tbuckley/cabot-search huggingface dataset:
Abstract 320: Frequency and patient characteristics of homologous recombination deficiency in metastatic cutaneous melanoma
Authors: Kevin B. Kim, Sherri Z. Millis, Jeffrey Ross, Laurie M. Gay, Elham Vosoughi, John Moretto, Stanley P. Leong, Mark I. Singer, Brian M. Parrett, David R. Minor, Mohammed Kashani-Sabet
Journal: Cancer Research (2018)

Abstract Purpose: In various cancer types, cells with a homologous recombination (HR) deficiency have been shown to be sensitive to PARP inhibitors. We investigated the frequency of HR pathway gene mutations in melanoma.Experimental Design: Next-generation sequencing analysis that included the entire coding sequence of 315 cancer-related genes was performed on formalin-fixed, paraffin-embedded melanoma samples. Clinical and pathologic characteristics of 62 patients with advanced melanoma were reviewed, and compared with a dataset of 1,986 melanoma patients with available molecular profiling data.Results: Nineteen (30.6%) patients had ≥1 functional HR mutation. The characteristics of patients with HR-deficient melanoma were: median age 69, male predominance (79%) and primary head and neck melanoma (53%). TMB was high in 12 (67%) patients and low in 1 (6%) patient. The most commonly mutated HR-associated gene was ARID2 (13%), followed by ARID1A, ATM, BRCA1, and FANCA (3% each). Among the 19 patients with HR mutation(s), concurrent NF1, NRAS, V600 BRAF, and KIT mutations were found in 7 (37%), 6 (32%), 5 (26%) and 1 (5%) patients, respectively. Presence of HR pathway mutation was associated with absence of ulceration at the primary site, high TMB and clinical response to checkpoint immunotherapy. A larger dataset analyzed by Foundation Medicine, Inc. (n=1,986) showed a similar frequency and pattern of HR mutations. Conclusions: HR pathway gene mutations are frequently observed in advanced melanoma. Melanomas with these alterations may represent a unique subset of patients who are more likely to benefit from checkpoint blockade, and also may be targeted with PARP inhibitors. Clinical and pathologic characteristics of patients with genetic HR mutationsHR mutation (n=19)Non HR mutation (n=43)p-valueUlceration statusn=16*n=33*0.0050Present2 (12.5%)18 (54.5%)0.0114Absent14 (87.5%)15 (45.5%)0.0479Tumor mutation burdenn=18*n=38*0.0114Low1 (5.6%)17 (44.7%)Intermediate5 (27.8%)8 (21.1%)High12 (66.7%)13 (34.2%)Response to anti-PD-1 antibody inhibitors (+/- ipilimumab)n=12*n=23*0.0479Response10 (83.3%)10 (43.5%)Early Progression1 (8.3%)10 (43.5%)Stable disease1 (8.3%)3 (13.0%) Citation Format: Kevin B. Kim, Sherri Z. Millis, Jeffrey Ross, Laurie M. Gay, Elham Vosoughi, John Moretto, Stanley P. Leong, Mark I. Singer, Brian M. Parrett, David R. Minor, Mohammed Kashani-Sabet. Frequency and patient characteristics of homologous recombination deficiency in metastatic cutaneous melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 320.
Dual receptor recognizing liposomes containing paclitaxel and hydroxychloroquine for primary and metastatic melanoma treatment via autophagy-dependent and independent pathways
Authors: Sheng Yin, Chunyu Xia, Yashi Wang, Dandan Wan, Jingdong Rao, Xian Tang, Jiaojie Wei, Xuhui Wang, Man Li, Zhirong Zhang, Ji Liu, Qin He
Journal: Journal of Controlled Release (2018)
Vascular Abnormalities and Elevated Blood Pressure in Mice Lacking Adrenomedullin Gene
Authors: TakayukiShindo, YukikoKurihara, HiroakiNishimatsu, NobuoMoriyama, MasaoKakoki, YuhuiWang, YasushiImai, AyaEbihara, TomoyukiKuwaki, Ki-HwanJu, NaotoMinamino, KenjiKangawa, TakatoshiIshikawa, MinoruFukuda, YoshihiroAkimoto, HayatoKawakami, TomihikoImai, HiroyukiMorita, YoshioYazaki, RyozoNagai, YasunobuHirata, HirokiKurihara
Journal: Circulation (2001)

Background Adrenomedullin (AM) is a vasodilating peptide involved in the regulation of circulatory homeostasis and in the pathophysiology of certain cardiovascular diseases. Levels of AM are markedly increased in the fetoplacental circulation during pregnancy, although its function there remains unknown. To clarify the physiological functions of AM, we chose a gene-targeting strategy in mice. Methods and Results Targeted null mutation of the AM gene is lethal in utero: the mortality rate among AM−/− embryos was >80% at E13.5. The most apparent abnormality in surviving AM−/− embryos at E13.5 to E14.0 was severe hemorrhage, readily observable under the skin and in visceral organs. Hemorrhage was not detectable at E12.5 to E13.0, although the yolk sac lacked well-developed vessels. Electron microscopic examination showed endothelial cells to be partially detached from the basement structure at E12.5 in vitelline vessels and hepatic capillaries, which allowed efflux of protoerythrocytes through the disrupted ...
Oral steroids fail to prevent hearing loss in children with otitis media with effusion, shows trial
Authors: Susan Mayor
Journal: BMJ (2018)

A short course of oral prednisolone is not an effective treatment for most children with persistent otitis media with effusion and confirmed hearing loss, results from a randomised trial have shown.1

The trial showed the rate of spontaneous resolution was high. Lead author Nick Francis, from the School of Medicine at Cardiff University, UK, said, “Discussions about watchful waiting and other interventions will be supported by this evidence.”

Otitis media affects 50-80% of children by the age of five years. Several treatment options—including antibiotics, topical intranasal steroids, and decongestants—have been shown to be ineffective, so interventions are limited to watchful waiting, hearing aids, or surgical insertion of ventilation tubes through the tympanic …
Abstract 15725: Heart-Type Fatty Acid Binding Protein for Risk Stratification in Patients With Pulmonary Embolism: A Meta-Analysis
Authors: AnuragBajaj, ParulRathor, AnkurSethi, AjayShetty, BesherKabak
Journal: Circulation (2014)

Background: The role of heart- type fatty acid binding protein(H-FABP) in risk stratification of acute pulmonary embolism is still undefined. We performed a meta-analysis of studies in patients with acute pulmonary embolism to assess the prognostic value of elevated H-FABP levels for short-term adverse outcomes. Methods: Two independent reviewers systematically searched “Pubmed”, “ Embase” and “Cochrane” database using the mesh word “heart type fatty acid binding protein” and “pulmonary embolism” through June 2014 . Additionally conference abstracts, review articles and bibliographies were searched. Prospective studies were included if those were done on hemodynamically stable pulmonary embolism patients and they had used H-FABP assay. Primary end point was 30 day adverse outcomes. Adverse outcomes were defined as composite of death, endotracheal intubation, pressors infusion cardiopulmonary resuscitation, or recurrent pulmonary embolism. A random-effects model was used to pool study results and I2 testin...
Abstract 5814: Synthetic lethal therapy to overcome resistance to AURKA inhibition in HPV-negative head and neck cancer
Authors: Alexander Y. Deneka, Margret B. Einarson, Jong Woo Lee, Anna S. Nikonova, Barbara Burtness, Erica A. Golemis
Journal: Cancer Research (2018)

Abstract Head and neck squamous cell carcinomas (HNSCC) affect more than a half million people annually worldwide. Most currently available treatments, which include cisplatin and irradiation, are associated with significant morbidity, while many targeted inhibitors show limited single agent efficacy: novel therapeutic approaches which combine efficacy and limited toxicity are needed. The most common mutational event in human papillomavirus (HPV)-negative HNSCC is mutation of TP53. As control of the G1/S transition is entirely p53-dependent, cells with TP53 mutations lose the G1/S checkpoint, and evade radiation- and cisplatin-induced cellular senescence. Targeting the serine/threonine mitotic kinase Aurora-A (AURKA) emerged as a promising synthetic lethal approach in this setting. AURKA is negatively regulated by p53, which causes upregulation of AURKA in the majority of cases of HNSCC, correlating with poor prognosis and cisplatin resistance. The single agent AURKA inhibitor MLN8237 (alisertib) had a 9% monotherapy response rate in treatment-refractory HNSCC, with all responses occurring in HPV-negative or -unknown disease. In our study, we used initial high throughput screening in multiple genomically characterized HNSCC cell lines to identify synergistic combinations involving AURKA inhibitors and 20 other inhibitors of cell cycle, and cell cycle checkpoint controls. This work has identified has several effective combinations, particularly in between alisertib (targeting AURKA), danusertib (AURKA and AURKB), LY2606368/prexasertib (CHK1), and reversine (MPS1). Multiplexing analysis with measures of cell metabolism, direct visualization of mitotic nuclei, and additional assays has allowed us to dissect distinct execution points for different drug combinations. We will describe in detail mechanistic interactions between specific combinations of value for HNSCC. These drug combinations are likely to represent a new and effective modality for treating TP53-mutated cancers. Citation Format: Alexander Y. Deneka, Margret B. Einarson, Jong Woo Lee, Anna S. Nikonova, Barbara Burtness, Erica A. Golemis. Synthetic lethal therapy to overcome resistance to AURKA inhibition in HPV-negative head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5814.
Abstract 1921: The sensitivity of ovarian cancer cells to the HDAC inhibitor belinostat is improved by inhibiting Bcl-xLor Mcl-1 anti-apoptotic proteins
Authors: Charlène Duboc, Edwige Abeilard, Anne Sophie Voisin-Chiret, Pascal Gauduchon, Laurent Poulain, Marie Villedieu
Journal: Cancer Research (2018)

Abstract The identification of novel therapeutic strategies is an important urgent requirement for the clinical management of ovarian cancers, which remain the leading cause of death from gynecologic cancer. Our previous studies have shown that the anti-apoptotic proteins Bcl-xL and Mcl-1 cooperate to protect resistant ovarian cancer cells from apoptosis as their concomitant inhibition results in massive apoptotic cell death. Moreover, their BH3-only pro-apoptotic partners Bim and Puma are crucial actors in the induced cell death. This suggests that ovarian cancer cell apoptosis can be triggered by inhibiting Bcl-xL and Mcl-1 and/or by promoting their BH3-only partners, especially Bim and Puma. The expression of these Bcl-2 family proteins has been reported to be modulated by HDAC (histone deacetylases) inhibitors in various cancer models. The objective of the present study was to evaluate the efficacy of the FDA-approved pan-HDAC inhibitor belinostat (i) to reduce the [Bcl-xL and Mcl-1] / BH3-only proteins ratio and (ii) to trigger apoptosis in chemoresistant ovarian cancer cell lines, alone or in combination with other pharmacological molecules that modulate these Bcl-2 family proteins. HDAC inhibition by belinostat led to a G2/M blockade and consequently reduced cell proliferation. Moreover, belinostat used at high concentrations (from 1000 to 2000 nM) efficiently triggered apoptosis in chemoresistant ovarian cancer cells. This cytotoxic effect was associated with both an up-regulation of Bim and Puma protein expression and an inhibition of Bcl-xL protein expression. Used at sub-toxic concentrations, belinostat also up-regulated Bim and Puma proteins but failed to down-regulate Bcl-xL and Mcl-1 protein expression. We therefore investigated whether Bcl-xL or Mcl-1 inhibition could sensitize ovarian cancer cells to sub-toxic concentrations of belinostat. Interestingly, the combination of belinostat with the BH3-mimetic ABT-737, that inhibits Bcl-xL, induced massive apoptosis. Moreover, Mcl-1 direct or indirect inhibition was also very efficient to sensitize ovarian cancer cells to belinostat. These results suggest that belinostat, alone or in association with pharmacological molecules that inhibit Mcl-1 or Bcl-xL, represents a promising approach for the treatment of chemoresistant ovarian cancers. Citation Format: Charlène Duboc, Edwige Abeilard, Anne Sophie Voisin-Chiret, Pascal Gauduchon, Laurent Poulain, Marie Villedieu. The sensitivity of ovarian cancer cells to the HDAC inhibitor belinostat is improved by inhibiting Bcl-xL or Mcl-1 anti-apoptotic proteins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1921.
Abstract 11564: A Key Role of PGC-1α Co-transcription Factor, but not HIF1α Transcription Factor, in Production of Vascular Endothelial Growth Factor (VEGF) by a Novel Angiogenic Agent COA-Cl in Cultured Human Fibroblasts
Authors: Ryuji Okamoto, Junsuke Igarashi, Tetsuo Yamashita, Takeshi Hashimoto, Sakiko Karita, Kazuyo Shoji, Yasuo Kubota, Maki Takata, Fuminori Yamaguchi, Masaaki Tokuda, Norikazu Sakakibara, Ikuko Tsukamoto, Ryoji Konishi, Katsuya Hirano
Journal: Circulation (2015)

We have recently demonstrated a potent angiogenic effect of a newly developed adenosine-like agent termed COA-Cl (Figure). COA-Cl exerts tube forming activity in human umbilical vein endothelial cells in the presence of normal human dermal fibroblasts (NHDF). We thus hypothesized that COA-Cl induces production of VEGF, a key promoter of angiogenesis, from fibroblasts. The present study addressed this hypothesis and elucidated the mechanism underlying COA-Cl-induced VEGF production. ELISA revealed that COA-Cl (100 μM, 48 h) promoted secretion of VEGF into culture medium of NHDF from 16±15 to 274±52 pg/mL (p&lt;0.01). COA-Cl also up-regulated the expression of VEGF mRNA by 2.1±0.3 fold (RT-PCR, p&lt;0.05). Two transcriptional regulatory proteins have been identified as major activators of VEGF gene: HIF1α, a transcription factor associated with hypoxic insult, and PGC-1α, a co-transcription factor associated with metabolic stress that activates a transcription factor ERRα. Immunoblot and RT-PCR analyses revealed that COA-Cl (100 μM) markedly upregulated the expression of PGC-1α protein (2.1±0.3 fold) and mRNA (4.2±0.5 fold) (p&lt;0.05, respectively). In contrast, COA-Cl had no effect on the expression of HIF1α protein/mRNA in both hypoxia (1% O 2 for 3h) and normoxia (20% O 2 ). Silencing PGC-1α gene by siRNA attenuated the ability of COA-Cl to promote VEGF secretion. HIF1α gene silencing was without effect. When PGC-1α and ERRα were co-transfected in COS-7 cells, COA-Cl (100 μM) upregulated expression of the endogenous VEGF mRNA (2.2±0.3 fold p&lt;0.05 vs. vehicle). COA-Cl had no effect in COS-7 cells transfected with HIF1α. Together, these results demonstrate the ability of COA-Cl to induce VEGF gene expression and protein secretion in fibroblasts. The co-transcription factor PGC-1α, in concert with ERRα, plays a key role in the COA-Cl-induced VEGF production, potentially representing a novel means to induce therapeutic angiogenesis.
Abstract 10977: Survival After Surgical or Percutaneous Revascularization in US Dialysis Patients Without Acute Myocardial Infarction
Authors: Gautam R Shroff, Craig A Solid, Charles A Herzog
Journal: Circulation (2013)

Background: Previously published data in US dialysis pts demonstrate that CABG has a higher initial mortality hazard but better long-term survival relative to PCI. However, previous studies failed to differentiate pts with acute myocardial infarction (AMI) in the analyses. We sought to evaluate the survival of dialysis pts without AMI undergoing coronary revascularization. Methods: Using the United States Renal Data System database, we identified 23,033 dialysis pts undergoing revascularization, 2004-2009 (6178 CABG; 11,844 DES, 5011 BMS). Pts with AMI (based on ICD-9 codes) were excluded from this cohort to identify pts undergoing revascularization in the non-AMI cohort (n=14,775, 64%). Long-term survival was estimated by Kaplan-Meier method and independent predictors of death examined in a comorbidity-adjusted Cox model. Results: Proportion of pts undergoing revascularization in non-AMI setting were 4358 (29.5%) CABG; 7634 (51.7%) DES; 2783 (18.8%) BMS. There was a significant initial mortality hazard w...
Author Correction: Metformin reverses established lung fibrosis in a bleomycin model
Authors: Sunad Rangarajan, Nathaniel B. Bone, Anna A. Zmijewska, Shaoning Jiang, Dae Won Park, Karen Bernard, Morgan L. Locy, Saranya Ravi, Jessy Deshane, Roslyn B. Mannon, Edward Abraham, Victor Darley-Usmar, Victor J. Thannickal, Jaroslaw W. Zmijewski
Journal: Nature Medicine (2018)
Abstract 1498: The role of tissues specific super-enhancers in mediating the genetic risk of ovarian cancer
Authors: Kevin C. Vavra, Rosario I. Corona, Ji-Heui Seo, Simon G. Coetzee, Janet M. Lee, Matthew L. Freedman, Paul D. Pharoah, Dennis J. Hazelett, Simon A. Gayther, Kate Lawrenson
Journal: Cancer Research (2018)

Abstract Super-enhancers demarcate regions of master regulators involved in cellular differentiation and tumorigenesis. While many trait-associated variants discovered through genome wide association studies are enriched in regulatory elements, the role of super-enhancers in disease susceptibility is less well understood. We evaluated the role of super-enhancers, defined by H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) analysis of epithelial ovarian cancers (EOC) and precursor cells, in mediating the genetic risk of EOC. We characterized super-enhancer-risk SNP intersections to identify a series of risk-associated loci where multiple candidate causal alleles overlap with ovarian super-enhancers (approximately 33% of candidate causal loci). In particular, a risk locus at 3q25 marked by SNP rs7651446, (odds ratio = 1.59, p = 1.5x10-34), is tagged by 79 candidate causal risk SNPs, more than half of which coincide with super-enhancers detected in EOC precursor cells (ovarian and fallopian tube epithelia) but not in ovarian cancer cell lines or primary tumors suggesting that loss of activity of this super-enhancer is associated with EOC development. We hypothesized that SNPs at the 3q25 locus modulate activity of super-enhancers that regulate in cis the expression of genes involved in the identity of normal tissue precursors, and that these genes are downregulated during tumorigenesis. We tested the effect of decreasing the binding affinity of BRD4, a protein that binds super-enhancer regions, using a small molecule inhibitor (JQ1). We measured the expression of genes at this locus following JQ1 treatment in EOC precursor cells, identifying three candidate genes, LEKR1, SSR3, and TiPARP, that show decreased expression due to BRD4 binding inhibition. For SSR3 and TIPARP, these expression level changes mirrored the differential expression observed between normal precursor cells and primary high grade serous ovarian cancer. We then established stable shRNA-mediated knockdown models for SSR3 and TIPARP in normal EOC precursor cell lines to establish a role for these genes in ovarian cancer development. In summary, we have identified a potential role for super-enhancers at a subset of EOC risk loci, and present a functional pipeline for identification of the target gene/genes and evaluation of their role in neoplastic transformation. Citation Format: Kevin C. Vavra, Rosario I. Corona, Ji-Heui Seo, Simon G. Coetzee, Janet M. Lee, Matthew L. Freedman, Paul D. Pharoah, Dennis J. Hazelett, Simon A. Gayther, Kate Lawrenson. The role of tissues specific super-enhancers in mediating the genetic risk of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1498.
EMA scales back transparency initiatives because of workload
Authors: Peter Doshi
Journal: BMJ (2018)

The European Medicines Agency has scaled back its landmark clinical trial data policies, the drug regulator has announced.

Policy 0043, which granted public access to documents in the regulators’ archives, including clinical trial data, is now limited to EU citizens only, and work related to publishing new data packages under its clinical data publication policy (policy 0070) has been suspended. The agency said that the cutbacks were a response to an “excessive workload”1 and were part of its planning amid substantial staff loss as it prepared for Brexit.2

Transparency advocates have described it as a blow to critical transparency efforts with potential patient safety ramifications.

“Deaths and other serious harms are much under-reported in published trials, and we therefore need unhindered and immediate access to clinical study reports and other relevant documentation that the EMA holds,” said Peter Gotzsche, director of the Nordic Cochrane Centre. Gotzsche is credited with “opening up” the EMA after his successful appeal to the European ombudsman over a denied request for data a decade ago.3 He said that the EMA’s announcements were “very …
Abstract 2695: Quantitative phosphoproteome analysis identifies novel functional pathways of tumor suppressor DLC1 in estrogen receptor-positive breast cancer
Authors: Yesim Gökmen-Polar, Jason D. True, Edyta Vieth, Yuan Gu, Xiaoping Gu, Guihong D. Qi, Amber L. Mosley, Sunil Badve
Journal: Cancer Research (2018)

Abstract Deleted in Liver Cancer-1 (DLC1), a member of the RhoGAP family of proteins, functions as a tumor suppressor in several cancers including breast cancer. However, its clinical relevance is unclear in breast cancer. In this study, expression of DLC1 was correlated with prognosis using publicly available breast cancer gene expression datasets and quantitative polymerase chain reaction (qPCR) in cohorts of Estrogen Receptor-positive (ER+) breast cancer. Mutation and methylation status of DLC1 were assessed in these datasets including The Cancer Genome Atlas (TCGA). To seek further insights in understanding the role of DLC1 in ER+ breast cancer, we developed a knock-in model of DLC1 in T47D breast cancer cells. Label-free global proteomic and TiO2 phosphopeptide enrichment assays were performed and validated using Western blotting. Data are available via ProteomeXchange with identifier PXD008220. Here, we report that low expression of DLC1 correlates with poor prognosis in patients with ER+ breast cancer with further decrease in metastatic lesions. Analysis of the TCGA data showed that down regulation of DLC1 is not due to methylation or mutations. Stable knock-in of DLC1-full-length inhibits cell colony formation significantly in vitro compared to its control counterpart. 6726 phosphopeptides were quantified by phosphoproteomics analysis in both conditons, whereas 205 and 122 were unique to DLC1 knock-in and T47D-control cells, respectively. Pathway analysis using DAVID showed the top three significant clusters of differentially identified phosphopeptides involving cell-cell adhesion, mRNA processing and splicing, and transcription regulation. Decreased phosphorylation of epithelial cell transforming sequence 2 (ECT2) at the residue T359, critical for its active conformational change, was validated. In conclusion, this data suggests that high expression of DLC1 reduces cell growth and is associated with favorable prognosis. Our results document an inverse relation between ECT2 phosphorylation and DLC1 expression, promising a novel strategy for treating ER+ breast cancer. Citation Format: Yesim Gökmen-Polar, Jason D. True, Edyta Vieth, Yuan Gu, Xiaoping Gu, Guihong D. Qi, Amber L. Mosley, Sunil Badve. Quantitative phosphoproteome analysis identifies novel functional pathways of tumor suppressor DLC1 in estrogen receptor-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2695.