tbuckley/cabot-search huggingface dataset:
FGFR3 Destabilizes PD-L1 via NEDD4 to Control T-cell–Mediated Bladder Cancer Immune Surveillance
Authors: Weiqiang Jing, Ganyu Wang, Zhiwei Cui, Gaozhong Xiong, Xin Jiang, Yue Li, Wushan Li, Bo Han, Shouzhen Chen, Benkang Shi
Journal: Cancer Research (2021)

Abstract Fibroblast growth factor receptor 3 (FGFR3) is frequently activated by mutation or overexpression, and it is a validated therapeutic target in urothelial carcinoma (UC) of the bladder. However, the role and detailed molecular mechanism of FGFR3 in the immune microenvironment of bladder cancer remain largely unknown. Here, we demonstrate that inhibition of FGFR3 in FGFR3-activated bladder cancer elevates PD-L1 protein levels by affecting its ubiquitination, thereby inhibiting the antitumor activity of CD8+ T cells. Tissue microarray analysis in human UC showed an inverse correlation between FGFR3 and PD-L1. Furthermore, NEDD4, an E3 ubiquitin ligase of the NEDD4 family of proteins, was phosphorylated by FGFR3 activation and served as a regulator of PD-L1 ubiquitination. Mechanistically, NEDD4 interacted with PD-L1 and catalyzed Lys48 (K48)-linked polyubiquitination of PD-L1. In mice bearing NEDD4 knockout bladder cancer, CD8+ T-cell infiltration and antitumor activity were significantly inhibited due to PD-L1 upregulation in bladder cancer cells. Furthermore, multiple FGFR3-activated tumor-bearing mouse models suggested that attenuated CD8+ T-cell–mediated antitumor efficacy following FGFR3-targeted therapy could be rescued by a combination with anti-PD-1 immunotherapy, which leads to effective tumor suppression. This study establishes a key molecular link between targeted therapy and immune surveillance and identifies NEDD4 as a crucial E3 ubiquitin ligase that targets PD-L1 for degradation in FGFR3-activated bladder cancer. These findings may potentially be exploited for combination therapies in UC of the bladder and possibly other malignancies with activated FGFR3. Significance: NEDD4 links two important molecules associated with targeted therapy and immune surveillance, providing mechanistic rationale and preclinical support for immuno-targeted combination therapy for FGFR3-activated bladder cancer.
The cost of crisis in clinical psychological science
Authors: Joshua B. Grubbs
Journal: Behavioral and Brain Sciences (2022)

Abstract Yarkoni has argued that psychology is facing a generalizability crisis, but the real cost of this crisis is obscured by a focus on topics from psychology's most academic subfields. Psychology is also filled with applied subfields, and it is within those subfields – especially clinical science – where the cost of a generalizability crisis will be most severe.
A Randomized Study of Bortezomib, Cyclophosphamide and Dexamethasone Induction (VCD) Versus VCD and Daratumumab Induction Followed By Daratumumab Maintenance (VCDD) for the Initial Treatment of Transplant-Ineligible Patients with Multiple Myeloma (AMaRC 03-16)
Authors: Peter Mollee, John Reynolds, Wojciech Janowski, Hang Quach, Philip Campbell, Simon D. Gibbs, Sophie Lee, James D'Rozario, Kerry Taylor, Tara Cochrane, Craig Thomas Wallington-Beddoe, Fiona Kwok, Nicholas Weber, Ian H Kerridge, Helen Weston, P. Joy Ho, Noemi Horvath, Flora Yuen, Andrew Spencer
Journal: Blood (2021)
Somatic and Germline Genomic Alterations in Very Young Women with Breast Cancer
Authors: Adrienne G. Waks, Dewey Kim, Esha Jain, Craig Snow, Gregory J. Kirkner, Shoshana M. Rosenberg, Coyin Oh, Philip D. Poorvu, Kathryn J. Ruddy, Rulla M. Tamimi, Jeffrey Peppercorn, Lidia Schapira, Virginia F. Borges, Steven E. Come, Elena F. Brachtel, Ellen Warner, Laura C. Collins, Ann H. Partridge, Nikhil Wagle
Journal: Clinical Cancer Research (2022)

Young age at breast cancer diagnosis correlates with unfavorable clinicopathologic features and worse outcomes compared with older women. Understanding biological differences between breast tumors in young versus older women may lead to better therapeutic approaches for younger patients.We identified 100 patients ≤35 years old at nonmetastatic breast cancer diagnosis who participated in the prospective Young Women's Breast Cancer Study cohort. Tumors were assigned a surrogate intrinsic subtype based on receptor status and grade. Whole-exome sequencing of tumor and germline samples was performed. Genomic alterations were compared with older women (≥45 years old) in The Cancer Genome Atlas, according to intrinsic subtype.Ninety-three tumors from 92 patients were successfully sequenced. Median age was 32.5 years; 52.7% of tumors were hormone receptor-positive/HER2-negative, 28.0% HER2-positive, and 16.1% triple-negative. Comparison of young to older women (median age 61 years) with luminal A tumors (N = 28 young women) revealed three significant differences: PIK3CA alterations were more common in older patients, whereas GATA3 and ARID1A alterations were more common in young patients. No significant genomic differences were found comparing age groups in other intrinsic subtypes. Twenty-two patients (23.9%) in the Young Women's Study cohort carried a pathogenic germline variant, most commonly (13 patients, 14.1%) in BRCA1/2.Somatic alterations in three genes (PIK3CA, GATA3, and ARID1A) occur at different frequencies in young versus older women with luminal A breast cancer. Additional investigation of these genes and associated pathways could delineate biological susceptibilities and improve treatment options for young patients with breast cancer. See related commentary by Yehia and Eng, p. 2209.
Outcomes of COVID-19 and risk factors in patients with cancer
Authors: Manju Sengar, Girish Chinnaswamy, Priya Ranganathan, Apurva Ashok, Shilpushp Bhosale, Sanjay Biswas, Pankaj Chaturvedi, Chetan Dhamne, Jigeeshu Divatia, Karishma D’Sa, Hasmukh Jain, Sarbani Laskar, Nirmalya Roy Moulik, Naveen Mummudi, Sindhu Nair, Lingaraj Nayak, Prakash Nayak, Shraddha Patkar, Preeti Pawaskar, Anant Ramaswamy, Omshree Shetty, Arjun Singh, Epari Sridhar, Jayashree Thorat, Rajendra Badwe, C. S. Pramesh, Ganesh Bakshi, Abhishek Chatterjee, Vikram Chaudhari, Sunil Chopade, Jeson Doctor, Nishu Singh Goel, Venkata Rama Mohan Gollamudi, Sarita Khobrekar, Gauravi Mishra, Gaurav Narula, Devayani Niyogi, Badira Cheriyalinkal Parambil, Swapnil Parab, Sumedha Patankar, Gagan Prakash, Pankaj Rajput, Sushmita Rath, Vinit Samant, Sandeep Sawakare, Shwetabh Sinha, Sujay Srinivas, Shyam Srinivasan, Sandeep Tandon, Purvi Thakkar, Shivakumar Thiagarajan, Virendra Tiwari
Journal: Nature Cancer (2022)
Stereotactic body radiotherapy plus pembrolizumab and trametinib versus stereotactic body radiotherapy plus gemcitabine for locally recurrent pancreatic cancer after surgical resection: an open-label, randomised, controlled, phase 2 trial
Authors: Xiaofei Zhu, Yangsen Cao, Wenyu Liu, Xiaoping Ju, Xianzhi Zhao, Lingong Jiang, Yusheng Ye, Gang Jin, Huojun Zhang
Journal: The Lancet Oncology (2022)
RHYTHM VERSUS RATE CONTROL IN PATIENTS WITH POSTOPERATIVE ATRIAL FIBRILLATION FOLLOWING CARDIAC SURGERY: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Muneeb Ahmed, Emilie Belley-Cote, Yuan Qiu, Peter Belesiotis, Brendan Tao, Alex Wolf, Hargun Kaur, Alex Ibrahim, Jeff S. Healey, David Conen, P.J. Devereaux, Richard Whitlock, William F. McIntyre
Journal: Journal of the American College of Cardiology (2022)
Report of the American College of Rheumatology Fellows‐in‐Training Subcommittee: experiences of rheumatology fellows early in the COVID‐19 pandemic
Authors: Didem Saygin, Jean Lin, Noelle A. Rolle, Mary Mamut
Journal: Arthritis & Rheumatology (2022)

Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Direct antimicrobial resistance prediction from clinical MALDI-TOF mass spectra using machine learning
Authors: Caroline Weis, Aline Cuénod, Bastian Rieck, Olivier Dubuis, Susanne Graf, Claudia Lang, Michael Oberle, Maximilian Brackmann, Kirstine K. Søgaard, Michael Osthoff, Karsten Borgwardt, Adrian Egli
Journal: Nature Medicine (2022)
Evorpacept alone and in combination with pembrolizumab or trastuzumab in patients with advanced solid tumours (ASPEN-01): a first-in-human, open-label, multicentre, phase 1 dose-escalation and dose-expansion study
Authors: Nehal J Lakhani, Laura Q M Chow, Justin F Gainor, Patricia LoRusso, Keun-Wook Lee, Hyun Cheol Chung, Jeeyun Lee, Yung-Jue Bang, Frank Stephen Hodi, Won Seog Kim, Rafael Santana-Davila, Philip Fanning, Pierre Squifflet, Feng Jin, Tracy C Kuo, Hong I Wan, Jaume Pons, Sophia S Randolph, Wells A Messersmith
Journal: The Lancet Oncology (2021)
Exposure to PM2.5 during Pregnancy and Fetal Growth in Eastern Massachusetts, USA
Authors: Michael Leung, Marc G. Weisskopf, Francine Laden, Brent A. Coull, Anna M. Modest, Michele R. Hacker, Blair J. Wylie, Yaguang Wei, Joel Schwartz, Stefania Papatheodorou
Journal: Environmental Health Perspectives (2022)

Background: Prior studies have examined the association between fine particulate matter [PM ≤2.5μm in aerodynamic diameter (PM2.5)] and fetal growth with either limited spatial or temporal resolution. Objectives: In this study, we examined the association between PM2.5 exposure during pregnancy and fetal growth measures (ultrasound parameters and birth weight) in a pregnancy cohort using spatiotemporally resolved PM2.5 in Eastern Massachusetts, USA. Methods: We used ultrasound measures of biparietal diameter (BPD), head circumference, femur length, and abdominal circumference (AC), in addition to birth weight, from 9,446 pregnancies that were delivered at the Beth Israel Deaconess Medical Center from 2011–2016. We used linear mixed-effects models to examine the associations of PM2.5 in two exposure windows (the first 16 wk of pregnancy and the cumulative exposure up until the assessment of fetal growth) with anatomic scans (ultrasound measures at<24 wk), growth scans (ultrasound measures at≥24wk), and birth weight. All models were adjusted for sociodemographic characteristics, long-term trends, and temperature. Results: Higher PM2.5 exposure in the first 16 wk was associated with smaller fetal growth measures, where associations were particularly strong for BPD, AC, and birth weight. For example, a 5-μg/m3 increase in PM2.5 was associated with a lower mean BPD z-score of −0.19 (95% CI: −0.31, −0.06) before 24 wk, a lower mean AC z-score of −0.15 (95% CI: −0.28, −0.01) after 24 wk, and a lower mean birth weight z-score of −0.11 (95% CI: −0.20, −0.01). Analyses examining the associations with cumulative PM2.5 exposure up until the assessment of fetal growth produced attenuated associations. Conclusions: Higher gestational exposure to PM2.5 was associated with smaller fetal growth measures at levels below the current national standards. https://doi.org/10.1289/EHP9824
Swan Song
Authors: Amrapali Maitra
Journal: Annals of Internal Medicine (2022)

On Being a DoctorFebruary 2022Swan SongAmrapali Maitra, MD, PhDAmrapali Maitra, MD, PhDBrigham and Women's Hospital Boston, MassachusettsSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M21-4125 Audio Reading - “Swan Song” Audio. Virginia L. Hood, MD, a physician from the University of Vermont, reads “Swan Song” by Amrapali Maitra, MD, PhD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail It is June 1, and the mother swan in the Esplanade has passed away. The news arrives in a flash of white on Twitter, where I subscribe to Boston parks: the Arboretum, Fresh Pond, and Charles River Esplanade. The mother died of unknown causes, and one cygnet drowned with her. Her longtime partner, father swan, minds the nest of three surviving cygnets. His name is Atticus.I park in the garage and walk to the hospital. The breeze licks my face, delicious. Outside, for now, we are maskless. Coffee balanced in one hand, I glance at my phone. Atticus settles ... Author, Article, and Disclosure InformationAffiliations: Brigham and Women's Hospital Boston, MassachusettsCorresponding Author: Amrapali Maitra, MD, PhD, 75 Francis Street, Boston, MA 02115; e-mail, [email protected]harvard.edu. PreviousarticleNextarticle Advertisement Audio Reading - “Swan Song” Audio. Virginia L. Hood, MD, a physician from the University of Vermont, reads “Swan Song” by Amrapali Maitra, MD, PhD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics February 2022Volume 175, Issue 2Page: 297-298 ePublished: 15 February 2022 Issue Published: February 2022 Copyright & PermissionsCopyright © 2022 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in EGFR Inhibitor–Resistant, <i>EGFR</i>-Mutated Non–Small Cell Lung Cancer
Authors: Pasi A. Jänne, Christina Baik, Wu-Chou Su, Melissa L. Johnson, Hidetoshi Hayashi, Makoto Nishio, Dong-Wan Kim, Marianna Koczywas, Kathryn A. Gold, Conor E. Steuer, Haruyasu Murakami, James Chih-Hsin Yang, Sang-We Kim, Michele Vigliotti, Rong Shi, Zhenhao Qi, Yang Qiu, Lihui Zhao, David Sternberg, Channing Yu, Helena A. Yu
Journal: Cancer Discovery (2021)

Receptor tyrosine-protein kinase ERBB3 (HER3) is expressed in most EGFR-mutated lung cancers but is not a known mechanism of resistance to EGFR inhibitors. HER3-DXd is an antibody-drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. This phase I, dose escalation/expansion study included patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor (TKI) therapy. Among 57 patients receiving HER3-DXd 5.6 mg/kg intravenously once every 3 weeks, the confirmed objective response rate by blinded independent central review (Response Evaluation Criteria in Solid Tumors v1.1) was 39% [95% confidence interval (CI), 26.0-52.4], and median progression-free survival was 8.2 (95% CI, 4.4-8.3) months. Responses were observed in patients with known and unknown EGFR TKI resistance mechanisms. Clinical activity was observed across a broad range of HER3 membrane expression. The most common grade ≥3 treatment-emergent adverse events were hematologic toxicities. HER3-DXd has clinical activity in EGFR TKI-resistant cancers independent of resistance mechanisms, providing an approach to treat a broad range of drug-resistant cancers. SIGNIFICANCE: In metastatic EGFR-mutated NSCLC, after disease progression on EGFR TKI therapy, treatment approaches include genotype-directed therapy targeting a known resistance mechanism or chemotherapy. HER3-DXd demonstrated clinical activity spanning known and unknown EGFR TKI resistance mechanisms. HER3-DXd could present a future treatment option agnostic to the EGFR TKI resistance mechanism.See related commentary by Lim et al., p. 16.This article is highlighted in the In This Issue feature, p. 1.
PEGR: a flexible management platform for reproducible epigenomic and genomic research
Authors: Danying Shao, Gretta D. Kellogg, Ali Nematbakhsh, Prashant K. Kuntala, Shaun Mahony, B. Franklin Pugh, William K. M. Lai
Journal: Genome biology (2022)

Abstract Reproducibility is a significant challenge in (epi)genomic research due to the complexity of experiments composed of traditional biochemistry and informatics. Recent advances have exacerbated this as high-throughput sequencing data is generated at an unprecedented pace. Here, we report the development of a P latform for E pi- G enomic R esearch (PEGR), a web-based project management platform that tracks and quality controls experiments from conception to publication-ready figures, compatible with multiple assays and bioinformatic pipelines. It supports rigor and reproducibility for biochemists working at the bench, while fully supporting reproducibility and reliability for bioinformaticians through integration with the Galaxy platform.
Genetic evidence suggests posttraumatic stress disorder as a subtype of major depressive disorder
Authors: Fuquan Zhang, Shuquan Rao, Hongbao Cao, Xiangrong Zhang, Qiang Wang, Yong Xu, Jing Sun, Chun Wang, Jiu Chen, Xijia Xu, Ning Zhang, Lin Tian, Jianmin Yuan, Guoqiang Wang, Lei Cai, Mingqing Xu, Ancha Baranova
Journal: Journal of Clinical Investigation (2021)

BACKGROUNDMajor depressive disorder (MDD) and posttraumatic stress disorder (PTSD) are highly comorbid and exhibit strong correlations with one another. We aimed to investigate mechanisms of underlying relationships between PTSD and 3 kinds of depressive phenotypes, namely, MDD, depressed affect (DAF), and depression (DEP, including both MDD and the broad definition of depression).METHODSGenetic correlations between PTSD and the depressive phenotypes were tested using linkage disequilibrium score regression. Polygenic overlap analysis was used to estimate shared and trait-specific causal variants across a pair of traits. Causal relationships between PTSD and the depressive phenotypes were investigated using Mendelian randomization. Shared genomic loci between PTSD and MDD were identified using cross-trait meta-analysis.RESULTSGenetic correlations of PTSD with the depressive phenotypes were in the range of 0.71-0.80. The estimated numbers of causal variants were 14,565, 12,965, 10,565, and 4,986 for MDD, DEP, DAF, and PTSD, respectively. In each case, causal variants contributing to PTSD were completely or largely covered by causal variants defining each of the depressive phenotypes. Mendelian randomization analysis indicated that the genetically determined depressive phenotypes confer a causal effect on PTSD (b = 0.21-0.31). Notably, genetically determined PTSD confers a causal effect on DEP (b = 0.14) and DAF (b = 0.15), but not MDD. Cross-trait meta-analysis of MDD and PTSD identified 47 genomic loci, including 29 loci shared between PTSD and MDD.CONCLUSIONEvidence from shared genetics suggests that PTSD is a subtype of MDD. This study provides support to the efforts in reducing diagnostic heterogeneity in psychiatric nosology.FUNDINGThe National Key Research and Development Program of China and the National Natural Science Foundation of China.
International Medullary Thyroid Carcinoma Grading System: A Validated Grading System for Medullary Thyroid Carcinoma
Authors: Bin Xu, Talia L. Fuchs, Sara Ahmadi, Mohammed Alghamdi, Bayan Alzumaili, Mohamed-Amine Bani, Eric Baudin, Angela Chou, Antonio De Leo, James A. Fagin, Ian Ganly, Anthony Glover, Dana Hartl, Christina Kanaan, Pierre Khneisser, Fedaa Najdawi, Aradhya Nigam, Alex Papachristos, Andrea Repaci, Philip M. Spanheimer, Erica Solaroli, Brian R. Untch, Justine A. Barletta, Giovanni Tallini, Abir Al Ghuzlan, Anthony J. Gill, Ronald A. Ghossein
Journal: Journal of Clinical Oncology (2021)

Medullary thyroid carcinoma (MTC) is an aggressive neuroendocrine tumor (NET) arising from the calcitonin-producing C cells. Unlike other NETs, there is no widely accepted pathologic grading scheme. In 2020, two groups separately developed slightly different schemes (the Memorial Sloan Kettering Cancer Center and Sydney grade) on the basis of proliferative activity (mitotic index and/or Ki67 proliferative index) and tumor necrosis. Building on this work, we sought to unify and validate an internationally accepted grading scheme for MTC.Tumor tissue from 327 patients with MTC from five centers across the United States, Europe, and Australia were reviewed for mitotic activity, Ki67 proliferative index, and necrosis using uniform criteria and blinded to other clinicopathologic features. After reviewing different cutoffs, a two-tiered consensus grading system was developed. High-grade MTCs were defined as tumors with at least one of the following features: mitotic index ≥ 5 per 2 mm2, Ki67 proliferative index ≥ 5%, or tumor necrosis.Eighty-one (24.8%) MTCs were high-grade using this scheme. In multivariate analysis, these patients demonstrated decreased overall (hazard ratio [HR] = 11.490; 95% CI, 3.118 to 32.333; P < .001), disease-specific (HR = 8.491; 95% CI, 1.461 to 49.327; P = .017), distant metastasis-free (HR = 2.489; 95% CI, 1.178 to 5.261; P = .017), and locoregional recurrence-free (HR = 2.114; 95% CI, 1.065 to 4.193; P = .032) survivals. This prognostic power was maintained in subgroup analyses of cohorts from each of the five centers.This simple two-tiered international grading system is a powerful predictor of adverse outcomes in MTC. As it is based solely on morphologic assessment in conjunction with Ki67 immunohistochemistry, it brings the grading of MTCs in line with other NETs and can be readily applied in routine practice. We therefore recommend grading of MTCs on the basis of mitotic count, Ki67 proliferative index, and tumor necrosis.
Very limited data in the Global Burden of Disease Study 2019 to estimate the prevalence of osteoarthritis in 204 countries over 30 years: comment on the article by Long et al
Authors: Qiuzhe Chen, Christopher G. Maher, Gustavo C. Machado
Journal: Arthritis & Rheumatology (2022)

Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Expansion, persistence, and efficacy of donor memory-like NK cells infused for posttransplant relapse
Authors: Roman M. Shapiro, Grace C. Birch, Guangan Hu, Juliana Vergara Cadavid, Sarah Nikiforow, Joanna Baginska, Alaa K. Ali, Mubin Tarannum, Michal Sheffer, Yasmin Z. Abdulhamid, Benedetta Rambaldi, Yohei Arihara, Carol Reynolds, Max S. Halpern, Scott J. Rodig, Nicole Cullen, Jacquelyn O. Wolff, Kathleen L. Pfaff, Andrew A. Lane, R. Coleman Lindsley, Corey S. Cutler, Joseph H. Antin, Vincent T. Ho, John Koreth, Mahasweta Gooptu, Haesook T. Kim, Karl-Johan Malmberg, Catherine J. Wu, Jianzhu Chen, Robert J. Soiffer, Jerome Ritz, Rizwan Romee
Journal: Journal of Clinical Investigation (2022)

Background. Responses to conventional donor lymphocyte infusion for postallogeneic hematopoietic cell transplantation (HCT) relapse are typically poor. Natural killer (NK) cell–based therapy is a promising modality to treat post-HCT relapse.