tbuckley/cabot-search huggingface dataset:
EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer
Authors: Vito Amodio, Rona Yaeger, Pamela Arcella, Carlotta Cancelliere, Simona Lamba, Annalisa Lorenzato, Sabrina Arena, Monica Montone, Benedetta Mussolin, Yu Bian, Adele Whaley, Marika Pinnelli, Yonina R. Murciano-Goroff, Efsevia Vakiani, Nicola Valeri, Wei-Li Liao, Anuja Bhalkikar, Sheeno Thyparambil, Hui-Yong Zhao, Elisa de Stanchina, Silvia Marsoni, Salvatore Siena, Andrea Bertotti, Livio Trusolino, Bob T. Li, Neal Rosen, Federica Di Nicolantonio, Alberto Bardelli, Sandra Misale
Journal: Cancer Discovery (2020)

Most patients with KRAS G12C-mutant non-small cell lung cancer (NSCLC) experience clinical benefit from selective KRASG12C inhibition, whereas patients with colorectal cancer bearing the same mutation rarely respond. To investigate the cause of the limited efficacy of KRASG12C inhibitors in colorectal cancer, we examined the effects of AMG510 in KRAS G12C colorectal cancer cell lines. Unlike NSCLC cell lines, KRAS G12C colorectal cancer models have high basal receptor tyrosine kinase (RTK) activation and are responsive to growth factor stimulation. In colorectal cancer lines, KRASG12C inhibition induces higher phospho-ERK rebound than in NSCLC cells. Although upstream activation of several RTKs interferes with KRASG12C blockade, we identify EGFR signaling as the dominant mechanism of colorectal cancer resistance to KRASG12C inhibitors. The combinatorial targeting of EGFR and KRASG12C is highly effective in colorectal cancer cells and patient-derived organoids and xenografts, suggesting a novel therapeutic strategy to treat patients with KRAS G12C colorectal cancer. SIGNIFICANCE: The efficacy of KRASG12C inhibitors in NSCLC and colorectal cancer is lineage-specific. RTK dependency and signaling rebound kinetics are responsible for sensitivity or resistance to KRASG12C inhibition in colorectal cancer. EGFR and KRASG12C should be concomitantly inhibited to overcome resistance to KRASG12C blockade in colorectal tumors.See related commentary by Koleilat and Kwong, p. 1094.This article is highlighted in the In This Issue feature, p. 1079.
Activating AKT1 and PIK3CA Mutations in Metastatic Castration-Resistant Prostate Cancer
Authors: Cameron Herberts, Andrew J. Murtha, Simon Fu, Gang Wang, Elena Schönlau, Hui Xue, Dong Lin, Anna Gleave, Steven Yip, Arkhjamil Angeles, Sebastien Hotte, Ben Tran, Scott North, Sinja Taavitsainen, Kevin Beja, Gillian Vandekerkhove, Elie Ritch, Evan Warner, Fred Saad, Nayyer Iqbal, Matti Nykter, Martin E. Gleave, Yuzhuo Wang, Matti Annala, Kim N. Chi, Alexander W. Wyatt
Journal: European Urology (2020)
Experimental Antiglomerular Basement Membrane GN Induced by a Peptide from Actinomyces
Authors: Qiu-hua Gu, Megan Huynh, Yue Shi, Xiao-yu Jia, Jie-jian Luo, Tai-jiao Jiang, Zhao Cui, Joshua D. Ooi, A. Richard Kitching, Ming-hui Zhao
Journal: Journal of the American Society of Nephrology (2020)

Significance Statement Antiglomerular basement membrane (anti-GBM) disease is associated with HLA-DRB1*1501 (the major predisposing genetic factor in the disease), with α 3 127–148 as a nephritogenic T and B cell epitope. Association of infections with anti-GBM disease has been long suspected. In this study, the authors used bioinformatic tools to search for peptides from microbes mimicking the critical motif of a pathogenic epitope for Goodpasture disease ( α 3 127–148 ). They identified a pathogenic peptide derived from Actinomyces , which was recognized by sera from patients with anti-GBM disease and that induced proteinuria, linear IgG deposition on GBM, and crescent formation in both WKY rats and humanized HLA-DR15 transgenic mice via crossreactivity of lymphocytes. These findings implicate a role for infection and molecular mimicry in the pathogenesis of anti-GBM disease. Background Antiglomerular basement membrane (anti-GBM) disease is associated with HLA-DRB1*1501 (the major predisposing genetic factor in the disease), with α 3 127–148 as a nephritogenic T and B cell epitope. Although the cause of disease remains unclear, the association of infections with anti-GBM disease has been long suspected. Methods To investigate whether microbes might activate autoreactive T and B lymphocytes via molecular mimicry in anti-GBM disease, we used bioinformatic tools, including BLAST, SYFPEITHI, and ABCpred, for peptide searching and epitope prediction. We used sera from patients with anti-GBM disease to assess peptides recognized by antibodies, and immunized WKY rats and a humanized mouse model (HLA-DR15 transgenic mice) with each of the peptide candidates to assess pathogenicity. Results On the basis of the critical motif, the bioinformatic approach identified 36 microbial peptides that mimic human α 3 127–148 . Circulating antibodies in sera from patients with anti-GBM recognized nine of them. One peptide, B7, derived from Actinomyces species, induced proteinuria, linear IgG deposition on the GBM, and crescent formation when injected into WKY rats. The antibodies to B7 also targeted human and rat α 3 127–148 . B7 induced T cell activation from human α 3 127–148 -immunized rats. T cell responses to B7 were detected in rats immunized by Actinomyces lysate proteins or recombinant proteins. We confirmed B7’s pathogenicity in HLA-DR15 transgenic mice that developed kidney injury similar to that observed in α 3 135–145 -immunized mice. Conclusions Sera from patients with anti-GBM disease recognized microbial peptides identified through a bioinformatic approach, and a peptide from Actinomyces induced experimental anti-GBM GN by T and B cell crossreactivity. These studies demonstrate that anti-GBM disease may be initiated by immunization with a microbial peptide.
Detection of Promoter DNA Methylation in Urine and Plasma Aids the Detection of Non–Small Cell Lung Cancer
Authors: Bin Liu, Julio Ricarte Filho, Apurva Mallisetty, Cassandra Villani, Anastasia Kottorou, Kristen Rodgers, Chen Chen, Tomoaki Ito, Kyla Holmes, Nicole Gastala, Klara Valyi-Nagy, Odile David, Ron C. Gaba, Christian Ascoli, Mary Pasquinelli, Lawrence E. Feldman, Malek G. Massad, Tza-Huei Wang, Ignacio Jusue-Torres, Enrico Benedetti, Robert A. Winn, Malcolm V. Brock, James G. Herman, Alicia Hulbert
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Low-dose CT screening can reduce lung cancer–related mortality. However, CT screening has an FDR of nearly 96%. We sought to assess whether urine samples can be a source for DNA methylation–based detection of non–small cell lung cancer (NSCLC). Experimental Design: This nested case–control study of subjects with suspicious nodules on CT imaging obtained plasma and urine samples preoperatively. Cases (n = 74) had pathologic confirmation of NSCLC. Controls (n = 27) had a noncancer diagnosis. We detected promoter methylation in plasma and urine samples using methylation on beads and quantitative methylation–specific real-time PCR for cancer-specific genes (CDO1, TAC1, HOXA7, HOXA9, SOX17, and ZFP42). Results: DNA methylation at cancer-specific loci was detected in both plasma and urine, and was more frequent in patients with cancer compared with controls for all six genes in plasma and in CDO1, TAC1, HOXA9, and SOX17 in urine. Univariate and multivariate logistic regression analysis showed that methylation detection in each one of six genes in plasma and CDO1, TAC1, HOXA9, and SOX17 in urine were significantly associated with the diagnosis of NSCLC, independent of age, race, and smoking pack-years. When methylation was detected for three or more genes in both plasma and urine, the sensitivity and specificity for lung cancer diagnosis were 73% and 92%, respectively. Conclusions: DNA methylation–based biomarkers in plasma and urine could be useful as an adjunct to CT screening to guide decision-making regarding further invasive procedures in patients with pulmonary nodules.
Implementation of Minimally Invasive Esophagectomy From a Randomized Controlled Trial Setting to National Practice
Authors: Sheraz R. Markar, Melody Ni, Suzanne S. Gisbertz, Leonie van der Werf, Jennifer Straatman, Donald van der Peet, Miguel A. Cuesta, George B. Hanna, Mark I. van Berge Henegouwen
Journal: Journal of Clinical Oncology (2020)

PURPOSE The aim of this study was to examine the external validity of the randomized TIME trial, when minimally invasive esophagectomy (MIE) was implemented nationally in the Netherlands, using data from the Dutch Upper GI Cancer Audit (DUCA) for transthoracic esophagectomy. METHODS Original patient data from the TIME trial were extracted along with data from the DUCA dataset (2011-2017). Multivariate analysis, with adjustment for patient factors, tumor factors, and year of surgery, was performed for the effect of MIE versus open esophagectomy on clinical outcomes. RESULTS One hundred fifteen patients from the TIME trial (59 MIE v 56 open) and 4,605 patients from the DUCA dataset (2,652 MIE v 1,953 open) were included. In the TIME trial, univariate analysis showed that MIE reduced pulmonary complications and length of hospital stay. On the contrary, in the DUCA dataset, MIE was associated with increased total and pulmonary complications and reoperations; however, benefits included increased proportion of R0 margin and lymph nodes harvested, and reduced 30-day mortality. Multivariate analysis from the TIME trial showed that MIE reduced pulmonary complications (odds ratio [OR], 0.19; 95% CI, 0.06 to 0.61). In the DUCA dataset, MIE was associated with increased total complications (OR, 1.36; 95% CI, 1.19 to 1.57), pulmonary complications (OR, 1.50; 95% CI, 1.29 to 1.74), reoperations (OR, 1.74; 95% CI, 1.42 to 2.14), and length of hospital stay. Multivariate analysis of the combined and MIE datasets showed that inclusion in the TIME trial was associated with a reduction in reoperations, Clavien-Dindo grade &gt; 1 complications, and length of hospital stay. CONCLUSION When adopted nationally outside the TIME trial, MIE was associated with an increase in total and pulmonary complications and reoperation rate. This may reflect nonexpert surgeons outside of high-volume centers performing this minimally invasive technique in a nonstandardized fashion outside of a controlled environment.
Impact of Beta-Blockers on Birth Weight in a High-Risk Cohort of Pregnant Women With CVD
Authors: Jasmine Grewal, Samuel C. Siu, Terry Lee, Rohan D’Souza, Merav Dvir, Joel Singer, Valerie Rychel, Marla Kiess, Mathew Sermer, Candice K. Silversides
Journal: Journal of the American College of Cardiology (2020)
Abstract 11149: Effect of Low-density Lipoprotein Cholesterol Lowering With Alirocumab on Stroke in ODYSSEY OUTCOMES
Authors: J Wouter Jukema, Michael Szarek, Laurien Zijlstra, Deepak L Bhatt, Vera A Bittner, Rafael Diaz, Heinz Drexel, Shaun G Goodman, Robert A Harrington, Yong-Un Kim, Michael J Louie, Robert Pordy, Zeljko Reiner, Matthew T Roe, Hung-Fat Tse, Pablo Carlos Montenegro Valdovinos, Harvey D White, Andreas M Zeiher, Gregory G Schwartz, Philippe G Steg
Journal: Circulation (2019)

Background: Lowering of atherogenic lipoproteins, including LDL-C, reduces the risk of ischemic stroke. However, concerns have been raised about intense lipid-lowering and a potential increased ris...
Immunodeficiency Disease and Malignancy
Authors: THOMAS A. WALDMANN
Journal: Annals of Internal Medicine (1972)

Patients with immunodeficiency have a markedly increased incidence of malignancy. Defects in cellular and circulating immunity common to these patients are caused by various pathophysiological mechanisms. Some have developmental disorders in their ability to synthesize lymphocytes and immunoglobulins, the effectors of immunity. Others have defects in antigen processing and recognition, an abnormality of the afferent limb of immunity. A third group of patients with increased malignancy has immunodeficiency due to shortened survival of effectors of immunity. Ataxia-telangiectasia, Wiskott-Aldrich syndrome, and intestinal lymphangiectasia are discussed as examples of these three categories of immunodeficiency. The association of malignancy with these immunologic disorders supports the concept that the immune system normally plays an important role in control of malignant disease, by surveillance and elimination of exogenous oncogenic viruses and tumor cells that possess new surface antigens and perhaps in preventing activation of latent viral genomes within the reticuloendothelial system.
Terminating contamination: large-scale search identifies more than 2,000,000 contaminated entries in GenBank
Authors: Martin Steinegger, Steven L. Salzberg
Journal: Genome biology (2020)

Abstract Genomic analyses are sensitive to contamination in public databases caused by incorrectly labeled reference sequences. Here, we describe Conterminator, an efficient method to detect and remove incorrectly labeled sequences by an exhaustive all-against-all sequence comparison. Our analysis reports contamination of 2,161,746, 114,035, and 14,148 sequences in the RefSeq, GenBank, and NR databases, respectively, spanning the whole range from draft to “complete” model organism genomes. Our method scales linearly with input size and can process 3.3 TB in 12 days on a 32-core computer. Conterminator can help ensure the quality of reference databases. Source code (GPLv3): https://github.com/martin-steinegger/conterminator
Enzymes of fructose metabolism in human liver
Authors: Fritz Heinz, Walther Lamprecht, Joachim Kirsch
Journal: Journal of Clinical Investigation (1968)

The enzyme activities involved in fructose metabolism were measured in samples of human liver. On the basis of U/g of wet-weight the following results were found: ketohexokinase, 1.23; aldolase (substrate, fructose-1-phosphate), 2.08; aldolase (substrate, fructose-1,6-diphosphate), 3.46; triokinase, 2.07; aldehyde dehydrogenase (substrate, D-glyceraldehyde), 1.04; D-glycerate kinase, 0.13; alcohol dehydrogenase (nicotinamide adenine dinucleotide [NAD]) substrate, D-glyceraldehyde), 3.1; alcohol dehydrogenase (nicotinamide adenine dinucleotide phosphate [NADP]) (substrate, D-glyceraldehyde), 3.6; and glycerol kinase, 0.62. Sorbitol dehydrogenases (25.0 U/g), hexosediphosphatase (4.06 U/g), hexokinase (0.23 U/g), and glucokinase (0.08 U/g) were also measured. Comparing these results with those of the rat liver it becomes clear that the activities of alcohol dehydrogenases (NAD and NADP) in rat liver are higher than those in human liver, and that the values of ketohexokinase, sorbitol dehydrogenases, and hexosediphosphatase in human liver are lower than those values found in rat liver. Human liver contains only traces of glycerate kinase. The rate of fructose uptake from the blood, as described by other investigators, can be based on the activity of ketohexokinase reported in the present paper. In human liver, ketohexokinase is present in a four-fold activity of glucokinase and hexokinase. This result may explain the well-known fact that fructose is metabolized faster than glucose.
A Global Survey on the Impact of COVID-19 on Urological Services
Authors: Jeremy Yuen-Chun Teoh, William Lay Keat Ong, Daniel Gonzalez-Padilla, Daniele Castellani, Justin M. Dubin, Francesco Esperto, Riccardo Campi, Kalyan Gudaru, Ruchika Talwar, Zhamshid Okhunov, Chi-Fai Ng, Nitesh Jain, Vineet Gauhar, Martin Chi-Sang Wong, Marcelo Langer Wroclawski, Yiloren Tanidir, Juan Gomez Rivas, Ho-Yee Tiong, Stacy Loeb
Journal: European Urology (2020)
PD1/PD-L1 targeting in advanced soft-tissue sarcomas: a pooled analysis of phase II trials
Authors: Antoine Italiano, Carine Bellera, Sandra D’Angelo
Journal: Journal of Hematology & Oncology (2020)

Immune checkpoint inhibitors, especially the programmed cell death receptor-1/ligand 1 (PD-1/L1) inhibitors, displayed promising efficacy in several solid tumor types and hematological malignancies. Data related to their activity in soft-tissue sarcomas (STS) are scarce.We performed a pooled analysis of clinical trials investigating a PD1 or PD-L1 antagonist in patients with advanced STS. Three hundred eighty-four patients were included in the pooled analysis; of those, 153 (39.8%) received a PD1/PD-L1 antagonist as a single agent. In patients treated with anti-PD1/PDL1 as a single agent, the overall response rate (ORR) and non-progression rate (NPR) were 15.1% and 58.5% respectively. In patients treated with a combination regimen, the ORR and NPR were 13.4% and 55.8% respectively. Analysis by histological subtype revealed that patients with alveolar soft part sarcoma and undifferentiated pleomorphic sarcoma exhibited the highest response rates and leiomyosarcoma the lowest. PD-L1 expression rate was low and inconsistently associated with objective response.PD-1/PD-L1 antagonists have limited activity in unselected STS. Future studies should implement histology and immune-based stratification of STS in their design as well as sequential blood and tissue sampling to better understand the mechanisms of resistance and response given sarcomas inherent heterogeneity.
Interleukin-6 deficiency exacerbates Huntington’s disease model phenotypes
Authors: Mary H. Wertz, S. Sebastian Pineda, Hyeseung Lee, Ruth Kulicke, Manolis Kellis, Myriam Heiman
Journal: Molecular Neurodegeneration (2020)

Abstract Huntington’s disease (HD) is an incurable neurodegenerative disorder caused by CAG trinucleotide expansions in the huntingtin gene. Markers of both systemic and CNS immune activation and inflammation have been widely noted in HD and mouse models of HD. In particular, elevation of the pro-inflammatory cytokine interleukin-6 (IL-6) is the earliest reported marker of immune activation in HD, and this elevation has been suggested to contribute to HD pathogenesis. To test the hypothesis that IL-6 deficiency would be protective against the effects of mutant huntingtin , we generated R6/2 HD model mice that lacked IL-6. Contrary to our prediction, IL-6 deficiency exacerbated HD-model associated behavioral phenotypes. Single nuclear RNA Sequencing (snRNA-seq) analysis of striatal cell types revealed that IL-6 deficiency led to the dysregulation of various genes associated with synaptic function, as well as the BDNF receptor Ntrk2 . These data suggest that IL-6 deficiency exacerbates the effects of mutant huntingtin through dysregulation of genes of known relevance to HD pathobiology in striatal neurons, and further suggest that modulation of IL-6 to a level that promotes proper regulation of genes associated with synaptic function may hold promise as an HD therapeutic target.
Abstract 16764: Aging-Related Myofibroblastic Transition in Aortic Valve Interstitial Cells Elevates Valvular Osteogenic Response to Oxidized Low Density Lipoprotein
Authors: Qingchun Zeng, Qingzhou Yao, Lihua Ao, Dingli Xu, David Furllerton, Xianzhong Meng
Journal: Circulation (2018)

Calcific aortic valve disease (CAVD) is the most prevalent heart valve disorder in the elderly. The pathobiology of this disease involves chronic inflammation, fibrosis and calcification. However, the molecular mechanism underlying CAVD progression remains obscure. Diseased aortic valves display higher levels of oxidized low-density lipoprotein (oxLDL), and oxLDL has the potential to interact with Toll-like receptors (TLRs) in aortic valve interstitial cells (AVICs) to elevate cellular osteogenic activity. We tested the hypotheses that aging-related myofibroblastic transition in AVICs elevates valvular osteogenic response to oxLDL. Methods and Results: AVICs from normal valves of young (20-30 years old) and older (60-70 years old) people were treated with oxLDL (40 μg/ml) for 3-14 days in vitro. OxLDL had a greater effect on the up-regulation of bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP), as well as on the induction of calcium deposition, in AVICs from older donors. The exaggerated pro-osteogenic effect of oxLDL in AVICs of older donors was associated with over-expression of myofibroblastic biomarker α-smooth muscle actin (α-SMA), and knockdown of α-SMA with lentiviral shRNA markedly attenuated the osteogenic response. Further, oxLDL induced greater activation of ERK1/2 and NF-κB in AVICs of older donors. Inhibition of ERK1/2 or NF-κB greatly diminished the effect of oxLDL on BMP-2 and ALP expression in AVICs from both young and older donors. Conclusions: The results of this study show that oxLDL exerts a greater impact on AVICs of older subjects to elevate the pro-osteogenic activity through activation of the ERK1/2 and NF-κB pathways. AVIC myofibroblastic transition associated with aging is responsible, at least in part, for the elevated osteogenic response to oxLDL. These findings reveal a novel mechanism underlying CAVD pathogenesis and indicate that suppression of AVIC myofibroblastic transition in the elderly patients may have the therapeutic potential for suppression of CAVD progression.
Venereal Disease Prophylaxis
Authors: Erwin H. Braff
Journal: JAMA (1976)

<h3>To the Editor.—</h3> Darrow and Wiesner (233:444-446, 1975) in their pessimistic assessment of venereal disease prophylaxis reflect the low priority placed on the primary prevention of venereal disease by the Public Health Service. The authors in reviewing the effectiveness of the three existing venereal disease prophylactic techniques (mechanical prophylaxis—condoms, local prophylaxis—soaps, antiseptic ointments, and others, and systemic prophylaxis—antibiotics) conclude that consumer rejection or improper use are the major factors that limit success of venereal disease prevention by these three approaches. Understandably, they were not optimistic in changing these patterns of consumer behavior. I would suggest a more positive approach, which would focus on what potential consumers of veneral disease prophylactic techniques would use. A well-designed study could confirm consumer interest and anticipated use of a venereal disease prophylactic method with acceptable characteristics. Findings of this study may generate the interest necessary to adequately fund research and development. If the agent is
Cross-border spread of blaNDM-1- and blaOXA-48-positive Klebsiella pneumoniae: a European collaborative analysis of whole genome sequencing and epidemiological data, 2014 to 2019
Authors: Catherine Ludden, Felix Lötsch, Erik Alm, Narender Kumar, Karin Johansson, Barbara Albiger, Te-Din Huang, Olivier Denis, Anette M Hammerum, Henrik Hasman, Jari Jalava, Kati Räisänen, Laurent Dortet, Agnès B Jousset, Sören Gatermann, Sebastian Haller, Martin Cormican, Wendy Brennan, Maria Del Grosso, Monica Monaco, Leo Schouls, Ørjan Samuelsen, Mateja Pirš, Tjaša Cerar, Jésus Oteo-Iglesias, Maria Pérez-Vázquez, Karin Sjöström, Petra Edquist, Katie L Hopkins, Marc J Struelens, Daniel Palm, Dominique L Monnet, Anke Kohlenberg
Journal: Eurosurveillance (2020)

Analysis of sequencing data for 143 blaNDM-1- and blaOXA-48-positive Klebsiella pneumoniae isolates from 13 European national collections and the public domain resulted in the identification of 15 previously undetected multi-country transmission clusters. For 10 clusters, cases had prior travel/hospitalisation history in countries outside of the European Union including Egypt, Iran, Morocco, Russia, Serbia, Tunisia and Turkey. These findings highlight the benefit of European whole genome sequencing-based surveillance and data sharing for control of antimicrobial resistance.