tbuckley/cabot-search huggingface dataset:
Comprehensive molecular characterization of lung tumors implicates AKT and MYC signaling in adenocarcinoma to squamous cell transdifferentiation
Authors: Alvaro Quintanal-Villalonga, Hirokazu Taniguchi, Yingqian A. Zhan, Maysun M. Hasan, Shweta S. Chavan, Fanli Meng, Fathema Uddin, Viola Allaj, Parvathy Manoj, Nisargbhai S. Shah, Joseph M. Chan, Metamia Ciampricotti, Andrew Chow, Michael Offin, Jordana Ray-Kirton, Jacklynn D. Egger, Umesh K. Bhanot, Irina Linkov, Marina Asher, Michael H. Roehrl, Katia Ventura, Juan Qiu, Elisa de Stanchina, Jason C. Chang, Natasha Rekhtman, Brian Houck-Loomis, Richard P. Koche, Helena A. Yu, Triparna Sen, Charles M. Rudin
Journal: Journal of Hematology & Oncology (2021)

Abstract Background Lineage plasticity, the ability to transdifferentiate among distinct phenotypic identities, facilitates therapeutic resistance in cancer. In lung adenocarcinomas (LUADs), this phenomenon includes small cell and squamous cell (LUSC) histologic transformation in the context of acquired resistance to targeted inhibition of driver mutations. LUAD-to-LUSC transdifferentiation, occurring in up to 9% of EGFR -mutant patients relapsed on osimertinib, is associated with notably poor prognosis. We hypothesized that multi-parameter profiling of the components of mixed histology (LUAD/LUSC) tumors could provide insight into factors licensing lineage plasticity between these histologies. Methods We performed genomic, epigenomics, transcriptomics and protein analyses of microdissected LUAD and LUSC components from mixed histology tumors, pre-/post-transformation tumors and reference non-transformed LUAD and LUSC samples. We validated our findings through genetic manipulation of preclinical models in vitro and in vivo and performed patient-derived xenograft (PDX) treatments to validate potential therapeutic targets in a LUAD PDX model acquiring LUSC features after osimertinib treatment. Results Our data suggest that LUSC transdifferentiation is primarily driven by transcriptional reprogramming rather than mutational events. We observed consistent relative upregulation of PI3K/AKT, MYC and PRC2 pathway genes. Concurrent activation of PI3K/AKT and MYC induced squamous features in EGFR -mutant LUAD preclinical models. Pharmacologic inhibition of EZH1/2 in combination with osimertinib prevented relapse with squamous-features in an EGFR-mutant patient-derived xenograft model, and inhibition of EZH1/2 or PI3K/AKT signaling re-sensitized resistant squamous-like tumors to osimertinib. Conclusions Our findings provide the first comprehensive molecular characterization of LUSC transdifferentiation, suggesting putative drivers and potential therapeutic targets to constrain or prevent lineage plasticity.
PXR activation impairs hepatic glucose metabolism partly via inhibiting the HNF4α–GLUT2 pathway
Authors: Peihua Liu, Ling Jiang, Weimin Kong, Qiushi Xie, Ping Li, Xiaonan Liu, Jiayi Zhang, Ming Liu, Zhongjian Wang, Liang Zhu, Hanyu Yang, Ying Zhou, Jianjun Zou, Xiaodong Liu, Li Liu
Journal: Acta Pharmaceutica Sinica B (2021)

Drug-induced hyperglycemia/diabetes is a global issue. Some drugs induce hyperglycemia by activating the pregnane X receptor (PXR), but the mechanism is unclear. Here, we report that PXR activation induces hyperglycemia by impairing hepatic glucose metabolism due to inhibition of the hepatocyte nuclear factor 4-alpha (HNF4α)‒glucose transporter 2 (GLUT2) pathway. The PXR agonists atorvastatin and rifampicin significantly downregulated GLUT2 and HNF4α expression, and impaired glucose uptake and utilization in HepG2 cells. Overexpression of PXR downregulated GLUT2 and HNF4α expression, while silencing PXR upregulated HNF4α and GLUT2 expression. Silencing HNF4α decreased GLUT2 expression, while overexpressing HNF4α increased GLUT2 expression and glucose uptake. Silencing PXR or overexpressing HNF4α reversed the atorvastatin-induced decrease in GLUT2 expression and glucose uptake. In human primary hepatocytes, atorvastatin downregulated GLUT2 and HNF4α mRNA expression, which could be attenuated by silencing PXR. Silencing HNF4α downregulated GLUT2 mRNA expression. These findings were reproduced with mouse primary hepatocytes. Hnf4α plasmid increased Slc2a2 promoter activity. Hnf4α silencing or pregnenolone-16α-carbonitrile (PCN) suppressed the Slc2a2 promoter activity by decreasing HNF4α recruitment to the Slc2a2 promoter. Liver-specific Hnf4α deletion and PCN impaired glucose tolerance and hepatic glucose uptake, and decreased the expression of hepatic HNF4α and GLUT2. In conclusion, PXR activation impaired hepatic glucose metabolism partly by inhibiting the HNF4α‒GLUT2 pathway. These results highlight the molecular mechanisms by which PXR activators induce hyperglycemia/diabetes.
Intensity of Macrophage Infiltration in Glomeruli Predicts Response to Immunosuppressive Therapy in Patients with IgA Nephropathy
Authors: Di Xie, Hao Zhao, Xin Xu, Zhanmei Zhou, Cailing Su, Nan Jia, Youhua Liu, Fan Fan Hou
Journal: Journal of the American Society of Nephrology (2021)

The lack of a tool for predicting the response to immunosuppressive therapy in IgA nephropathy (IgAN) limits patient-specific risk stratification and early treatment decision making. Models for predicting response to immunosuppression in IgAN that can be applied at the time of kidney biopsy are needed.This prospective cohort study involved 621 Chinese patients with IgAN who were at high risk for disease progression and had persistent proteinuria ≥1 g/d, despite 3 months of optimized supportive care with renin-angiotensin system inhibitors. Participants received immunosuppressive therapy for a median of 18 months. We used immunochemistry to identify macrophage and lymphocyte infiltrates in biopsy specimens and digital image analysis to quantify them. The outcome was response to immunosuppression, defined as complete or partial remission within 12 months of immunosuppression.Kidney infiltration of CD68 + and CD206 + macrophages increased in patients with IgAN. Having higher levels of glomerular CD206 + macrophage infiltration was associated with a 40-fold increased probability of response to immunosuppression in adjusted analysis compared with having lower levels. Patients with a higher intensity of glomerular CD68 + infiltrates had a 13-fold increase in probability of responding to immunosuppression. Intensity of glomerular CD206 + and CD68 + macrophage infiltration predicted the response to immunosuppression (area under the curve [AUC], 0.84; 95% CI, 0.81 to 0.88). The AUC increased to 0.87 (95% CI, 0.84 to 0.91) in a model combining the infiltration score of CD206 + and CD68 + infiltrates with the MEST-C score and clinical data at biopsy.Intensity of glomerular macrophage infiltration predicted response to immunosuppressive therapy in patients with IgAN who were at high risk of progression, and may help physicians identify patients who will benefit from such treatment.
Workshop proceedings: GWAS summary statistics standards and sharing
Authors: Jacqueline A.L. MacArthur, Annalisa Buniello, Laura W. Harris, James Hayhurst, Aoife McMahon, Elliot Sollis, Maria Cerezo, Peggy Hall, Elizabeth Lewis, Patricia L. Whetzel, Orli G. Bahcall, Inês Barroso, Robert J. Carroll, Michael Inouye, Teri A. Manolio, Stephen S. Rich, Lucia A. Hindorff, Ken Wiley, Helen Parkinson
Journal: Cell Genomics (2021)

Genome-wide association studies (GWASs) have enabled robust mapping of complex traits in humans. The open sharing of GWAS summary statistics (SumStats) is essential in facilitating the larger meta-analyses needed for increased power in resolving the genetic basis of disease. However, most GWAS SumStats are not readily accessible because of limited sharing and a lack of defined standards. With the aim of increasing the availability, quality, and utility of GWAS SumStats, the National Human Genome Research Institute-European Bioinformatics Institute (NHGRI-EBI) GWAS Catalog organized a community workshop to address the standards, infrastructure, and incentives required to promote and enable sharing. We evaluated the barriers to SumStats sharing, both technological and sociological, and developed an action plan to address those challenges and ensure that SumStats and study metadata are findable, accessible, interoperable, and reusable (FAIR). We encourage early deposition of datasets in the GWAS Catalog as the recognized central repository. We recommend standard requirements for reporting elements and formats for SumStats and accompanying metadata as guidelines for community standards and a basis for submission to the GWAS Catalog. Finally, we provide recommendations to enable, promote, and incentivize broader data sharing, standards and FAIRness in order to advance genomic medicine.
Seroepidemiology and model-based prediction of SARS-CoV-2 in Ethiopia: longitudinal cohort study among front-line hospital workers and communities
Authors: Esayas Kebede Gudina, Solomon Ali, Eyob Girma, Addisu Gize, Birhanemeskel Tegene, Gadissa Bedada Hundie, Wondewosen Tsegaye Sime, Rozina Ambachew, Alganesh Gebreyohanns, Mahteme Bekele, Abhishek Bakuli, Kira Elsbernd, Simon Merkt, Lorenzo Contento, Michael Hoelscher, Jan Hasenauer, Andreas Wieser, Arne Kroidl
Journal: The Lancet Global Health (2021)

BackgroundOver 1 year since the first reported case, the true COVID-19 burden in Ethiopia remains unknown due to insufficient surveillance. We aimed to investigate the seroepidemiology of SARS-CoV-2 among front-line hospital workers and communities in Ethiopia.MethodsWe did a population-based, longitudinal cohort study at two tertiary teaching hospitals involving hospital workers, rural residents, and urban communities in Jimma and Addis Ababa. Hospital workers were recruited at both hospitals, and community participants were recruited by convenience sampling including urban metropolitan settings, urban and semi-urban settings, and rural communities. Participants were eligible if they were aged 18 years or older, had provided written informed consent, and were willing to provide blood samples by venepuncture. Only one participant per household was recruited. Serology was done with Elecsys anti-SARS-CoV-2 anti-nucleocapsid assay in three consecutive rounds, with a mean interval of 6 weeks between tests, to obtain seroprevalence and incidence estimates within the cohorts.FindingsBetween Aug 5, 2020, and April 10, 2021, we did three survey rounds with a total of 1104 hospital workers and 1229 community residents participating. SARS-CoV-2 seroprevalence among hospital workers increased strongly during the study period: in Addis Ababa, it increased from 10·9% (95% credible interval [CrI] 8·3–13·8) in August, 2020, to 53·7% (44·8–62·5) in February, 2021, with an incidence rate of 2223 per 100 000 person-weeks (95% CI 1785–2696); in Jimma Town, it increased from 30·8% (95% CrI 26·9–34·8) in November, 2020, to 56·1% (51·1–61·1) in February, 2021, with an incidence rate of 3810 per 100 000 person-weeks (95% CI 3149–4540). Among urban communities, an almost 40% increase in seroprevalence was observed in early 2021, with incidence rates of 1622 per 100 000 person-weeks (1004–2429) in Jimma Town and 4646 per 100 000 person-weeks (2797–7255) in Addis Ababa. Seroprevalence in rural communities increased from 18·0% (95% CrI 13·5–23·2) in November, 2020, to 31·0% (22·3–40·3) in March, 2021.InterpretationSARS-CoV-2 spread in Ethiopia has been highly dynamic among hospital worker and urban communities. We can speculate that the greatest wave of SARS-CoV-2 infections is currently evolving in rural Ethiopia, and thus requires focused attention regarding health-care burden and disease prevention.FundingBavarian State Ministry of Sciences, Research, and the Arts; Germany Ministry of Education and Research; EU Horizon 2020 programme; Deutsche Forschungsgemeinschaft; and Volkswagenstiftung.
A Policy Prescription for Reducing Health Disparities—Achieving Pharmacoequity
Authors: Utibe R. Essien, Stacie B. Dusetzina, Walid F. Gellad
Journal: JAMA (2021)

This Viewpoint discusses pharmacoequity, which is the goal of ensuring that all individuals have access to the highest-quality medications required to manage their health needs, and ways in which this can be achieved.
Allogeneic blood or marrow transplantation with haploidentical donor and post-transplantation cyclophosphamide in patients with myelofibrosis: a multicenter study
Authors: Siddharth Kunte, Lisa Rybicki, Auro Viswabandya, Roni Tamari, Asad Bashey, Alla Keyzner, Madiha Iqbal, Michael R. Grunwald, Bhagirathbhai Dholaria, Hany Elmariah, Michael Ozga, Anurag Singh, Sameem Abedin, Amy E. DeZern, Richard J. Jones, Vikas Gupta, Aaron T. Gerds, Tania Jain
Journal: Leukemia (2021)
P48.09 Body Mass Index Predicts Benefit From Adding Metformin to EGFR-TKIs in Patients With Lung Adenocarcinoma: Subanalysis From an RCT
Authors: O. Arrieta, J. Turcott, F. Barrón, M. Ramos, S. Yendamuri, L. Zatarain Barron, A. Cardona Zorrilla, R. Rosell
Journal: Journal of Thoracic Oncology (2021)
A gene expression–based model predicts outcome in children with intermediate-risk classical Hodgkin lymphoma
Authors: Rebecca L. Johnston, Anja Mottok, Fong Chun Chan, Aixiang Jiang, Arjan Diepstra, Lydia Visser, Adèle Telenius, Randy D. Gascoyne, Debra L. Friedman, Cindy L. Schwartz, Kara M. Kelly, David W. Scott, Terzah M. Horton, Christian Steidl
Journal: Blood (2021)

Classical Hodgkin lymphoma (cHL) is a common malignancy in children and adolescents. Although cHL is highly curable, treatment with chemotherapy and radiation often come at the cost of long-term toxicity and morbidity. Effective risk-stratification tools are needed to tailor therapy. Here, we used gene expression profiling (GEP) to investigate tumor microenvironment (TME) biology, to determine molecular correlates of treatment failure, and to develop an outcome model prognostic for pediatric cHL. A total of 246 formalin-fixed, paraffin-embedded tissue biopsies from patients enrolled in the Children's Oncology Group trial AHOD0031 were used for GEP and compared with adult cHL data. Eosinophil, B-cell, and mast cell signatures were enriched in children, whereas macrophage and stromal signatures were more prominent in adults. Concordantly, a previously published model for overall survival prediction in adult cHL did not validate in pediatric cHL. Therefore, we developed a 9-cellular component model reflecting TME composition to predict event-free survival (EFS). In an independent validation cohort, we observed a significant difference in weighted 5-year EFS between high-risk and low-risk groups (75.2% vs 90.3%; log-rank P = .0138) independent of interim response, stage, fever, and albumin. We demonstrate unique disease biology in children and adolescents that can be harnessed for risk-stratification at diagnosis. This trial was registered at www.clinicaltrials.gov as #NCT00025259.
Abstract 11062: Association of the Mediterrean Diet Pattern With Measures of Endothelial Function in Women
Authors: Riddhi Shah, Nour Makarem, Memet Emin, Ming Liao, Sanja Jelic, Brooke Aggarwal
Journal: Circulation (2018)

Background: The Mediterranean Diet, characterized by higher intakes of plant foods including plant proteins, monounsaturated fat, fish, and lower consumption of animal products and saturated fat, h...
Bleeding Risk Assessment By Sonoclot in Severe Immune Thrombocytopenia
Authors: Kundan Mishra, Pankaj Malhotra, Aditya Jandial, Lad Deepesh Pravin Kumar, Neelam Varma, R K Dhiman, Uday Yanamandra, Alka Khadwal, Gaurav Prakash, Jasmina Ahluwalia, Subhash Varma
Journal: Blood (2017)
MA09.05 PD1-Positive Tertiary Lymphoid Structure as a Predictive Factor of Durable Clinical Effect in Immunotherapy for NSCLC
Authors: Y. Matsumura, S. Inomata, H. Yamaguchi, H. Mine, H. Takagi, M. Watanabe, Y. Ozaki, S. Muto, N. Okabe, Y. Shio, H. Suzuki
Journal: Journal of Thoracic Oncology (2021)
P45.08 Lorlatinib for Previously Treated ALK-Positive Advanced NSCLC: Primary Efficacy and Safety Data from a Phase 2 Study in China
Authors: S. Lu, Q. Zhou, X. Liu, Y. Du, Y. Fan, Y. Cheng, J. Fang, Y. Lu, C. Huang, J. Zhou, Y. Song, K. Wang, H. Pan, N. Yang, J. Li, G. Chen, J. Chang, J. Cui, Z. Liu, C. Bai, H. Zhang, H. Thurm, G. Peltz, H. Li, H. Zhao, Y. Wu
Journal: Journal of Thoracic Oncology (2021)
Treatment of Women After Bilateral Salpingo-oophorectomy Performed Prior to Natural Menopause
Authors: Andrew M. Kaunitz, Ekta Kapoor, Stephanie Faubion
Journal: JAMA (2021)

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Dermatoscopy of nodular/plaque-type primary cutaneous T- and B-cell lymphomas: A retrospective comparative study with pseudolymphomas and tumoral/inflammatory mimickers by the International Dermoscopy Society
Authors: Enzo Errichetti, Shamir Geller, Iris Zalaudek, Caterina Longo, Athanassios Kyrgidis, Bengu Nisa Akay, Vincenzo Piccolo, Patricia Myskowski, Paola Vitiello, Teresa Russo, Giuseppe Argenziano, Martyna Sławińska, Małgorzata Sokołowska-Wojdyło, Michał Sobjanek, Ruzica Jurakic Toncic, Jaka Rados, Daniela Ledic Drvar, Romana Ceovic, Grażyna Kaminska-Winciorek, Pedro Zaballos, Camilla Reggiani, Zorana Kremic, Sven Lanssens, Ayşe Tülin Güleç, Alejandro Lobato-Berezo, Giovanni Damiani, Vincenzo Maione, Piergiacomo Calzavara-Pinton, Elena Sotiriou, Giuseppe Stinco, Zoe Apalla, Aimilios Lallas
Journal: Journal of the American Academy of Dermatology (2021)
P59.22 Biomarker Testing for Advanced Lung Cancer by Next-Generation Sequencing in Real World Practice
Authors: J.N. Minatta, Y. Ferreira, A. Antivero, J. Pandolfi, H. Garcia Rivello, M. Dalurzo, F. Cayol, C. Franco Cortes, L. Lupinacci, F. Jauk
Journal: Journal of Thoracic Oncology (2021)
OA16.01 Plasma NGS At Time of Diagnostic Tissue Biopsy – Impact on Time to Treatment: Results From a Pilot Prospective Study
Authors: J. Thompson, C. Aggarwal, J. Wong, V. Nimgaonkar, M. Andronov, D. Dibardino, C. Hutchinson, K. Ma, A. Lanfranco, E. Moon, A. Haas, A. Vachani, E. Carpenter
Journal: Journal of Thoracic Oncology (2021)
Platinum–copper alloy nanoparticles armored with chloride ion transporter to promote electro-driven tumor inhibition
Authors: Tong Chen, Gaorong Han, Xiang Li
Journal: Bioactive Materials (2021)

The induction of oxidative species, driven by oscillating electric field (E), has recently emerged as an effective approach for tumor inhibition, so-called electrodynamic therapy (EDT). While it offers a series of advantages attracting considerable attention, the fundamental mechanism and improvement strategies for EDT approach are being endeavored extensively with the aid of new material explorations. An interesting phenomenon observed in early studies is that the on-site concentration of chloride ion is highly favored for the induction of oxidative species and the efficacy of tumor inhibition. Following this discovery ignored previously, here for the first time, fine Pt/Cu alloy nanoparticles (PtCu3 NPs) are integrated with chloride ion transporter (CIT) for EDT-based combinational therapy. In this system, while PtCu3 NPs induce oxidative species under an electric field, it also effectively transforms endogenous H2O2 into •OH and consumes intracellular glutathione (GSH). More importantly, with the aid of CIT, PtCu3[email protected] NPs promote the intracellular concentration of chloride ion (Cl−) by transporting extracellular Cl−, facilitating the generation of oxidative species considerably. Meanwhile, CIT delivered intracellularly increases lysosomal pH, leading to the disruption of cellular autophagy and weakening the treatment resistance. In consequence, significant tumor inhibition is enabled both in vitro and in vivo, due to the combination of unique characteristics offered by PtCu3[email protected]
Identification of conserved SARS-CoV-2 spike epitopes that expand public cTfh clonotypes in mild COVID-19 patients
Authors: Xiuyuan Lu, Yuki Hosono, Masamichi Nagae, Shigenari Ishizuka, Eri Ishikawa, Daisuke Motooka, Yuki Ozaki, Nicolas Sax, Yuichi Maeda, Yasuhiro Kato, Takayoshi Morita, Ryo Shinnakasu, Takeshi Inoue, Taishi Onodera, Takayuki Matsumura, Masaharu Shinkai, Takashi Sato, Shota Nakamura, Shunsuke Mori, Teru Kanda, Emi E. Nakayama, Tatsuo Shioda, Tomohiro Kurosaki, Kiyoshi Takeda, Atsushi Kumanogoh, Hisashi Arase, Hironori Nakagami, Kazuo Yamashita, Yoshimasa Takahashi, Sho Yamasaki
Journal: The Journal of Experimental Medicine (2021)

Adaptive immunity is a fundamental component in controlling COVID-19. In this process, follicular helper T (Tfh) cells are a subset of CD4+ T cells that mediate the production of protective antibodies; however, the SARS-CoV-2 epitopes activating Tfh cells are not well characterized. Here, we identified and crystallized TCRs of public circulating Tfh (cTfh) clonotypes that are expanded in patients who have recovered from mild symptoms. These public clonotypes recognized the SARS-CoV-2 spike (S) epitopes conserved across emerging variants. The epitope of the most prevalent cTfh clonotype, S864–882, was presented by multiple HLAs and activated T cells in most healthy donors, suggesting that this S region is a universal T cell epitope useful for booster antigen. SARS-CoV-2–specific public cTfh clonotypes also cross-reacted with specific commensal bacteria. In this study, we identified conserved SARS-CoV-2 S epitopes that activate public cTfh clonotypes associated with mild symptoms.