tbuckley/cabot-search huggingface dataset:
Abstract 11844: Viral Gene Signatures in Patients With Cardiomyopathy After Chemotherapy
Authors: Kyle Varkoly, Shaoyuan Tan, Roxana Beladi, Simona Kraberger, Ayman Fath, Jordan Yaron, Liqiang Zhang, Carl J Pepine, Arvind Varsani, Chintan Shah, Jan Moreb, Stacey Schultz-Cherry, Alexandra R Lucas
Journal: Circulation (2021)

Introduction: Chemotherapy for hematologic malignancies can cause severe cardiomyopathy. Chemotherapeutic agents also induce immune suppression increasing the risk of opportunistic infections. Hypothesis: We have hypothesized that immunosuppression after chemotherapy increases opportunistic viral infections, myocarditis and cardiomyopathy. Methods: Viral gene sequences were identified using an unbiased high-throughput sequencing approach of patient blood samples following chemotherapy treatment for hematological malignancies (N = 28). Detected viral sequences were correlated with cardiac ejection fraction (LVEF) measured before and after treatment. Results: In a blinded analysis undertaken by two investigators viral sequences were identified in blood samples from patients after chemotherapy. Low levels of Influenza A, orthomyxovirus and Avian Paramyxovirus sequences were detected but identified individual virus sequences did not have a significant correlation to reduced LVEF post chemotherapy (r = 0.177-0.293). Detected sequences for all RNA viruses combined did indicate some correlation with LVEF, r = 0.621, suggesting potential for nonspecific RNA virus detection ( p &lt; 0.0078). In a secondary broad screen, data mining was performed including all detectable viral sequences without the filtering of human related sequences. In this broad analysis a significant correlation was detected for Paramyxovirus with reduced cardiac LVEF (r = 0.592 post, compared to r = 0.464 prior to chemotherapy; P &lt; .0096). For detected Orthomyxovirus sequences correlations were similar for LVEF pre- and post- chemotherapy (R = 0.483, P &lt; 0.0451). Retroviruses reads were increased but suspect due to human genome retrovirus sequences (R= 0.512; P &lt; 0.0351). No correlation was seen for Anellovirus, a DNA virus. Reduced LVEF did not correlate with chemotherapy (p = NS). Conclusions: This is the first report of screening for RNA viruses in the circulating blood of patients post chemotherapy using a high-throughput sequencing approach. Influenza Orthomyxovirus and Avian Paramyxovirus sequences were detectable in patients with reduced LVEF after chemotherapy. Further analysis for RNA virus infections in cardiomyopathy after chemotherapy is warranted.
Organoid Sensitivity Correlates with Therapeutic Response in Patients with Pancreatic Cancer
Authors: Joseph E. Grossman, Lakshmi Muthuswamy, Ling Huang, Dipikaa Akshinthala, Sofia Perea, Raul S. Gonzalez, Leo L. Tsai, Jonah Cohen, Bruno Bockorny, Andrea J. Bullock, Benjamin Schlechter, Mary Linton B. Peters, Catherine Conahan, Supraja Narasimhan, Christine Lim, Roger B. Davis, Robert Besaw, Mandeep S. Sawhney, Douglas Pleskow, Tyler M. Berzin, Martin Smith, Tara S. Kent, Mark Callery, Senthil K. Muthuswamy, Manuel Hidalgo
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) remains a significant health issue. For most patients, there are no options for targeted therapy, and existing treatments are limited by toxicity. The HOPE trial (Harnessing Organoids for PErsonalized Therapy) was a pilot feasibility trial aiming to prospectively generate patient-derived organoids (PDO) from patients with PDAC and test their drug sensitivity and correlation with clinical outcomes. Experimental Design: PDOs were established from a heterogeneous population of patients with PDAC including both basal and classical PDAC subtypes. Results: A method for classifying PDOs as sensitive or resistant to chemotherapy regimens was developed to predict the clinical outcome of patients. Drug sensitivity testing on PDOs correlated with clinical responses to treatment in individual patients. Conclusions: These data support the investigation of PDOs to guide treatment in prospective interventional trials in PDAC.
Annals Graphic Medicine - Awaiting Their Turn to the Emergency Room
Authors: Arun Thekkekarott Kuruvila, Nikita Hegde
Journal: Annals of Internal Medicine (2022)

Web ExclusivesMarch 2022Annals Graphic Medicine - Awaiting Their Turn to the Emergency RoomFREEArun Thekkekarott Kuruvila, MBBS, MD and Nikita Hegde, MBBS, MDArun Thekkekarott Kuruvila, MBBS, MDAsante Rogue Regional Medical Center, Medford, Oregon (A.T.K.)Search for more papers by this author and Nikita Hegde, MBBS, MDA.J. Institute of Medical Sciences, Mangalore, India (N.H.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G21-0083 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAuthors: Arun Thekkekarott Kuruvila, MBBS, MD; Nikita Hegde, MBBS, MDAffiliations: Asante Rogue Regional Medical Center, Medford, Oregon (A.T.K.)A.J. Institute of Medical Sciences, Mangalore, India (N.H.)Disclosures: Authors have reported no disclosures of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G21-0083.Author/Illustrator Information: Arun Thekkekarott Kuruvila, MBBS, MD, is a hospitalist in Oregon and an acclaimed artist who has displayed his artwork at high-quality exhibitions in India and the United States (e-mail, [email protected]com). Nikita Hegde, MBBS, MD, is an anesthesiologist and art enthusiast (e-mail, [email protected]com).This article was published at Annals.org on 1 February 2022. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics March 2022Volume 175, Issue 3Page: W35-W36 ePublished: 1 February 2022 Issue Published: March 2022 Copyright & PermissionsCopyright © 2022 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Three-Year Follow-Up and Response–Survival Relationship of Nivolumab in Previously Treated Patients with Advanced Esophageal Squamous Cell Carcinoma (ATTRACTION-3)
Authors: Morihito Okada, Ken Kato, Byoung Chul Cho, Masanobu Takahashi, Chen-Yuan Lin, Keisho Chin, Shigenori Kadowaki, Myung-Ju Ahn, Yasuo Hamamoto, Yuichiro Doki, Chueh-Chuan Yen, Yutaro Kubota, Sung-Bae Kim, Chih-Hung Hsu, Eva Holtved, Ioannis Xynos, Yasuhiro Matsumura, Akira Takazawa, Yuko Kitagawa
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Limited long-term data are available on immune checkpoint inhibitor use in patients with advanced esophageal squamous cell carcinoma (ESCC). We report 3-year follow-up data from our study of nivolumab versus chemotherapy (paclitaxel or docetaxel) in patients with previously treated ESCC. Patients and Methods: ATTRACTION-3 was a randomized, multicenter, open-label, phase III trial. Overall survival (OS), time from randomization to death from any cause, was the primary endpoint. An exploratory subanalysis assessed OS according to the best overall response (BOR) with and without landmark at 4 months. Results: Of the enrolled patients, 210 received nivolumab and 209 received chemotherapy. With a minimum follow-up of 36.0 months, OS was longer in the nivolumab versus the chemotherapy group (median, 10.9 vs. 8.5 months; HR, 0.79; P = 0.0264), with 3-year OS rates of 15.3% and 8.7%, respectively. The median OS was longer with nivolumab versus chemotherapy irrespective of the BOR (complete response/partial response: 19.9 vs. 15.4 months; stable disease: 17.4 vs. 8.8 months; and progressive disease: 7.6 vs. 4.2 months). Grade 3 or higher treatment-related adverse events were reported in 40 patients (19.1%) in the nivolumab group and 133 patients (63.9%) in the chemotherapy group. Conclusions: Nivolumab as second-line therapy demonstrated clinically meaningful long-term improvement in OS compared with chemotherapy in previously treated patients with advanced ESCC. The OS was consistently improved in the nivolumab group compared with the chemotherapy group regardless of BOR. Nivolumab was well tolerated over the 3-year follow-up. See related commentary by Yoon et al., p. 3173
CRISPR/Cas9-Induced DNA Damage Enriches for Mutations in a p53-Linked Interactome: Implications for CRISPR-Based Therapies
Authors: Long Jiang, Katrine Ingelshed, Yunbing Shen, Sanjaykumar V. Boddul, Vaishnavi Srinivasan Iyer, Zsolt Kasza, Saikiran Sedimbi, David P. Lane, Fredrik Wermeling
Journal: Cancer Research (2021)

Inactivating p53 mutations are the most abundant genetic alterations found in cancer. Here we show that CRISPR/Cas9-induced double-stranded DNA breaks enrich for cells deficient in p53 and in genes of a core CRISPR-p53 tumor suppressor interactome. Such enrichment could predispose to cancer development and thus pose a challenge for clinical CRISPR use. Transient p53 inhibition could suppress the enrichment of cells with these mutations. The level of DNA damage response induced by an sgRNA influenced the enrichment of p53-deficient cells and could be a relevant parameter in sgRNA design to limit cellular enrichment. Furthermore, a dataset of >800 human cancer cell lines identified additional factors influencing the enrichment of p53-mutated cells, including strong baseline CDKN1A expression as a predictor for an active CRISPR-p53 axis. Taken together, these data provide details about p53 biology in the context of CRISPR-induced DNA damage and identify strategies to enable safer CRISPR use. SIGNIFICANCE: CRISPR-mediated DNA damage enriches for cells with escape mutations in a core CRISPR-p53 interactome, which can be suppressed by transient inhibition of p53.
Sodium-Glucose Cotransporter 2 Inhibitors and Risk of Hyperkalemia in People With Type 2 Diabetes: A Meta-Analysis of Individual Participant Data From Randomized, Controlled Trials
Authors: Brendon L. Neuen, Megumi Oshima, Rajiv Agarwal, Clare Arnott, David Z. Cherney, Robert Edwards, Anna Maria Langkilde, Kenneth W. Mahaffey, Darren K. McGuire, Bruce Neal, Vlado Perkovic, Annpey Pong, Marc S. Sabatine, Itamar Raz, Tadashi Toyama, Christoph Wanner, David C. Wheeler, Stephen D. Wiviott, Bernard Zinman, Hiddo J.L. Heerspink
Journal: Circulation (2022)

Background: Hyperkalemia increases risk of cardiac arrhythmias and death and limits the use of renin-angiotensin-aldosterone system inhibitors and mineralocorticoid receptor antagonists, which improve clinical outcomes in people with chronic kidney disease or systolic heart failure. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of cardiorenal events in people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease. However, their effect on hyperkalemia has not been systematically evaluated. Methods: A meta-analysis was conducted using individual participant data from randomized, double-blind, placebo-controlled clinical outcome trials with SGLT2 inhibitors in people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease in whom serum potassium levels were routinely measured. The primary outcome was time to serious hyperkalemia, defined as central laboratory–determined serum potassium ≥6.0 mmol/L, with other outcomes including investigator-reported hyperkalemia events and hypokalemia (serum potassium ≤3.5 mmol/L). Cox regression analyses were performed to estimate treatment effects from each trial with hazards ratios and corresponding 95% CIs pooled with random-effects models to obtain summary treatment effects, overall and across key subgroups. Results: Results from 6 trials were included comprising 49 875 participants assessing 4 SGLT2 inhibitors. Of these, 1754 participants developed serious hyperkalemia, and an additional 1119 investigator-reported hyperkalemia events were recorded. SGLT2 inhibitors reduced the risk of serious hyperkalemia (hazard ratio, 0.84 [95% CI, 0.76–0.93]), an effect consistent across studies ( P heterogeneity =0.71). The incidence of investigator-reported hyperkalemia was also lower with SGLT2 inhibitors (hazard ratio, 0.80 [95% CI, 0.68–0.93]; P heterogeneity =0.21). Reductions in serious hyperkalemia were observed across a range of subgroups, including baseline kidney function, history of heart failure, and use of renin-angiotensin-aldosterone system inhibitor, diuretic, and mineralocorticoid receptor antagonist. SGLT2 inhibitors did not increase the risk of hypokalemia (hazard ratio, 1.04 [95% CI, 0.94–1.15]; P heterogeneity =0.42). Conclusions: SGLT2 inhibitors reduce the risk of serious hyperkalemia in people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease without increasing the risk of hypokalemia.
Endotyping Chronic Obstructive Pulmonary Disease, Bronchiectasis, and the “Chronic Obstructive Pulmonary Disease–Bronchiectasis Association”
Authors: Jeffrey T.-J. Huang, Erin Cant, Holly R. Keir, Alun K. Barton, Elena Kuzmanova, Morven Shuttleworth, Jennifer Pollock, Simon Finch, Eva Polverino, Mathieu Bottier, Alison J. Dicker, Amelia Shoemark, James D. Chalmers
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Bronchiectasis and chronic obstructive pulmonary disease (COPD) are two disease entities with overlapped clinical features, and codiagnosis frequently occurs (termed the "COPD-bronchiectasis association"). Objectives: To investigate the sputum microbiome and proteome in patients with bronchiectasis, COPD, and the COPD-bronchiectasis association with the aim of identifying endotypes that may inform treatment. Methods: Sputum microbiome and protein profiling were carried out using 16S rRNA amplicon sequencing and a label-free proteomics workflow, respectively, in a cohort comprising patients with COPD (n = 43), bronchiectasis (n = 30), and the COPD-bronchiectasis association (n = 48). Results were validated in an independent cohort of 91 patients (n = 28-31 each group) using targeted measurements of inflammatory markers, mucins, and bacterial culture. Measurements and Main Results: Principal component analysis of sputum microbiome and protein profiles showed a partial separation between the COPD and the "COPD-bronchiectasis association" group. Further analyses revealed that patients with the "COPD-bronchiectasis association" had a higher abundance of proteobacteria, higher expression of mucin-5AC and proteins from the "neutrophil degranulation" pathway compared to those with COPD. In contrast, patients with COPD had an elevated expression of mucin-5B and several peptidase inhibitors, higher abundance of common commensal taxa, and a greater microbiome diversity. The profiles of "COPD-bronchiectasis association" and bronchiectasis groups were largely overlapping. Five endotypes were proposed with differential inflammatory, mucin, and microbiological features. The key features related to the "COPD-bronchiectasis association" were validated in an independent cohort. Conclusions: Neutrophilic inflammation, differential mucin expression, and Gram-negative infection are dominant traits in patients with the "COPD-bronchiectasis association."
Multi-scale integrative analyses identify THBS2<sup>+</sup> cancer-associated fibroblasts as a key orchestrator promoting aggressiveness in early-stage lung adenocarcinoma
Authors: Haitang Yang, Beibei Sun, Liwen Fan, Wenyan Ma, Ke Xu, Sean R. R. Hall, Zhexin Wang, Ralph A. Schmid, Ren-Wang Peng, Thomas M. Marti, Wen Gao, Jianlin Xu, Weiwei Yang, Feng Yao
Journal: Theranostics (2022)

Rationale: Subsets of patients with early-stage lung adenocarcinoma (LUAD) have a poor post-surgical course after curative surgery. However, biomarkers stratifying this high-risk subset and molecular underpinnings underlying the aggressive phenotype remain unclear. Methods: We integrated bulk and single-cell transcriptomics, proteomics, secretome and spatial profiling of clinical early-stage LUAD samples to identify molecular underpinnings that promote the aggressive phenotype. Results: We identified and validated THBS2, at multi-omic levels, as a tumor size-independent biomarker that robustly predicted post-surgical survival in multiple independent clinical cohorts of early-stage LUAD. Furthermore, scRNA-seq data revealed that THBS2 is exclusively derived from a specific cancer-associated fibroblast (CAF) subset that is distinct from CAFs defined by classical markers. Interestingly, our data demonstrated that THBS2 was preferentially secreted via exosomes in early-stage LUAD tumors with high aggressiveness, and its levels in the peripheral plasma associated with short recurrence-free survival. Further characterization showed that THBS2-high early-stage LUAD was characterized by suppressed antitumor immunity. Specifically, beyond tumor cells, THBS2+ CAFs mainly interact with B and CD8+ T lymphocytes as well as macrophages within tumor microenvironment of early-stage LUAD, and THBS2-high LUAD was associated with decreased immune cell infiltrates but increased immune exhaustion marker. Clinically, high THBS2 expression predicted poor response to immunotherapies and short post-treatment survival of patients. Finally, THBS2 recombinant protein suppressed ex vivo T cells proliferation and promoted in vivo LUAD tumor growth and distant micro-metastasis. Conclusions: Our multi-level analyses uncovered tumor-specific THBS2+ CAFs as a key orchestrator promoting aggressiveness in early-stage LUAD.
Vaccine-Induced Thrombocytopenia with Severe Headache
Authors: Farid Salih, Linda Schönborn, Siegfried Kohler, Christiana Franke, Martin Möckel, Thomas Dörner, Hans C Bauknecht, Christian Pille, Jan A Graw, Angelika Alonso, Johann Pelz, Hauke Schneider, Antonios Bayas, Monika Christ, Joji B Kuramatsu, Thomas Thiele, Andreas Greinacher, Matthias Endres
Journal: New England Journal of Medicine (2021)
Sex differences in mortality among binational cohort of people with chronic kidney disease: population based data linkage study
Authors: Nicole L De La Mata, Brenda Rosales, Grace MacLeod, Patrick J Kelly, Philip Masson, Rachael L Morton, Kate Wyburn, Angela C Webster
Journal: BMJ (2021)

Abstract Objective To evaluate sex differences in mortality among people with kidney failure compared with the general population. Design Population based cohort study using data linkage. Setting The Australian and New Zealand Dialysis and Transplant Registry (ANZDATA), which includes all patients receiving kidney replacement therapy in Australia (1980-2019) and New Zealand (1988-2019). Data were linked to national death registers to determine deaths and their causes, with additional details obtained from ANZDATA. Participants Of 82 844 people with kidney failure, 33 329 were female (40%) and 49 555 were male (60%); 49 376 deaths (20 099 in female patients; 29 277 in male patients) were recorded over a total of 536 602 person years of follow-up. Main outcome measures Relative measures of survival, including standardised mortality ratios, relative survival, and years of life lost, using general population data to account for background mortality (adjusting for country, age, sex, and year). Estimates were stratified by dialysis modality (haemodialysis or peritoneal dialysis) and for the subpopulation of kidney transplant recipients. Results Few differences in outcomes were found between male and female patients with kidney failure. However, compared with the general population, female patients with kidney failure had greater excess all cause deaths than male patients (female patients: standardised mortality ratio 11.3, 95% confidence interval 11.2 to 11.5, expected deaths 1781, observed deaths 20 099; male patients: 6.9, 6.8 to 6.9, expected deaths 4272, observed deaths 29 277). The greatest difference was observed among younger patients and those who died from cardiovascular disease. Relative survival was also consistently lower in female patients, with adjusted excess mortality 11% higher (95% confidence interval 8% to 13%). Average years of life lost was 3.6 years (95% confidence interval 3.6 to 3.7) greater in female patients with kidney failure compared with male patients across all ages. No major differences were found in mortality by sex for haemodialysis or peritoneal dialysis. Kidney transplantation reduced but did not entirely remove the sex difference in excess mortality, with similar relative survival (P=0.83) and years of life lost difference reduced to 2.3 years (95% confidence interval 2.2 to 2.3) between female and male patients. Conclusions Compared with the general population, female patients had greater excess deaths, worse relative survival, and more years of life lost than male patients, however kidney transplantation reduced these differences. Future research should investigate whether systematic differences exist in access to care and possible strategies to mitigate excess mortality among female patients.
Abstract 10395: Did Prescription Practice Change After Publication of a Landmark Trial for Children and Young Adults with Marfan Syndrome
Authors: Dwight M Robertson, Dongngan Truong, Daniel Cox, Luann MINICH, Harris Carmichael, Zhining Ou, Richard V Williams, Elif Seda S Selamet Tierney
Journal: Circulation (2021)

Intro: The Pediatric Heart Network (PHN) trial of β-blockers (BB) vs. angiotensin receptor blockers (ARB) for aortic root dilation in Marfan Syndrome showed similar efficacy, but its impact on prescribing practices is unknown. We hypothesized there would be an increase in single and combination use of BB and ARB after publication in 2014. Methods: Prescription data (2007-2016) were derived from outpatient encounters (IBM Marketscan) for children and young adults aged 6 mo to 25 yrs diagnosed with Marfan Syndrome who had ≥4 encounters with an adult or pediatric cardiologist or geneticist. Excluding 2014 as washout, data were divided into 2 time periods: 2007-2013 and 2015-2016. Categories included BB, ARB, angiotensin converting enzyme inhibitors (ACEI), combination (BB/ARB and/or BB/ACEI), and no drug use. We performed interrupted time-series analysis to assess the immediate level change and the change in slope for the prescription trend. We reported odds ratios (OR) and 95% confidence intervals (CI) from logistic regressions with generalized estimating equation methods to account for correlation of prescriptions within subjects. Results: Of 1499 patients (mean age 14.1 yrs, 59% female), BB had a downtrend [OR 0.91 (0.89, 0.93), p&lt;0.001] and ARB trended higher [OR 1.12 (1.07, 1.18), p&lt;0.001] 2007-2013, while combination, ACEI, and no drug use remained stable. There was no immediate effect after publication (2013-2015). Although the trend persisted for BB and ARB use (see Figure), the change in slope was not significant (2015-2016). Combination, ACEI and no drug use remained consistent. Conclusions: In short term follow-up, the impact of the PHN trial on prescription practices for aortic root dilation in Marfan Syndrome in children and young adults did not reach statistical significance. This may be due to early adoption of ARBs with subsequent confirmation of their usefulness. Longer term data are needed to fully explore the trial’s impact on practice change.
Trastuzumab with trimodality treatment for oesophageal adenocarcinoma with HER2 overexpression (NRG Oncology/RTOG 1010): a multicentre, randomised, phase 3 trial
Authors: Howard P Safran, Kathryn Winter, David H Ilson, Dennis Wigle, Thomas DiPetrillo, Michael G Haddock, Theodore S Hong, Lawrence P Leichman, Lakshmi Rajdev, Murray Resnick, Lisa A Kachnic, Samantha Seaward, Harvey Mamon, Dayssy Alexandra Diaz Pardo, Carryn M Anderson, Xinglei Shen, Anand K Sharma, Alan W Katz, Jonathan Salo, Kara L Leonard, Jennifer Moughan, Christopher H Crane
Journal: The Lancet Oncology (2022)