tbuckley/cabot-search huggingface dataset:
Effect of mammographic screening from age 40 years on breast cancer mortality (UK Age trial): final results of a randomised, controlled trial
Authors: Stephen W Duffy, Daniel Vulkan, Howard Cuckle, Dharmishta Parmar, Shama Sheikh, Robert A Smith, Andrew Evans, Oleg Blyuss, Louise Johns, Ian O Ellis, Jonathan Myles, Peter D Sasieni, Sue M Moss
Journal: The Lancet Oncology (2020)

BackgroundThe appropriate age range for breast cancer screening remains a matter of debate. We aimed to estimate the effect of mammographic screening at ages 40–48 years on breast cancer mortality.MethodsWe did a randomised, controlled trial involving 23 breast screening units across Great Britain. We randomly assigned women aged 39–41 years, using individual randomisation, stratified by general practice, in a 1:2 ratio, to yearly mammographic screening from the year of inclusion in the trial up to and including the calendar year that they reached age 48 years (intervention group), or to standard care of no screening until the invitation to their first National Health Service Breast Screening Programme (NHSBSP) screen at approximately age 50 years (control group). Women in the intervention group were recruited by postal invitation. Women in the control group were unaware of the study. The primary endpoint was mortality from breast cancers (with breast cancer coded as the underlying cause of death) diagnosed during the intervention period, before the participant's first NHSBSP screen. To study the timing of the mortality effect, we analysed the results in different follow-up periods. Women were included in the primary comparison regardless of compliance with randomisation status (intention-to-treat analysis). This Article reports on long-term follow-up analysis. The trial is registered with the ISRCTN registry, ISRCTN24647151.Findings160 921 women were recruited between Oct 14, 1990, and Sept 24, 1997. 53 883 women (33·5%) were randomly assigned to the intervention group and 106 953 (66·5%) to the control group. Between randomisation and Feb 28, 2017, women were followed up for a median of 22·8 years (IQR 21·8–24·0). We observed a significant reduction in breast cancer mortality at 10 years of follow-up, with 83 breast cancer deaths in the intervention group versus 219 in the control group (relative rate [RR] 0·75 [95% CI 0·58–0·97]; p=0·029). No significant reduction was observed thereafter, with 126 deaths versus 255 deaths occurring after more than 10 years of follow-up (RR 0·98 [0·79–1·22]; p=0·86).InterpretationYearly mammography before age 50 years, commencing at age 40 or 41 years, was associated with a relative reduction in breast cancer mortality, which was attenuated after 10 years, although the absolute reduction remained constant. Reducing the lower age limit for screening from 50 to 40 years could potentially reduce breast cancer mortality.FundingNational Institute for Health Research Health Technology Assessment programme.
Toward Better Understanding and Management of CAR-T Cell–Associated Toxicity
Authors: Andrea Schmidts, Marc Wehrli, Marcela V. Maus
Journal: Annual Review of Medicine (2020)

Adoptive transfer of T cells modified with chimeric antigen receptors (CAR-T cells) has changed the therapeutic landscape of hematological malignancies, particularly for acute lymphoblastic leukemia and large B cell lymphoma, where two different CAR-T products are now considered standard of care. Furthermore, intense research efforts are under way to expand the clinical application of CAR-T cell therapy for the benefit of patients suffering from other types of cancers. Nevertheless, CAR-T cell treatment is associated with toxicities such as cytokine release syndrome, which can range in severity from mild flu-like symptoms to life-threatening vasodilatory shock, and a neurological syndrome termed ICANS (immune effector cell-associated neurotoxicity syndrome), which can also range in severity from a temporary cognitive deficit lasting only a few hours to lethal cerebral edema. In this review, we provide an in-depth discussion of different types of CAR-T cell-associated toxicities, including an overview of clinical presentation and grading, pathophysiology, and treatment options. We also address future perspectives and opportunities, with a special focus on hematological malignancies.
Prediction of immune checkpoint inhibition with immune oncology-related gene expression in gastrointestinal cancer using a machine learning classifier
Authors: Zhihao Lu, Huan Chen, Xi Jiao, Wei Zhou, Wenbo Han, Shuang Li, Chang Liu, Jifang Gong, Jian Li, Xiaotian Zhang, Xicheng Wang, Zhi Peng, Changsong Qi, Zhenghang Wang, Yanyan Li, Jie Li, Yan Li, Malcolm Brock, Henghui Zhang, Lin Shen
Journal: Journal for ImmunoTherapy of Cancer (2020)

Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of gastrointestinal cancer. However, biomarkers correlated with the efficacy of ICIs in gastrointestinal cancer are still lacking. In this study, we performed 395-plex immune oncology (IO)-related gene target sequencing in tumor samples from 96 patients with metastatic gastrointestinal cancer patients treated with ICIs, and a linear support vector machine learning strategy was applied to construct a predictive model. ResultsAll 96 patients were randomly assigned into the discovery (n=72) and validation (n=24) cohorts. A 24-gene RNA signature (termed the IO-score) was constructed from 395 immune-related gene expression profiling using a machine learning strategy to identify patients who might benefit from ICIs. The durable clinical benefit rate was higher in patients with a high IO-score than in patients with a low IO-score (discovery cohort: 92.0% vs 4.3%, p<0.001; validation cohort: 85.7% vs 17.6%, p=0.004). The IO-score may exhibit a higher predictive value in the discovery (area under the receiver operating characteristic curve (AUC)=0.97)) and validation (AUC=0.74) cohorts compared with the programmed death ligand 1 positivity (AUC=0.52), tumor mutational burden (AUC=0.69) and microsatellite instability status (AUC=0.59) in the combined cohort. Moreover, patients with a high IO-score also exhibited a prolonged overall survival compared with patients with a low IO-score (discovery cohort: HR, 0.29; 95% CI 0.15 to 0.56; p=0.003; validation cohort: HR, 0.32; 95% CI 0.10 to 1.05; p=0.04). Taken together, our results indicated the potential of IO-score as a biomarker for immunotherapy in patients with gastrointestinal cancers.
Response by Amin et al to Letters Regarding Article, “The Evolving Landscape of Impella Use in the United States Among Patients Undergoing Percutaneous Coronary Intervention With Mechanical Circulatory Support”
Authors: Amit P. Amin, Sunil V. Rao, Richard G. Bach, Jeptha P. Curtis, Nihar Desai, Christian McNeely, Firas Al-Badarin, John A. House, Hemant Kulkarni, Frederick A. Masoudi, John A. Spertus
Journal: Circulation (2020)
EFFECT OF TUMOR TREATING FIELDS (TTFIELDS) ON HEALTH-RELATED QUALITY OF LIFE (HRQoL) IN NEWLY DIAGNOSED GLIOBLASTOMA. RESULTS OF THE EF-14 RANDOMIZED PHASE III TRIAL
Authors: M.J.B. Taphoorn, L. Dirven, S. Taillibert, J. Honnorat, T. Chen, J. Sroubek, S.H. Paek, J.B. Escuder, J.C. Easaw, C.A. David, C.Y. Kim, R.D. Desai, Y. Kew, A. Olivi, G.A. Nicholas, G. Lavy-Shahaf, E.D. Kirson, Z. Ram, R. Stupp
Journal: Neuro-Oncology (2017)
Combined analysis of transcriptomic and genetic data for the identification of loci involved in glucocorticosteroid response in asthma
Authors: Natalia Hernandez‐Pacheco, Mario Gorenjak, Staša Jurgec, Almudena Corrales, Andrea Jorgensen, Leila Karimi, Susanne J. Vijverberg, Vojko Berce, Maximilian Schieck, Marialbert Acosta‐Herrera, Martin Kerick, Lesly‐Anne Samedy‐Bates, Roger Tavendale, Jesús Villar, Somnath Mukhopadhyay, Munir Pirmohamed, Katia M. C. Verhamme, Michael Kabesch, Daniel B. Hawcutt, Steve Turner, Colin N. Palmer, Esteban G. Burchard, Anke H. Maitland‐van der Zee, Carlos Flores, Uroš Potočnik, Maria Pino‐Yanes
Journal: Allergy (2020)

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New Caledonian crows afford invaluable comparative insights into human cumulative technological culture
Authors: Christian Rutz, Gavin R. Hunt
Journal: Behavioral and Brain Sciences (2020)

Abstract The New Caledonian crow may be the only non-primate species exhibiting cumulative technological culture. Its foraging tools show clear signs of diversification and progressive refinement, and it seems likely that at least some tool-related information is passed across generations via social learning. Here, we explain how these remarkable birds can help us uncover the basic biological processes driving technological progress.
Strain-level epidemiology of microbial communities and the human microbiome
Authors: Yan Yan, Long H. Nguyen, Eric A. Franzosa, Curtis Huttenhower
Journal: Genome Medicine (2020)

Abstract The biological importance and varied metabolic capabilities of specific microbial strains have long been established in the scientific community. Strains have, in the past, been largely defined and characterized based on microbial isolates. However, the emergence of new technologies and techniques has enabled assessments of their ecology and phenotypes within microbial communities and the human microbiome. While it is now more obvious how pathogenic strain variants are detrimental to human health, the consequences of subtle genetic variation in the microbiome have only recently been exposed. Here, we review the operational definitions of strains (e.g., genetic and structural variants) as they can now be identified from microbial communities using different high-throughput, often culture-independent techniques. We summarize the distribution and diversity of strains across the human body and their emerging links to health maintenance, disease risk and progression, and biochemical responses to perturbations, such as diet or drugs. We list methods for identifying, quantifying, and tracking strains, utilizing high-throughput sequencing along with other molecular and “culturomics” technologies. Finally, we discuss implications of population studies in bridging experimental gaps and leading to a better understanding of the health effects of strains in the human microbiome.
Early epitope-specific IgE antibodies are predictive of childhood peanut allergy
Authors: Maria Suprun, Scott H. Sicherer, Robert A. Wood, Stacie M. Jones, Donald Y.M. Leung, Alice K. Henning, Peter Dawson, A. Wesley Burks, Robert Lindblad, Robert Getts, Mayte Suárez-Fariñas, Hugh A. Sampson
Journal: Journal of Allergy and Clinical Immunology (2020)
Genetic Variants Associated With Increased Plasma Levels of Triglycerides, via Effects on the Lipoprotein Lipase Pathway, Increase Risk of Acute Pancreatitis
Authors: Signe E.J. Hansen, Christian M. Madsen, Anette Varbo, Anne Tybjærg-Hansen, Børge G. Nordestgaard
Journal: Clinical Gastroenterology and Hepatology (2020)
An Inactivated Virus Candidate Vaccine to Prevent COVID-19
Authors: Mark J. Mulligan
Journal: JAMA (2020)

Shengli Xia, BS; Kai Duan, PhD; Yuntao Zhang, PhD; Dongyang Zhao, BS; Huajun Zhang, PhD; Zhiqiang Xie, MD; Xinguo Li, MD; Cheng Peng, MD; Yanbo Zhang, MD; Wei Zhang, MD; Yunkai Yang, MD; Wei Chen, MSc; Xiaoxiao Gao, PhD; Wangyang You, MD; Xuewei Wang, MD; Zejun Wang, PhD; Zhengli Shi, PhD; Yanxia Wang, BS; Xuqin Yang, MD; Lianghao Zhang, MSc; Lili Huang, BS; Qian Wang, MD; Jia Lu, PhD; Yongli Yang, PhD; Jing Guo, PhD; Wei Zhou, PhD; Xin Wan, MD; Cong Wu, MD; Wenhui Wang, MD; Shihe Huang, PhD; Jianhui Du, MD; Ziyan Meng, MD; An Pan, PhD; Zhiming Yuan, PhD; Shuo Shen, PhD; Wanshen Guo, BS; Xiaoming Yang, MD
National Pathology Exchange provides robust infrastructure to covid-19 response
Authors: Susan Clamp, Rose Crees
Journal: BMJ (2020)

The effect of gentamicin exposure was investigated in LLC-PK1 cells in culture. Gentamicin (0.5-2.0 mM) was added to the medium of cells which had been grown to confluency in the absence of antibiotics and antimycotics. Exposure to gentamicin (1-4 days) did not effect total cellular protein or DNA levels, total cell number or the release of various marker enzymes to the medium. ATP levels in gentamicin-treated cells did not differ from control cells; however, medium from the gentamicin-treated cells contained significantly lower lactic acid levels. Morphological examination by electron microscopy revealed gentamicin-elicited myeloid body formation. Furthermore, total phospholipid level was elevated markedly in gentamicin-treated cells. Analysis of specific phospholipid classes showed only phosphatidylcholine, phosphatidylinositol and polyphosphoinositide phospholipid levels increased in a time-dependent manner. Phosphatidylinositol showed the highest percentage of increase. Raising the normal medium calcium concentration (0.2 mg/ml) 1.5-, 2.0- or 3.0-fold did not alter gentamicin-induced elevation in cellular phosphatidylinositol and phosphatidylcholine. Gentamicin exposure also resulted in a concentration-dependent increase in the turnover of LLC-PK1 cell-free fatty acids, monoglyceride, diglyceride and nonesterified cholesterol and a decrease in triglyceride turnover. Calcium transport into and through the cell monolayer was inhibited markedly by gentamicin despite the fact that 45Ca++ binding to gentamicin-treated cells was greater. These results demonstrate that manifestations of gentamicin toxicity in LLC-PK1 cells parallel those reported in the whole animal thus making the LLC-PK1 cell in culture a valid system for elucidating the mechanism of gentamicin-elicited alterations in renal epithelium.
Fontan-Associated Liver Disease
Authors: Juliet Emamaullee, Ali N. Zaidi, Thomas Schiano, Jeffrey Kahn, Pamela L. Valentino, Ryan E. Hofer, Timucin Taner, Joyce W. Wald, Kim M. Olthoff, John Bucuvalas, Ryan Fischer
Journal: Circulation (2020)

Surgical innovation and multidisciplinary management have allowed children born with univentricular physiology congenital heart disease to survive into adulthood. An estimated global population of 70 000 patients have undergone the Fontan procedure and are alive today, most of whom are &lt;25 years of age. Several unexpected consequences of the Fontan circulation include Fontan-associated liver disease. Surveillance biopsies have demonstrated that virtually 100% of these patients develop clinically silent fibrosis by adolescence. As they mature, there are increasing reports of combined heart-liver transplantation resulting from advanced liver disease, including bridging fibrosis, cirrhosis, and hepatocellular carcinoma, in this population. In the absence of a transplantation option, these young patients face a poor quality of life and overall survival. Acknowledging that there are no consensus guidelines for diagnosing and monitoring Fontan-associated liver disease or when to consider heart transplantation versus combined heart-liver transplantation in these patients, a multidisciplinary working group reviewed the literature surrounding Fontan-associated liver disease, with a specific focus on considerations for transplantation.
Recommendations for Testing and Treating Outpatient Cancer Patients in the Era of COVID-19
Authors: Diane Reidy-Lagunes, Leonard Saltz, , Michael Postow, , Michael Scordo, Alison Moskowitz, William Tew, Dmitriy Zamarin, Gil Redelman-Sidi
Journal: JNCI Journal of the National Cancer Institute (2020)

The clinical spectrum of coronavirus disease 2019 (COVID-19) is still not fully understood. Cancer patients are uniquely vulnerable to COVID-19, and many have been or will be infected. Although an unfortunate minority will die from the infection, most will recover. This poses a challenge in which clinicians must weigh the benefits of initiation or resumption of antineoplastic therapy against the risks that antineoplastic treatment may worsen outcomes related to COVID-19 infection. A recent study of 423 patients at our institution found that patients in active cancer treatment who develop COVID-19 infection did not fare any worse than other hospitalized patients, yet guidance as to who requires testing prior to antineoplastic therapy and when to resume therapy post-COVID-19 diagnosis remains unknown. Our institution, therefore, commissioned a task force to help create guidelines for treating oncologists using available published literature. The task force focused on the ambulatory care testing guidelines only, because all inpatients receiving antineoplastic therapy are tested for COVID-19 prior to hospital admission. The guidelines focus solely on the safety and well-being of the individual patient undergoing antineoplastic therapy and are not designed to address infection control issues.
Combined Nanoparticle Delivery of PARP and DNA-PK Inhibition for Multiple Myeloma
Authors: Pritesh Patel, Santosh Misra, Natalie S. Rodriguez, Gururaja Vulugundam, Annie L. Oh, Vitalyi Senyuk, Nadim Mahmud, Damiano Rondelli, Dipanjan Pan
Journal: Blood (2017)
Immune Checkpoint Inhibitor Cardiotoxicity: Understanding Basic Mechanisms and Clinical Characteristics and Finding a Cure
Authors: Sarah Waliany, Daniel Lee, Ronald M. Witteles, Joel W. Neal, Patricia Nguyen, Mark M. Davis, Joe-Elie Salem, Sean M. Wu, Javid J. Moslehi, Han Zhu
Journal: The Annual Review of Pharmacology and Toxicology (2020)

Immune checkpoint inhibitors (ICIs) attenuate mechanisms of self-tolerance in the immune system, enabling T cell responses to cancerous tissues and revolutionizing care for cancer patients. However, by loweringbarriers against self-reactivity, ICIs often result in varying degrees of autoimmunity. Cardiovascular complications, particularly myocarditis but also arrhythmias, pericarditis, and vasculitis, have emerged as significant complications associated with ICIs. In this review, we examine the clinical aspects and basic science principles that underlie ICI-associated myocarditis and other cardiovascular toxicities. In addition, we discuss current therapeutic approaches. We believe a better mechanistic understanding of ICI-associated toxicities can lead to improved patient outcomes by reducing treatment-related morbidity.
Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020
Authors: Erik Alm, Eeva K Broberg, Thomas Connor, Emma B Hodcroft, Andrey B Komissarov, Sebastian Maurer-Stroh, Angeliki Melidou, Richard A Neher, Áine O’Toole, Dmitriy Pereyaslov
Journal: Eurosurveillance (2020)

We show the distribution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic clades over time and between countries and outline potential genomic surveillance objectives. We applied three genomic nomenclature systems to all sequence data from the World Health Organization European Region available until 10 July 2020. We highlight the importance of real-time sequencing and data dissemination in a pandemic situation, compare the nomenclatures and lay a foundation for future European genomic surveillance of SARS-CoV-2.
Von Willebrand Factor Levels in Polycythemia Vera Are Not Reduced and Can be Predicted By Erythrocyte Counts
Authors: Paola Ranalli, Monica Sacco, Alfredo Dragani, Mauro Di Ianni, Paolo Di Bartolomeo, Stefano Lancellotti, Giovanna Petrucci, Bianca Rocca, Raimondo De Cristofaro
Journal: Blood (2017)
Clinical activity of pembrolizumab in metastatic prostate cancer with microsatellite instability high (MSI-H) detected by circulating tumor DNA
Authors: Pedro Barata, Neeraj Agarwal, Roberto Nussenzveig, Benjamin Gerendash, Ellen Jaeger, Whitley Hatton, Elisa Ledet, Brian Lewis, Jodi Layton, Hani Babiker, Alan Bryce, Rohan Garje, Cy Stein, Lesli Kiedrowski, Philip Saylor, Oliver Sartor
Journal: Journal for ImmunoTherapy of Cancer (2020)

To report a multi-institutional case series of patients with advanced microsatellite instability high (MSI-H) prostate adenocarcinoma identified with clinical cell-free DNA (cfDNA) next-generation sequencing (NGS) testing and treated with immune checkpoint inhibitors. Retrospective analysis of patients with metastatic castration-resistant prostate cancer (mCRPC) and MSI-H tumor detected by a commercially available cfDNA NGS assay Guardant360 (G360, Guardant Health) at eight different Academic Institutions in the USA, from September 2018 to April 2020. From a total of 14 MSI-H metastatic prostate cancer patients at participating centers, nine patients with mCRPC with 56% bone, 33% nodal, 11% liver and 11% soft-tissue metastases and a median PSA of 29.3 ng/dL, were treated with pembrolizumab after 2 lines of therapy for CRPC. The estimated median time on pembrolizumab was 9.9 (95% CI 1.0 to 18.8) months. Four patients (44%) achieved PSA50 after a median of 4 (3–12) weeks after treatment initiation including three patients with &gt;99% PSA decline. Among the patients evaluable for radiographic response (n=5), the response rate was 60% with one complete response and two partial responses. Best response was observed after a median of 3.3 (1.4–7.6) months. At time of cut-off, four patients were still on pembrolizumab while four patients discontinued therapy due to progressive disease and one due to COVID-19 infection. Half of the patients with PSA50 had both MSI-H and pathogenic alterations in BRCA1 and BRCA2 in their G360 assays. The use of liquid biopsy to identify metastatic prostate cancer patients with MSI-H is feasible in clinical practice and may overcome some of the obstacles associated with prostate cancer tumor tissue testing. The robust activity of pembrolizumab in selected patients supports the generalized testing for MSI-H.
Caught in a Flare
Authors: Alisa A. Mueller, Anand Vaidya, Laura L. Tarter, Joshua P. Klein, Ebrahim Barkoudah
Journal: New England Journal of Medicine (2020)

A 24-year-old woman presented to her primary care doctor with a 1-month history of worsening fatigue, diffuse arthralgias, a rash on her face and arms, and swelling in her legs. She also reported frequent urination. . . .