tbuckley/cabot-search huggingface dataset:
Assessment of Clinical Activity of PD-1 Checkpoint Inhibitor Combination Therapies Reported in Clinical Trials
Authors: Emmett V. Schmidt, Michael J. Chisamore, Marya F. Chaney, Marie E. Maradeo, James Anderson, Gretchen A. Baltus, Elaine M. Pinheiro, Victor N. Uebele
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Because cancer drugs given in combination have the potential for increased tumor-cell killing, finding the best combination partners for programmed cell death 1 (PD-1) checkpoint inhibitors could improve clinical outcomes for patients with cancer. <h3>Objective</h3> To identify optimal strategies for combining PD-1 immune checkpoint inhibitors with other cancer therapies. <h3>Design, Setting, and Participants</h3> This cross-sectional study compiled 319 results from 98 clinical trials testing PD-1 pathway inhibitors alone or in combination with other agents among 24 915 patients with metastatic cancer. All clinical trials had a primary completion date before September 16, 2018. Data analysis was conducted from November 2018 to August 2019. <h3>Exposures</h3> Patients with metastatic cancer were treated with PD-1 immune checkpoint inhibitors alone or with other cancer therapies. <h3>Main Outcomes and Measures</h3> Clinical activity was measured as objective response rates (ORRs). Combination measures included fold change from monotherapy to combination ORR, comparison of observed combination ORRs with estimated combination ORRs based on independent additivity, and a computational model to assess clinical synergy. To assess whether the ORRs of various combinations may be greater than the independent contribution of each agent, a Bliss independent activity model was used to analyze observed combination ORRs, and a<i>Z</i>score, measuring the difference between observed and calculated ORRs, was generated. <h3>Results</h3> In 319 results from 98 clinical trials among 24 915 patients, ORRs for monotherapy were compared with combination data by indication and line of therapy, demonstrating an increased ORR in 105 of 127 results (82.7%) where ORRs were available for both PD-1 pathway inhibitor monotherapy and combination therapy. A few combinations showed increases above the Bliss-estimated activity, possibly identifying limited clinical synergy. The mean (SD)<i>Z</i>score for all trials was 0.0430 (0.0243). The mean (SD)<i>Z</i>score was 0.0923 (0.0628) for platinum chemotherapy regimen combinations, 0.0547 (0.0821) for vascular endothelial growth factor or vascular endothelial growth factor receptor tyrosine kinase inhibitor combinations, 0.0893 (0.086) for indoleamine 2,3-dioxygenase inhibitor combinations, and 0.0558 (0.0849) for cytotoxic T-lymphocyte–associated protein 4 inhibitor combinations. <h3>Conclusions and Relevance</h3> In this cross-sectional study, most combination trials showed the expected benefit of combining 2 active anticancer agents, but few combination trials showed clinical synergy according to the Bliss independent activity model.
Dysregulations of Functional RNA Modifications in Cancer, Cancer Stemness and Cancer Therapeutics
Authors: Mohammad Burhan Uddin, Zhishan Wang, Chengfeng Yang
Journal: Theranostics (2020)

More than a hundred chemical modifications in coding and non-coding RNAs have been identified so far.Many of the RNA modifications are dynamic and reversible, playing critical roles in gene regulation at the posttranscriptional level.The abundance and functions of RNA modifications are controlled mainly by the modification regulatory proteins: writers, erasers and readers.Modified RNA bases and their regulators form intricate networks which are associated with a vast array of diverse biological functions.RNA modifications are not only essential for maintaining the stability and structural integrity of the RNA molecules themselves, they are also associated with the functional outcomes and phenotypic attributes of cells.In addition to their normal biological roles, many of the RNA modifications also play important roles in various diseases particularly in cancer as evidenced that the modified RNA transcripts and their regulatory proteins are aberrantly expressed in many cancer types.This review will first summarize the most commonly reported RNA modifications and their regulations, followed by discussing recent studies on the roles of RNA modifications in cancer, cancer stemness as wells as functional RNA modification machinery as potential cancer therapeutic targets.It is concluded that, while advanced technologies have uncovered the contributions of many of RNA modifications in cancer, the underlying mechanisms are still poorly understood.Moreover, whether and how environmental pollutants, important cancer etiological factors, trigger abnormal RNA modifications and their roles in environmental carcinogenesis remain largely unknown.Further studies are needed to elucidate the mechanism of how RNA modifications promote cell malignant transformation and generation of cancer stem cells, which will lead to the development of new strategies for cancer prevention and treatment.
Extracellular vesicles from human cardiovascular progenitors trigger a reparative immune response in infarcted hearts
Authors: Bruna Lima Correa, Nadia El Harane, Ingrid Gomez, Hocine Rachid Hocine, José Vilar, Manon Desgres, Valérie Bellamy, Kamaleswaran Keirththana, Chloé Guillas, Maria Perotto, Laetitia Pidial, Paul Alayrac, Thi Tran, Sisareuth Tan, Thomas Hamada, Dominique Charron, Alain Brisson, Nisa K Renault, Reem Al-Daccak, Philippe Menasché, Jean-Sébastien Silvestre
Journal: Cardiovascular Research (2020)

Abstract Aims The cardioprotective effects of human induced pluripotent stem cell-derived cardiovascular progenitor cells (CPC) are largely mediated by the paracrine release of extracellular vesicles (EV). We aimed to assess the immunological behaviour of EV-CPC, which is a prerequisite for their clinical translation. Methods and results Flow cytometry demonstrated that EV-CPC expressed very low levels of immune relevant molecules including HLA Class I, CD80, CD274 (PD-L1), and CD275 (ICOS-L); and moderate levels of ligands of the natural killer (NK) cell activating receptor, NKG2D. In mixed lymphocyte reactions, EV-CPC neither induced nor modulated adaptive allogeneic T cell immune responses. They also failed to induce NK cell degranulation, even at high concentrations. These in vitro effects were confirmed in vivo as repeated injections of EV-CPC did not stimulate production of immunoglobulins or affect the interferon (IFN)-γ responses from primed splenocytes. In a mouse model of chronic heart failure, intra-myocardial injections of EV-CPC, 3 weeks after myocardial infarction, decreased both the number of cardiac pro-inflammatory Ly6Chigh monocytes and circulating levels of pro-inflammatory cytokines (IL-1α, TNF-α, and IFN-γ). In a model of acute infarction, direct cardiac injection of EV-CPC 2 days after infarction reduced pro-inflammatory macrophages, Ly6Chigh monocytes, and neutrophils in heart tissue as compared to controls. EV-CPC also reduced levels of pro-inflammatory cytokines IL-1α, IL-2, and IL-6, and increased levels of the anti-inflammatory cytokine IL-10. These effects on human macrophages and monocytes were reproduced in vitro; EV-CPC reduced the number of pro-inflammatory monocytes and M1 macrophages, while increasing the number of anti-inflammatory M2 macrophages. Conclusions EV-CPC do not trigger an immune response either in in vitro human allogeneic models or in immunocompetent animal models. The capacity for orienting the response of monocyte/macrophages towards resolution of inflammation strengthens the clinical attractiveness of EV-CPC as an acellular therapy for cardiac repair.
2020 ACC/HFSA/ISHLT Lifelong Learning Statement for Advanced Heart Failure and Transplant Cardiology Specialists
Authors: Clyde W. Yancy, Mark H. Drazner, Samuel Tristram Coffin, William Cornwell, Shashank Desai, John P. Erwin, Mahazarin Ginwalla, Karol S. Harshaw-Ellis, Tamara Horwich, Michelle Kittleson, Anuradha Lala, Sabra C. Lewsey, Joseph E. Marine, Cindy M. Martin, Karen Meehan, David A. Morrow, Kelly Schlendorf, Jason W. Smith, Gerin R. Stevens
Journal: Journal of the American College of Cardiology (2020)
非色素皮膚腫瘍の診断法:デルモスコピーで観察された血管構造の展望:I.メラニン細胞性皮膚腫瘍
Authors: I Zalaudek, J Kreusch, J Giacomel, G Ferrara, C Catrical, G Argenziano
Journal: Journal of the American Academy of Dermatology (2010)
Response by Kuwabara et al to Letter Regarding Article, “Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75): A Randomized Controlled Trial”
Authors: Masanari Kuwabara, Jun Sasaki, Tetsunori Saikawa, Yasuyoshi Ouchi
Journal: Circulation (2020)
Legal Solutions for Universal Health Coverage
Authors: Lawrence O. Gostin
Journal: JAMA (2020)

Among all global health initiatives — such as the Global Polio Eradication Initiative, Roll Back Malaria, and the Stop TB Partnership — universal health coverage (often abbreviated as UHC) has garnered the most political attention. The “sustainable development goals” adopted by all United Nations (UN) member states in 2015, have a single health goal, to ensure healthy lives and as well as promote well-being “for all at all ages.” Its most important target is to achieve universal health coverage by 2030.
Abstract 13619: Metabolomic Profiles of Coronary Artery Calcium and Incident Coronary Heart Disease in African Americans: The Jackson Heart Study
Authors: Daniel E Cruz, Bennet Peterson, Debby Ngo, Mark Benson, Zsu Zsu Chen, Usman Tahir, Yan Gao, Thomas J Wang, Adolfo Correa, Clary Clish, James Wilson, Robert E Gerszten
Journal: Circulation (2019)

Introduction: African Americans (AA) suffer disproportionately from coronary heart disease (CHD) yet have been found to have significantly lower coronary artery calcium scores than other population...
Circular RNA MAPK4 (circ-MAPK4) inhibits cell apoptosis via MAPK signaling pathway by sponging miR-125a-3p in gliomas
Authors: Jiehua He, Zuoyu Huang, Mingliang He, Jianyou Liao, Qianqian Zhang, Shengwen Wang, Lin Xie, Leping Ouyang, H. Phillip Koeffler, Dong Yin, Anmin Liu
Journal: Molecular Cancer (2020)

Abstract Background Recent evidences have shown that circular RNAs (circRNAs) are frequently dysregulated and play paramount roles in various cancers. circRNAs are abundant in central nervous system (CNS); however, few studies describe the clinical significance and role of circRNAs in gliomas, which is the most common and aggressive primary malignant tumor in the CNS. Methods A bioinformatics analysis was performed to profile and screen the dyregulated circRNAs during early neural development. Quantitative real-time PCR was used to detect the expression of circ-MAPK4 and target miRNAs. Glioma cells were transfected with circ-MAPK4 siRNAs, then cell proliferation, apoptosis, transwell assays, as well as tumorigenesis and TUNEL assays, were performed to examine effect of circ-MAPK4 in vitro and vivo . Biotinylated-circ-MAPK4 probe based pull-down assay was conducted to confirm the relationship between circ-MAPK4 and miR-125-3p. Results In this study, we identified a circRNA, circ-MAPK4 (has_circ_0047688), which was downregulated during early neural differentiation. In gliomas, circ-MAPK4 acted as an oncogene, was inversely upregulated and linked to clinical pathological stage of gliomas ( P &lt; 0.05). Next, we verified that circ-MAPK4 promoted the survival and inhibited the apoptosis of glioma cells in vitro and in vivo. Furthermore, we proved that circ-MAPK4 was involved in regulating p38/MAPK pathway, which affected glioma proliferation and apoptosis. Finally, miR-125a-3p, a miRNA exhibited tumor-suppressive function through impairing p38/MAPK pathway, which was increased by inhibiting circ-MAPK4 and could be pulled down by circ-MAPK4. Inhibition of miR-125a-3p could partly rescue the increased phosphorylation levels of p38/MAPK and the elevated amount of apoptosis inducing by knockdown of circ-MAPK4. Conclusions Our findings suggest that circ-MAPK4 is a critical player in glioma cell survival and apoptosis via p38/MAPK signaling pathway through modulation of miR-125a-3p, which can serve as a new therapeutic target for treatment of gliomas.
Machine learning in infection management using routine electronic health records: tools, techniques, and reporting of future technologies
Authors: C.F. Luz, M. Vollmer, J. Decruyenaere, M.W. Nijsten, C. Glasner, B. Sinha
Journal: Clinical Microbiology and Infection (2020)

Machine learning (ML) is increasingly being used in many areas of health care. Its use in infection management is catching up as identified in a recent review in this journal. We present here a complementary review to this work.To support clinicians and researchers in navigating through the methodological aspects of ML approaches in the field of infection management.A Medline search was performed with the keywords artificial intelligence, machine learning, infection∗, and infectious disease∗ for the years 2014-2019. Studies using routinely available electronic hospital record data from an inpatient setting with a focus on bacterial and fungal infections were included.Fifty-two studies were included and divided into six groups based on their focus. These studies covered detection/prediction of sepsis (n = 19), hospital-acquired infections (n = 11), surgical site infections and other postoperative infections (n = 11), microbiological test results (n = 4), infections in general (n = 2), musculoskeletal infections (n = 2), and other topics (urinary tract infections, deep fungal infections, antimicrobial prescriptions; n = 1 each). In total, 35 different ML techniques were used. Logistic regression was applied in 18 studies followed by random forest, support vector machines, and artificial neural networks in 18, 12, and seven studies, respectively. Overall, the studies were very heterogeneous in their approach and their reporting. Detailed information on data handling and software code was often missing. Validation on new datasets and/or in other institutions was rarely done. Clinical studies on the impact of ML in infection management were lacking.Promising approaches for ML use in infectious diseases were identified. But building trust in these new technologies will require improved reporting. Explainability and interpretability of the models used were rarely addressed and should be further explored. Independent model validation and clinical studies evaluating the added value of ML approaches are needed.
Soyasaponin II protects against acute liver failure through diminishing YB-1 phosphorylation and Nlrp3-inflammasome priming in mice
Authors: Fangzhao Wang, Shenhai Gong, Teng Wang, Lei Li, Haihua Luo, Junhao Wang, Chenyang Huang, Hongwei Zhou, Guiming Chen, Zhanguo Liu, Qifan Zhang, Yong Jiang, Peng Chen
Journal: Theranostics (2020)

Acute liver failure is characterized by the rapid development of liver dysfunction and remarkably high mortality. Accumulating evidence suggests that soyasaponin possesses potential anti-inflammatory activities. Here, we aimed to investigate the potential role of soyasaponin II in acute liver failure and establish the underlying mechanism.
Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records
Authors: Huijun Chen, Juanjuan Guo, Chen Wang, Fan Luo, Xuechen Yu, Wei Zhang, Jiafu Li, Dongchi Zhao, Dan Xu, Qing Gong, Jing Liao, Huixia Yang, Wei Hou, Yuanzhen Zhang
Journal: The Lancet (2020)

Previous studies on the pneumonia outbreak caused by the 2019 novel coronavirus disease (COVID-19) were based on information from the general population. Limited data are available for pregnant women with COVID-19 pneumonia. This study aimed to evaluate the clinical characteristics of COVID-19 in pregnancy and the intrauterine vertical transmission potential of COVID-19 infection.Clinical records, laboratory results, and chest CT scans were retrospectively reviewed for nine pregnant women with laboratory-confirmed COVID-19 pneumonia (ie, with maternal throat swab samples that were positive for severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) who were admitted to Zhongnan Hospital of Wuhan University, Wuhan, China, from Jan 20 to Jan 31, 2020. Evidence of intrauterine vertical transmission was assessed by testing for the presence of SARS-CoV-2 in amniotic fluid, cord blood, and neonatal throat swab samples. Breastmilk samples were also collected and tested from patients after the first lactation.All nine patients had a caesarean section in their third trimester. Seven patients presented with a fever. Other symptoms, including cough (in four of nine patients), myalgia (in three), sore throat (in two), and malaise (in two), were also observed. Fetal distress was monitored in two cases. Five of nine patients had lymphopenia (<1·0 × 10⁹ cells per L). Three patients had increased aminotransferase concentrations. None of the patients developed severe COVID-19 pneumonia or died, as of Feb 4, 2020. Nine livebirths were recorded. No neonatal asphyxia was observed in newborn babies. All nine livebirths had a 1-min Apgar score of 8-9 and a 5-min Apgar score of 9-10. Amniotic fluid, cord blood, neonatal throat swab, and breastmilk samples from six patients were tested for SARS-CoV-2, and all samples tested negative for the virus.The clinical characteristics of COVID-19 pneumonia in pregnant women were similar to those reported for non-pregnant adult patients who developed COVID-19 pneumonia. Findings from this small group of cases suggest that there is currently no evidence for intrauterine infection caused by vertical transmission in women who develop COVID-19 pneumonia in late pregnancy.Hubei Science and Technology Plan, Wuhan University Medical Development Plan.
Estimates of Medication Diversion in Hospice
Authors: John G. Cagle, Mary Lynn McPherson, Jodi J. Frey, Paul Sacco, Orrin D. Ware, Debra L. Wiegand, Jack M. Guralnik
Journal: JAMA (2020)

This study uses a random survey of US hospice agencies to estimate rates of confirmed and suspected cases of medication diversion away from patients in hospice and association of diversion rates with agency characteristics and state opioid death rates.
Myc-Miz-1 signaling promotes self-renewal of leukemia stem cells by repressing Cebpα and Cebpδ
Authors: Lei Zhang, Jing Li, Hui Xu, Xianyu Shao, Li Fu, Ye Hou, Caiqing Hao, Wenyan Li, Kanak Joshi, Wei Wei, Yan Xu, Feng Zhang, Shaojun Dai, Peter W. Breslin, S.J., Jiwang Zhang, Jun Zhang
Journal: Blood (2020)
Model-Based Inference and Classification of Immunologic Control Mechanisms from TKI Cessation and Dose Reduction in Patients with CML
Authors: Tom Hähnel, Christoph Baldow, Joëlle Guilhot, François Guilhot, Susanne Saussele, Satu Mustjoki, Stefanie Jilg, Philipp J. Jost, Stephanie Dulucq, François-Xavier Mahon, Ingo Roeder, Artur C. Fassoni, Ingmar Glauche
Journal: Cancer Research (2020)

Recent clinical findings in patients with chronic myeloid leukemia (CML) suggest that the risk of molecular recurrence after stopping tyrosine kinase inhibitor (TKI) treatment substantially depends on an individual's leukemia-specific immune response. However, it is still not possible to prospectively identify patients that will remain in treatment-free remission (TFR). Here, we used an ordinary differential equation model for CML, which explicitly includes an antileukemic immunologic effect, and applied it to 21 patients with CML for whom BCR-ABL1/ABL1 time courses had been quantified before and after TKI cessation. Immunologic control was conceptually necessary to explain TFR as observed in about half of the patients. Fitting the model simulations to data, we identified patient-specific parameters and classified patients into three different groups according to their predicted immune system configuration ("immunologic landscapes"). While one class of patients required complete CML eradication to achieve TFR, other patients were able to control residual leukemia levels after treatment cessation. Among them were a third class of patients that maintained TFR only if an optimal balance between leukemia abundance and immunologic activation was achieved before treatment cessation. Model simulations further suggested that changes in the BCR-ABL1 dynamics resulting from TKI dose reduction convey information about the patient-specific immune system and allow prediction of outcome after treatment cessation. This inference of individual immunologic configurations based on treatment alterations can also be applied to other cancer types in which the endogenous immune system supports maintenance therapy, long-term disease control, or even cure. SIGNIFICANCE: This mathematical modeling approach provides strong evidence that different immunologic configurations in patients with CML determine their response to therapy cessation and that dose reductions can help to prospectively infer different risk groups.See related commentary by Triche Jr, p. 2083.
Drug survival and postdrug survival of systemic treatments in a national French cohort of children with atopic dermatitis
Authors: E. Chambrelan, S. Barbarot, L. Bekel, F. Poizeau, E. Mahé, E. Puzenat, J. Delaunay, S. Mallet, D. Bessis, A. Maruani, J. Miquel, N. Raison‐Peyron, C. Abasq, A. Phan, A. Du Thanh, I. Kupfer, B. Bonniaud, G. Bouzille, A. Dupuy, C. Droitcourt
Journal: British Journal of Dermatology (2020)

All data were collected from medical records using a standardized questionnaire * At the initiation of first-
Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy
Authors: Jeremy M. Sullivan, William W. Motley, Janel O. Johnson, William H. Aisenberg, Katherine L. Marshall, Katy E.S. Barwick, Lingling Kong, Jennifer S. Huh, Pamela C. Saavedra-Rivera, Meriel M. McEntagart, Marie-Helene Marion, Lucy A. Hicklin, Hamid Modarres, Emma L. Baple, Mohamed H. Farah, Aamir R. Zuberi, Cathleen M. Lutz, Rachelle Gaudet, Bryan J. Traynor, Andrew H. Crosby, Charlotte J. Sumner
Journal: Journal of Clinical Investigation (2020)

Notch signaling is a highly conserved intercellular pathway with tightly regulated and pleiotropic roles in normal tissue development and homeostasis. Dysregulated Notch signaling has also been implicated in human disease, including multiple forms of cancer, and represents an emerging therapeutic target. Successful development of such therapeutics requires a detailed understanding of potential on-target toxicities. Here, we identify autosomal dominant mutations of the canonical Notch ligand Jagged1 (or JAG1) as a cause of peripheral nerve disease in 2 unrelated families with the hereditary axonal neuropathy Charcot-Marie-Tooth disease type 2 (CMT2). Affected individuals in both families exhibited severe vocal fold paresis, a rare feature of peripheral nerve disease that can be life-threatening. Our studies of mutant protein posttranslational modification and localization indicated that the mutations (p.Ser577Arg, p.Ser650Pro) impair protein glycosylation and reduce JAG1 cell surface expression. Mice harboring heterozygous CMT2-associated mutations exhibited mild peripheral neuropathy, and homozygous expression resulted in embryonic lethality by midgestation. Together, our findings highlight a critical role for JAG1 in maintaining peripheral nerve integrity, particularly in the recurrent laryngeal nerve, and provide a basis for the evaluation of peripheral neuropathy as part of the clinical development of Notch pathway-modulating therapeutics.
Helen Salisbury: Responding to racism
Authors: Helen Salisbury
Journal: BMJ (2020)

I try hard, but I know that I make mistakes. I practise unfamiliar names to myself before calling patients in from the waiting room, and I ask to be corrected on pronunciation. I like to know where my patients are from, and I hope that asking this demonstrates my interest—but what if it’s construed as intrusive or, worse, as questioning their right to be here seeing a doctor? Sometimes I ask, “Where is your name from?” which is more about heritage than personal history but still could be misconstrued.

The problem with privilege, which I undoubtedly have, is that …