tbuckley/cabot-search huggingface dataset:
Community-wide hackathons to identify central themes in single-cell multi-omics
Authors: Kim-Anh Lê Cao, Al J. Abadi, Emily F. Davis-Marcisak, Lauren Hsu, Arshi Arora, Alexis Coullomb, Atul Deshpande, Yuzhou Feng, Pratheepa Jeganathan, Melanie Loth, Chen Meng, Wancen Mu, Vera Pancaldi, Kris Sankaran, Dario Righelli, Amrit Singh, Joshua S. Sodicoff, Genevieve L. Stein-O’Brien, Ayshwarya Subramanian, Joshua D. Welch, Yue You, Ricard Argelaguet, Vincent J. Carey, Ruben Dries, Casey S. Greene, Susan Holmes, Michael I. Love, Matthew E. Ritchie, Guo-Cheng Yuan, Aedin C. Culhane, Elana Fertig
Journal: Genome biology (2021)

We wish to acknowledge the following funding bodies:

National Health of Medical Research Council Career Development Fellowship AU, (KALC); Chan Zuckerberg initiative (AJA, VJC, ACC);

Australian Research Council (AJA, KALC, MER);

National Institute of Health, (EFDM, AD, SH);

National Cancer Institute, (EFDM, VJC, CSG, GCY, EJF);

Chair of bioinformatics in oncology of the CRCT (INSERM, Fondation Toulouse Cancer Sante, Pierre Fabre Research Institute, (AC, VP);

Fondation Toulouse Cancer Sante, (AC, VP);

Pierre Fabre Research Institute, (AC, VP);

Michael Smith Foundation for Health Research, (AS);

Mitacs, (AS);

Kavli Neuroscience Discovery Institute, (GLSO);

Johns Hopkins Provost Postdoctoral Fellowship, (GLSO);

National Human Genome Research Institute, NIH, (JDW, VJC, CSG, WM, MIL);

National Institute of Allergy and Infectious Diseases, NIH, (JDW, SH);

National Institute of Mental Health, NIH, (JDW, MIL);

EMBL PhD program, (RA);

National Institutes of Health, National Institute on Aging, (GCY);

DoD, (ACC);

National Institute of Health, National Institute of Dental and Craniofacial Research, (EJF);

Lustgarten Foundation, (EJF);

Emerson Foundation, (EJF);

Allegheny Health Network, (EJF).
Prediction of Immunotherapy Response in Melanoma through Combined Modeling of Neoantigen Burden and Immune-Related Resistance Mechanisms
Authors: Charles W. Abbott, Sean M. Boyle, Rachel Marty Pyke, Lee D. McDaniel, Eric Levy, Fábio C.P. Navarro, Dattatreya Mellacheruvu, Simo V. Zhang, Mengyao Tan, Rose Santiago, Zeid M. Rusan, Pamela Milani, Gabor Bartha, Jason Harris, Rena McClory, Michael P. Snyder, Sekwon Jang, Richard Chen
Journal: Clinical Cancer Research (2021)

Abstract Purpose: While immune checkpoint blockade (ICB) has become a pillar of cancer treatment, biomarkers that consistently predict patient response remain elusive due to the complex mechanisms driving immune response to tumors. We hypothesized that a multi-dimensional approach modeling both tumor and immune-related molecular mechanisms would better predict ICB response than simpler mutation-focused biomarkers, such as tumor mutational burden (TMB). Experimental Design: Tumors from a cohort of patients with late-stage melanoma (n = 51) were profiled using an immune-enhanced exome and transcriptome platform. We demonstrate increasing predictive power with deeper modeling of neoantigens and immune-related resistance mechanisms to ICB. Results: Our neoantigen burden score, which integrates both exome and transcriptome features, more significantly stratified responders and nonresponders (P = 0.016) than TMB alone (P = 0.049). Extension of this model to include immune-related resistance mechanisms affecting the antigen presentation machinery, such as HLA allele-specific LOH, resulted in a composite neoantigen presentation score (NEOPS) that demonstrated further increased association with therapy response (P = 0.002). Conclusions: NEOPS proved the statistically strongest biomarker compared with all single-gene biomarkers, expression signatures, and TMB biomarkers evaluated in this cohort. Subsequent confirmation of these findings in an independent cohort of patients (n = 110) suggests that NEOPS is a robust, novel biomarker of ICB response in melanoma.
Novel EGFRvIII-CAR transgenic mice for rigorous preclinical studies in syngeneic mice
Authors: Pavlina Chuntova, Yafei Hou, Ryosuke Naka, Akane Yamamichi, Tiffany Chen, Yitzhar Goretsky, Ryusuke Hatae, Takahide Nejo, Gary Kohanbash, Abigail L Mende, Megan Montoya, Kira M Downey, David Diebold, Jayne Skinner, Hong-Erh Liang, Bjoern Schwer, Hideho Okada
Journal: Neuro-Oncology (2021)

Rigorous preclinical studies of chimeric antigen receptor (CAR) immunotherapy will require large quantities of consistent and high-quality CAR-transduced T (CART) cells that can be used in syngeneic mouse glioblastoma (GBM) models. To this end, we developed a novel transgenic (Tg) mouse strain with a fully murinized CAR targeting epidermal growth factor receptor variant III (EGFRvIII).We first established the murinized version of EGFRvIII-CAR and validated its function using a retroviral vector (RV) in C57BL/6J mice bearing syngeneic SB28 GBM expressing EGFRvIII. Next, we created C57BL/6J-background Tg mice carrying the anti-EGFRvIII-CAR downstream of a Lox-Stop-Lox cassette in the Rosa26 locus. We bred these mice with CD4-Cre Tg mice to allow CAR expression on T cells and evaluated the function of the CART cells both in vitro and in vivo. To inhibit immunosuppressive myeloid cells within SB28 GBM, we also evaluated a combination approach of CART and an anti-EP4 compound (ONO-AE3-208).Both RV- and Tg-CART cells demonstrated specific cytotoxic activities against SB28-EGFRvIII cells. A single intravenous infusion of EGFRvIII-CART cells prolonged the survival of glioma-bearing mice when preceded by a lymphodepletion regimen with recurrent tumors displaying profound EGFRvIII loss. The addition of ONO-AE3-208 resulted in long-term survival in a fraction of CART-treated mice and those survivors demonstrated delayed growth of subcutaneously re-challenged both EGFRvIII+ and parental EGFRvIII- SB28.Our new syngeneic CAR Tg mouse model can serve as a useful tool to address clinically relevant questions and develop future immunotherapeutic strategies.
Cost-Effectiveness Analysis of Durvalumab Plus Chemotherapy in the First-Line Treatment of Extensive-Stage Small Cell Lung Cancer
Authors: Dong Ding, Huabin Hu, Shuosha Li, Youwen Zhu, Yin Shi, Mengting Liao, Jin Liu, Xu Tian, Aiting Liu, Jin Huang
Journal: Journal of the National Comprehensive Cancer Network (2021)

Background: In the CASPIAN trial, durvalumab + chemotherapy demonstrated significant improvements in overall survival compared with chemotherapy alone in patients with extensive-stage small cell lung cancer (SCLC). We aimed to assess the cost-effectiveness of durvalumab in patients with extensive-stage SCLC from the US healthcare system perspective. Patients and Methods: A comprehensive Markov model was adapted to evaluate cost and effectiveness of durvalumab combination versus platinum/etoposide alone in the first-line therapy of extensive-stage SCLC based on data from the CASPIAN study. The main endpoints included total costs, life years (LYs), quality-adjusted life-years (QALYs), and incremental cost-e-ectiveness ratios (ICERs). Model robustness was assessed with sensitivity analysis, and additional subgroup analyses were also performed. Results: Durvalumab + chemotherapy therapy resulted in an additional 0.27 LYs and 0.20 QALYs, resulting in an ICER of $464,711.90 per QALY versus the chemotherapy treatment. The cost of durvalumab has the greatest inﬂuence on this model. Subgroup analyses showed that the ICER remained higher than $150,000/QALY (the willingness-to-pay threshold in the United States) across all patient subgroups. Conclusions: Durvalumab in combination with platinum/etoposide is not a cost-effective option in the first-line treatment of patients with extensive-stage SCLC.
The Learning Environment and Medical Student Burnout
Authors: Charles H. Griffith
Journal: JAMA Network Open (2021)

Physician burnout is a national epidemic, with many studies suggesting a prevalence of 50% or more in the United States. 1 The causes are legion but include excessive clerical workload (especially as it relates to the electronic health record), inefficient work processes, lack of input or control by physicians of decisions made for patient care, and work-home conflicts. 2This epidemic has consequences for patient care (medical error, lower patient satisfaction and quality of care), the health system (increased physician turnover and early retirement, less patient access, increased costs), and physician health (poor self-care, substance abuse, depression, and suicide).
High‐dose pollen intralymphatic immunotherapy: Two RDBPC trials question the benefit of dose increase
Authors: Laila Hellkvist, Eric Hjalmarsson, Dan Weinfeld, Åslög Dahl, Agneta Karlsson, Marit Westman, Karin Lundkvist, Ola Winqvist, Susanna Kumlien Georén, Ulla Westin, Lars Olaf Cardell
Journal: Allergy (2021)

Abstract Background The same dosing schedule, 1000 SQ‐U times three, with one‐month intervals, have been evaluated in most trials of intralymphatic immunotherapy (ILIT) for the treatment of allergic rhinitis (AR). The present studies evaluated if a dose escalation in ILIT can enhance the clinical and immunological effects, without compromising safety. Methods Two randomized double‐blind placebo‐controlled trials of ILIT for grass pollen‐induced AR were performed. The first included 29 patients that had recently ended 3 years of SCIT and the second contained 39 not previously vaccinated patients. An up‐dosage of 1000–3000–10,000 (5000 + 5000 with 30 minutes apart) SQ‐U with 1 month in between was evaluated. Results Doses up to 10,000 SQ‐U were safe after recent SCIT. The combined symptom‐medication scores (CSMS) were reduced by 31% and the grass‐specific IgG4 levels in blood were doubled. In ILIT de novo, the two first patients that received active treatment developed serious adverse reactions at 5000 SQ‐U. A modified up‐dosing schedule; 1000–3000–3000 SQ‐U appeared to be safe but failed to improve the CSMS. Flow cytometry analyses showed increased activation of lymph node‐derived dendritic but not T cells. Quality of life and nasal provocation response did not improve in any study. Conclusion Intralymphatic immunotherapy in high doses after SCIT appears to further reduce grass pollen‐induced seasonal symptoms and may be considered as an add‐on treatment for patients that do not reach full symptom control after SCIT. Up‐dosing schedules de novo with three monthly injections that exceeds 3000 SQ‐U should be avoided.
A highly potent and stable pan-coronavirus fusion inhibitor as a candidate prophylactic and therapeutic for COVID-19 and other coronavirus diseases
Authors: Jie Zhou, Wei Xu, Zezhong Liu, Chao Wang, Shuai Xia, Qiaoshuai Lan, Yanxing Cai, Shan Su, Jing Pu, Lixiao Xing, Youhua Xie, Lu Lu, Shibo Jiang, Qian Wang
Journal: Acta Pharmaceutica Sinica B (2021)

The development of broad-spectrum antivirals against human coronaviruses (HCoVs) is critical to combat the current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants, as well as future outbreaks of emerging CoVs. We have previously identified a polyethylene glycol-conjugated (PEGylated) lipopeptide, EK1C4, with potent pan-CoV fusion inhibitory activity. However, PEG linkers in peptide or protein drugs may reduce stability or induce anti-PEG antibodies in vivo. Therefore, we herein report the design and synthesis of a series of dePEGylated lipopeptide-based pan-CoV fusion inhibitors featuring the replacement of the PEG linker with amino acids in the heptad repeat 2 C-terminal fragment (HR2-CF) of HCoV-OC43. Among these lipopeptides, EKL1C showed the most potent inhibitory activity against infection by SARS-CoV-2 and its spike (S) mutants, as well as other HCoVs and some bat SARS-related coronaviruses (SARSr-CoVs) tested. The dePEGylated lipopeptide EKL1C exhibited significantly stronger resistance to proteolytic enzymes, better metabolic stability in mouse serum, higher thermostability than the PEGylated lipopeptide EK1C4, suggesting that EKL1C could be further developed as a candidate prophylactic and therapeutic for COVID-19 and other coronavirus diseases.
Optimization of cerebral organoids: a more qualified model for Alzheimer’s disease research
Authors: Feng-Chen Bi, Xin-He Yang, Xiao-Yu Cheng, Wen-Bin Deng, Xiao-Li Guo, Hui Yang, Yin Wang, Juan Li, Yao Yao
Journal: Translational Neurodegeneration (2021)

Alzheimer's disease (AD) is a neurodegenerative disease that currently cannot be cured by any drug or intervention, due to its complicated pathogenesis. Current animal and cellular models of AD are unable to meet research needs for AD. However, recent three-dimensional (3D) cerebral organoid models derived from human stem cells have provided a new tool to study molecular mechanisms and pharmaceutical developments of AD. In this review, we discuss the advantages and key limitations of the AD cerebral organoid system in comparison to the commonly used AD models, and propose possible solutions, in order to improve their application in AD research. Ethical concerns associated with human cerebral organoids are also discussed. We also summarize future directions of studies that will improve the cerebral organoid system to better model the pathological events observed in AD brains.
5 Examination of the relationship between changes in workload and changes in loaded countermovement jump during a rugby union season
Authors: Rob Strong, Daniel West, Joe Kupsarevic
Journal: British Journal of Sports Medicine (2021)

Background The loaded countermovement jump (CMJ) is a variation on the normal CMJ (bodyweight-only), used routinely in sport settings as a measure of neuromuscular fatigue (NMF). Although commonplace, the CMJ variables that are most sensitive to NMF remain somewhat unclear. Purpose The aim of this study was to examine the relationship between changes in workload and changes in the loaded CMJ; specifically, to determine its suitability for assessment of NMF. Methods Eighteen professional rugby union players performed loaded CMJ tests on seven occasions over the course of thirteen weeks, during an English top-flight season. Eight CMJ variables were measured, assessing different aspects of the CMJ. Workload was measured by GPS total distance and was the sum of the previous week’s data, recorded in on-field training and match-play. Spearman’s rank-order correlations were calculated to identify the relationship between changes in workload and changes in loaded CMJ variables. Results No significant relationships were found between loaded CMJ variables and workload with no lag or workload lagged one week. Significant relationships were found between workload lagged 2 weeks and flight time/contact time (FT-CT; r s =-0.35 ; p = 0.04) and time to peak power (TtPP; r s =0.35; p =0.05). Conclusion This study suggests loaded CMJ is not a suitable test to monitor acute changes to NMF. However, results also indicate that FT-CT and TtPP, are associated with changes in workload lagged 2-weeks. Therefore, certain CMJ variables may prove useful to help prescribe alterations to athlete training plans following periods of heavy workload.
SO-11 KISIMA-01 trial: Safety, tolerability and immunogenicity of ATP128 with or without ezabenlimab (BI 754091) in patients with stage IV colorectal cancer – preliminary results from a phase 1b study
Authors: S. Kopetz, H. Prenen, S. Sharma, E. Van Cutsem, J. Mayol, F. Trapani, T. Bogenrieder, H. Lenz
Journal: Annals of Oncology (2021)
Obesity-related IL-18 Impairs T-Regulatory Cell Function and Promotes Lung Ischemia–Reperfusion Injury
Authors: Tatiana Akimova, Tianyi Zhang, Lanette M. Christensen, Zhonglin Wang, Rongxiang Han, Dmitry Negorev, Arabinda Samanta, Isaac E. Sasson, Trivikram Gaddapara, Jing Jiao, Liqing Wang, Tricia R. Bhatti, Matthew H. Levine, Joshua M. Diamond, Ulf H. Beier, Rebecca A. Simmons, Edward Cantu, David S. Wilkes, David J. Lederer, Michaela Anderson, Jason D. Christie, Wayne W. Hancock
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Primary graft dysfunction (PGD) is a severe form of acute lung injury, leading to increased early morbidity and mortality after lung transplant. Obesity is a major health problem, and recipient obesity is one of the most significant risk factors for developing PGD. Objectives: We hypothesized that T-regulatory cells (Tregs) are able to dampen early ischemia–reperfusion events and thereby decrease the risk of PGD, whereas that action is impaired in obese recipients. Methods: We evaluated Tregs, T cells, and inflammatory markers, plus clinical data, in 79 lung transplant recipients and 41 liver or kidney transplant recipients and studied two groups of mice on a high-fat diet (HFD), which did (“inflammatory” HFD) or did not (“healthy” HFD) develop low-grade inflammation with decreased Treg function. Measurements and Main Results: We identified increased levels of IL-18 as a previously unrecognized mechanism that impairs Tregs’ suppressive function in obese individuals. IL-18 decreases levels of FOXP3, the key Treg transcription factor, decreases FOXP3 di- and oligomerization, and increases the ubiquitination and proteasomal degradation of FOXP3. IL-18–treated Tregs or Tregs from obese mice fail to control PGD, whereas IL-18 inhibition ameliorates lung inflammation. The IL-18–driven impairment in Tregs’ suppressive function before transplant was associated with an increased risk and severity of PGD in clinical lung transplant recipients. Conclusions: Obesity-related IL-18 induces Treg dysfunction that may contribute to the pathogenesis of PGD. Evaluation of Tregs’ suppressive function together with evaluation of IL-18 levels may serve as a screening tool to identify obese individuals with an increased risk of PGD before transplant.
High-dose methotrexate is effective for prevention of isolated CNS relapse in diffuse large B cell lymphoma
Authors: Shin Yeu Ong, Sanjay de Mel, Nicholas Francis Grigoropoulos, Yunxin Chen, Yan Chin Tan, Melinda Si Yun Tan, Lawrence Cheng Kiat Ng, Yuh Shan Lee, Colin Phipps, Yeow Tee Goh, Kar Ying Yong, Xin Liu, Wee Joo Chng, Soon Thye Lim, Chandramouli Nagarajan
Journal: Blood Cancer Journal (2021)

The role of central nervous system (CNS) prophylaxis with high-dose methotrexate (HDMTX) in DLBCL is controversial. In this retrospective study, we evaluated the efficacy of prophylactic HDMTX on isolated CNS relapse, concomitant CNS and systemic relapse, systemic relapse, and survival outcomes in 226 patients with newly diagnosed DLBCL and high-risk CNS International Prognostic Index (CNS-IPI) score treated with RCHOP. The three-year risk of isolated CNS relapse was significantly lower in patients who received HDMTX, at 3.1% compared to 14.6% (P = 0.032) in those who did not. However, neither concomitant CNS-systemic relapse rates, systemic relapse rates, nor three-year PFS and OS were significantly different between treatment groups in multivariable analysis. Among propensity score-matched patients (N = 102), HDMTX was also associated with significantly lower isolated CNS relapse rates (HR 0.06, 95% CI 0.004-0.946, P = 0.046). HDMTX was well tolerated with manageable toxicities when given at a dose of 3 g/m2 by day 3 of RCHOP chemotherapy. Using propensity score matching and multivariable regression to yield treatment groups with well-balanced covariates, we showed that prophylactic HDMTX improved isolated CNS relapse rates but did not decrease concomitant CNS-systemic relapse rates, systemic relapse rates, or improve survival outcomes.
Blood Cholesterol Measurement in Young Adults
Authors: Carol Lewis
Journal: JAMA (1993)

<h3>To the Editor.</h3> —We are investigators for the National Heart, Lung, and Blood Institute-funded demonstration project Assisting Primary Care Physicians With Lipid-Lowering Interventions (APPLI); we and our APPLI colleagues are concerned about the recent article by Hulley et al.<sup>1</sup>(The APPLI is studying the application of current cholesterol treatment guidelines in routine community practice.) Hulley et al question whether we should be measuring blood cholesterol levels in men younger than 35 years and women younger than 45 years, as has been recommended by the National Cholesterol Education Program Adult Treatment Panel.<sup>2</sup>They argue that (1) cholesterol intervention in low-risk adults is not cost-effective and may cause more harm than benefit, and (2) intervention in middle age can prevent CHD. They dismiss dietary treatment as ineffective and unacceptable. The Population Panel of the National Cholesterol Education Program does not emphasize cholesterol screening to identify high-risk persons—the focus of Hulley
HIV-1 matrix-tRNA complex structure reveals basis for host control of Gag localization
Authors: Charles Bou-Nader, Frauke Muecksch, Janae B. Brown, Jackson M. Gordon, Ashley York, Chen Peng, Rodolfo Ghirlando, Michael F. Summers, Paul D. Bieniasz, Jinwei Zhang
Journal: Cell Host & Microbe (2021)

The HIV-1 virion structural polyprotein, Gag, is directed to particle assembly sites at the plasma membrane by its N-terminal matrix (MA) domain. MA also binds to host tRNAs. To understand the molecular basis of MA-tRNA interaction and its potential function, we present a co-crystal structure of HIV-1 MA-tRNA
Fold Evolution before LUCA: Common Ancestry of SH3 Domains and OB Domains
Authors: Claudia Alvarez-Carreño, Petar I Penev, Anton S Petrov, Loren Dean Williams
Journal: Molecular Biology and Evolution (2021)

SH3 and OB are the simplest, oldest, and most common protein domains within the translation system. SH3 and OB domains are β-barrels that are structurally similar but are topologically distinct. To transform an OB domain to a SH3 domain, β-strands must be permuted in a multistep and evolutionarily implausible mechanism. Here, we explored relationships between SH3 and OB domains of ribosomal proteins, initiation, and elongation factors using a combined sequence- and structure-based approach. We detect a common core of SH3 and OB domains, as a region of significant structure and sequence similarity. The common core contains four β-strands and a loop, but omits the fifth β-strand, which is variable and is absent from some OB and SH3 domain proteins. The structure of the common core immediately suggests a simple permutation mechanism for interconversion between SH3 and OB domains, which appear to share an ancestor. The OB domain was formed by duplication and adaptation of the SH3 domain core, or vice versa, in a simple and probable transformation. By employing the folding algorithm AlphaFold2, we demonstrated that an ancestral reconstruction of a permuted SH3 sequence folds into an OB structure, and an ancestral reconstruction of a permuted OB sequence folds into a SH3 structure. The tandem SH3 and OB domains in the universal ribosomal protein uL2 share a common ancestor, suggesting that the divergence of these two domains occurred before the last universal common ancestor.