tbuckley/cabot-search huggingface dataset:
Gossypol(-), a potent small molecule inhibitor of Bcl-2/xl, improves response to radiation therapy and results in tumor regression of human prostate cancer
Authors: Liang Xu, Dajun Yang, Shaomeng Wang, Wenhua Tang, Marc E. Lippman
Journal: Cancer Research (2004)

4153  Majority of human prostate cancers overexpress Bcl-2 and/or Bcl-XL, the important negative regulators of apoptosis. Gossypol(-), a natural product from cottonseed, has recently been identified as a potent small molecule inhibitor of both Bcl-2 and Bcl-XL. In the current study, we tested our hypothesis that Gossypol(-) may improve prostate cancer’s response to radiation by inhibiting the anti-apoptosis activity of Bcl-2/XL and making cancer cells more sensitive to radiation therapy. Our data show that Gossypol(-) inhibits tumor cell growth and induces apoptosis in human prostate cancer PC-3 cells with high levels of Bcl-2/XL proteins, but has minimal effect on normal cells with low Bcl-2/XL. In clonogenic assays, treatment of PC-3 cells with Gossypol(-) significantly reduced radiation resistance of PC-3, resulted in 10- and 20-fold reduction of colony formation at 8 Gy. Fluorescence resonance energy transfer (FRET) assay using Bcl-XL-CFP and Bax-YFP or Bad-YFP co-transfected cells suggests that Gossypol(-) potently blocks the interaction of Bcl-xl with Bax and Bad in live cells, in a time- and dose-dependent manner, supporting that Gossypol(-) induces apoptosis, at least in part, through inhibition of the anti-apoptotic protein Bcl-XL. Our in vivo studies using PC-3 xenograft models in nude mice show that orally administered Gossypol(-) has limited anti-tumor activity but achieves a much greater efficacy with tumor regression when used in combination with X-ray irradiation. Combination therapy of Gossypol(-) 10 mg/kg, p.o. q.d.5 x 4 weeks, with fractionated X-ray irradiation, 2 Gy q.d.5 x 3 weeks, achieved 96% tumor growth inhibition (T/C = 3.4%), significantly more effective than either Gossypol(-) or radiation alone (T/C = 96% and 37%, respectively) (p
An Uncomplicated Delivery in a Patient with Covid-19 in the United States
Authors: Sara N. Iqbal, Rachael Overcash, Neggin Mokhtari, Haleema Saeed, Stacey Gold, Tamika Auguste, Muhammad-Usman Mirza, Maria-Elena Ruiz, Joeffrey J. Chahine, Masashi Waga, Glenn Wortmann
Journal: New England Journal of Medicine (2020)

Uncomplicated Delivery in a Patient with Covid-19 The peripartum care of a woman with Covid-19 at 39 weeks of gestation is described. The woman and the neonate were discharged home on hospital day ...
Likelihood of survival of coronavirus disease 2019
Authors: Shigui Ruan
Journal: The Lancet Infectious Diseases (2020)

Likelihood of survival of coronavirus disease 2019A case fatality ratio of an infectious disease measures the proportion of all individuals diagnosed with a disease who will die from that disease.For an emerging infectious disease, this ratio is thus a very important indicator not only of disease severity but also of its significance as a public health problem.For instance, WHO estimated a case fatality ratio of approximately 14-15% for severe acute respiratory syndrome (SARS) in 2003, 1 and approxi mately 35% for Middle East respiratory syndrome (MERS) in 2012. 2 The ongoing pandemic of coronavirus disease 2019 (COVID19) is caused by a virus, severe acute respiratory syndrome coronavirus 2 (SARSCoV2), belonging to a large family of coronaviruses that also includes SARS coronavirus (SARSCoV) and MERS coronavirus (MERSCoV).COVID19 was first reported in December, 2019, in Wuhan, in the Hubei province of China, and spread very rapidly to all other prefectures in Hubei, as well as all other provinces, autonomous regions, municipalities, and special administrative regions of China, and more than 180 other countries and territories.As of March 21, 2020, there have been 292 142 confirmed
Applying genome-wide CRISPR-Cas9 screens for therapeutic discovery in facioscapulohumeral muscular dystrophy
Authors: Angela Lek, Yuanfan Zhang, Keryn G. Woodman, Shushu Huang, Alec M. DeSimone, Justin Cohen, Vincent Ho, James Conner, Lillian Mead, Andrew Kodani, Anna Pakula, Neville Sanjana, Oliver D. King, Peter L. Jones, Kathryn R. Wagner, Monkol Lek, Louis M. Kunkel
Journal: Science Translational Medicine (2020)

The emergence of CRISPR-Cas9 gene-editing technologies and genome-wide CRISPR-Cas9 libraries enables efficient unbiased genetic screening that can accelerate the process of therapeutic discovery for genetic disorders. Here, we demonstrate the utility of a genome-wide CRISPR-Cas9 loss-of-function library to identify therapeutic targets for facioscapulohumeral muscular dystrophy (FSHD), a genetically complex type of muscular dystrophy for which there is currently no treatment. In FSHD, both genetic and epigenetic changes lead to misexpression of DUX4, the FSHD causal gene that encodes the highly cytotoxic DUX4 protein. We performed a genome-wide CRISPR-Cas9 screen to identify genes whose loss-of-function conferred survival when DUX4 was expressed in muscle cells. Genes emerging from our screen illuminated a pathogenic link to the cellular hypoxia response, which was revealed to be the main driver of DUX4-induced cell death. Application of hypoxia signaling inhibitors resulted in increased DUX4 protein turnover and subsequent reduction of the cellular hypoxia response and cell death. In addition, these compounds proved successful in reducing FSHD disease biomarkers in patient myogenic lines, as well as improving structural and functional properties in two zebrafish models of FSHD. Our genome-wide perturbation of pathways affecting DUX4 expression has provided insight into key drivers of DUX4-induced pathogenesis and has identified existing compounds with potential therapeutic benefit for FSHD. Our experimental approach presents an accelerated paradigm toward mechanistic understanding and therapeutic discovery of a complex genetic disease, which may be translatable to other diseases with well-established phenotypic selection assays.
Abstract P1-17-12: The influence of social demographics on genomic sequencing in metastatic breast cancer
Authors: Zoe Wecht, Adam Brufsky, Tiffaney Hsia, Margaret Q Rosenzweig
Journal: Cancer Research (2020)

Abstract BACKGROUND: With the potential for medications targeted to somatic mutations, the utilization of whole genome sequencing (WGS) in MBC is increasingly important. The current clinical protocols surrounding the routine testing of WGS in MBC are amorphic. AIMS: We explored a cohort of patients with MBC to determine the prevalence and timing of WGS. Demographic and tumor characteristics of sequenced vs. non sequenced women with MBC were compared. Patient understanding of genomic sequencing was assessed. METHODS: Retrospective chart review of all MBC patients of the Magee-Womens Cancer Center between October 2016 and May 2019 for collection of demographic information, including neighborhood deprivation index (NDI) (zip code derived 0-10; higher scores= higher deprivation), clinical data and sequencing results (FoundationOne®, Guardant360®, Tempus, Caris®). Of those sequenced - Patient questionnaires included test of genetic knowledge (higher = more knowledge). Descriptive statistics, chi square and independent sample t tests used for analysis. Results: There has been an overall increase in the frequency of WGS in MBC; n=15 in 2016, n=30 in 2017, n=39 in 2018 and n=25 in the first 5 months of 2019. Of 418 total MBC patients, 31.3% (N=131) had whole genome sequencing, while 68.7% (N=287) did not. The sequenced patients were more likely to be triple negative, 74.4%, (n=96) than non-sequenced 25.6%, (n=33), p=.001. Most patients were sequenced once (n=112, 88.2%). First sequencing occurred within a mean of 4.9 months (SD 2.2; range 1-9) from MBC diagnosis. No clinical trials were accessed as a direct result of sequencing. There was no racial difference in sequencing prevalence, but non sequenced patients were from more highly deprived neighborhoods (p=.000). Of the patients sequenced, n=27 were interviewed. Mean knowledge of basic genetics was high at 12 (SD-2.1; Range 8-16). Knowledge of WGS and implication was poor. N=15 (80%) patients did not understand reasons and implications of sequencing while n=5 (20%) did. All who understood WGS and its implications were from non-deprived neighborhoods. Conclusion: WGS is increasingly being utilized as a tool in MBC, particularly for triple negative patients, without strict clinical protocol or direct change in treatment. Patient understanding of WGS and its implication is poor. Citation Format: Zoe Wecht, Adam Brufsky, Tiffaney Hsia, Margaret Q Rosenzweig. The influence of social demographics on genomic sequencing in metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-17-12.
Ten-Year Outcomes After Drug-Eluting Stents Versus Coronary Artery Bypass Grafting for Left Main Coronary Disease
Authors: Duk-Woo Park, Jung-Min Ahn, Hanbit Park, Sung-Cheol Yun, Do-Yoon Kang, Pil Hyung Lee, Young-Hak Kim, Do-Sun Lim, Seung-Woon Rha, Gyung-Min Park, Hyeon-Cheol Gwon, Hyo-Soo Kim, In-Ho Chae, Yangsoo Jang, Myung-Ho Jeong, Seung-Jea Tahk, Ki Bae Seung, Seung-Jung Park
Journal: Circulation (2020)

Long-term comparative outcomes after percutaneous coronary intervention (PCI) with drug-eluting stents and coronary-artery bypass grafting (CABG) for left main coronary artery disease are highly debated.In the PRECOMBAT trial (Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease), patients with unprotected left main coronary artery disease were randomly assigned to undergo PCI with sirolimus-eluting stents (n=300) or CABG (n=300) in 13 hospitals in Korea from April 2004 to August 2009. The follow-up was extended to at least 10 years for all patients (median, 11.3 years). The primary outcome was the incidence of major adverse cardiac or cerebrovascular events (composite of death from any cause, myocardial infarction, stroke, or ischemia-driven target-vessel revascularization).At 10 years, a primary outcome event occurred in 29.8% of the PCI group and in 24.7% of the CABG group (hazard ratio [HR] with PCI vs CABG, 1.25 [95% CI, 0.93-1.69]). The 10-year incidence of the composite of death, myocardial infarction, or stroke (18.2% vs 17.5%; HR 1.00 [95% CI, 0.70-1.44]) and all-cause mortality (14.5% vs 13.8%; HR 1.13 [95% CI, 0.75-1.70]) were not significantly different between the PCI and CABG groups. Ischemia-driven target-vessel revascularization was more frequent after PCI than after CABG (16.1% vs 8.0%; HR 1.98 [95% CI, 1.21-3.21).Ten-year follow-up of the PRECOMBAT trial of patients with left main coronary artery disease randomized to PCI or CABG did not demonstrate significant difference in the incidence of major adverse cardiac or cerebrovascular events. Because the study was underpowered, the results should be considered hypothesis-generating, highlighting the need for further research. Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03871127 and NCT00422968.
Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia
Authors: Anouchka P. Laurent, Aurélie Siret, Cathy Ignacimouttou, Kunjal Panchal, M'Boyba Diop, Silvia Jenni, Yi-Chien Tsai, Damien Roos-Weil, Zakia Aid, Nais Prade, Stephanie Lagarde, Damien Plassard, Gaelle Pierron, Estelle Daudigeos, Yann Lecluse, Nathalie Droin, Beat C. Bornhauser, Laurence C. Cheung, John D. Crispino, Muriel Gaudry, Olivier A. Bernard, Elizabeth Macintyre, Carole Barin Bonnigal, Rishi S. Kotecha, Birgit Geoerger, Paola Ballerini, Jean-Pierre Bourquin, Eric Delabesse, Thomas Mercher, Sebastien Malinge
Journal: Clinical Cancer Research (2020)

Children with Down syndrome (constitutive trisomy 21) that develop acute lymphoblastic leukemia (DS-ALL) have a 3-fold increased likelihood of treatment-related mortality coupled with a higher cumulative incidence of relapse, compared with other children with B-cell acute lymphoblastic leukemia (B-ALL). This highlights the lack of suitable treatment for Down syndrome children with B-ALL.To facilitate the translation of new therapeutic agents into clinical trials, we built the first preclinical cohort of patient-derived xenograft (PDX) models of DS-ALL, comprehensively characterized at the genetic and transcriptomic levels, and have proven its suitability for preclinical studies by assessing the efficacy of drug combination between the MEK inhibitor trametinib and conventional chemotherapy agents.Whole-exome and RNA-sequencing experiments revealed a high incidence of somatic alterations leading to RAS/MAPK pathway activation in our cohort of DS-ALL, as well as in other pediatric B-ALL presenting somatic gain of the chromosome 21 (B-ALL+21). In murine and human B-cell precursors, activated KRASG12D functionally cooperates with trisomy 21 to deregulate transcriptional networks that promote increased proliferation and self renewal, as well as B-cell differentiation blockade. Moreover, we revealed that inhibition of RAS/MAPK pathway activation using the MEK1/2 inhibitor trametinib decreased leukemia burden in several PDX models of B-ALL+21, and enhanced survival of DS-ALL PDX in combination with conventional chemotherapy agents such as vincristine.Altogether, using novel and suitable PDX models, this study indicates that RAS/MAPK pathway inhibition represents a promising strategy to improve the outcome of Down syndrome children with B-cell precursor leukemia.
Abstract P5-05-13: Inhibition of NOTCH signaing with g-secretase inhibitor AL101 contributes to overcome resistance against HER2-targeted therapy in HER2 amplified breast cancer cells
Authors: Bothaina Nakad, Esther Channah Broner, David Sidransky, Evgeny Izumchenko
Journal: Cancer Research (2020)

Abstract Notch signaling affects multiple cellular processes including stem cell maintenance, differentiation, proliferation, motility and survival. Activated NOTCH signaling and up-regulation of tumor-promoting NOTCH target genes are well documented in human breast cancer. Growing evidence suggest the novel role of NOTCH pathway as a survival resistance mechanism against HER2-targeted therapy in the HER2 amplified breast cancer subgroup, accounting for 20% of breast cancers. It was reported that tumor cells that develop intrinsic or acquired resistance to HER2 targeted therapy (at either relapse of the dormant resistant cells or at the progression of HER2 disease), express higher levels of NOTCH pathway genes. The small molecule AL101 is an γ-secretase inhibitor that potently inhibits the activation of all 4 NOTCH receptors (NOTCH1-4). We hypothesize that treatment with AL101, could potentially block activation of this intrinsic resistance mechanism and/or inhibit the acquisition of the acquired resistance. The goal of this study is: (a) to test the efficacy of first line treatment of anti-HER2 drugs combined with AL101, and (b) to test the efficacy of the AL101 as a second line therapy for anti-HER2 resistance breast cancer cells lines. Our study demonstrates the potential utility of HER2-targeted therapy in combination with AL101 as a novel strategy for overcoming the NOTCH signaling induced survival resistance mechanism in HER2 amplified breast cancer cells, and suggests NOTCH inhibitors as potential second-line therapy for recurrent or resistant HER2 amplified breast cancer tumors. Citation Format: Bothaina Nakad, Esther Channah Broner, David Sidransky, Evgeny Izumchenko. Inhibition of NOTCH signaing with g-secretase inhibitor AL101 contributes to overcome resistance against HER2-targeted therapy in HER2 amplified breast cancer cells [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-05-13.
Screening faecal microbiota transplant donors for SARS-CoV-2 by molecular testing of stool is the safest way forward
Authors: Christopher A Green, Mohammed N Quraishi, Sahida Shabir, Naveen Sharma, Richard Hansen, Daniel R Gaya, Ailsa L Hart, Nicholas J Loman, Tariq H Iqbal
Journal: The Lancet. Gastroenterology & hepatology (2020)
Abstract P4-05-17: ESR1 related chromothripsis enhances concordant gene transcription on chromosome 17q11.1-q24.1 in luminal breast cancer
Authors: Chun-Lin Lin
Journal: Cancer Research (2020)

Abstract Chromothripsis is an event of genomic instability leading to complex chromosomal alterations in cancer. Although studies have proposed models to explain its initiation, few discussed how transcription factors (TFs) influence chromothripsis for tumor progression. Frequent long-range chromatin interactions between TFs and targets may promote extensive translocations and copy-number alterations in proximal contact regions through inappropriate DNA stitching. Herein we surveyed genomic alterations of chromosome 17 in 1,014 breast tumors in the Cancer Genome Atlas (TCGA) cohort and found five adjoining regions from 17q11.1 to 17q24.1 being hotspots of chromothripsis. Inter-/intra-chromosomal rearrangements of these regions occurred more frequently in ERα-positive tumors than in ERα-negative tumors. In addition, the rearrangement sites were often mapped within or close to dense estrogen receptor 1 (ESR1) sites localized on the regions or other chromosomes. This chromothriptic event was linked to concordant upregulation of 96 loci that predominantly regulate cell-cycle machineries in advanced luminal tumors. Genome-editing analysis confirmed that an ESR1 transcription hub localized on 20q13 coordinately regulates a subset of these loci localized on 17q23 through long-range chromosome interactions. One of these loci, Tousled Like Kinase 2 (TLK2) known to participate in DNA damage checkpoint control, is an actionable target using phenothiazine antipsychotics (PTZs). The antiproliferative effect of PTZs was prominent in high TLK2-expressing cells, compared to low expressing cells. Collectively, we identified a group of luminal breast tumors displaying 17q-related chromothripsis for which antipsychotics can be repurposed as treatment adjuncts. Citation Format: Chun-Lin Lin. ESR1 related chromothripsis enhances concordant gene transcription on chromosome 17q11.1-q24.1 in luminal breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-05-17.
Plant‐Based and Animal‐Based Low‐Carbohydrate Diets and Risk of Hepatocellular Carcinoma Among US Men and Women
Authors: Yue Liu, Wanshui Yang, Trang VoPham, Yanan Ma, Tracey G. Simon, Xiang Gao, Andrew T. Chan, Jeffrey A. Meyerhardt, Edward L. Giovannucci, Xuehong Zhang
Journal: Hepatology (2020)

Background and Aims Little is known about the role of low‐carbohydrate diets (LCDs) in the development of hepatocellular carcinoma (HCC). We prospectively evaluated the associations between plant‐based and animal‐based LCDs and risk of HCC in the Nurses’ Health Study (NHS) and the Health Professionals Follow‐up Study (HPFS). Approach and Results Dietary intake was assessed every 4 years using validated food frequency questionnaires. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). HRs are shown for a 1‐standard deviation (SD) increment with variables modeled as continuous. During 3,664,769 person‐years of follow‐up, there were 156 incident HCC cases. Although there were no associations between overall or animal‐based LCD score and risk of HCC, plant‐based LCD score was inversely associated with HCC risk (HR, 0.83; 95% CI, 0.70‐0.98; P trend = 0.03). Carbohydrate intake, especially from refined grains (HR, 1.18; 95% CI, 1.00‐1.39; P trend = 0.04), was positively, while plant fat (HR, 0.78; 95% CI, 0.65‐0.95; P trend = 0.01) was inversely associated with HCC risk. Substituting 5% of energy from plant fat and protein for carbohydrate (HR, 0.74; 95% CI, 0.58‐0.93; P trend = 0.01) or refined grains (HR, 0.70; 95% CI, 0.55‐0.90; Ptrend = 0.006) was associated with lower HCC risk. In conclusion, a plant‐based LCD and dietary restriction of carbohydrate from refined grains were associated with a lower risk of HCC. Substituting plant fat and protein for carbohydrate, particularly refined grains, may decrease HCC incidence. Conclusions Our findings support a potential benefit in emphasizing plant sources of fat and protein in the diet for HCC primary prevention; additional studies that carefully consider hepatitis B and C virus infections and chronic liver diseases are needed to confirm our findings.
AB0214 The second physician behind the use of colchicine for the treatment of familial mediterranean fever
Authors: O Aral, H Ozdogan, H Yazici
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> In 1972 Dr. Goldfinger of the Massachusetts General Hospital in Boston published one of the most quoted ‘letters to the editor’ in New England Journal of Medicine, ‘Colchicine for Familial Mediterranean Fever’, (FMF).<sup>1</sup> Here he described 5 patients whose FMF attacks resolved by the continuous administration of colchicine. This 30 year old observation has been reproduced by numerous controlled studies and changed the prognosis of this disease dramatically. <h3>Objectives</h3> To document the contribution of Professor Emir Özkan MD, on the use of colchicine in FMF. <h3>Methods</h3> <h3>Results</h3> What is not widely known is the contribution of another physician, Dr. Emir Özkan, professor of cardiology in the Medical Faculty of University of Istanbul, to the treatment of FMF. Dr. Özkan and his colleagues published their findings in an article entitled ‘A New Approach to the Treatment of Periodic Fever’ in the Medical Bulletin of Istanbul Medical Faculty.<sup>2</sup> This article included their favourable results in 14 patients with FMF and also reported the disappearance of proteinuria in a patient with amyloidosis after 6 months of colchicine treatment. The authors had submitted this article on April 17, 1972, some 8 months before the appearance of the Goldfinger article in the New England Journal of Medicine which appeared in the December 21 issue of the journal. <h3>Conclusion</h3> A Goldfinger-Özkan Award for Excellence in Clinical Science and Management of FMF, was given for the first time during the II. International Congress of FMF in Antalya, Turkey, in May 2000. <h3>References</h3> Goldfinger SE. Colchicine for familial Mediterranean fever. N Engl J Med. 1972;287:1302 Özkan E, Okur Ö, Ekmekci A, Özcan R, Tag T. A new approach to the treatment of periodic fever. Med Bull Istanbul. 1972;5:44–9