accompanied by a significant reduction in the expression of 3-NT residues and enhanced PGI2 rates. Therefore, luteolin is effective in reducing ROS thereby improving NO availability in venous endothelial cells. Besides, luteolin-induced decrease in 3-NT residues may correlate with the enhancement in endothelial PGI2 bioavailability. These findings suggest the future application of this flavonoid as a protective agent by improving endothelial function in several circulatory disorders related to venous insufficiency.

Does sphingosine-1 phosphoate suppress epiregulin?

Sphingosine-1 phosphate induces epiregulin (EREG) gene expression.

BACKGROUND AND AIMS: Sphingosine-1 phosphate (S1P) is a lysosphingolipid present in the ovarian follicular fluid. The role of the lysosphingolipid in gonads of the female is widely unclear. At omolar concentrations, S1P binds and activates five specific G protein-coupled receptors (GPCRs), known as S1P1-5, modulating different signaling pathways. S1P1 and S1P3 are highly expressed in human primary granulosa lutein cells (hGLC), as well as in the immortalized human primary granulosa cell line hGL5. In this study, we evaluated the signaling cascade activated by S1P and its synthetic analogues in hGLC and hGL5 cells, exploring the biological relevance of S1PR-stimulation in this context. METHODS AND RESULTS: hGLC and hGL5 cells were treated with a fixed dose (0.1 μM) of S1P, or by S1P1- and S1P3-specific agonists SEW2871 and CYM5541. In granulosa cells, S1P and, at a lesser extent, SEW2871 and CYM5541, potently induced CREB phosphorylation. No cAMP production was detected and pCREB activation occurred even in the presence of the PKA inhibitor H-89. Moreover, S1P-dependent CREB phosphorylation was dampened by the mitogen-activate protein kinase (MEK) inhibitor U0126 and by the L-type Ca2+ channel blocker verapamil. The complete inhibition of CREB phosphorylation occurred by blocking either S1P2 or S1P3 with the specific receptor antagonists JTE-013 and TY52156, or under PLC/PI3K depletion. S1P-dependent CREB phosphorylation induced FOXO1 and the EGF-like epiregulin-encoding gene (EREG), confirming the exclusive role of gonadotropins and interleukins in this process, but did not affect steroidogenesis. However, S1P or agonists did not modulate granulosa cell viability and proliferation in our conditions. CONCLUSIONS: This study demonstrates for the first time that S1P may induce a cAMP-independent activation of pCREB in granulosa cells, although this is not sufficient to induce intracellular steroidogenic signals and progesterone synthesis. S1P-induced FOXO1 and EREG gene expression suggests that the activation of S1P-S1PR axis may cooperate with gonadotropins in modulating follicle development.

Which is the literature-based database of phenotypes?

PheneBank is a Web-portal for retrieving human phenotype-disease associations that have been text-mined from the whole of Medline. This approach exploits state-of-the-art machine learning for concept identification by utilising an expert annotated rare disease corpus from the PMC Text Mining subset. Evaluation of the system for entities is conducted on a gold-standard corpus of rare disease sentences and for associations against the Monarch initiative data.

MOTIVATION: Significant effort has been spent by curators to create coding systems for phenotypes such as the Human Phenotype Ontology, as well as disease-phenotype annotations. We aim to support the discovery of literature-based phenotypes and integrate them into the knowledge discovery process. RESULTS: PheneBank is a Web-portal for retrieving human phenotype-disease associations that have been text-mined from the whole of Medline. Our approach exploits state-of-the-art machine learning for concept identification by utilizing an expert annotated rare disease corpus from the PMC Text Mining subset. Evaluation of the system for entities is conducted on a gold-standard corpus of rare disease sentences and for associations against the Monarch initiative data. AVAILABILITY AND IMPLEMENTATION: The PheneBank Web-portal freely available at http://www.phenebank.org. Annotated Medline data is available from Zenodo at DOI: 10.5281/zenodo.1408800. Semantic annotation software is freely available for non-commercial use at GitHub: https://github.com/pilehvar/phenebank. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Idecabtagene vicleucel can be used for treatment of which disease?

Idecabtagene vicleucel was shown to be effective for Relapsed and Refractory Multiple Myeloma.

BACKGROUND AND OBJECTIVE: Registrational trials for ciltacabtagene autoleucel [cilta-cel]) and idecabtagene vicleucel [ide-cel] chimeric antigen receptor T-cell (CAR-T) therapies were single-arm studies conducted with relapse refractory multiple myeloma (MM) patients who were triple-class-exposed (TCE) or triple-class-refractory (TCR). It is critical for researchers conducting comparative effectiveness research (CER) to carefully consider the most appropriate data sources and comparable patient populations. The aim of this study was to identify potential data sources and populations for comparing to single-arm CAR-T trials CARTITUDE-1 (cilta-cel) and KarMMa (ide-cel). METHODS: A 2-part global systematic literature search produced a review of (1) clinical trials of National Comprehensive Cancer Network (NCCN) guideline preferred regimens in previously treated MM, and (2) real-world data cohorts of TCE or TCR populations, published between 1/1/2015 and 12/10/2020, with sample sizes of > 50 patients and reporting survival-related outcomes. Implications on CER and accepted best practices are discussed. RESULTS: Nine clinical trials of NCCN preferred regimens were identified along with five real-world data-based publications. No clinical trials evaluated patients with TCE or TCR MM. Among the real-world data-based publications, two evaluated patients exclusively with TCR MM, two analyzed a mixed population of patients with TCE or TCR MM, and one publication assessed patients exclusively with TCE MM. Real-world data treatment patterns were heterogeneous. CONCLUSION: Current NCCN preferred regimens were not specifically studied in TCE or TCR MM patients, although some studies do include a proportion of these types of patients. Therefore, appropriate matching of populations using either real-world data or patient level clinical trial data is critical to putting trials of novel CAR-Ts (i.e., CARTITUDE-1 or KarMMa) into appropriate comparative context. BACKGROUND: Idecabtagene vicleucel (ide-cel, also called bb2121), a B-cell maturation antigen-directed chimeric antigen receptor (CAR) T-cell therapy, has shown clinical activity with expected CAR T-cell toxic effects in patients with relapsed and refractory multiple myeloma. METHODS: In this phase 2 study, we sought to confirm the efficacy and safety of ide-cel in patients with relapsed and refractory myeloma. Patients with disease after at least three previous regimens including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody were enrolled. Patients received ide-cel target doses of 150 × 106 to 450 × 106 CAR-positive (CAR+) T cells. The primary end point was an overall response (partial response or better); a key secondary end point was a complete response or better (comprising complete and stringent complete responses). RESULTS: Of 140 patients enrolled, 128 received ide-cel. At a median follow-up of 13.3 months, 94 of 128 patients (73%) had a response, and 42 of 128 (33%) had a complete response or better. Minimal residual disease (MRD)-negative status (<10-5 nucleated cells) was confirmed in 33 patients, representing 26% of all 128 patients who were treated and 79% of the 42 patients who had a complete response or better. The median progression-free survival was 8.8 months (95% confidence interval, 5.6 to 11.6). Common toxic effects among the 128 treated patients included neutropenia in 117 patients (91%), anemia in 89 (70%), and thrombocytopenia in 81 (63%). Cytokine release syndrome was reported in 107 patients (84%), including 7 (5%) who had events of grade 3 or higher. Neurotoxic effects developed in 23 patients (18%) and were of grade 3 in 4 patients (3%); no neurotoxic effects higher than grade 3 occurred. Cellular kinetic analysis confirmed CAR+ T cells in 29 of 49 patients (59%) at 6 months and 4 of 11 patients (36%) at 12 months after infusion. CONCLUSIONS: Ide-cel induced responses in a majority of heavily pretreated patients with refractory and relapsed myeloma; MRD-negative status was achieved in 26% of treated patients. Almost all patients had grade 3 or 4 toxic effects, most commonly hematologic toxic effects and cytokine release syndrome. (Funded by bluebird bio and Celgene, a Bristol-Myers Squibb company; KarMMa ClinicalTrials.gov number, NCT03361748.). Idecabtagene vicleucel (ide-cel, bb2121), a chimeric antigen receptor (CAR) T cell therapy, has been investigated in patients with relapsed and refractory multiple myeloma (RRMM) who have received an immunomodulatory drug, proteasome inhibitor, and anti-CD38 antibody in the single-arm phase 2 KarMMa clinical trial. Two therapies with distinct mechanisms of action - selinexor plus dexamethasone (Sd) and belantamab mafodotin (BM) - are currently approved in the United States for heavily pretreated patients, including those who are triple-class refractory. To compare ide-cel versus Sd and ide-cel versus BM, matching-adjusted indirect comparisons were performed. Ide-cel extended progression-free survival (PFS) and overall survival (OS) versus both Sd and BM (hazard ratio (HR); 95% confidence interval (CI)). PFS: ide-cel versus Sd, 0.46; 0.28-0.75; ide-cel versus BM, 0.45; 0.27-0.77. OS: ide-cel versus Sd, 0.23; 0.13-0.42; ide-cel versus BM, 0.35; 0.14-0.87. These results suggest ide-cel offers clinically meaningful improvements over currently approved regimens for patients with heavily pretreated RRMM. The development of several treatment options over the last 2 decades has led to a notable improvement in the survival of patients with multiple myeloma. Despite these advances, the disease remains incurable for most patients. Moreover, standard combinations of alkylating agents, immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies targeting CD38 and corticoids are exhausted relatively fast in a proportion of high-risk patients. Such high-risk patients account for over 20% of cases and currently represent a major unmet medical need. The challenge of drug resistance requires the development of highly active new agents with a radically different mechanism of action. Several immunotherapeutic modalities, including antibody-drug conjugates and T-cell engagers, appear to be promising choices for patients who develop resistance to standard combinations. Chimeric antigen-receptor-modified T cells (CAR-Ts) targeting B-cell maturation antigen have demonstrated encouraging efficacy and an acceptable safety profile compared with alternative options. Multiple CAR-Ts are in early stages of clinical development, but the first phase III trials with CAR-Ts are ongoing for two of them. After the recent publication of the results of a phase II trial confirming a notable efficacy and acceptable safety profile, idecabtagene vicleucel is the first CAR-T to gain regulatory US Food and Drug Administration approval to treat refractory multiple myeloma patients who have already been exposed to antibodies against CD38, proteasome inhibitors, and immunomodulatory agents and who are refractory to the last therapy. Here, we will discuss the preclinical and clinical development of idecabtagene vicleucel and its future role in the changing treatment landscape of relapsed and refractory multiple myeloma. Conflict of interest statement: S.J. served as a consultant for Bristol Myers Squibb (BMS), Janssen, Legend Biotech, Sanofi, and Takeda. Y.L. served as a consultant for Kite/Gilead, Celgene (a BMS Company), Juno Therapeutics (a BMS Company), bluebird bio, Janssen, Legend Biotech, Gamida Cells, and Novartis; received research funding from Kite/Gilead, Celgene (a BMS Company), bluebird bio, Janssen, Merck, and Takeda; is a member of Sorrento Therapeutics Data and Safety Monitoring Board. H.G. received grants and/or provision of investigational medicinal product from Amgen, BMS, Celgene (a BMS Company), Chugai, Dietmar-Hopp-Foundation, Janssen, Johns Hopkins University, and Sanofi; received research funding from Amgen, BMS, Celgene (a BMS Company), Chugai, Janssen, Incyte, Molecular Partners, Merck, Sharp and Dohme, Sanofi, Mundipharma, Takeda, and Novartis; served as a member of advisory board for Adaptive Biotechnologies, Amgen, BMS, Janssen, Sanofi, and Takeda; participated in the speakers’ bureau for Amgen, BMS, Celgene (a BMS Company), Chugai, GlaxoSmithKline (GSK), Janssen, Novartis, and Sanofi. D.R. served as a consultant for Celgene (a BMS Company), Janssen, Takeda, Amgen, and Karyopharm; received honoraria from Celgene (a BMS Company), Janssen, Takeda, and Amgen; received research funding from Celgene (a BMS Company), Janssen, Takeda, Otsuka, Merck, and BMS; provided expert testimony for Celgene (a BMS Company) and Amgen. A.N. served as a consultant for Spectrum Pharmaceuticals, BMS, Adaptive Biotechnologies, Amgen, Celgene (a BMS Company), Takeda, Karyopharm, Oncopeptides, GSK, and Janssen; received research funding from BMS, Amgen, Celgene (a BMS Company), Takeda, Karyopharm, GSK, and Janssen. P.R.O. served as a consultant for Celgene (a BMS Company), Janssen, AbbVie, Kite Pharma, and Sanofi; participated in the speakers’ bureau for Celgene (a BMS Company), Janssen, and Amgen; received travel funding from Celgene (a BMS Company). K.M. received honoraria from Celgene (a BMS Company), Takeda, and Janssen. N.S. served as a consultant for Genentech, Seagen Inc., Oncopeptides, Karyopharm, Surface Oncology, Precision Biosciences, GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi, and BMS; received research funding from Celgene (a BMS Company), Janssen, bluebird bio, Sutro Biopharma, and Teneobio. L.D.A. served as a consultant for Amgen, BMS, GSK, Janssen, and Karyopharm; received research funding and honoraria from GSK, BMS, Janssen, Karyopharm, and Amgen. K.W., H.V.L., A.A. are employees and equity owners with BMS. A.S.S. was an employee of BMS at the time the work was completed. D.S.S. served as a consultant for Amgen, Celgene (a BMS Company), Takeda, Janssen, BMS, Karyopharm, and Merck; participated in the speakers’ bureau for Amgen, Celgene (a BMS Company), Takeda, Janssen, and BMS; received research funding from Celgene (a BMS Company); is an equity owner with Celularity. A.S., R.P., and M.S. declare no conflict of interest. OBJECTIVE: This study estimated the comparative efficacy of ciltacabtagene autoleucel (cilta-cel) versus the approved idecabtagene vicleucel (ide-cel) dose range of 300-460 × 106 CAR-positive T-cells for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) who were previously treated with a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody (i.e. triple-class exposed) using matching-adjusted indirect treatment comparisons (MAICs). METHODS: MAICs were performed with individual patient data for cilta-cel (CARTITUDE-1; NCT03548207) and published summary-level data for ide-cel (KarMMa; NCT03361748). Treated patients from CARTITUDE-1 who satisfied the eligibility criteria for KarMMa were included in the analyses. The MAIC adjusted for unbalanced baseline covariates of prognostic significance identified in the literature and by clinical expertise. Comparative efficacy was estimated for overall response rate (ORR), complete response or better (≥CR) rate, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). RESULTS: Cilta-cel was associated with statistically significantly improved ORR (odds ratio [OR]: 94.93 [95% confidence interval [CI]: 21.86, 412.25; p < .0001]; relative risk [RR]: 1.34), ≥CR rate (OR: 5.49 [95% CI: 2.47, 12.21; p < .0001]; RR: 2.21), DoR (hazard ratio [HR]: 0.50 [95% CI: 0.29, 0.87; p = .0137]), and PFS (HR: 0.37 [95% CI: 0.22, 0.62; p = .0002]) when compared with ide-cel. For OS, the results were in favor of cilta-cel and clinically meaningful but with a CI overlapping one (HR: 0.55 [95% CI: 0.29, 1.05; p = .0702]). CONCLUSIONS: These analyses demonstrate improved efficacy with cilta-cel versus ide-cel for all outcomes, highlighting its therapeutic potential in patients with triple-class exposed RRMM. Whereas the treatment of MM was dependent solely on alkylating agents and corticosteroids during the prior three decades, the landscape of therapeutic measures to treat the disease began to expand enormously early in the current century. The introduction of new classes of small-molecule drugs, such as proteasome blockers (bortezomib and carfilzomib), immunomodulators (lenalidomide and pomalidomide), nuclear export inhibitors (selinexor), and histone deacetylase blockers (panobinostat), as well as the application of autologous stem cell transplantation (ASCT), resulted in a seismic shift in how the disease is treated. The picture changed dramatically once again starting with the 2015 FDA approval of two monoclonal antibodies (mAbs) - the anti-CD38 daratumumab and the anti-SLAMF7 elotuzumab. Daratumumab, in particular, has had a great impact on MM therapy and today is often included in various regimens to treat the disease, both in newly diagnosed cases and in the relapse/refractory setting. Recently, other immunotherapies have been added to the arsenal of drugs available to fight this maligcy. These include isatuximab (also anti-CD38) and, in the past year, the antibody-drug conjugate (ADC) belantamab mafodotin and the chimeric antigen receptor (CAR) T-cell product idecabtagene vicleucel (ide-cel). While the accumulated benefits of these newer agents have resulted in a doubling of the disease's five-year survival rate to more than 5 years and improved quality of life, the disease remains incurable. Almost without exception patients experience relapse and/or become refractory to the drugs used, making the search for innovative therapies all the more essential. This review covers the current scope of anti-myeloma immunotherapeutic agents, both those in clinical use and on the horizon, including naked mAbs, ADCs, bi- and multi-targeted mAbs, and CAR T-cells. Emphasis is placed on the benefits of each along with the challenges that need to be overcome if MM is to be considered curable in the future. Important advances in the treatment landscape of multiple myeloma (MM) had been seen over the past two decades leading to improved overall survival but despite the progress multiple myeloma is still considered incurable and the prognosis of the pentarefractory patients have been poor. The development of immunotherapy and in particular adoptive cell therapy with chimeric antigen receptor (CAR) T cells have dramatically improved the outcomes of heavily pretreated relapsed/refractory MM patients. The bulk of CAR T-cell constructs currently in clinical development target the B-cell maturation antigen (BCMA) and to date only idecabtagene vicleucel (ide-cel) is approved by the Food and Drug Administration (FDA) for commercial use in adult patients with relapsed or refractory MM based on the promising clinical responses and positive safety record shown in the pivotal KarMMa study. This review focus on the development of CAR T-cell therapy for multiple myeloma as well as a brief review of the mechanisms of resistance, toxicity and new approaches under development.

LINC00339 is a diagnostic, prognostic and treatment efficacy biomarker for what disease?

LINC00339 as a cancer diagnostic, prognostic and treatment efficacy biomarker.

Glioma is recognized as a highly angiogenic maligt brain tumor. Vasculogenic mimicry (VM) greatly restricts the therapeutic effect of anti-angiogenic tumor therapy for glioma patients. However, the molecular mechanisms of VM formation in glioma remain unclear. Here, we demonstrated that LINC00339 was upregulated in glioma tissue as well as in glioma cell lines. The expression of LINC00339 in glioma tissues was positively correlated with glioma VM formation. Knockdown of LINC00339 inhibited glioma cell proliferation, migration, invasion, and tube formation, meanwhile downregulating the expression of VM-related molecular MMP-2 and MMP-14. Furthermore, knockdown of LINC00339 significantly increased the expression of miR-539-5p. Both bioinformatics and luciferase reporter assay revealed that LINC00339 regulated the above effects via binding to miR-539-5p. Besides, overexpression of miR-539-5p resulted in decreased expression of TWIST1, a transcription factor known to play an oncogenic role in glioma and identified as a direct target of miR-539-5p. TWIST1 upregulated the promoter activities of MMP-2 and MMP-14. The in vivo study showed that nude mice carrying tumors with knockdown of LINC00339 and overexpression of miR-539-5p exhibited the smallest tumor volume through inhibiting VM formation. In conclusion, LINC00339 may be used as a novel therapeutic target for VM formation in glioma. Non-small cell lung cancer (NSCLC) is one of leading causes of cancer-related death worldwide. Long noncoding RNAs (lncRNAs) has been identified to modulate the tumorigenesis of NSCLC. However, the precise molecular mechanism of lncRNAs in the course is still unclear. Results showed that LINC00339 was significantly up-regulated in NSCLC tissue and cells, which indicated the poor prognosis of NSCLC patients. Loss-of-function experiments showed that LINC00339 silencing inhibited the proliferation and invasion, accelerated the apoptosis, and suppressed the tumor growth of NSCLC cells in vitro and in vivo. Luciferase reporter assay and RNA immunoprecipitation (RIP) revealed that LINC00339 promoted the NSCLC progression via FOXM1 via targeting miR-145. In conclusion, our results identify the important role of the LINC00339/miR-145/FOXM1 axis in the NSCLC tumorigenesis, providing neoteric mechanism for the NSCLC tumorigenesis. Laryngeal squamous cell carcinoma (LSCC) is a very common neoplasm of the head and neck in the world. Long noncoding RNAs play key roles in cell infiltration, fate, apoptosis, and invasion. However, the functional role and expression of LINC00339 remains unclear in LSCC. In this study, we showed that the expression level of LINC00339 was upregulated in LSCC tissues and cell lines. LINC00339 silencing suppressed the proliferation, invasion, and epithelial-mesenchymal transition (EMT) progression of LSCC cells. In addition, we showed that LINC00339 acted as a sponge of miR-145, and LINC00339 silencing promoted the expression of miR-145 in Hep2 cell. Furthermore, the expression of miR-145 was lower in LSCC tissues than in their paired normal samples and the miR-145 expression level was negatively correlated with LINC00339 expression in LSCC tissues. The knockdown of miR-145 promoted the proliferation, invasion, and EMT progression of LSCC cells. Finally, we indicated that LINC00339 silencing inhibited the proliferation, invasion, and EMT progression of LSCC cells by suppressing the miR-145 expression. These data suggested that LINC00339 acted as an oncogene in the development of LSCC, partly by regulating the miR-145 expression. Recently, long noncoding RNAs (lncRNAs) have become the key gene regulators and prognostic biomarkers in various cancers. Through microarray data, Linc00339 was identified as a candidate oncogenic lncRNA. We compared the expression levels of Linc00339 in several breast cancer cell lines and normal mammary gland epithelial cell line. The effects of Linc00339 on tumor progression were examined both in vitro and in vivo. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays were applied to evaluate the functions of Linc00339, miR-377-3p, and HOXC6 on cell proliferation. Flow cytometry analysis was used to detect apoptosis and cell cycle distribution. Overall survival (OS) was analyzed using data from The Cancer Genome Atlas and molecular taxonomy of breast cancer international consortium (METABRIC). Dual luciferase assay and RNA immunoprecipitation were performed to confirm the interaction between Linc003339 and miR-377-3p. Linc00339 was increased in breast cancer cell lines compared with the normal epithelial cell. Through in vitro and in vivo experiments, Linc00339 overexpression promoted triple-negative breast cancer (TNBC) proliferation, inhibited cell cycle arrest, and suppressed apoptosis. Silencing of Linc00339 obtained the opposite effects. Mechanistic investigations demonstrated that Linc00339 could sponge miR-377-3p and regulate its expression. Higher expression of miR-377-3p indicated longer OS in breast cancer patients, especially in TNBC patients. Overexpression of miR-377-3p retarded TNBC cell growth through regulating cell cycle distribution and apoptosis. And miR-377-3p was involved in Linc00339-mediated TNBC proliferation through regulating HOXC6 expression. Knockdown of HOXC6 inhibited TNBC progression. In conclusion, our results illuminated that the novel Linc00339/miR-377-3p/HOXC6 axis played a critical role in TNBC progression and might be a promising therapeutic target for TNBC treatment. BACKGROUND/AIMS: Emerging evidence have demonstrated that long noncoding RNAs are involved in the development and metastasis of various cancers including hepatocellular carcinoma (HCC). However, the role of LINC00339 in HCC progression is still unknown. METHODS: The LINC00339 expression in HCC cancer cells (HUH7, HepG2, HUH-6, and SK-Hep-1) and tissues was assessed by quantitative real-time polymerase chain reaction (qRT-PCR). Functional experiments including cell counting Kit-8 wound-healing assay and transwell assay were used to explore the cell proliferation, migration, and invasion, respectively. The related molecular mechanisms were determined by Western blot. The RNA pull-down assay, luciferase reporters assay, qRT-PCR, and Western blot were performed to explore and confirm the interaction between LINC00339 and miR-152, between miR-152 and ROCK1. The role of LINC00339 in tumor formation and metastasis were explored through in vivo experiments. RESULTS: LINC00339 was highly expressed in HCC tissues and cell lines. LINC00339 promoted the cell proliferation, migration, and invasion of HCC cells, while knockout of LINC00339 showed the opposite trends. The proliferation and migration of HCC cells induced by LINC00339 overexpression were mostly reversed after transfected with miR-152 mimics. LINC00339 exerted oncogenesis effect on HCC progression by targeting miR-152/ROCK1, and the expression of LINC00339 was negatively correlated with miR-152 expression and positively correlated with ROCK1 expression in clinical HCC samples. Moreover, we also proved that LINC00339 overexpression exacerbated the tumor formation and metastases in nude mice and LINC00339 silence showed the opposite results. CONCLUSION: LINC00339 might act as a potential therapeutic target for HCC. PURPOSE: To investigate the role and mechanism of long non-coding (lnc) RNA LINC00339 in pancreatic cancer (PANC), and provided a potential target for its biological diagnosis and treatment. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of LINC00339 in PANC tissue specimens and cell lines. The experimental cell lines differentially expressing LINC00339 were constructed by using small interfering RNA and lentivirus transfection. Cell proliferation was examined by cell counting kit-8 (CCK-8) and colony formation experiments and transwell experiments were used to assess cell invasion and migration abilities. The luciferase assay and RNA immunoprecipitation (RIP) were employed to study the target gene for LINC00339, and western blot analysis was utilized to measure protein expression of the downstream gene. RESULTS: The level of LINC00339 expression in PANC tissues or cells was significantly higher than that in their respective control groups. Interfering expression of LINC00339 could notably inhibit the proliferation, invasion and migration of SW1990 cells, while the over-expressing expression of LINC00339 obviously increased the growth and metastasis abilities of PANC-1 cells. LINC00339 could act as a miR-497-5p sponge, adsorbing miR-497-5p, thereby inhibiting its action by increasing the expression of its target gene IGF1R. The expression of miR-497-5p and its target gene IGF1R could be significantly altered by altering the expression of LINC00339. CONCLUSIONS: LINC00339 was markedly over-expressed in PANC tissues and cells and promoted cell proliferation, invasion, and migration via sponging miR-497-5p, thereby increasing IGF1R expression. Our study could provide a novel target for PANC diagnosis and biotherapy. Background: Extensive research has shown that long noncoding RNA (lncRNA) is involved in tumorigenesis, including hepatocellular carcinoma (HCC). The lncRNA LINC00339 was reported to regulate the development of lung cancer or breast cancer. However, whether LINC00339 participates in HCC progression remains unclear. Here, our results showed that LINC00339 was upregulated in HCC. Methods: qRT-PCR and in situ hybridization (ISH) was used to analyze LINC00339 expression in tumor tissues and cell lines. CCK8 and colony formation assays were used to analyze cell proliferation. Transwell assay was used to analyze cell migration and invasion. Xenograft experiment was used to test tumor growth in vivo. Results: LINC00339 overexpression was correlated with an advanced stage, metastasis, and bad prognosis in HCC patients. Functional investigation showed that LINC00339 knockdown significantly suppressed HCC cell proliferation, migration, and invasion. Moreover, decreased LINC00339 expression inhibited HCC growth in vivo. Mechanistically, LINC00339 could interact with miR-1182 to promote SKA1 expression. We also demonstrated that SKA1 acted as an oncogene and SKA1 upregulation reversed the effect of LINC00339 silencing. Conclusion: Our results illustrated that the LINC00339/miR-1182/SKA1 axis plays an essential role in HCC progression. Objective: To investigate the expression of long non-coding RNA LINC00339 in colorectal cancer patients and its effect and mechanism on proliferation and apoptosis of colorectal cancer cells. Methods: A retrospective analysis of 158 pathology-confirmed colorectal cancer patients, who were enrolled from August 2015 to January 2017, was performed. LINC00339 expression in colorectal cancer tissues and adjacent colorectal sampleswas detected by Real-time PCR. The correlation between LINC00339 expression and clinicopathological features as well as the relationship between LINC00339 and microRNA (miR)-218 expression was assayed. The interaction between LINC00339 and miR-218 was further confirmed by dual luciferase report system. Downregulation of LINC00339 was performed by siRNA interference technology in LoVo and HCT116 cells. Real-time PCR was used to detect miR-218 expression. 3-(4,5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) analysis was carried out to examine cell viability. Flow cytometry was used to determine cell apoptosis. Additionally, LINC00339 siRNA and miR-218 antagomirs (anti-miR-218) were co-transfected into LoVo and HCT116 cells, and then cell viability and apoptosis were detected. Results: LINC00339 expression was significantly increased in colorectal cancer tissues compared with adjacent colorectal tissues (4.69±1.52 vs 1.02±0.38, P<0.05). LINC00339 expression was not related to the age and gender of patients (P>0.05), but was associated with TNM stage, lymphatic metastasis, tumor maximum diameters, and differentiation degree (all P<0.05). LINC00339 expression was negatively correlated with miR-218 expression in colorectal cancer tissues (P<0.05). miR-218 mimics remarkably suppressed the fluorescence intensity of wild-type LINC00339 plasmid (P=0.001), but did not affect the fluorescence intensity of the mutant ones(P=0.88). Knockdown of LINC00339 remarkably inhibited proliferation, but promoted apoptosis of LoVo and HCT116 cells (all P<0.05). Compared with cells transfected with LINC00339 siRNA only, downregulation of miR-218 elevated proliferation and decreased apoptosis of LoVoand HCT116 cells. Conclusions: LINC00339 expression is upregulated in colorectal cancer tissues and correlated with patients' clinicopathological features. LINC00339 promotes proliferation, and suppresses apoptosis of colorectal cancer cells via downregulating miR-218. Huaier, as known as Trametes robiniophila Murr, is a traditional Chinese medicine. Various studies have demonstrated that Huaier could inhibit cancer progression and improve the prognosis of patients. In the present study, we comprehensively screened the expression profiles of lncRNAs, miRNAs, and mRNAs in Huaier-treated breast cancer cells. Using bioinformatic analysis, hub genes were identified and functionally annotated. Weighted gene coexpression network analysis was applied to construct the molecular network influenced by Huaier. Linc00339 was then found to play a critical role in Huaier-mediated cancer suppression. To validate the effects of linc00339 and identify the downstream targets, we performed in vitro and in vivo experiments. Finally, we identified that Huaier could inhibit the proliferation of breast cancer cells through modulating linc00339/miR-4656/CSNK2B signaling pathway. Differential expression of LINC00339 is involved in the maligcy of multiple human cancer types. Nonetheless, the expression profile, functions, and potential mechanisms of action of LINC00339 in gastric cancer are yet to be fully elucidated. This study aimed at measuring LINC00339 expression in gastric cancer and examining the prognostic significance of LINC00339 in patients with gastric cancer. The detailed functions of LINC00339 with regard to the aggressive characteristics of gastric cancer cells and the underlying molecular mechanisms were investigated. Here, we found that LINC00339 expression was aberrantly high in gastric cancer and significantly associated with lymph node metastasis, invasive depth, and TNM stage. Patients with gastric cancer in a LINC00339 high-expression group showed shorter overall survival than patients in a LINC00339 low-expression group. A knockdown of LINC00339 suppressed gastric cancer cell proliferation, migration, and invasion and induced apoptosis in vitro and slowed tumor growth in vivo. In terms of the mechanism, LINC00339 was found to act as a molecular sponge on microRNA-539 (miR-539). SRY-box 9 (SOX9) was confirmed as a direct target gene of miR-539 in gastric cancer cells. An miR-539 knockdown attenuated the effects of the LINC00339 knockdown on the maligt characteristics of gastric cancer cells. Overall, LINC00339 plays a critical role in the maligcy of gastric cancer by regulating SOX9 via sponging of miR‑539. Our findings highlight the importance of the LINC00339-miR-539-SOX9 pathway in gastric cancer pathogenesis and may point to novel targets for the diagnosis, prognosis, and/or treatment of gastric cancer. INTRODUCTION: Accumulating evidence has indicated that long noncoding RNAs (lncRNAs) are pivotal regulators involved in the pathogenesis of cancer; however, the molecular mechanism of LINC00339 in colorectal cancer (CRC) remains unclear. METHODS: The quantitative real-time polymerase chain reaction for the expression of LINC00339 and miR-378a-3p and Western blots for MED19 were performed. A dual-luciferase assay was used to investigate the interaction between LIN00339 and miR-378a-3p, as well as between miR-378a-3p and MED19. Cell proliferation was determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and 5-ethynyl-2'-deoxyuridine (EdU) assay. The cell cycle was analyzed by propidium iodide staining followed by flow cytometry analysis. The wound-healing and transwell invasion assays were used to evaluate cell migration and invasion. RESULTS: The expression of LINC00339 was significantly upregulated in CRC cells and tissues, and high LINC00339 expression indicated an advanced tumor stage. Further experiments demonstrated that SP1 activated LINC00339 expression by binding to its promoter region. Luciferase activity and RNA pull-down assays demonstrated a direct interaction between LINC00339 and miR-378a-3p. miR-378a-3p expression was decreased in CRC samples and negatively correlated with LINC00339 expression in tumors. Gain- and loss-of-function assays indicated that LINC00339 contributed to cell proliferation, cell cycle progression, migration, and invasion, while miR-378a-3p reversed these effects. Furthermore, cotransfection of wild-type MED19 3'-UTR reporters and miR-378a-3p significantly reduced luciferase activity. MED19 mRNA and protein expression was inhibited and enhanced by miR-378a-3p and LINC00339, respectively. MED19 overexpression reversed the effect of miR-378a-3p on cellular processes. Moreover, LINC00339 promoted tumor growth in vivo and induced epithelial-mesenchymal transition (EMT) and activated the Wnt/β-catenin signaling pathway in cells. CONCLUSION: Our findings demonstrate the regulatory role of the SP1/LINC00339/miR-378a-3p/MED19 axis in CRC tumorigenesis and provide novel insight into the molecular mechanism underlying CRC. In recent years, triple-negative breast cancer (TNBC) has emerged as the most aggressive subtype of breast cancer and is usually associated with increased mortality worldwide. The severity of TNBC is primarily observed in younger women, with cases ranging from approximately 12%-24% of all breast cancer cases. The existing hormonal therapies offer limited clinical solutions in completely circumventing the TNBC, with chemoresistance and tumor recurrences being the common hurdles in the path of TNBC treatment. Accumulating evidence has correlated the dysregulation of long noncoding RNAs (lncRNAs) with increased cell proliferation, invasion, migration, tumor growth, chemoresistance, and decreased apoptosis in TNBC. Various clinical studies have revealed that aberrant expression of lncRNAs in TNBC tissues is associated with poor prognosis, lower overall survival, and disease-free survival. Due to these specific characteristics, lncRNAs have emerged as novel diagnostic and prognostic biomarkers for TNBC treatment. However, the underlying mechanism through which lncRNAs perform their actions remains unclear, and extensive research is being carried out to reveal it. Therefore, understanding of mechanisms regulating the modulation of lncRNAs will be a substantial breakthrough in effective treatment therapies for TNBC. This review highlights the association of several lncRNAs in TNBC progression and treatment, along with their possible functions and mechanisms. BACKGROUND: Liver hepatocellular carcinoma (LIHC) is a lethal cancer. This study aimed to identify the N6 -methyladenosine (m6 A)-targeted long non-coding RNA (lncRNA) related to LIHC prognosis and to develop an m6 A-targeted lncRNA model for prognosis prediction in LIHC. METHODS: The expression matrix of mRNA and lncRNA was obtained, and differentially expressed (DE) mRNAs and lncRNAs between tumor and normal samples were identified. Univariate Cox and pathway enrichment analyses were performed on the m6 A-targeted lncRNAs and the LIHC prognosis-related m6 A-targeted lncRNAs. Prognostic analysis, immune infiltration, and gene DE analyses were performed on LIHC subgroups, which were obtained from unsupervised clustering analysis. Additionally, a multi-factor Cox analysis was used to construct a prognostic risk model based on the lncRNAs from the LASSO Cox model. Univariate and multivariate Cox analyses were used to assess prognostic independence. RESULTS: A total of 5031 significant DEmRNAs and 292 significant DElncRNAs were screened, and 72 LIHC-specific m6 A-targeted binding lncRNAs were screened. Moreover, a total of 29 LIHC prognosis-related m6 A-targeted lncRNAs were obtained and enriched in cytoskeletal, spliceosome, and cell cycle pathways. An 11-m6 A-lncRNA prognostic model was constructed and verified; the top 10 lncRNAs included LINC00152, RP6-65G23.3, RP11-620J15.3, RP11-290F5.1, RP11-147L13.13, RP11-923I11.6, AC092171.4, KB-1460A1.5, LINC00339, and RP11-119D9.1. Additionally, the two LIHC subgroups, Cluster 1 and Cluster 2, showed significant differences in the immune microenvironment, m6 A enzyme genes, and prognosis of LIHC. CONCLUSION: The m6 A-lncRNA prognostic model accurately and effectively predicted the prognostic survival of LIHC. Immune cells, immune checkpoints (ICs), and m6 A enzyme genes could act as novel therapeutic targets for LIHC.

What is the role of PCAT6 in human cancers?

PCAT6, is a carcinogenic lncRNA. It is abnormally elevated in various human malignant tumors. PCAT6 has been found to sponge various miRNAs to activate the signaling pathways, which further affects tumor cell proliferation, migration, invasion, cycle, apoptosis, radioresistance, and chemoresistance. It is believed to have diagnostic and prognostic value and clinical applications in various human malignancies.

Long noncoding RNAs (lncRNAs) play crucial roles in tumor development of osteosarcoma (OS). LncRNA PCAT6 was involved in the progression of multiple human cancers. However, the biological function of PCAT6 in OS remains largely unknown. We found that PCAT6 was elevated in OS tissues relative to that in their adjacent normal tissues. The upregulation of PCAT6 was positively associated with metastasis status and advanced stages and predicted poor overall and progression-free survivals in patients with OS. Functionally, silencing PCAT6 inhibited the proliferation, migration and invasion abilities of OS cells. Mechanistically, PCAT6, acting as a competitive endogenous RNA, upregulated expression of TGFBR1 and TGFBR2 to activate TGF-β pathway via sponging miR-185-5p. This study uncovers a novel underlying molecular mechanism of PCAT6-miR-185-5p-TGFBR1/2-TGF-β signaling axis in promoting tumor progression in OS, which indicates that PCAT6 may serve as a promising prognostic factor and therapeutic target again OS. LncRNAs are involved in the occurrence and progressions of multiple cancers. Emerging evidence has shown that PCAT6, a newly discovered carcinogenic lncRNA, is abnormally elevated in various human maligt tumors. Until now, PCAT6 has been found to sponge various miRNAs to activate the signaling pathways, which further affects tumor cell proliferation, migration, invasion, cycle, apoptosis, radioresistance, and chemoresistance. Moreover, PCAT6 has been shown to exert biological functions beyond ceRNAs. In this review, we summarize the biological characteristics of PCAT6 in a variety of human maligcies and describe the biological mechanisms by which PCAT6 can facilitate tumor progression. Finally, we discuss its diagnostic and prognostic values and clinical applications in various human maligcies.

Can whole genome sequencing be used for diagnosis of mitochondrial disease?

Yes. Whole genome sequencing is a useful diagnostic test in patients with suspected mitochondrial disorders, yielding a diagnosis in a further 31% after exclusion of common causes. Most diagnoses were non-mitochondrial disorders and included developmental disorders with intellectual disability, epileptic encephalopathies, other metabolic disorders, cardiomyopathies, and leukodystrophies. These would have been missed if a targeted approach was taken, and some have specific treatments.

What are the targets of avapritinib?

Avapritinib is a novel inhibitor of KIT/PDGFRA. It is approved in the U.S. for the treatment of adults with PDGFRA exon 18-mutant unresectable or metastatic gastrointestinal stromal tumors.

In a phase I trial of avapritinib (formerly BLU-285), which targets D816V mutant KIT, for the treatment of advanced systemic mastocytosis, patients experienced rapid and durable disease control. The overall response rate was 72%, and 56% of patients experienced a complete or partial response. No patients discontinued treatment due to adverse events, most of which were mild to moderate in nature. The frequent occurrence of multidrug resistance (MDR) conferred by the overexpression of ATP-binding cassette (ABC) transporters ABCB1 and ABCG2 in cancer cells remains a therapeutic obstacle for scientists and clinicians. Consequently, developing or identifying modulators of ABCB1 and ABCG2 that are suitable for clinical practice is of great importance. Therefore, we have explored the drug repositioning approach to identify candidate modulators of ABCB1 and ABCG2 from tyrosine kinase inhibitors with known pharmacological properties and anticancer activities. In this study, we discovered that avapritinib (BLU-285), a potent, selective, and orally bioavailable tyrosine kinase inhibitor against mutant forms of KIT and platelet-derived growth factor receptor alpha (PDGFRA), attenuates the transport function of both ABCB1 and ABCG2. Moreover, avapritinib restores the chemosensitivity of ABCB1- and ABCG2-overexpressing MDR cancer cells at nontoxic concentrations. These findings were further supported by results of apoptosis induction assays, ATP hydrolysis assays, and docking of avapritinib in the drug-binding pockets of ABCB1 and ABCG2. Altogether, our study highlights an additional action of avapritinib on ABC drug transporters, and a combination of avapritinib with conventional chemotherapy should be further investigated in patients with MDR tumors. Metastatic vulvar melanoma is a rare and aggressive disease and survival is usually poor. Vulvar melanomas harbor BRAF V600 mutations only infrequently; consequently, target therapy is a rare therapeutic option and immunotherapy usually has only a weak effect. On the other hand, KIT mutations are rare in cutaneous melanomas, but relatively frequent in mucosal melanomas, particularly in vulvar-vaginal melanomas, and can be a therapeutic target. Herein, we report a clinical case of a patient with metastatic vulvar melanoma, harboring an exon 17 c-KIT mutation, treated with avapritinib (BLU-285) - a highly potent and selective oral kinase inhibitor designed to treat imatinib-resistant gastro-intestinal stromal tumors (GIST) by targeting KIT/PDGFRα activation loop mutants (exons 17/18). After failure of the combination of ipilimumab + nivolumab first and then nivolumab alone, the patient received avapritinib 300 mg/daily for central nervous system (CNS), lymph-nodal, right adrenal gland, lung, and subcutaneous metastases. Best response was partial remission, according to RECIST 1.1 criteria. Time to treatment progression was 11 months. Main toxicities were grade 2 cutaneous vasculitis that required avapritinib discontinuation, and grade 2 uveitis of unknown origin, treated by vitrectomy and empiric antibiotic and antiviral therapy due to negative cultural tests. Uveitis was detected at the time of progression and therapy was definitively discontinued. In conclusion, avapritinib proved to be effective even in the presence of a pretreated disease, a high tumor burden, and brain metastases. In our experience, treatment was feasible and toxicity manageable. Considering the lack of effective therapies and the poor outcome of the disease, determination of c-KIT mutations should be performed routinely in cases of metastatic mucosal melanoma. Author information: (1)Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany. (2)DKTK partner site Essen, German Cancer Consortium (DKTK), Heidelberg, Germany. (3)Portland VA Health Care System, Portland, Oregon; Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon; and Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon. (4)Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany. (5)Drug Discovery Hub Dortmund (DDHD) am Zentrum für Integrierte Wirkstoffforschung (ZIW), Dortmund, Germany. (6)Gerhard-Domagk-Institute of Pathology, University of Münster Medical Center, Münster, Germany. (7)Institute of Pathology, University Medical Center Essen, Essen, Germany. (8)Department of Visceral Surgery, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany. (9)Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. (10)Blueprint Medicines, Cambridge, Massachusetts. (11)Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany. [email protected]. (#)Contributed equally BACKGROUND: Avapritinib, a novel inhibitor of KIT/PDGFRA, is approved in the U.S. for the treatment of adults with PDGFRA exon 18-mutant unresectable or metastatic gastrointestinal stromal tumors (U/M GISTs). We assessed the safety of avapritinib and provide evidence-based guidance on management of avapritinib-associated adverse events (AEs), including cognitive effects and intracranial bleeding. MATERIALS AND METHODS: We performed a post hoc analysis of data from a two-part, single-arm dose escalation/expansion phase I study (NAVIGATOR; NCT02508532) in patients with U/M GISTs treated with oral avapritinib 30-600 mg once daily. The primary endpoints were safety and tolerability; the impact of dose modification (interruption and/or reduction) on progression-free survival (PFS) was a secondary endpoint. Efficacy analyses were limited to patients who started avapritinib at 300 mg (approved dose). RESULTS: Of 250 patients enrolled in the study, 74.0% presented with KIT mutation and 24.8% presented with PDGFRA exon 18-mutation; 66.8% started avapritinib at 300 mg. The most common treatment-related AEs (any grade) were nausea (59.2%), fatigue (50.0%), periorbital edema (42.0%), anemia (39.2%), diarrhea (36.0%), vomiting (36.0%), and increased lacrimation (30.8%). No treatment-related deaths occurred. Among 167 patients starting on 300 mg avapritinib, all-cause cognitive effects rate (grade 1-2) was 37.0% in all patients and 52.0% in patients ≥65 years. Cognitive effects improved to a lower grade more quickly with dose modification (1.3-3.1 weeks) than without (4.9-7.6 weeks). Median PFS was 11.4 months with dose modification and 7.2 months without. CONCLUSION: Tolerability-guided dose modification of avapritinib is an effective strategy for managing AEs in patients with GISTs. IMPLICATIONS FOR PRACTICE: Early recognition of adverse events and tailored dose modification appear to be effective approaches for managing treatment-related adverse events and maintaining patients on avapritinib. Dose reduction does not appear to result in reduced efficacy. Patients' cognitive function should be assessed at baseline and monitored carefully throughout treatment with avapritinib for the onset of cognitive adverse events. Dose interruption is recommended at the first sign of any cognitive effect, including grade 1 events. INTRODUCTION: 90% of gastrointestinal stromal tumors (GISTs) harbor an activating mutation in the KIT or PDGFRα oncogene, and these are known to confer imatinib sensitivity. AREAS COVERED: The author reviews the data regarding the current management of GIST, mechanisms of resistance to imatinib, and new drugs currently in clinical development and provides his unique perspectives on the subject matter. EXPERT OPINION: Several studies have shown that the response to imatinib in GIST patients mainly depends on the mutational status of KIT or PDGFRα. Moreover, most, if not all, patients treated with imatinib for advanced GIST will develop a secondary progressive disease under the treatment. In most cases, such progressions are the result of acquired resistance due to the occurrence of secondary c-KIT mutations, especially in GISTs with primary exon 11 mutations. Sunitinib and regorafenib are inhibitors of multiple tyrosine kinases, including KIT, PDGFRα, PDGFRβ, and VEGFRs, and are approved for the management of imatinib- and imatinib/sunitinib-refractory GIST patients, respectively. Clearly, better knowledge of the molecular mechanisms underlying the resistance to imatinib as well as the development of a new class of broad-spectrum tyrosine kinase inhibitors such as avapritinib and ripretinib will provide new individualized therapeutic strategies for GIST patients. BACKGROUND: Most gastrointestinal stromal tumors (GIST) driven by KIT or platelet-derived growth factor receptor A (PDGFRA) mutations develop resistance to available tyrosine kinase inhibitor (TKI) treatments. NAVIGATOR is a two-part, single-arm, dose escalation and expansion study designed to evaluate safety and antineoplastic activity of avapritinib, a selective, potent inhibitor of KIT and PDGFRA, in patients with unresectable or metastatic GIST. MATERIALS AND METHODS: Eligible patients were 18 years or older with histologically or cytologically confirmed unresectable GIST and Eastern Cooperative Oncology Group performance status ≤2 and initiated avapritinib at 300 mg or 400 mg once daily. Primary endpoints were safety in patients who initiated avapritinib at 300 mg or 400 mg once daily and overall response rate (ORR) in patients in the safety population with three or more previous lines of TKI therapy. RESULTS: As of November 16, 2018, in the safety population (n = 204), the most common adverse events (AEs) were nausea (131 [64%]), fatigue (113 [55%]), anemia (102 [50%]), cognitive effects (84 [41%]), and periorbital edema (83 [41%]); 17 (8%) patients discontinued due to treatment-related AEs, most frequently confusion, encephalopathy, and fatigue. ORR in response-evaluable patients with GIST harboring KIT or non-D842V PDGFRA mutations and with at least three prior therapies (n = 103) was 17% (95% confidence interval [CI], 10-25). Median duration of response was 10.2 months (95% CI, 7.2-10.2), and median progression-free survival was 3.7 months (95% CI, 2.8-4.6). CONCLUSION: Avapritinib has manageable toxicity with meaningful clinical activity as fourth-line or later treatment in some patients with GIST with KIT or PDGFRA mutations. IMPLICATIONS FOR PRACTICE: In the NAVIGATOR trial, avapritinib, an inhibitor of KIT and platelet-derived growth factor receptor A tyrosine kinases, provided durable responses in a proportion of patients with advanced gastrointestinal stromal tumors (GIST) who had received three or more prior therapies. Avapritinib had a tolerable safety profile, with cognitive adverse events manageable with dose interruptions and modification in most cases. These findings indicate that avapritinib can elicit durable treatment responses in some patients with heavily pretreated GIST, for whom limited treatment options exist. Conflict of interest statement: Conflict of interest statement Dr Jones reported receiving grants from MSD; and personal fees from Adaptimmune, Athenex, Blueprint Medicines Corporation, Clinigen, Eisai, Eli Lilly, Epizyme, Daichii Sankyo, Deciphera Pharmaceuticals, Helsinn, Immunedesign, Merck, PharmaMar, Tracon and UptoDate outside the submitted work. Dr Serrano reported receiving other support from Bayer, Blueprint Medicines Corporation, Deciphera Pharmaceuticals, Eli Lilly, Novartis, Pfizer and PharmaMar; and grants from Bayer, Deciphera Pharmaceuticals and Pfizer outside the submitted work. Dr von Mehren reported receiving other support from Blueprint Medicines Corporation during the conduct of the study; and other support from Arog Pharmaceuticals, Deciphera Pharmaceuticals, Exelixis and Novartis outside the submitted work. Dr George reported receiving research support to her institution from Ariad, Bayer, Blueprint Medicines Corporation, Daiichi Sankyo, Deciphera Pharmaceuticals, Novartis and Pfizer; and advisory board/consulting fees from AstraZeneca, Blueprint Medicines Corporation, Daiichi Sankyo, Deciphera Pharmaceuticals and Eli Lilly. Dr Heinrich reported receiving grants and personal fees from Blueprint Medicines Corporation; and personal fees and other support from Molecular MD during the conduct of the study; personal fees and other from Novartis; and grants and personal fees from Deciphera Pharmaceuticals outside the submitted work. Dr Heinrich also has a patent “Treatment of Gastrointestinal Stromal Tumors” licenced to Novartis, and a patent “Activating Mutations of PDGFRA” issued. Dr Kang reported receiving personal fees from ALX Oncology, Amgen, Bristol Myers Squibb, Daehwa Pharmaceutical, MacroGenics, Novartis, Surface Oncology and Zymeworks outside the submitted work. Dr Schöffski reported receiving personal fees from Deciphera Pharmaceuticals; other support from Adaptimmune, Blueprint Medicines Corporation, Deciphera Pharmaceuticals, Exelixis, Eisai, Eli Lilly, Ellipses Pharma, Genmab, Intellisphere, Loxo Oncology, Merck, Plexxikon, Servier and Transgene; and grants from Ipsen and MSD outside the submitted work. Dr Cassier reported receiving personal fees from Blueprint Medicines Corporation during the conduct of the study; other support from AbbVie, Bayer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Merck Serono, MSD, Novartis and Roche/Genentech; personal fees from Amgen, Bristol Myers Squibb, MSD, Novartis and Roche/Genentech; non-ficial support from MSD and Novartis; and grants from Novartis outside the submitted work. Dr Mir reported receiving consulting fees from Eli Lilly, Janssen, Lundbeck, Pfizer, Roche, Servier and Vifor Pharma; and owns stock options from Amplitude Surgical, Transgene and Ipsen. Dr Chawla reported receiving funding from ADI, Amgen, GlaxoSmithKline, Ignyta, Immix Bopharma, Inhibrx, Janssen, Karyopharm Therapeutics, Roche, SARC and Tracon outside the submitted work. Dr Eskens has nothing to disclose. Dr Rutkowski reported receiving personal fees from Blueprint Medicines Corporation, Bristol Myers Squibb, Merck, MSD, Novartis, Pierre Fabre, Pfizer, Roche and Sanofi outside the submitted work. Dr Tap reported receiving other support from Blueprint Medicines Corporation during the conduct of the study; receiving personal fees from Agios Pharmaceuticals, Blueprint Medicines Corporation, Daiichi Sankyo, Deciphera Pharmaceuticals, Eli Lilly, EMD Serono, Eisai, GlaxoSmithKline, Janssen, Immune Design, Loxo Oncology and NanoCarrier outside the submitted work; having a patent Companion Diagnostic for CDK4 inhibitors – 14/854,329 pending to MSKCC/SKI; attending scientific advisory boards for Atropos Therapeutics and Certis Oncology Solutions; being a consultant for Daiichi Sankyo; having stock ownership in Atropos Therapeutics and Daiichi Sankyo; and having involvement in an FDA ODAC meeting for pexidartinib. Dr Zhou is a former employee of Blueprint Medicines Corporation. Dr Roche reported receiving other support from Epizyme outside the submitted work; and being a current employee and shareholder of Blueprint Medicines Corporation. Dr Bauer reported receiving grants from Blueprint Medicines Corporation, Incyte and Novartis; personal fees from Bayer, Blueprint Medicines Corporation, Deciphera Pharmaceuticals, Exelixis and Novartis during the conduct of the study; and personal fees from ADC Therapeutics, Daiichi Sankyo, Eli Lilly, Exelixis, Janssen-Cilag, Nanobiotix, PharmaMar and Plexxikon outside the submitted work. Gastrointestinal stromal tumors (GIST) are rare neoplasms arising from the interstitial cell of Cajal in the gastrointestinal tract. Two thirds of GIST in adult patients have c-Kit mutation and smaller fractions have platelet derived growth factor receptor alpha (PDGFRA) mutation. Surgery is the only curative treatment for localized disease. Imatinib improves survival when used adjuvantly and in advanced disease. Several targeted therapies have also improved survival in GIST patients after progression on imatinib including sunitinib and regorafenib. Recently, United States Federal and Drug Administration (FDA) approved two new tyrosine kinase inhibitors for the treatment of heavily pretreated advanced/unresectable GIST including avapritinib (a selective inhibitor for PDGFRA exon 18 mutation including D842V mutations) and ripretinib (a broad-spectrum kinase inhibitor of c-Kit and PDGFRA). In this article, we will provide a comprehensive review of GIST including the current standard of care treatment and exploring future paradigm shifts in therapy. Avapritinib is a protein kinase inhibitor designed to selectively inhibit oncogenic KIT and platelet-derived growth factor receptor alpha (PDGFRA) mutants by targeting the active conformation of the kinase. On 24 September 2020, a marketing authorisation valid through the European Union was issued for avapritinib as treatment of adult patients with unresectable or metastatic gastrointestinal stromal tumours (GIST) harbouring the PDGFRA D842V mutation. The drug was evaluated in an open-label, phase I, first-in-human, dose-escalation, open-label study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of avapritinib in adults with unresectable or metastatic GIST. The benefit of avapritinib was observed in patients with GIST harbouring the PDGFRA D842V mutation. The overall response rate was 95% (95% confidence interval 82.3%-99.4%), with a median duration of response of 22.1 months (95% confidence interval 14.1-not estimable months). The most common adverse events were nausea, fatigue, anaemia, periorbital and face oedema, hyperbilirubinaemia, diarrhoea, vomiting, increased lacrimation, and decreased appetite. Most of the reported cognitive effects were mild memory impairment. Rarer events were cases of severe encephalopathy and intracranial or gastrointestinal bleeding. The aim of this manuscript is to summarise the scientific review of the application leading to regulatory approval in the European Union. Conflict of interest statement: Yoon-Koo KangConsulting or Advisory Role: DAEHWA Pharmaceutical, Bristol Myers Squibb, Zymeworks, ALX Oncology, Amgen, Novartis, Macrogenics, Surface Oncology, Blueprint Medicines Suzanne GeorgeStock and Other Ownership Interests: Abbott LaboratoriesConsulting or Advisory Role: Blueprint Medicines, Deciphera, Bayer, Lilly, UpToDate, Research to Practice, MORE Health, Daiichi, KayotheraResearch Funding: Blueprint Medicines, Deciphera, Daiichi Sankyo RD Novare, Merck, Eisai, SpringWorks TherapeuticsPatents, Royalties, Other Intellectual Property: UptoDateExpert Testimony: BayerOther Relationship: Research to Practice, WCG Robin L. JonesConsulting or Advisory Role: Lilly, Immune Design, Merck Serono, Adaptimmune, Daiichi Sankyo, Eisai, Morphotek, TRACON Pharma, Immodulon Therapeutics, Deciphera, PharmaMar, Blueprint Medicines, Clinigen Group, Epizyme, Boehringer Ingelheim, Bayer, Karma Oncology, UpToDateResearch Funding: GlaxoSmithKlineTravel, Accommodations, Expenses: PharmaMar Piotr RutkowskiHonoraria: Bristol Myers Squibb, MSD, Novartis, Roche, Lilly, Pfizer, Pierre Fabre, Sanofi, MerckConsulting or Advisory Role: Novartis, Blueprint Medicines, Bristol Myers Squibb, Pierre Fabre, MSD, AmgenSpeakers' Bureau: Pfizer, Novartis, LillyResearch Funding: Novartis, Roche, Bristol Myers SquibbTravel, Accommodations, Expenses: Orphan Europe, Pierre Fabre Olivier MirStock and Other Ownership Interests: Transgene, Amplitude Surgical, IpsenHonoraria: RocheConsulting or Advisory Role: Lilly, Pfizer, Roche, Lundbeck, JanssenSpeakers' Bureau: Lilly, Roche, PfizerResearch Funding: Ipsen, AstraZeneca, Blueprint MedicinesTravel, Accommodations, Expenses: Roche, Pfizer Shreyaskumar PatelConsulting or Advisory Role: Novartis, Immune Design, MaxiVax, Epizyme, Janssen, Lilly, Daiichi Sankyo, Bayer, Dova Pharmaceuticals, DecipheraResearch Funding: Blueprint Medicines, Hutchinson Med Pharma Margaret von MehrenConsulting or Advisory Role: Deciphera, ExelixisResearch Funding: ArQule, Novartis, Blueprint Medicines, Deciphera, Gradalis, Springworks Therapeutics, Lilly, Arog, Genmab, ASCOTravel, Accommodations, Expenses: Deciphera Pharmaceuticals, NCCNOther Relationship: NCCN Peter HohenbergerHonoraria: Roche, AstraZeneca, GlaxoSmithKline, BLUMedicine, NovartisConsulting or Advisory Role: Nanobiotix, PfizerResearch Funding: Novartis, Siemens Healthcare DiagnosticsTravel, Accommodations, Expenses: PharmaMar Victor VillalobosEmployment: Janssen OncologyConsulting or Advisory Role: Janssen, Lilly, Novartis, AbbVie, Ignyta, Agios, Epizyme, Blueprint Medicines, Springworks Therapeutics, NanoCarrier, Daiichi SankyoTravel, Accommodations, Expenses: Lilly, Janssen, Xencor, GenMab, Epizyme Mehdi BrahmiExpert Testimony: BayerTravel, Accommodations, Expenses: PharmaMar, Mundipharma William D. TapLeadership: Certis Oncology Solutions, Atropos, Innova TherapeuticsStock and Other Ownership Interests: Certis Oncology Solutions, AtroposConsulting or Advisory Role: EMD Serono, Lilly, Daiichi Sankyo, Blueprint Medicines, Agios, NanoCarrier, Deciphera, C4 Therapeutics, Mundipharma, Adcendo, Ayala Pharmaceuticals, Kowa Pharmaceutical, Servier, AbMaxBioResearch Funding: Novartis, Lilly, Plexxikon, Daiichi Sankyo, TRACON Pharma, Blueprint Medicines, Immune Design, BioAtla, DecipheraPatents, Royalties, Other Intellectual Property: Companion Diagnostic for CDK4 inhibitors—14/854,329, Enigma and CDH18 as companion Diagnostics for CDK4 inhibition—SKI2016-021-03 Jonathan TrentConsulting or Advisory Role: Novartis, Lilly, Janssen, Blueprint Medicines, Deciphera, Daiichi Sankyo, Epizyme, Agios, C4 Therapeutics, Bayer Patrick SchöffskiHonoraria: Deciphera, Blueprint Medicines, Boehringer IngelheimConsulting or Advisory Role: Blueprint Medicines, Ellipses Pharma, Adaptimmune, Intellisphere, Transgene, Deciphera, Exelixis, Boehringer Ingelheim, Medscape, Guided Clarity, Ysios Capital, Studiecentrum voor KernenergieResearch Funding: CoBioRes NV, Eisai, G1 Therapeutics, Novartis, PharmaMarTravel, Accommodations, Expenses: MSD, Ipsen, Boehringer Ingelheim Kevin HeEmployment: Blueprint Medicines, AgiosStock and Other Ownership Interests: Blueprint Medicines, Agios, Incyte Paggy HewEmployment: Blueprint MedicinesStock and Other Ownership Interests: Blueprint MedicinesTravel, Accommodations, Expenses: Blueprint Medicines Kate NewberryEmployment: Blueprint MedicinesStock and Other Ownership Interests: Blueprint Medicines Maria RocheEmployment: Blueprint Medicines, EpizymeStock and Other Ownership Interests: Blueprint Medicines, Epizyme Michael C. HeinrichStock and Other Ownership Interests: MolecularMDHonoraria: NovartisConsulting or Advisory Role: MolecularMD, Novartis, Blueprint Medicines, Deciphera, Theseus PharmaceuticalsPatents, Royalties, Other Intellectual Property: Patent on treatment of GIST-licensed to NovartisExpert Testimony: Novartis Sebastian BauerHonoraria: Novartis, Pfizer, Bayer, Pharmamar, GlaxoSmithKlineConsulting or Advisory Role: Blueprint Medicines, Bayer, Lilly, Deciphera, Nanobiotix, Daiichi Sankyo, Exelixis, Janssen-Cilag, ADC Therapeutics, Mundipharma, GlaxoSmithKlineResearch Funding: Blueprint Medicines, Novartis, IncyteTravel, Accommodations, Expenses: PharmamarNo other potential conflicts of interest were reported. Author information: (1)Medical Oncology Department, University Hospital Fundación Jimenez Diaz, Madrid, Spain. [email protected]. (2)University Hospital General de Villalba, Madrid, Spain. (3)Instituto de Investigacion Sanitaria Fundacion Jimenez Diaz (IIS/FJD), Madrid, Spain. (4)Institute of Biomedicine of Sevilla (IBIS, HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain. (5)Pathology Department, University Hospital Son Espases, Mallorca, Spain. (6)Soft Tissue and Bone Pathology, Histopathology and Pediatric Pathology Unit, Diagnostic Pathology and Laboratory Medicine Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Nazionale Tumori, Milan, Italy. (7)Pathology Department, University Hospital Vall D'Hebron, Barcelona, Spain. (8)Centro de Investigación Biomédica en RED (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain. (9)Pathology Department, Santa Creu I Sant Pau Hospital, Barcelona, Spain. (10)Anatomic Pathology Unit, Humanitas Clinical and Research Center - IRCCS -, Rozzano (MI), Italy. (11)Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy. (12)Pathology Department, Service d'Anatomie Pathologique, Institut Bergonié, Bordeaux, France. (13)Bergonie Institute, Department of Biopathology, Bordeaux, and Bordeaux University, Talence, France. (14)Clinical Bioinformatics Area. Fundación Progreso y Salud (FPS). CDCA, Hospital Virgen del Rocio, Sevilla, Spain. (15)Bioinformatics in Rare Diseases (BiER). Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), FPS, Hospital Virgen del Rocio, Sevilla, Spain. (16)INB-ELIXIR-es FPS, Hospital Virgen del Rocío, Sevilla, Spain. (17)Department of Anatomy and Pathological Histology, IRCCS, Istituto Ortopedico Rizzoli, Bologna, Italy. (18)Research and Statistics Infrastructure, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy. (19)Chemotherapy Unit, IRCCS, Istituto Ortopedico Rizzoli, Bologna, Italy. (20)Cancer Medicine Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori, Milan, Italy. (21)Department of Surgery, Istituto Clinico Humanitas, Rozzano, Italy. (22)Medical Oncology Department, Santa Creu I Sant Pau Hospital, Barcelona, Spain. (23)Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy. (24)Department of Medical Oncology, Centre Léon Bérard & Université Claude Bernard Lyon I, Lyon, France. (25)Department of Oncology, Medical Oncology 1 Unit, Istituto Oncologico Veneto IOV, IRCCS, Padova, Italy. (26)Hematology Department, Son Espases University Hospital, Mallorca, Spain. (27)Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain. (28)Medical Oncology Department, University Hospital Fundación Jimenez Diaz, Madrid, Spain. (29)Department of Pathology, Treviso General Hospital, Treviso, Italy. (30)University of Padua, Padova, Italy. (31)Laboratory of Oncologic Research, Istituto Ortopedico Rizzoli, Bologna, Italy. (32)Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. (#)Contributed equally

What is Jackhammer esophagus?

Jackhammer esophagus (JE) is a hypercontractile esophageal motor disorder defined by at least two swallows with a distal contractile integral (DCI) >8000 mm Hg.s.cm during high-resolution manometry (HRM).

Nutcracker esophagus and jackhammer esophagus are largely unknown motility disorders, also sometimes called hypertensive and hypercontractile peristalsis, respectively. There is currently no standardized diagnostic or management plan for these diseases. Here, we report on three patients with jackhammer/nutcracker esophagus who were treated with either peroral endoscopic myotomy or a systemic steroid regimen, focusing particularly on two novel presentations of nutcracker and jackhammer esophagus involving eosinophilic infiltration into the muscularis propria, and their responses to both interventions. BACKGROUND: Jackhammer Esophagus is defined as intact esophageal peristaltic contractions with extremely elevated amplitudes. We conducted a retrospective study to identify the frequency of esophageal hypercontractility and the clinical characteristics of Jackhammer Esophagus. METHODS: Charts for the patients referred for manometric study at a tertiary-care motility center were reviewed. Data were collected utilizing the new Chicago classification criteria for Jackhammer Esophagus. Concomitant clinical variables were also explored. RESULTS: Eight patients were identified with Jackhammer Esophagus from a total of 205 (127 female/77 male) patients referred for high-resolution esophageal manometry. Jackhammer patients had an average distal contractile integral (DCI) of 9061 mmHg/ sec/ cm and median maximal DCI of 16,433 mmHg/ sec/ cm. The greatest DCI from 15 swallows was 28,875 mmHg/ sec/ cm. Hypercontractility was associated with multipeaked contractions in every Jackhammer patient. The mean lower esophageal sphincter (LES) pressure was 41 mm Hg with 4 patients having a hypertensive pressure of >40 mm Hg. Three of the 8 (37.5%) Jackhammer group had incomplete LES relaxation by integrated relaxation pressure criteria (>15 mm Hg residual pressure). Dysphagia (8/8) was the domit indication for the manometric study, whereas the clinical background setting was gastroesophageal reflux disease (4/8) and hiatal hernia (1/8). Treatments included smooth muscle relaxation, antireflux regimens, and pneumatic dilation of the LES. CONCLUSIONS: Jackhammer Esophagus, an extreme manometric phenotype, was identified in 4.0% of patients referred to a University Motility Center. The patients with these esophageal hypercontractility states present mainly with dysphagia. A subgroup of Jackhammer did have accompanying incomplete LES relaxation and responded to targeted therapy with pneumatic dilatation. BACKGROUND AND STUDY AIMS: With the success of peroral endoscopic myotomy (POEM) in treatment of achalasia, its successful application to other spastic esophageal motility disorders such as Jackhammer esophagus has been noted. The question of whether the lower esophageal sphincter (LES) should be included in the myotomy for Jackhammer esophagus is a topic of current debate. Here, we report our experience and results with four patients with Jackhammer esophagus treated with POEM. The clinical and manometric results are presented and their potential implications are discussed. PATIENTS AND METHODS: Between January 2014 and July 2015, four patients underwent POEM for treatment of Jackhammer esophagus at our center. Manometry was performed prior to and after POEM. All patients met the Chicago classification criteria for Jackhammer esophagus and received a barium esophagram and endoscopic examination before having POEM. RESULTS: All patients had uneventful procedures without any intraoperative or post-procedure complications. Patients in which the LES was included during POEM had resolution or significant improvement in symptoms. One patient in whom the LES was preserved had resolution of chest pain but developed significant dysphagia and regurgitation. Subsequently this individual received a repeat POEM which included the LES, resulting in symptom resolution. CONCLUSIONS: POEM is a suitable treatment for patients with Jackhammer esophagus. Until there are larger-scale randomized studies, we speculate that based on our clinical experience and physiologic and manometric observations, obligatory inclusion of the LES is justified to reduce the risk of symptom development from iatrogenic ineffective esophageal motility or subsequent progression to achalasia. Hypercontractile esophagus (nicknamed jackhammer esophagus) is a recently defined disease within the esophageal motility disorders classification. Responses to treatments for jackhammer esophagus have been inconsistent in previous trials, possibly due to its heterogeneous manifestation. Thus, we reviewed 10 patients diagnosed with jackhammer esophagus and compared their clinical and manometric features at baseline. Additionally, manometric and symptomatic responses after treatment with known smooth muscle relaxants, including anticholinergic drugs (cimetropium bromide and scopolamine butylbromide) and a phosphodiesterase-5 inhibitor (sildenafil) were compared. We observed two distinct subgroups in the findings: one with hypercontractility and normal distal latencies ("classic jackhammer esophagus," n=7) and the other with hypercontractility and short distal latencies ("spastic jackhammer esophagus," n=3). The two types also differed in their responses to medications in that symptoms improved upon treatment with an anticholinergic agent in classic jackhammer esophagus patients, while spastic jackhammer esophagus was unresponsive to both the anticholinergic drugs and the phosphodiesterase-5 inhibitor. In conclusion, hypercontractile esophagus may be a heterogeneous disease with different underlying pathophysiologies. We introduced two novel terms, "classic jackhammer esophagus" and "spastic jackhammer esophagus," to distinguish the two types. BACKGROUND: Jackhammer esophagus (JE) is a rare esophageal motility disorder defined in the Chicago Classification of Esophageal Motility by presence of excessively high distal contractile integral (DCI) on high-resolution manometry (HRM), with unknown natural manometric course. We examined the development of achalasia over time in patients with JE. METHODS: Through a retrospective longitudinal design, patients with Jackhammer contractions who had more than one HRM between 2005 and 2015 were identified. Any change in manometric finding was assessed for the presence of achalasia. Demographic and manometric risk factors for this progression were then sought in univariate analysis. KEY RESULTS: Of 3363 HRM studies, 229 subjects had multiple manometries, accounting for 528 studies. Twelve subjects met our inclusion criteria for JE on any of the multiple tests, represented by 27 studies for a total of 347 patient-months of manometric follow-up. Subjects with JE whose manometry included impedance demonstrated consistent esophageal bolus clearance. Of 12 subjects with Jackhammer contractions, three subjects progressed to type III achalasia, over a mean of 24 months (range: 19-31 months). At the time of diagnosis with JE, impaired esophago-gastric junction relaxation was seen in all three subjects and was the only risk factor that could predict progression to achalasia (P<.01). CONCLUSIONS & INFERENCES: In this unique study of the natural course of JE, we have shown that JE can progress to achalasia. Manometric findings at the time of JE diagnosis might predict this progression. GOALS: The aim of our study was to characterize jackhammer esophagus symptoms and their relationship with the distal contractile integral (DCI) and bolus transit. BACKGROUND: Jackhammer esophagus is defined by the Chicago Classification version 3.0. This diagnosis is relatively new, with the most current definition being established in 2014. The forerunners of this diagnosis, nutcracker (or hypercontractile) esophagus, have been associated with noncardiac chest pain (NCCP). STUDY: A retrospective chart review was performed of motility studies from 2011 to 2016. Studies with a diagnosis of jackhammer esophagus, hypercontractile esophagus, nutcracker, esophagogastric junction outflow obstruction, or hypertensive lower esophageal sphincter were reread using Chicago Classification version 3.0, and were included if they met criteria for jackhammer esophagus. Unpaired t-tests were used for analysis (P≤0.05). RESULTS: In total, 142 studies were identified with the above diagnoses. After excluding 84 studies, 58 remained for analysis and 17 were found to have jackhammer esophagus (29%). The mean age was 54 (28 to 75), 5 (29%) were males and 12 (71%) were females. The primary indications were NCCP (5), dysphagia (8), and other causes (4) (cough, heartburn, or regurgitation). The mean DCIs were 17,245 mm Hg×s×cm (NCCP), 14,669 mm Hg×s×cm (dysphagia), and 11,264 mm Hg×s×cm (other causes). The mean DCIs were compared: NCCP versus dysphagia (P=0.41), and NCCP versus other causes (P=0.05). Fifteen (88%) had normal bolus transit for both liquid and viscous swallows. CONCLUSIONS: In our small sample size, dysphagia was frequently the presenting symptom followed by NCCP. Those with NCCP have a trend toward a higher DCI. Bolus transit appeared to be normal in this patient population. More data are needed to further elucidate the genesis of symptoms and how they relate to the degree of contractility. The jackhammer esophagus is a rare hypercontractile disorder and diagnosis is based on high-resolution manometry. Peroral endoscopic myotomy (POEM) of the spastic esophagus segments has been described. We report a pediatric patient with jackhammer esophagus that was treated endoscopically. This trial was designed to assess the prevalence and characteristics of Jackhammer esophagus (JE), a novel hypercontractile disorder associated with progression to achalasia and limited outcomes following anti-reflux surgery in patients with typical symptoms of GERD and responsiveness to proton pump inhibitor (PPI) therapy. Consecutive patients, who were referred for surgical therapy because of PPI responsive typical symptoms of GERD, were prospectively assessed between January 2014 and May 2017. Patients diagnosed with JE subsequently underwent rigorous clinical screening including esophagogastroduodenoscopy (EGD), ambulatory pH impedance monitoring off PPI and a PPI trial. Out of 2443 evaluated patients, 37 (1.5%) subjects with a median age of 56.3 (51.6; 65) years were diagnosed with JE and left for final analysis. Extensive testing resulted in 16 (43.2%) GERD positive patients and 5 (13.9%) participants were observed to have an acid hypersensitive esophagus. There were no clinical parameters that differentiated phenotypes of JE. The prevalence of JE in patients with typical symptoms of GERD and response to PPI therapy is low. True GERD was diagnosed in less than half of this selected cohort, indicating the need for objective testing to stratify phenotypes of JE. (NCT03347903). Jackhammer esophagus (JE) is a hypercontractile disorder, the pathogenesis of which is incompletely understood. Multiple rapid swallows (MRS) and rapid drink challenge (RDC) are complementary tests used during high-resolution manometry (HRM) that evaluate inhibitory and excitatory neuromuscular function and latent obstruction, respectively. Our aim was to evaluate esophageal pathophysiology using MRS and RDC in 83 JE patients (28 men; median age: 63 yr; IQR: 54-70 yr). Twenty-one healthy subjects (11 men; median age: 28 yr; range: 26-30 yr) were used as a control group. All patients underwent solid-state HRM with ten 5-ml single swallows (SS) and one to three 10-ml MRS; 34 patients also underwent RDC. Data are shown as median (interquartile range). Abnormal motor inhibition was noted during at least one MRS test in 48% of JE patients compared with 29% of controls ( P = 0.29). Mean distal contractile integral (DCI) after MRS was significantly lower than after SS [6,028 (3,678-9,267) mmHg·cm·s vs. 7,514 (6,238-9,197) mmHg·cm·s, P = 0.02], as was highest DCI ( P < 0.0001). Consequently, 66% of JE patients had no contraction reserve. At least one variable of obstruction during RDC (performed in 34 patients) was outside the normal range in 25 (74%) of JE patients. Both highest DCI after SS and pressure gradient across the esophagogastric junction (EGJ) during RDC were higher in patients with dysphagia versus those without ( P = 0.04 and 0.01, respectively). Our data suggest altered neural control in JE patients with heterogeneity in inhibitory function. Furthermore, some patients had latent EGJ obstruction during RDC, which correlated with the presence of dysphagia. NEW & NOTEWORTHY Presence of abnormal inhibition was observed during multiple rapid swallows (MRS) in some but not all patients with jackhammer esophagus (JE). Unlike healthy subjects, JE patients were more strongly stimulated after single swallows than after MRS. An obstructive pattern was frequently observed during rapid drink challenge (RDC) and was related to presence of dysphagia. MRS and RDC during high-resolution manometry are useful to show individual pathophysiological patterns in JE and may guide optimal therapeutic strategies. BACKGROUND: Jackhammer esophagus is a hypercontractile esophageal disorder recently brought to light with the advent of high resolution manometry (HRM). As little is known about its clinical presentation, the aim of this study was to identify the clinical characteristics associated with this new gastrointestinal motility disorder. METHODS: A retrospective study was conducted on patients visiting the CHUM's Gastro-Intestinal Motility Center from January 2015 to December 2017. The HRM diagnoses were collated in a database along with age and sex of every individual. The latest Chicago classification (version 3.0) was used. Among all the patients subjected to HRM, those diagnosed with Jackhammer esophagus were included in the study. Patient charts were reviewed to collect relevant demographic and clinical data. KEY RESULTS: A total of 36 patients with Jackhammer esophagus were included (62 ± 13 years age, 89% females). Their main symptoms were dysphagia (72%), pyrosis (42%), retrosternal chest pain (36%), and epigastralgia (33%). Other manometric findings were hypertonia (22%) and/or inadequate relaxation (19%) of the lower esophageal sphincter. Among the 26 patients who had esogastroduodenoscopy, hiatal hernia was seen in 3 patients. Pathological gastroesophageal reflux was found in 4 of the 10 patients investigated by pH-monitoring. CONCLUSIONS AND INFERENCES: Jackhammer esophagus represents 3% of the HRM diagnoses in this study, with a significant female preponderance. In more than two-thirds of cases, the clinical presentation of Jackhammer esophagus is dysphagia. BACKGROUND/AIMS: Jackhammer esophagus (JE) is a hypercontractile esophageal motor disorder defined by at least two swallows with a distal contractile integral (DCI) >8000 mm Hg.s.cm during high-resolution manometry (HRM). The relationship between symptoms and hypercontractility and the response to therapies have been poorly evaluated. The aim of this study was to determine the clinical presentation, manometric diagnosis, and therapeutic results in a large cohort of JE patients. METHODS: Patients with JE diagnosed among the HRM tests performed in nine academic French centers from 01/01/2010 to 08/31/2016 were included. Patient charts were reviewed to collect clinical and therapeutic data. RESULTS: Among the 16 264 HRM tests performed during this period, 227 patients (60.8 ± 13.8 years, 151 male) had JE (1.7%). Dysphagia was the most frequent symptom (74.6%), followed by regurgitation (37.1%) and chest pain (36.6%); 4.7% of the patients were asymptomatic. The diagnostic workup was heterogeneous, and only a minority of patients had esophageal biopsies. None of the individual symptoms were significantly associated with any of the manometric parameters defined, except for dysphagia, which was significantly associated with the mean of all DCIs >8000 mm Hg.s.cm (P = .04). Additionally, the number of symptoms was not associated with any manometric parameter. Medical treatment and endoscopic treatments had poor efficacy and a high relapse rate. CONCLUSION: Jackhammer esophagus is a rare motility disorder. Diagnostic workup is heterogeneous and should be standardized. Symptoms are poorly associated with manometric parameters. The medical treatments and endoscopic therapies currently used are inefficient. Hypercontractile esophagus (HE), also known as jackhammer esophagus, is an esophageal motility disorder. Nowadays, high-resolution manometry (HRM) is used to diagnose the disorder. According to the latest iteration of the Chicago classification, HE is present when at least 2 out 10 liquid swallow-induced peristaltic waves have an abnormally high Distal Contractile Integral. In the era of conventional manometry, a similar condition, referred to as nutcracker esophagus, was diagnosed when the peristaltic contractions had an abnormally high mean amplitude. Although the HRM diagnosis of HE is relatively straight-forward, effective management of the disorder is challenging as the correlation with symptoms is variable and treatment effects are dubious. In this mini-review, we discuss the most troublesome uncertainties that still surround HE, in the light of new data on etiology and epidemiology published in this issue of Neurogastroenterology and Motility. Jackhammer esophagus (JE) is a recently recognized esophageal motility disorder that is characterized by hypercontractile peristalsis. More than 500 cases have been reported in the literature. Among patients referred for esophageal motility disorders, the prevalence of JE ranges from 0.42% to 9%, with most series describing a prevalence of 2% to 4%. Most cases are women (60.5%). The mean reported age of patients with JE is 65.2 years, and patients commonly have dysphagia (62.8%). Reflux symptoms occur in ∼40% of patients, and chest pain affects more than one-third of patients (36.4%). JE is a heterogenous disorder that is associated with several conditions, including obesity, opioid use, lung transplantation, eosinophilic infiltration of the esophagus, neoplasia, and systemic diseases. The cause and pathogenesis remain unknown, but several observations suggest that it is the result of multiple conditions that likely precipitate increased excitation and abnormal inhibition of neuromuscular function. The natural course of JE also is unknown, but progression to achalasia has been observed in a few patients. Treatment is challenging, in part because of the insufficient understanding of the disorder's underlying mechanisms. Various therapeutic modalities have been used, ranging from observation only to pharmacologic and endoscopic interventions (eg, botulinum toxin injection) to peroral endoscopic myotomy. Treatment efficacy remains largely anecdotal and insufficiently studied. BACKGROUND: Jackhammer esophagus is a rare esophageal motility disorder that can result in dysphagia, chest pain, and gastro-esophageal reflux symptoms. High-resolution manometry is the gold standard for diagnosis, while corkscrew esophagus on upper gastrointestinal endoscopy is an uncommon manifestation. CASE PRESENTATION: 72-year-old man who presented with progressive dysphagia for three months without symptoms of chest pain or heartburn. Initial workup showed a corkscrew esophagus on upper gastrointestinal endoscopy; subsequently, high-resolution manometry revealed an esophago-gastric junction outflow obstruction with hypercontractile (jackhammer) esophagus. Treatment with calcium channel blockers and proton pump inhibitors was successful and relieved his symptoms near completion. CONCLUSIONS: Even though the corkscrew esophagus is typically for distal esophageal spasm, the hypercontractile (jackhammer) esophagus can appear. The high-resolution manometry can help to distinguish each specific motility disorder. BACKGROUND/AIMS: Jackhammer esophagus is an uncommon heterogeneous motility disorder associated with a distal contractile integral > 8000 mmHg∙sec∙cm. The spectrum of abnormality ranges from a relatively normal looking contraction to chaotic repetitive contractions akin to a jackhammer. Although previous studies have shown an uncertain correlation between peristaltic vigor and symptoms, we hypothesize that symptoms may be more severe with repetitive contractions as opposed to an elevated contractile measure. Thus, this study aims to investigate whether symptom severity is related to the contraction pattern in the patients with hypercontractile esophagus. METHODS: Patients with hypercontractile esophagus were retrospectively identified, their demographic and high-resolution manometry characteristics were collected. Contraction pattern on high-resolution manometry was categorized into single-peak and multiple-peak. Comparison was performed between patients with single-peak and multiple-peak. RESULTS: Altogether 35 patients (age range, 45-70 years; female:male, 24:11) were included. Seven patients presented with single-peak hypercontractile swallows, while 28 patients presented with multiple-peak hypercontractile swallows. The patients with multiple-peak showed higher Brief Esophageal Dysphagia Questionnaire scores compared with patients with single-peak. The jackhammer swallows with multiple-peak were associated with higher distal contractile integral values, longer distal latency intervals, and a lower integrated relaxation pressure. CONCLUSIONS: Repetitive contractions akin to a jackhammer were common amongst patients with hypercontractile esophagus. Patients with the jackhammer pattern also presented with more severe symptoms. Further distinction of hypercontractile esophagus into a jackhammer domit subtype may be warranted.

Can METTL3 methylate long noncoding RNAs?

Yes, METTL3 can modulate methylation and expression of lncRNA.

OBJECTIVES: This study aimed to explore the regulatory mechanism of methyltransferase3 (METTL3) -mediated long non-coding RNA (lncRNA) N6-methyladenosine (m6A) modification in the osteogenic differentiation of human adipose-derived stem cells (hASCs) induced by NEL-like 1 protein (NELL-1). MATERIALS AND METHODS: Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and high- throughput sequencing for RNA (RNA-seq) were performed on hASCs. Osteogenic ability was detected by alkaline phosphatase (ALP) staining, Alizarin Red S(ARS) staining, ALP quantification and Quantitative real-time polymerase chain reaction analysis (qRT-PCR). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis predicted the osteogenesis-related pathways enriched for the lncRNAs and identified the target lncRNAs. After overexpression and knockdown of METTL3, methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) and qRT-PCR were used to detect the levels of m6A modification and the expression of the target lncRNA, and the binding of both was confirmed by RNA binding protein immunoprecipitation (RIP) assay. The effects of lncRNA and METTL3 on phosphorylation of the key proteins of the pathway were detected by western blot analysis. RESULTS: In vitro experiments showed that METTL3 can promote osteogenic differentiation and that its expression level is upregulated. KEGG pathway analysis predicted that lncRNAs with differentially upregulated methylated peaks were enriched mostly in the mitogen-activated protein kinase (MAPK) signaling pathway, in which Serine/threonine protein kinase 3 (STK3) was the predicted target gene of the lncRNA RP11-44 N12.5. The m6A modification and expression of RP11-44 N12.5 were both regulated by METTL3. Subsequently, lncRNA RP11-44 N12.5 and METTL3 were found to regulate the phosphorylation levels of three key proteins in the MAPK signaling pathway, ERK, JNK and p38. CONCLUSIONS: This study shows, for the first time, that METTL3 can activate the MAPK signaling pathway by regulating the m6A modification and expression of a lncRNA, thereby enhancing the osteogenic differentiation of hASCs.

Which disease is caused by repeat expansion in VWA1?

An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy.

Author information: (1)NIHR Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. (2)Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, UK. (3)Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, National Institutes of Health, Bethesda, MD, USA. (4)Department of Human Genetics, Sidra Medicine, Doha, Qatar. (5)Institute of Human Genetics, Center for Molecular Medicine Cologne (CMMC), Institute of Genetics, and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany. (6)William Harvey Research Institute, Queen Mary University of London, London, UK. (7)Genomics England, London, UK. (8)Centogene AG, Rostock, Germany. (9)Medical Genetics Laboratory, Alzahra University Hospital, Isfahan University of Medical Sciences, Isfahan, Iran. (10)Department of Neurology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. (11)The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle, UK. (12)Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK. (13)Department of Paediatric Neurology - Neuromuscular Service, Evelina Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, UK. (14)Department of Neurology, Royal Devon and Exeter NHS Trust, Exeter, UK. (15)Randall Division of Cell and Molecular Biophysics Muscle Signalling Section, King's College London, London, UK. (16)Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. (17)Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands. (18)Department of Neurology, Salford Royal NHS Foundation Trust, Manchester, UK. (19)Department of Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands. (20)West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham, UK. (21)Divisions of Neurology and Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. (22)Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Sweden. (23)The Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL Great Ormond Street Institute of Child Health, and Great Ormond Street Hospital Trust, London, UK. (24)GeneDx, Gaithersburg, 20877 MD, USA. (25)Mitochondrial Medicine Frontier Program, Division of Human Genetics, Children's Hospital of Philadelphia, PA, USA. (26)Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. (27)Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Trust, Oxford, UK. (28)Department of Neurology, King's College Hospital, London, UK. (29)Peninsula Clinical Genetics Service, Royal Devon and Exeter NHS Trust, Exeter, UK. (30)Division of Pediatric Neurology, The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (31)Department of Pediatrics, Perelman School of Medicine, Philadelphia, PA, USA. (32)Department of Neurology, Center for Rare Diseases Cologne, University Hospital Cologne, Cologne, Germany. (33)College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar. (34)Department of Genetic Medicine, Weill Cornell Medical College, Doha, Qatar. (35)School of Health Science, Division Biomedicine and Translational Medicine, University of Skovde, Sweden.

What is the use of the Apfel Score?

The Apfel simplified risk score, developed in 1999, is the most widely used tool for risk stratification of postoperative nausea and vomiting.

PURPOSE: To compare two of the latest published scores for predicting postoperative nausea and vomiting (PONV) in potentially high-risk patients. METHODS: Adult in-patients scheduled for throat, thyroid, breast or gynecological surgery under general inhalational anesthesia were studied prospectively over 24 hr for PONV. The latest published score considers four risk factors: female gender, previous history of PONV or motion sickness, non-smoking status and postoperative use of opioids (Apfel-score). The previously published score includes, in addition to these factors, duration, type of anesthesia and surgery (Sinclair-score). The two scores were compared by calculating the area under a receiver operating characteristic (ROC)-curve and plotting calibration curves of the predicted and the observed incidence of PONV. RESULTS: Five hundred consecutive patients were studied and patients who received prophylactic antiemetics were excluded. Of the remaining 428 patients 49.5% suffered from PONV. Multivariable analysis revealed that age, gender, previous history of PONV or motion sickness and postoperative use of opioids had an impact on PONV. The area under the ROC-curve was significantly greater for the Apfel-score compared to the Sinclair-score (0.71 vs 0.64, P=0.008). The correlation between the predicted (x) and the observed (y) incidence for the Apfel-score and for the Sinclair-score was y=1.08x - 0.07 and y=0.93x + 0.27. CONCLUSION: In our hospital, the simplified Apfel-score presented with favourable discriminating and calibration properties for predicting the risk of PONV. Therefore, we have implemented this score in our daily clinical practice as well as in an ongoing antiemetic trial. OBJECTIVE: Postoperative nausea and vomiting (PONV) still represent an important problem in surgery. Treatment and prevention of PONV requires accurate risk stratification. The simplified Apfel-score includes the four factors female gender, no smoking, postoperative use of opioides and previous PONV or motion-sickness in patients' history. Each of these risk factors is supposed to elevate the PONV-incidence about 20%. The aim of the study was to validate this clinical risk assessment score in patients with high risk for PONV. METHODS: In a prospective study 93 patients with high risk preoperative score for PONV (Apfel Score III and IV) were analyzed. Patients and nurses were interviewed using a standardized questionnaire at the time of discharge from the post-anesthesia care unit (PACU) as well as 6 hours and 24 hours after admission to the PACU. General anaesthesia was applied as total intravenous anaesthesia (TIVA) with mivacurium, propofol and remifentanil (no nitrous oxide / FI 02 0.5) RESULTS: In the group with Apfel score III PONV occurred in 59.7% of patients and in the Apfel score group IV in 91.3% of all patients. The incidence of PONV corresponds to the predicted values of 60% for Apfel III and 80% for Apfel IV although the use of TIVA should have reduced the incidence of PONV about 26%. This apparent overestimation could be explained by the frequent questioning of patients and nurses for PONV leading to assessment of very minor symptoms. CONCLUSION: The Apfel-score is a useful and simple tool for stratification of patients with high risk for PONV. A common predictive measure of postoperative nausea and vomiting (PONV) is the Apfel score. Although tested in many different operations, it has not been tested extensively in oral and maxillofacial surgery (OMFS). This study was designed to determine whether it applied to OMFS and whether there were other factors in this population that would improve its accuracy. A retrospective chart review was carried out on a randomly selected group of patients who had OMFS during a 10-month period. In addition to the Apfel score risk factors, PONV data were collected in relation to type of anesthetic induction and maintece, type of surgery, use of maxillomandibular fixation (MMF), use of opioids, and anesthesia and surgery times. One-hundred and sixty-seven patients were included in the analysis; 24% had nausea and 11% had nausea and vomiting. Patients who had orthognathic or temporomandibular joint surgery had the highest rate of PONV. Young age, anesthesia and operation time, and use of MMF were also associated with increased PONV. Adding age, MMF or limited postoperative mouth opening, and surgery type to the Apfel score should make it more predictive in OMFS. Author information: (1)Associate Professor of Anesthesiology, University of Central Florida, Orlando, FL, USA. [email protected]. (2)Envision Healthcare, Saint Augustine, FL, USA. [email protected]. (3)Anesthesiology and Surgery, Tufts University School of Medicine, Boston, USA. (4)Anesthesia for Research and Development, Department of Anesthesiology and Critical Care, VA Boston Healthcare System, Boston, USA. (5)Surgery, Vanderbilt University Medical Center, Nashville, USA. (6)Bariatric and Minimally Invasive Surgery, Yale School of Medicine, New Haven, USA. (7)Associate Professor of Anesthesiology, University of California, San Diego, CA, USA. (8)Outcomes Research Consortium, Cleveland, USA. (9)International Society for the Perioperative Care of Obese Patients, Louisville, USA. BACKGROUND: The incidence and risk factors of postoperative nausea and vomiting (PONV) and early PONV (ePONV) were evaluated in patients who underwent breast surgery with volatile anesthesia. METHODS: In this retrospective study, multivariate logistic regression was used to determine incidence and identify risk factors for PONV. RESULTS: Among 928 patients, 166 (18%) and 220 (24%) had ePONV and PONV, respectively. In multivariate analysis, anesthesia duration and use of desflurane were independent risk factors for ePONV. For PONV, anesthesia duration and Apfel score were independent risk factors. CONCLUSIONS: Our results indicate that desflurane was the main cause of ePONV. However, during the delayed phase, a higher Apfel score was the strongest predictor. In the early and delayed phases, long anesthesia duration was associated with high risk of PONV. Thus, prolonged anesthesia and desflurane use should be avoided for patients at high risk of PONV, particularly those with high Apfel scores. Publisher: RéSUMé: OBJECTIF: Le score simplifié d’Apfel, mis au point en 1999, est l’outil le plus utilisé pour la stratification des risques de nausées et vomissements postopératoires (NVPO). Il comprend quatre facteurs de risque : le sexe féminin, un statut de non-fumeur, les antécédents de NVPO ou de mal des transports, et l’utilisation d’opioïdes postopératoires. Néanmoins, il existe une hétérogénéité considérable dans la définition et l’application de ces facteurs de risque dans la recherche sur les NVPO. Notre objectif était de déterminer comment ces facteurs de risque étaient appliqués dans les études utilisant le score Apfel. MéTHODE: Les citations comportant dans leur index une mention du score d’Apfel entre le 1er septembre 1999 et le 1er septembre 2019 ont été identifiées dans la base de données Scopus. Les comptes rendus originaux en texte intégral en anglais mesurant les quatre facteurs de risque ont été inclus dans notre analyse. Les données recueillies comprenaient la définition, le moment et la méthode de collecte des quatre facteurs de risque. RéSULTATS: Parmi les études identifiées, 255 sur 535 documentaient les quatre facteurs de risque, et les scores d’Apfel calculés ont été rapportés dans 116 des 255 (46 %) articles. Le tabagisme, les NVPO, le mal des transports et l’utilisation postopératoire d’opioïdes ont été définis dans quatre (2 %), zéro (0 %), un (0,4 %) et sept (3 %) articles, respectivement. La consommation postopératoire d’opioïdes a été définie comme « anticipée » dans 138 (54 %) études et « réelle » dans 72 (18 %) études, et n’était pas claire dans 45 (28 %) études. CONCLUSION: Il existe d’importantes variations dans la façon dont les facteurs de risque d’Apfel sont définis et appliqués dans la recherche sur les NVPO, particulièrement en ce qui concerne l’utilisation postopératoire d’opioïdes. Des recommandations plus claires pour l’application de cet outil pourraient optimiser l’estimation des risques et la prophylaxie pour les NVPO, et potentiellement améliorer la qualité de la recherche. Postoperative nausea and vomiting (PONV) degrades patient experience and increases healthcare costs. Estimates of PONV range from 10% to 80%. The Apfel Simplified Score is an evidence-based instrument for determining individual risk of PONV. Scoring enables anesthesia providers to match antiemetic strategies with the calculated risk of PONV. Data were collected across 3 times. After the Apfel scoring system was automated into the electronic medical record, providers were more likely to increase PONV prophylaxis for patients at highest risk and reduce prophylaxis for patients at lowest risk. Rates of PONV remained similar at baseline (34.7%) and in the early postimplementation period (38.8%); a modest reduction was observed in the final period (26.5%). Intravenous ondansetron, the most common antiemetic at baseline, was not available in the early postimplementation period, which may partially explain the initial increase in PONV. While ondansetron was unavailable, providers began using 3 other antiemetics, a practice that persisted once intravenous ondansetron returned. The Apfel score is an evidence-based tool that providers can use to reduce the risk of PONV. This electronic tool and the reminder cards have been shared across the US Military Health System, fostering an organizational culture that values targeted prophylaxis for PONV. BACKGROUND: Simplified risk models, such as the Apfel score, have been developed to calculate the risk of postoperative nausea-vomiting (PONV) for adult patients. In the absence of any risk factors, PONV risk is assumed to be 10%. While the presence of one of the four risk factors determined as female gender, non-smoking, PONV/car sickness history, and postoperative opioid use is associated with 20% risk for PONV, the risk increases by 20% with the addition of each risk factor, and reaches to 80% if four factors are present. AIM: : Our aim in this study is to investigate the prevalence of PONV, and whether the scoring systems used for nausea-vomiting in the literature are still valid. PATIENTS AND METHODS: Five groups of patients were included in the study with an Apfel score of 0, 1, 2, 3, 4. Each case was taken to the recovery room at the end of the operation. They were observed whether had nausea-vomiting was recorded according to the Abramowitz emesis score. RESULTS: While the PONV risk for women is 24.637 times higher than men, the PONV risk of those who had gynecological surgery is 6.27 times higher than that of the other type of surgery. Those who had urological surgery are 0.345 times less than the other type of surgery. Those who had lower abdominal surgery had a risk of PONV of 4.56 times higher than the others. As the duration of the case increases, the risk of PONV increases 1.01 times (P values P < 0.001, P < 0.001, P < 0.001, P = 0.048, P < 0.001, respectively). CONCLUSION: As a result, our PONV prevalence is considerably lower than the frequency rates mentioned in the literature. PONV scoring systems need long-term studies with larger populations to be updated.

Is PPROM a condition that occurs in males or females?

Preterm premature rupture of fetal membranes (PPROM) occurs in pregnant females.

Objective: To show that infants delivered prematurely because of preterm premature rupture of the membranes (PPROM) show a tendency for asymmetric intrauterine growth retardation (IUGR). At the same time, to demonstrate that these pregcies exhibit nutritional deprivation by the presence of correspondingly smaller placentas, as demonstrated by the placental-fetal ratio.Study Design: A prospective study was performed over 2 years comparing the tendency for IUGR in infants born of pregcies with PPROM (N = 86), as compared to normal term controls (N = 351). The tendency for growth restriction in the neonate was determined using the ponderal index at birth. Exclusion criteria included pregcies complicated by diabetes, hypertension, preeclampsia, multiple gestations, genetic, and other recognized causes of IUGR. Four controls were selected for each study patient who delivered the same day. The mean ponderal index (PI(m)) was compared, as were the mean placental-fetal weight ratios (PWt/PI)(m), for both groups. A comparison of the PI(m) and (PWt/PI)(m) for infants delivered prematurely with and without rupture of membranes was also noted. Analysis was by the paired Student's t test and chi(2) test.Results: The newborn PI was found to be independent of maternal age, gravidy, and parity. The number of male and female infants were not significantly different in the control and study groups. The PI(m) for the PPROM group (PI(m) = 2.33, SD = 0.29) was significantly smaller than that for the controls (PI(m) = 2.52, SD = 0.23) (P <.0005). Similarly the (PWt/PI)(m) for the PPROM group (mean = 194.8, SD = 49.9) was significantly smaller than that for the control group (mean = 273.4, SD = 54.2) (P <.0005). Mean values of PI and PWt/PI for preterm deliveries with, as compared to without rupture of membranes, showed no significant differences.Conclusions: Using the ponderal index to detect IUGR, a significant association of IUGR is noted in infants delivered subsequent to PPROM. This growth impairment is accompanied by significantly smaller placentas. A 32-year-old Caucasian woman of body mass index (BMI) 46 presented with urinary symptoms to accident and emergency (A&E). Acute pyelonephritis was the diagnosis. Transabdominal scan revealed a live term fetus. Both the partners were unaware of the ongoing pregcy until diagnosed. She underwent emergency cesarean under general anaesthesia (GA) for nonreassuring CTG, severe chorioamnionitis, and moderate preecclampsia. A live male baby weighing 4400 grams delivered in poor condition. Placental tissue on culture exhibited scanty growth of pseudomonas aeruginosa. Chorioamnionitis due to pseudomonas is rare, with high neonatal morbidity and mortality. It is mostly reported among preterm prelabor rupture of membranes (PPROM). Educating the community especially morbidly obese women if they put on excessive weight or with irregular periods should seek doctor's advice and exclude pregcy. For the primary care provider, it is of great importance to exclude pregcy in any reproductive woman presenting with abdominal complaints. This case also brings to clinicians notice that pseudomonas can be community-acquired and can affect term pregcies with intact or prolonged rupture of membranes. The preterm premature rupture of membranes (PPROM) is a common condition in pregt women and is associated with significant maternal and perinatal morbidity. Most of the time, the diagnosis is done during physical examination. However, in 10%-20% of equivocal cases, biological markers are needed to confirm the diagnosis, especially when leakage of fluid is low or intermittent. In these cases, a quick and reliable diagnosis is necessary for applying the appropriate measures to reduce perinatal complications. The prognosis in PPROM is linked to maternal inflammatory markers that might predict perinatal infection, and therefore be helpful to decide the timing of the delivery. Nevertheless, further research is needed to identify robust biological markers for the diagnosis of PPROM in equivocal cases and for the prognosis. OBJECTIVES: Preterm premature rupture of membranes (PPROM) is defined as a rupture of the amniotic membranes occurring before 37 weeks of gestation and before the onset of labor. Extreme PPROM occurs prior to 26 weeks gestation and contributes to an increased risk of prematurity, leading to maternal and fetal complications. This study aims to estimate the risk factors associated with various maternal complications and to determine the worst outcomes in Omani females with extreme PPROM. METHODS: A retrospective cohort study was conducted on 44 women with extreme PPROM, who delivered at Sultan Qaboos University Hospital (SQUH) from January 2006 to December 2011. Women with incomplete information, multiple gestations, or a preterm delivery resulting from medical intervention, as well as women who delivered elsewhere were excluded from the study. RESULTS: Forty-four women with extreme PPROM were included in our study. The results revealed the most important risk factor to be history of infection, which was noted in 24 study participants. The mean maternal age was 30 years. The mean gestational age at PPROM and at delivery were 20.7±3.2 (range: 16-26 weeks) and 29.7±7.6 weeks (range: 17-40 weeks), respectively. The maternal complications observed in this study included; infection which was seen in 20 (45%) patients, antepartum hemorrhage in 11 (25%) patients, and cesarean section which was required in 12 (27%) patients. There was no significant association between risk factors such as gestational age at delivery, parity, maternal age at PPROM, or maternal Body Mass Index (BMI) and cesarean section rate. Infection played a major role, both as a risk factor and in causing extreme PPROM, which in turn increased in 12 patients (27%). In the multivariable model for predicting the need for cesarean section (gestational age at delivery, parity, maternal age at PPROM in years and maternal BMI), none of the factors were statistically significant. CONCLUSION: Overall, concurrent infection rate was high among patients presenting with extreme PPROM. None of the baseline maternal factors predicted the need for cesarean section. This is likely due to the small sample size; hence, larger prospective studies are needed to confirm these findings. AIM: To determine whether preterm premature rupture of membranes (PPROM) before 24 weeks is an independent risk factor for poor outcome in preterm neonates. METHODS: A retrospective comparative cohort study was conducted, including viable premature infants born between 25 and 34-weeks gestation. Each preterm case with early PPROM was matched with two preterm controls of the same gestational age at birth, sex and birth date and who were born spontaneously with intact membranes. Logistic regression was performed to identify independent risk factors associated with composite respiratory and perinatal adverse outcomes for the overall population of preterm infants. RESULTS: Thirty-five PPROM cases were matched with 70 controls. Extreme prematurity (26-28 weeks) was an independent risk factor for composite perinatal adverse outcomes [odds ratio (OR) 43.9; p = 0.001]. Extreme prematurity (OR 42.9; p = 0.001), PPROM (OR 7.1; p = 0.01), male infant (OR 5.2; p = 0.02) and intrauterine growth restriction (IUGR, OR 4.8; p = 0.04) were factors for composite respiratory adverse outcomes. CONCLUSION: Preterm premature rupture of membranes before viability represents an independent risk factor for composite respiratory adverse outcomes in preterm neonates. Extreme prematurity may represent the main risk factor for both composite respiratory and perinatal adverse outcomes. Preterm premature rupture of membranes (PPROM) is defined as rupture of membrane that happens before the onset of labor and 37 weeks. Subclinical intrauterine infection is major etiological factor in the pathogenesis that increases mortality and morbidity associated with PPROM. This study was performed to evaluate the levels of maternal serum urokinase plasminogen activator receptor (uPAR), ST2 and interleukin (IL)-33 in PPROM and its relation with maternofetal infectious and morbidity. A total of 74 pregt women, of which 49 with PPROM between 24 and 34 weeks gestation, and 25 normal pregt women without PPROM were included in the study. Study group was seperated into 2 subgroups as PPROM and PPROM-histological chorioamnionitis (PPROM-HC). The blood samples were taken before the any medication. The mean serum IL-33, ST2, and uPAR values in the PPROM-HC group were significantly higher than PPROM and control group. The cut-off values of IL-33, ST2, and uPAR were determined as 5.2, 2 and 6.4 ng/mL, respectively. A cut-off value of IL-33 of 5.2 ng/mL, the cut-off of ST2 of 2 ng/mL and the cut-off of uPAR of 6.4 ng/mL showed similar sensitivity, specificity to IL-6 and the better sensitivity and specificity as compared to C-reactive protein and total leucocyte count in predicting infection in PPROM. We evaluated the predictive value of uPAR, ST2 and IL-33 in PPROM and we concluded that all of them can be used as reliable biomarkers to determine infection without any clinical signs but it is necessary to be studied in different cohort groups and infectious diseases. Preterm premature rupture of membranes (PPROM) occurs in 1% to 2% of births. Impact of PPROM is greatest in low- and middle-income countries where prematurity-related deaths are most common. Recent investigations identify cytokine and matrix metalloproteinase activation, oxidative stress, and apoptosis as primary pathways to PPROM. These biological processes are initiated by heterogeneous etiologies including infection/inflammation, placental bleeding, uterine overdistention, and genetic polymorphisms. We hypothesize that pathways to PPROM overlap and act synergistically to weaken membranes. We focus our discussion on membrane composition and strength, pathways linking risk factors to membrane weakening, and future research directions to reduce the global burden of PPROM. Preterm premature rupture of membranes (PPROM) is a condition leading to an increased risk of maternal and neonatal morbidity and mortality in pregt women. To prevent this complication, some studies have proposed using prophylactic progesterone. However, due to lack of sufficient relevant data, there is still need for further studies in this regard. This study was performed to determine the effect of rectal progesterone on the latent phase and maternal and neonatal outcome variables in females with PPROM. During the present randomized clinical trial study (IRCT201512077676N4), a total of 120 patients with PPROM at pregcy ages between 26 and 32 weeks were randomly assigned to 2 equal intervention and control groups. In the intervention group, progesterone suppositories (400 mg per night) were administered until delivery or completion of the 34th gestational week and was compared with placebo effect in control group. The latent phase and maternal and neonatal outcome variables were compared between the two groups. The mean age of patients was 29.56±5.66 (19-42) and 29.88±5.57 (17-40) years in the intervention and control group, respectively. The two groups were almost identical in the confounding factors. The median latent phase was 8.5 days in the intervention group vs. 5 days in the control group in the 28th-30th weeks of gestation, which was significantly higher in the intervention group (P=0.001). Among maternal and neonatal outcome variables, only the mean birth-weight was significantly higher in the intervention group than that in the controls (1609.92±417.28 gr vs. 1452.03±342.35 gr, P=0.03). Administration of progesterone suppository in patients with PPROM at gestational ages of 28 to 30 weeks is effective in elongating the latent phase and increasing birth-weight with no significant complications. Objective: To evaluate the efficacy and safety of amniopatch in pregcies associated with spontaneous preterm premature rupture of fetal membranes (PPROM).Methods: A randomized controlled trial that involved 100 women diagnosed with PPROM between 24 and 34 weeks of gestational age. Participants were randomized equally into two groups. Group I in which amniopatch was done in addition to the routine management. Group II was treated with routine management including antibiotics and corticosteroids.Results: Amniopatch was successful in complete sealing of the membrane defect in 6/50 (12%) of women while none the control group have undergone similar sealing (p = .0144, RR = 0.88). Women in the amniopatch group showed a significant increase of AFI compared to controls (12 versus 0, p = .0001, RR = 0.56).Conclusion: The amniopatch procedure is a successful technique that safely enhances sealing of fetal membranes and restore the AFI.Clinical trial registration: NCT03473210SynopsisThe amniopatch procedure is a successful technique that could be done safely to enhance sealing the fetal membranes and restoring the AFI after PPROM. Background: Placental dysfunction, inflammation and degradation of fetal membranes has been hypothesized as a cause of preterm prelabor of rupture of membranes.Objective: To examine the effect of aspirin, an anti-inflammatory agent, on the prevalence of preterm prelabor rupture of membranes (PPRoMs).Methods: A retrospective analysis was conducted to examine the effect of aspirin on the prevalence of PPRoM. Aspirin (150 mg, nocte) was prescribed to women who were identified through a screening program at 11-13+6 weeks' gestation as being at high risk for developing early-onset preeclampsia. Women who were at low risk for developing preeclampsia did not receive aspirin. The prevalence of PPRoM was compared with an observational cohort.Results: In the observational cohort, there were 3027 women, including 32 (1.1%) cases of PPRoM. The prevalence of PPRoM in the high risk group was 3.1% (4/128) and was statistically significantly higher compared to the low risk group (1.0%) (28/2899). The relative risk was 3.02 (95% CI 1.2-7.7; p= .04). In the interventional cohort, there were 7280 women, with 114 (1.6%) cases of PPRoM. The prevalence of PPRoM in the high risk group who were treated with aspirin was 1.8% (14/766) compared to 1.5% (100/6516) in the low risk group (p= .54). The prevalence of PPRoM in high risk patients in the observational group (who did not receive aspirin) compared with the high risk patients in the interventional group (who were treated with aspirin) was not statistically significant (p= .31).Conclusions: PPRoM is significantly associated with a description of high risk for ePET; although, this algorithm is not a good screening tool for predicting PPRoM. Aspirin treatment of women deemed high risk for ePET is safe in the context of PPRoM and there may be some reduction in prevalence of PPRoM in treated high risk women; although, this study was not powered to demonstrate a small reduction in the prevalence of PPRoM. The findings merit further investigation through a larger prospective study with adequate sample size. OBJECTIVE: The primary aim of this study was to assess the rate and load of amniotic fluid Chlamydia trachomatis DNA and their associations with intra-amniotic infection and intra-uterine inflammatory complications in women with preterm prelabor rupture of membranes (PPROM). The secondary aim was to assess the short-term morbidity of newborns from PPROM pregcies complicated by amniotic fluid C. trachomatis DNA. METHODS: A retrospective study of 788 women with singleton pregcies complicated by PPROM between 24 + 0 and 36 + 6 weeks of gestation was performed. Transabdominal amniocenteses were performed at the time of admission. C. trachomatis DNA in the amniotic fluid was assessed by real-time polymerase chain reaction using a commercial AmpliSens® C. trachomatis/Ureaplasma/Mycoplasma hominis-FRT kit, and the level of Ct DNA was quantified. RESULTS: Amniotic fluid C. trachomatis DNA complicated 2% (16/788) of the PPROM pregcies and was present in very low loads (median 57 copies DNA/mL). In addition to amniotic fluid C. trachomatis DNA, other bacteria were detected in 62% (10/16) of the C. trachomatis DNA-complicated PPROM pregcies. Amniotic fluid C. trachomatis DNA was associated with intra-amniotic infection, histologic chorioamnionitis (HCA), and funisitis in 31%, 47%, and 33%, respectively. The presence of C. trachomatis DNA accompanied by Ureaplasma species in the amniotic fluid was associated with a higher rate of HCA than the presence of amniotic fluid C. trachomatis DNA alone. The composite neonatal morbidity in newborns from PPROM pregcies with amniotic fluid C. trachomatis DNA was 31%. CONCLUSION: The presence of C. trachomatis DNA in the amniotic fluid is a relatively rare condition in PPROM. Amniotic fluid C. trachomatis DNA in PPROM is not related to intensive intra-amniotic and intr-auterine inflammatory responses or adverse short-term neonatal outcomes. OBJECTIVES: The purpose of this study was to examine the potential impact of severe Ovarian hyper stimulation syndrome (OHSS) on the risk of preterm birth. Severe ovarian hyperstimulation syndrome is a serious complication in the methods of in vitro fertilization. The pathophysiology of this process is not clear enough and the treatment is symptomatic. Human chorionic gonadotropin (h-CG) is the most important known cause of this condition. Findings of other authors often do not match when it comes to complications that may occur in pregcy. METHODS: In the Gynecology and Obstetrics Clinic "Narodni Front" a case control study was conducted on 50 female patients with severe forms of OHSS in the period from January 2008 to March 2015. A control group was created based on age and it involved 59 patients with pregcy achieved with IVF/ICSI during the same period, but in which OHSS did not occur. RESULTS: Patients with the pregcy complicated by OHSS, had a considerably higher rate of preterm labor, whether this was labor before gestation week 37 (56.0% vs. 30.5%) or before gestation week 34 (34.0% vs. 6.8%); significantly lower weight of newborns, as in the newborns with low body weight <2500g (45.6% vs. 25.0%) and specially in the newborn with very low body weight <1500 grams (19.1% vs. 3.8%), as well as preterm premature rupture of membranes (PPROM), (11.76% vs. 1.59%). CONCLUSIONS: Pregcy achieved by the IVF/ICSI method in which severe form of OHSS has been developed could have an increased risk of preterm birth. BACKGROUND: Bronchopulmonary dysplasia (BPD), a major source of morbidity in premature neonates, has been associated with intrauterine infection and preterm birth. Both preterm premature rupture of membranes (PPROM) and spontaneous preterm labor (sPTL) are linked with intrauterine inflammation. Whether PPROM and sPTL, as two phenotypic categories of preterm birth, are associated with exposure to different degrees and durations of inflammation that might impact fetal lung development is unknown. PPROM may be associated with longer latency until delivery, which is beneficial for neonatal mortality, but may impart greater injury risk to the developing fetal lungs. It is unknown if PPROM is associated with a greater risk of adverse neonatal respiratory outcomes than sPTL. OBJECTIVE: The objective of this study was to determine if PPROM imparts a differentially greater risk for neonatal BPD than sPTL. A secondary objective was to determine if PPROM was associated with a greater risk of adverse neonatal respiratory outcomes other than BPD and whether gestational latency following PPROM or sPTL diagnosis constitutes a risk factor for fetal lung injury. STUDY DESIGN: We conducted a retrospective secondary analysis of a large cohort of women at risk for spontaneous preterm birth, who were originally enrolled in a randomized controlled trial of magnesium sulfate versus placebo examining neuroprotection. For our study, we included women with a singleton pregcy complicated by PPROM or sPTL and delivery between 24 and 34 weeks gestational age. Cases with multiple gestation, congenital anomalies, maternal seropositivity for human immunodeficiency virus, or hypertensive diseases of pregcy (including preeclampsia) were excluded. The primary outcome was BPD. Secondary outcomes were respiratory distress syndrome (RDS), transient tachypnea of the newborn (TTN), requirement for mechanical ventilation, pneumonia, neonatal sepsis, fetal or neonatal death, and a composite of adverse neonatal respiratory outcomes including (BPD, pneumonia, RDS, and TTN). Statistical analyses included chi-square, Student's t-test and logistic and multiple regression. RESULTS: A total of 1729 women were included in this analysis including 1554 with PPROM and 175 with sPTL. Women in the PPROM group were more likely to be older, not of Hispanic race, married, more educated, have smoked during pregcy and have a greater body mass index. The BPD rate was not significantly different following PPROM versus sPTL. Neonates in the PPROM group experienced a lower rate of pneumonia (p = .001), neonatal sepsis (p = .009) and patent ductus arterious (PDA) requiring either medical or surgical therapy (p < .001) than neonates in the sPTL group. Chorioamnionitis was more common in the PPROM group (p = .008) than the sPTL group. After multivariable logistic regression with BPD or composite of adverse neonatal respiratory outcomes as the dependent outcomes, and controlling for gestational age at delivery, maternal smoking history, duration of mechanical ventilation and RDS, there was no significant difference between PPROM and sPTL. CONCLUSIONS: BPD rates were not significantly different in neonates born to women following PPROM versus sPTL. However, PPROM was associated with lower rates of pneumonia, neonatal sepsis, and PDA requiring therapy in the univariate analysis, but not the multivariate analysis. Neonatal respiratory outcomes may have a similar phenotypic overlap regardless of whether preterm birth follows PPROM or sPTL.

What is EpiMethylTag?

EpiMethylTag is a fast, low-input, low sequencing depth method, that combines ATAC-seq or ChIP-seq (M-ATAC or M-ChIP) with bisulfite conversion, to simultaneously examine accessibility/TF binding and methylation on the same DNA.

Author information: (1)New York University Langone Health, New York, NY, USA. (2)New York Genome Center, New York, NY, USA. (3)Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (4)Laura and Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY, USA. (5)Skirball Institute of Biomolecular Medicine, Department of Cell Biology, Helen L. and Martin S. Kimmel Center for Biology and Medicine, Laura and Isaac Perlmutter Cancer Center, New York, NY, USA. (6)Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (7)Institute of Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA. (8)New York University Langone Health, New York, NY, USA. [email protected]. (9)Skirball Institute of Biomolecular Medicine, Department of Cell Biology, Helen L. and Martin S. Kimmel Center for Biology and Medicine, Laura and Isaac Perlmutter Cancer Center, New York, NY, USA. [email protected].

What is the target of Sutimlimab?

Sutimlimab is a novel humanized monoclonal antibody directed against classical pathway complement factor C1s.

Cold agglutinin disease is a difficult-to-treat autoimmune hemolytic anemia in which immunoglobulin M antibodies bind to erythrocytes and fix complement, resulting in predomitly extravascular hemolysis. This trial tested the hypothesis that the anti-C1s antibody sutimlimab would ameliorate hemolytic anemia. Ten patients with cold agglutinin disease participated in the phase 1b component of a first-in-human trial. Patients received a test dose of 10-mg/kg sutimlimab followed by a full dose of 60 mg/kg 1 to 4 days later and 3 additional weekly doses of 60 mg/kg. All infusions were well tolerated without premedication. No drug-related serious adverse events were observed. Seven of 10 patients with cold agglutinin disease responded with a hemoglobin increase >2 g/dL. Sutimlimab rapidly increased hemoglobin levels by a median of 1.6 g/dL within the first week, and by a median of 3.9 g/dL (interquartile range, 1.3-4.5 g/dL; 95% confidence interval, 2.1-4.5) within 6 weeks (P = .005). Sutimlimab rapidly abrogated extravascular hemolysis, normalizing bilirubin levels within 24 hours in most patients and normalizing haptoglobin levels in 4 patients within 1 week. Hemolytic anemia recurred when drug levels were cleared from the circulation 3 to 4 weeks after the last dose of sutimlimab. Reexposure to sutimlimab in a named patient program recapitulated the control of hemolytic anemia. All 6 previously transfused patients became transfusion-free during treatment. Sutimlimab was safe, well tolerated, and rapidly stopped C1s complement-mediated hemolysis in patients with cold agglutinin disease, significantly increasing hemoglobin levels and precluding the need for transfusions. This trial was registered at www.clinicaltrials.gov as #NCT02502903. Conflict of interest statement: S Berentsen has received research support from Mundipharma, travel support from Alexion and Apellis, lecture honoraria from Alexion, Bioverativ, and Janssen-Cilag, and has consulted for Apellis, Bioverativ, Momenta Pharmaceuticals, and True North Therapeutics, outside the submitted work. A Röth has received research support from Alexion and Roche, travel support from Alexion and AbbVie, lecture honoraria from Alexion, Roche, and Novartis, and has consulted for Alexion, Bioverativ, Novartis, and True North Therapeutics, outside the submitted work. U Randen reports no conflicts of interest. B Jilma has received reimbursement for travel for presentations and scientific advice from True North Therapeutics (a Bioverativ Company), outside the submitted work. GE Tjønnfjord has received research support from Mundipharma, Janssen-Cilag and Alexion Pharma, and lecture honoraria from Janssen-Cilag, Alexion Pharma, and Roche Pharma, outside the submitted work. Deposition of autoantibodies (α-BP180 and BP230) and complement along the dermal-epidermal-junction is a hallmark of bullous pemphigoid and was shown to be important for pathogenesis. Given the adverse effects of standard treatment (glucocorticoids, immunosuppressants), there is an unmet need for safe and effective therapies. In this phase 1 trial, we evaluated the safety and activity of BIVV009 (sutimlimab, previously TNT009), a targeted C1s inhibitor, in 10 subjects with active or past bullous pemphigoid (NCT02502903). Four weekly 60 mg/kg infusions of BIVV009 proved sufficient for inhibition of the classical complement pathway in all patients, as measured by CH50. C3c deposition along the dermal-epidermal junction was partially or completely abrogated in 4 of 5 patients, where it was present at baseline. BIVV009 was found to be safe and tolerable in this elderly population, with only mild to moderate adverse events reported (e.g., headache, fatigue). One serious adverse event (i.e., fatal cardiac decompensation) occurred at the end of the post-treatment observation period in an 84-year-old patient with a history of diabetes and heart failure, but was deemed unlikely to be related to the study drug. This trial provides the first results with a complement-targeting therapy in bullous pemphigoid, to our knowledge, and supports further studies on BIVV009's efficacy and safety in this population. Complement-mediated hemolytic anemias can either be caused by deficiencies in regulatory complement components or by autoimmune pathogenesis that triggers inappropriate complement activation. In paroxysmal nocturnal hemoglobinuria (PNH) hemolysis is entirely complement-driven. Hemolysis is also thought to be complement-dependent in cold agglutinin disease (CAD) and in paroxysmal cold hemoglobinuria (PCH), whereas warm antibody autoimmune hemolytic anemia (wAIHA) is a partially complement-mediated disorder, depending on the subtype of wAIHA and the extent of complement activation. The pathophysiology, clinical presentation, and current therapies for these diseases are reviewed in this article. Novel, complement-directed therapies are being rapidly developed. Therapeutic terminal complement inhibition using eculizumab has revolutionized the therapy and prognosis in PNH but has proved less efficacious in CAD. Upstream complement modulation is currently being investigated and appears to be a highly promising therapy, and two such agents have entered phase II and III trials. Of these, the anti-C1s monoclonal antibody sutimlimab has shown favorable activity in CAD, while the anti-C3 cyclic peptide pegcetacoplan appears to be promising in PNH as well as CAD, and may also have a therapeutic potential in wAIHA. Cold agglutinin disease (CAD) causes predomitly extravascular hemolysis and anemia via complement activation. Sutimlimab is a novel humanized monoclonal antibody directed against classical pathway complement factor C1s. We aimed to evaluate the safety and efficacy of long-term maintece treatment with sutimlimab in patients with CAD. Seven CAD patients treated with sutimlimab as part of a phase 1B study were transitioned to a named patient program. After a loading dose, patients received biweekly (once every 2 weeks) infusions of sutimlimab at various doses. When a patient's laboratory data showed signs of breakthrough hemolysis, the dose of sutimlimab was increased. Three patients started with a dose of 45 mg/kg, another 3 with 60 mg/kg, and 1 with a fixed dose of 5.5 g every other week. All CAD patients responded to re-treatment, and sutimlimab increased hemoglobin from a median initial level of 7.7 g/dL to a median peak of 12.5 g/dL (P = .016). Patients maintained near normal hemoglobin levels except for a few breakthrough events that were related to underdosing and which resolved after the appropriate dose increase. Four of the patients included were eventually treated with a biweekly 5.5 g fixed-dose regimen of sutimlimab. None of them had any breakthrough hemolysis. All patients remained transfusion free while receiving sutimlimab. There were no treatment-related serious adverse events. Overlapping treatment with erythropoietin, rituximab, or ibrutinib in individual patients was safe and did not cause untoward drug interactions. Long-term maintece treatment with sutimlimab was safe, effectively inhibited hemolysis, and significantly increased hemoglobin levels in re-exposed, previously transfusion-dependent CAD patients. The last decades have seen great progress in the treatment of cold agglutinin disease (CAD). Comparative trials are lacking, and recommendations must be based mainly on nonrandomized trials and will be influenced by personal experience. Herein, current treatment options are reviewed and linked to 3 cases, each addressing specific aspects of therapy. Two major steps in CAD pathogenesis are identified, clonal B-cell lymphoproliferation and complement-mediated hemolysis, each of which constitutes a target of therapy. Although drug treatment is not always indicated, patients with symptomatic anemia or other bothersome symptoms should be treated. The importance of avoiding ineffective therapies is underscored. Corticosteroids should not be used to treat CAD. Studies on safety and efficacy of relevant drugs and combinations are briefly described. The author recommends that B cell-directed approaches remain the first choice in most patients requiring treatment. The 4-cycle bendamustine plus rituximab combination is highly efficacious and sufficiently safe and induces durable responses in most patients, but the time to response can be many months. Rituximab monotherapy should be preferred in frail patients. The complement C1s inhibitor sutimlimab is an emerging option in the second line and may also find its place in the first line in specific situations. BACKGROUND: Cold agglutinin disease is a rare autoimmune hemolytic anemia characterized by hemolysis that is caused by activation of the classic complement pathway. Sutimlimab, a humanized monoclonal antibody, selectively targets the C1s protein, a C1 complex serine protease responsible for activating this pathway. METHODS: We conducted a 26-week multicenter, open-label, single-group study to assess the efficacy and safety of intravenous sutimlimab in patients with cold agglutinin disease and a recent history of transfusion. The composite primary end point was a normalization of the hemoglobin level to 12 g or more per deciliter or an increase in the hemoglobin level of 2 g or more per deciliter from baseline, without red-cell transfusion or medications prohibited by the protocol. RESULTS: A total of 24 patients were enrolled and received at least one dose of sutimlimab; 13 patients (54%) met the criteria for the composite primary end point. The least-squares mean increase in hemoglobin level was 2.6 g per deciliter at the time of treatment assessment (weeks 23, 25, and 26). A mean hemoglobin level of more than 11 g per deciliter was maintained in patients from week 3 through the end of the study period. The mean bilirubin levels normalized by week 3. A total of 17 patients (71%) did not receive a transfusion from week 5 through week 26. Clinically meaningful reductions in fatigue were observed by week 1 and were maintained throughout the study. Activity in the classic complement pathway was rapidly inhibited, as assessed by a functional assay. Increased hemoglobin levels, reduced bilirubin levels, and reduced fatigue coincided with inhibition of the classic complement pathway. At least one adverse event occurred during the treatment period in 22 patients (92%). Seven patients (29%) had at least one serious adverse event, none of which were determined by the investigators to be related to sutimlimab. No meningococcal infections occurred. CONCLUSIONS: In patients with cold agglutinin disease who received sutimlimab, selective upstream inhibition of activity in the classic complement pathway rapidly halted hemolysis, increased hemoglobin levels, and reduced fatigue. (Funded by Sanofi; CARDINAL ClinicalTrials.gov number, NCT03347396.). Complement is an elaborate system of innate immunity. Genetic variants and autoantibodies leading to excessive complement activation are implicated in a variety of human diseases. Among them, the hematologic disease paroxysmal nocturnal hemoglobinuria (PNH) remains the prototypic model of complement activation and inhibition. Eculizumab, the first-in-class complement inhibitor, was approved for PNH in 2007. Addressing some of the unmet needs, a long-acting C5 inhibitor, ravulizumab, and a C3 inhibitor, pegcetacoplan, have also now been approved for PNH. Novel agents, such as factor B and factor D inhibitors, are under study, with very promising results. In this era of several approved targeted complement therapeutics, selection of the proper drug must be based on a personalized approach. Beyond PNH, complement inhibition has also shown efficacy and safety in cold agglutinin disease, primarily with the C1s inhibitor of the classical complement pathway sutimlimab, as well as with pegcetacoplan. Furthermore, C5 inhibition with eculizumab and ravulizumab, as well as inhibition of the lectin pathway with narsoplimab, is being investigated in transplantation-associated thrombotic microangiopathy. With this revolution of next-generation complement therapeutics, additional hematologic entities, such as delayed hemolytic transfusion reaction or immune thrombocytopenia, might also benefit from complement inhibitors. Therefore, this review aims to describe state-of-the-art knowledge of targeting complement in hematologic diseases, focusing on (1) complement biology for the clinician, (2) complement activation and therapeutic inhibition in prototypic complement-mediated hematologic diseases, (3) hematologic entities under investigation for complement inhibition, and (4) other complement-related disorders of potential interest to hematologists.

Can parasite infections by Schistosoma japonicum prevent or improve asthma?

A peptide named as SJMHE1 from Schistosoma japonicum can suppress asthma in mice.

A number of epidemiological and clinical studies have suggested an inverse association between allergy and helminth infection, such as Schistosomiasis. Therefore, we hypothesize that Schistosoma japonicum egg antigens, a type of native antigen, can induce production of CD4(+) CD25(+) T cells with regulatory activity, modulating airway inflammation and inhibiting asthma development. The frequency of CD4(+) CD25(+) T cells was determined by flow cytometry for mice treated with ovalbumin (OVA), CD25(+) depletion/OVA, schistosome egg antigens, schistosome egg antigens/OVA and for control mice. The ability of CD25(+) T cells from these mice to suppress T-cell proliferation and cytokine production was investigated both in vivo and in vitro. Results showed that the CD4(+) CD25(+) T cells of OVA-treated mice exhibited impaired control of dysregulated mucosal T helper 2 responses compared to the controls (P < 0.05). Depletion of CD25(+) cells accelerated OVA-induced airway inflammation and increased the expression of interleukin (IL)-5 and IL-4. Treatment with schistosome egg antigens increased the number and suppressive activity of CD4(+) CD25(+) T cells, which made IL-10, but little IL-4. In a murine model of asthma, S. japonicum egg antigens decreased the expression of Th2 cytokines, relieved antigen-induced airway inflammation, and inhibited asthma development. Thus, we provided evidence that S. japonicum egg antigens induced the production of CD4(+) CD25(+) T cells, resulting in constitutive immunosuppressive activity and inhibition of asthma development. These results reveal a novel form of protection against asthma and suggest a mechanistic explanation for the protective effect of helminth infection on the development of allergy. Asthma, a chronic inflammatory disorder of the airways, is coordinated by Th2 cells in both human asthmatics and animal models of allergic asthma. It has been shown that helminth infections including Schistosoma mansoni may modulate atopic diseases including asthma. In the present study, BALB/c mice were infected with bisexual and unisexual (male) S. japonicum, respectively, prior to ovalbumin (OVA) sensitization and challenge. Compared to mice with OVA sensitization/challenge alone, S. japonicum infection led to a significant decrease of eosinophil accumulation in bronchoalveolar lavage fluid (BALF) collected 48 h postchallenge, as well as to a marked reduction in inflammatory cell infiltration around the airways and pulmonary blood vessels. Compared to OVA-immunized uninfected mice, the level of OVA-specific serum IgE as well as interleukin (IL)-4 and IL-5 in BALF were reduced, but IL-10 was strongly elevated in mice with preexisting S. japonicum infection prior to OVA immunization. These results suggest that both bisexual and male S. japonicum infections may modulate the development of allergic asthma. In areas where schistosomiasis is endemic, a negative correlation is observed between atopy and helminth infection, associated with a low prevalence of asthma. We investigated whether Schistosoma mansoni infection or injection of parasite eggs can modulate airway allergic inflammation in mice, examining the mechanisms of such regulation. We infected BALB/c mice with 30 S. mansoni cercariae or intraperitoneally injected 2,500 schistosome eggs, and experimental asthma was induced by ovalbumin (OVA). The number of eosinophils in bronchoalveolar lavage fluid was higher in the asthmatic group than in asthmatic mice infected with S. mansoni or treated with parasite eggs. Reduced Th2 cytokine production, characterized by lower levels of interleukin-4 (IL-4), IL-5, and immunoglobulin E, was observed in both S. mansoni-treated groups compared to the asthmatic group. There was a reduction in the number of inflammatory cells in lungs of S. mansoni-infected and egg-treated mice, demonstrating that both S. mansoni infection and the egg treatment modulated the lung inflammatory response to OVA. Only allergic animals that were treated with parasite eggs had increased numbers of CD4(+) CD25(+) Foxp3(+) T cells and increased levels of IL-10 and decreased production of CCL2, CCL3, and CCL5 in the lungs compared to the asthmatic group. Neutralization of IL-10 receptor or depletion of CD25(+) T cells in vivo confirmed the critical role of CD4(+) CD25(+) Foxp3(+) regulatory T cells in experimental asthma modulation independent of IL-10. The "hygiene hypothesis" is a theory try to explain the dramatic increases in the prevalence of autoimmune and allergic diseases over the past two to three decades in developed countries. According to this theory, reduced exposure to parasites and microorganisms in childhood is the main cause for the increased incidences of both T helper 1 (Th1)-mediated autoimmunity and Th2-mediated allergy. In this study, we investigated the impact of Schistosoma japonicum infection on the allergic airway inflammation induced by repeated intracheal inoculations of house dust mites (HDM), which is a Th17 and neutrophils domit murine asthma model, mimicking severe asthma. We found that S. japonicum infection downregulated airway hyperresponsiveness. The infiltrating cells, Th17 and Th2 effector cytokines in the bronchoalveolar lavage (BAL) fluids and lungs were significantly reduced in the infected mice. Our findings indicated that S. japonicum infection was able to effectively inhibit host's allergic airway inflammation, which may be related to the upregulated Treg cells upon infection. To our knowledge, it is the first study to reveal the impact of S. japonicum infection on house dust mite induced severe asthma. More in depth investigation is need to elucidate the underlying mechanisms. Helminths and their products can shape immune responses by modulating immune cells, which are dysfunctional in inflammatory diseases such as asthma. We previously identified SJMHE1, a small molecule peptide from the HSP60 protein of Schistosoma japonicum. SJMHE1 can inhibit delayed-type hypersensitivity and collagen-induced arthritis in mice. In the present study, we evaluated this peptide's potential intervention effect and mechanism on ovalbumin-induced asthma in mice. SJMHE1 treatment suppressed airway inflammation in allergic mice, decreased the infiltrating inflammatory cells in the lungs and bronchoalveolar lavage fluid, modulated the production of pro-inflammatory and anti-inflammatory cytokines in the splenocytes and lungs of allergic mice, reduced the percentage of Th2 cells and increased the proportion of Th1 and regulatory T cells (Tregs). At the same time, Foxp3 and T-bet expression increased, and GATA3 and RORγt decreased in the lungs of allergic mice. We proved that SJMHE1 can interrupt the development of asthma by diminishing airway inflammation in mice. The down-regulation of Th2 response and the up-regulation of Th1 and Tregs response may contribute to the protection induced by SJMHE1 in allergic mice. SJMHE1 can serve as a novel therapy for asthma and other allergic or inflammatory diseases. Schistosoma japonicum infection showed protective effects against allergic airway inflammation (AAI). However, controversial findings exist especially regarding the timing of the helminth infection and the underlying mechanisms. Most previous studies focused on understanding the preventive effect of S. japonicum infection on asthma (infection before allergen sensitization), whereas the protective effects of S. japonicum infection (allergen sensitization before infection) on asthma were rarely investigated. In this study, we investigated the protective effects of S. japonicum infection on AAI using a mouse model of OVA-induced asthma. To explore how the timing of S. japonicum infection influences its protective effect, the mice were percutaneously infected with cercaria of S. japonicum at either 1 day (infection at lung-stage during AAI) or 14 days before ovalbumin (OVA) challenge (infection at post-lung-stage during AAI). We found that lung-stage S. japonicum infection significantly ameliorated OVA-induced AAI, whereas post-lung-stage infection did not. Mechanistically, lung-stage S. japonicum infection significantly upregulated the frequency of regulatory T cells (Treg cells), especially OVA-specific Treg cells, in lung tissue, which negatively correlated with the level of OVA-specific immunoglobulin E (IgE). Depletion of Treg cells in vivo partially counteracted the protective effect of lung-stage S. japonicum infection on asthma. Furthermore, transcriptomic analysis of lung tissue showed that lung-stage S. japonicum infection during AAI shaped the microenvironment to favor Treg induction. In conclusion, our data showed that lung-stage S. japonicum infection could relieve OVA-induced asthma in a mouse model. The protective effect was mediated by the upregulated OVA-specific Treg cells, which suppressed IgE production. Our results may facilitate the discovery of a novel therapy for AAI. Diabetes and obesity have become the most popular metabolic diseases in the world. A large number of previous studies have shown that glucose and lipid metabolism disorder is an important risk factor and a main cause of diabetes and obesity. Schistosoma is a parasite transmitted by freshwater snails. It can induce a series of inflammatory and immune reactions after infecting the human body, causing schistosomiasis. However, in recent years, studies have found that Schistosoma infection or Schistosoma related products can improve or prevent some immune and inflammatory diseases, such as severe asthma, inflammatory bowel disease, diabetes and so on. Further experiments have also revealed that Schistosoma can promote the secretion of anti-inflammatory factors and regulate the glucose and lipid metabolism in the host body by polarizing immune cells such as T cells, B cells and dendritic cells (DCs). In this review, we summarize studies that investigated Schistosoma and Schistosoma-derived products and their relationship with glycolipid metabolism and related diseases, highlighting potential protective mechanisms.

Describe Multilocus Inherited Neoplasia Allele Syndrome (MINAS)

Genetic testing of hereditary cancer using comprehensive gene panels can identify patients with more than one pathogenic mutation in high and/or moderate-risk-associated cancer genes. This phenomenon is known as multilocus inherited neoplasia alleles syndrome (MINAS), which has been potentially linked to more severe clinical manifestations.

IMPORTANCE: Genetic testing of hereditary cancer using comprehensive gene panels can identify patients with more than one pathogenic mutation in high and/or moderate-risk-associated cancer genes. This phenomenon is known as multilocus inherited neoplasia alleles syndrome (MINAS), which has been potentially linked to more severe clinical manifestations. OBJECTIVE: To determine the prevalence and clinical features of MINAS in a large cohort of adult patients with hereditary cancer homogeneously tested with the same gene panel. PATIENTS AND METHODS: A cohort of 1023 unrelated patients with suspicion of hereditary cancer was screened using a validated panel including up to 135 genes associated with hereditary cancer and phakomatoses. RESULTS: Thirteen (1.37%) patients harbouring two pathogenic mutations in domit cancer-predisposing genes were identified, representing 5.7% (13/226) of patients with pathogenic mutations. Most (10/13) of these cases presented clinical manifestations associated with only one of the mutations identified. One case showed mutations in MEN1 and MLH1 and developed tumours associated with both cancer syndromes. Interestingly, three of the double mutants had a young age of onset or severe breast cancer phenotype and carried mutations in moderate to low-risk DNA damage repair-associated genes; two of them presented biallelic inactivation of CHEK2. We included these two patients for the sake of their clinical interest although we are aware that they do not exactly fulfil the definition of MINAS since both mutations are in the same gene. CONCLUSIONS AND RELEVANCE: Genetic analysis of a broad cancer gene panel identified the largest series of patients with MINAS described in a single study. Overall, our data do not support the existence of more severe manifestations in double mutants at the time of diagnosis although they do confirm previous evidence of severe phenotype in biallelic CHEK2 and other DNA repair cancer-predisposing genes.