tbuckley/cabot-search huggingface dataset:
Effect of tailoring anticoagulant treatment duration by applying a recurrence risk prediction model in patients with venous thromboembolism compared to usual care: A randomized controlled trial
Authors: Geert-Jan Geersing, Janneke M. T. Hendriksen, Nicolaas P. A. Zuithoff, Kit C. Roes, Ruud Oudega, Toshihiko Takada, Roger E. G. Schutgens, Karel G. M. Moons
Journal: PLoS Medicine (2020)

Background Patients with unprovoked (i.e., without the presence of apparent transient risk factors such as recent surgery) venous thromboembolism (VTE) are at risk of recurrence if anticoagulants are stopped after 3–6 months, yet their risk remains heterogeneous. Thus, prolonging anticoagulant treatment should be considered in high-risk patients, whereas stopping is likely preferred in those with a low predicted risk. The Vienna Prediction Model (VPM) could aid clinicians in estimating this risk, yet its clinical effects and external validity are currently unknown. The aim of this study was to investigate the clinical impact of this model on reducing recurrence risk in patients with unprovoked VTE, compared to usual care. Methods and findings In a randomized controlled trial, the decision to prolong or stop anticoagulant treatment was guided by predicted recurrence risk using the VPM (n = 441), which was compared with usual care (n = 442). Patients with unprovoked VTE were recruited from local thrombosis services in the Netherlands (in Utrecht, Harderwijk, Ede, Amersfoort, Zwolle, Hilversum, Rotterdam, Deventer, and Enschede) between 22 July 2011 and 30 November 2015, with 24-month follow-up complete for all patients by early 2018. The primary outcome was recurrent VTE during 24 months of follow-up. Secondary outcomes included major bleeding and clinically relevant non-major (CRNM) bleeding. In the total study population of 883 patients, mean age was 55 years, and 507 (57.4%) were men. A total of 96 recurrent VTE events (10.9%) were observed, 46 in the intervention arm and 50 in the control arm (risk ratio 0.92, 95% CI 0.63–1.35, p = 0.67). Major bleeding occurred in 4 patients, 2 in each treatment arm, whereas CRNM bleeding occurred in 20 patients (12 in intervention arm versus 8 in control arm). The VPM showed good discriminative power (c-statistic 0.76, 95% CI 0.69–0.83) and moderate to good calibration, notably at the lower spectrum of predicted risk. For instance, in 284 patients with a predicted risk of >2% to 4%, the observed rate of recurrence was 2.5% (95% CI 0.7% to 4.3%). The main limitation of this study is that it did not enroll the preplanned number of 750 patients in each study arm due to declining recruitment rate. Conclusions Our results show that application of the VPM in all patients with unprovoked VTE is unlikely to reduce overall recurrence risk. Yet, in those with a low predicted risk of recurrence, the observed rate was also low, suggesting that it might be safe to stop anticoagulant treatment in these patients. Trial registration Netherlands Trial Register NTR2680
YAP Enhances Tumor Cell Dissemination by Promoting Intravascular Motility and Reentry into Systemic Circulation
Authors: David C. Benjamin, Joon Ho Kang, Bashar Hamza, Emily M. King, John M. Lamar, Scott R. Manalis, Richard O. Hynes
Journal: Cancer Research (2020)

Abstract The oncogene YAP has been shown previously to promote tumor growth and metastasis. However, how YAP influences the behavior of tumor cells traveling within the circulatory system has not been as well explored. Given that rate-limiting steps of metastasis are known to occur while tumor cells enter, travel through, or exit circulation, we sought to study how YAP influences tumor cell behavior within the circulatory system. Intravital imaging in live zebrafish embryos revealed that YAP influenced the distribution of tumor cells within the animal following intravenous injection. Control cells became lodged in the first capillary bed encountered in the tail, whereas cells overexpressing constitutively active YAP were able to travel through this capillary plexus, reenter systemic circulation, and seed in the brain. YAP controlled transit through these capillaries by promoting active migration within the vasculature. These results were corroborated in a mouse model following intravenous injection, where active YAP increased the number of circulating tumor cells over time. Our results suggest a possible mechanism whereby tumor cells can spread to organs beyond the first capillary bed downstream from the primary tumor. These results also show that a specific gene can affect the distribution of tumor cells within an animal, thereby influencing the global pattern of metastasis in that animal. Significance: These findings demonstrate that YAP endows tumor cells with the ability to move through capillaries, allowing them to return to and persist in circulation, thereby increasing their metastatic spread. See related commentary by Davidson, p. 3797
The EAT/mcl-1 gene, an inhibitor of apoptosis, is up-regulated in the early stage of acute myocardial infarction
Authors: Matsushita K, Iwanaga S, Oda T, Kimura K, Okita H, Shimada M, Tanaka M, Umezawa A, Ogawa S, Hata J
Journal: Circulation (1999)
Dampened VEPH1 activates mTORC1 signaling by weakening the TSC1/TSC2 association in hepatocellular carcinoma
Authors: Pingping Dong, Xiaoxiao Wang, Longzi Liu, Wenqing Tang, Lijie Ma, Wenjiao Zeng, Shaoyang Sun, Li Zhang, Ningping Zhang, Xizhong Shen, Harry L.A. Janssen, Ling Dong, Si Zhang, She Chen
Journal: Journal of Hepatology (2020)
Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults
Authors: Katherine Mackey, Valerie J. King, Susan Gurley, Michael Kiefer, Erik Liederbauer, Kathryn Vela, Payten Sonnen, Devan Kansagara
Journal: Annals of Internal Medicine (2020)

An update is available for this article.
Metabolic engineering against the arginine microenvironment enhances CAR-T cell proliferation and therapeutic activity
Authors: Livingstone Fultang, Sarah Booth, Orli Yogev, Barbara Martins da Costa, Vanessa Tubb, Silvia Panetti, Victoria Stavrou, Ugo Scarpa, Andris Jankevics, Gavin Lloyd, Andrew Southam, Steven P. Lee, Warwick B. Dunn, Louis Chesler, Francis Mussai, Carmela De Santo
Journal: Blood (2020)
DNA Repair Gene Mutations as Predictors of Immune Checkpoint Inhibitor Response beyond Tumor Mutation Burden
Authors: David Hsiehchen, Antony Hsieh, Robert M. Samstein, Tianshi Lu, Muhammad S. Beg, David E. Gerber, Tao Wang, Luc G.T. Morris, Hao Zhu
Journal: Cell Reports Medicine (2020)

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, but prediction of their benefit is challenging. Neoantigens generated through impaired non-mismatch DNA repair may result in greater ICI activity. By analyzing 1,661 ICI-treated patients, we show that deletions and mutations in nucleotide excision repair (NER) and homologous repair (HR) pathways are predictors of ICI benefit independent of tumor mutation burden and tumor type. NER and HR mutations are also associated with objective response rates to ICIs in esophagogastric and non-small-cell lung cancers. In a cohort of 40,181 unique patients, NER and HR mutations are present in 3.4% and 13.9% of cancers, respectively. These results indicate that NER and HR gene mutations occur in a subpopulation of cancer patients and may aid patient selection for ICI therapy. Assessing NER and HR mutations in the context of other biomarkers may yield powerful predictors of ICI activity across different cancer types.
Tom Arie: pioneer in the development of psychiatric services for elderly people
Authors: Rebecca Wallersteiner
Journal: BMJ (2020)

Photo credit: Laura Ingrams

Tom Arie was born Tomas Arje in Prague, to parents Otto, a lawyer, and Hedy (nee Glaser), a modern language teacher. He recalled a happy early childhood until the Germans invaded Czechoslovakia. He vividly remembered attending the local school and visiting his paternal grandparents in Dobris, outside Prague, where his grandfather was the rabbi. Less happily, he also remembered the destruction of the synagogue and the discrimination his mother faced when obtaining an exit visa to leave Czechoslovakia, and his beloved German nanny having to leave the family after the Nuremberg race laws. Aided by a refugee organisation, the Arje family fled Prague on 17 August 1939, on the penultimate train out of the city.

Although he spoke little English, Arie quickly settled into an English primary school. He was evacuated during the blitz and only allowed back when his parents found accommodation with an air raid shelter. The man who took his family in, George House, later became a Labour MP for St Pancras. Otto Arie trained as a welder but found work with the BBC monitoring service. Arie attended Reading School and was always grateful for the excellent education he received there.

He read classics at Oxford before he switched to medicine. He was interested in the sociology of medicine and finally specialised in psychiatry, becoming an expert in “old age psychiatry.” He underwent further training in psychiatry at the Maudsley Hospital and in social medicine at the Medical Research …
Genomic analyses implicate noncoding de novo variants in congenital heart disease
Authors: Felix Richter, Sarah U. Morton, Seong Won Kim, Alexander Kitaygorodsky, Lauren K. Wasson, Kathleen M. Chen, Jian Zhou, Hongjian Qi, Nihir Patel, Steven R. DePalma, Michael Parfenov, Jason Homsy, Joshua M. Gorham, Kathryn B. Manheimer, Matthew Velinder, Andrew Farrell, Gabor Marth, Eric E. Schadt, Jonathan R. Kaltman, Jane W. Newburger, Alessandro Giardini, Elizabeth Goldmuntz, Martina Brueckner, Richard Kim, George A. Porter, Daniel Bernstein, Wendy K. Chung, Deepak Srivastava, Martin Tristani-Firouzi, Olga G. Troyanskaya, Diane E. Dickel, Yufeng Shen, Jonathan G. Seidman, Christine E. Seidman, Bruce D. Gelb
Journal: Nature Genetics (2020)
A large scale waterborne Campylobacteriosis outbreak, Havelock North, New Zealand
Authors: Brent J. Gilpin, Tiffany Walker, Shevaun Paine, Jill Sherwood, Graham Mackereth, Tim Wood, Tammy Hambling, Chris Hewison, Angela Brounts, Maurice Wilson, Paula Scholes, Beth Robson, Susan Lin, Angela Cornelius, Lucia Rivas, David T.S. Hayman, Nigel P. French, Ji Zhang, David A. Wilkinson, Anne C. Midwinter, Patrick J. Biggs, Anita Jagroop, Rachel Eyre, Michael G. Baker, Nicholas Jones
Journal: Journal of Infection (2020)
Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study
Authors: Aravinthan Varatharaj, Naomi Thomas, Mark A Ellul, Nicholas W S Davies, Thomas A Pollak, Elizabeth L Tenorio, Mustafa Sultan, Ava Easton, Gerome Breen, Michael Zandi, Jonathan P Coles, Hadi Manji, Rustam Al-Shahi Salman, David K Menon, Timothy R Nicholson, Laura A Benjamin, Alan Carson, Craig Smith, Martin R Turner, Tom Solomon, Rachel Kneen, Sarah L Pett, Ian Galea, Rhys H Thomas, Benedict D Michael, Claire Allen, Neil Archibald, James Arkell, Peter Arthur-Farraj, Mark Baker, Harriet Ball, Verity Bradley-Barker, Zoe Brown, Stefania Bruno, Lois Carey, Christopher Carswell, Annie Chakrabarti, James Choulerton, Mazen Daher, Ruth Davies, Rafael Di Marco Barros, Sofia Dima, Rachel Dunley, Dipankar Dutta, Richard Ellis, Alex Everitt, Joseph Fady, Patricia Fearon, Leonora Fisniku, Ivie Gbinigie, Alan Gemski, Emma Gillies, Effrossyni Gkrania-Klotsas, Julie Grigg, Hisham Hamdalla, Jack Hubbett, Neil Hunter, Anne-Catherine Huys, Ihmoda Ihmoda, Sissi Ispoglou, Ashwani Jha, Ramzi Joussi, Dheeraj Kalladka, Hind Khalifeh, Sander Kooij, Guru Kumar, Sandar Kyaw, Lucia Li, Edward Littleton, Malcolm Macleod, Mary Joan Macleod, Barbara Madigan, Vikram Mahadasa, Manonmani Manoharan, Richard Marigold, Isaac Marks, Paul Matthews, Michael Mccormick, Caroline Mcinnes, Antonio Metastasio, Philip Milburn-McNulty, Clinton Mitchell, Duncan Mitchell, Clare Morgans, Huw Morris, Jasper Morrow, Ahmed Mubarak Mohamed, Paula Mulvenna, Louis Murphy, Robert Namushi, Edward Newman, Wendy Phillips, Ashwin Pinto, David Ashley Price, Harald Proschel, Terry Quinn, Deborah Ramsey, Christine Roffe, Amy Ross Russell, Neshika Samarasekera, Stephen Sawcer, Walee Sayed, Lakshmanan Sekaran, Jordi Serra-Mestres, Victoria Snowdon, Gayle Strike, James Sun, Christina Tang, Mark Vrana, Ryckie Wade, Chris Wharton, Lou Wiblin, Iryna Boubriak, Katie Herman, Gordon Plant
Journal: The Lancet Psychiatry (2020)
Hematopoietic stem cells acquire survival advantage by loss of RUNX1 methylation identified in familial leukemia
Authors: Takayoshi Matsumura, Ayako Nakamura-Ishizu, Siva Sai Naga Anurag Muddineni, Darren Qiancheng Tan, Chelsia Qiuxia Wang, Kenji Tokunaga, Roberto Tirado-Magallanes, Stephanie Sian, Touati Benoukraf, Tsukasa Okuda, Norio Asou, Masao Matsuoka, Motomi Osato, Toshio Suda
Journal: Blood (2020)
Randomized Phase II Trial of Carboplatin–Paclitaxel Compared with Carboplatin–Paclitaxel–Trastuzumab in Advanced (Stage III–IV) or Recurrent Uterine Serous Carcinomas that Overexpress Her2/Neu (NCT01367002): Updated Overall Survival Analysis
Authors: Amanda N. Fader, Dana M. Roque, Eric Siegel, Natalia Buza, Pei Hui, Osama Abdelghany, Setsuko Chambers, Angeles Alvarez Secord, Laura Havrilesky, David M. O'Malley, Floor J. Backes, Nicole Nevadunsky, Babak Edraki, Dirk Pikaart, William Lowery, Karim ElSahwi, Paul Celano, Stefania Bellone, Masoud Azodi, Babak Litkouhi, Elena Ratner, Dan-Arin Silasi, Peter E. Schwartz, Alessandro D. Santin
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Uterine-serous-carcinoma (USC) is an aggressive variant of endometrial cancer. On the basis of preliminary results of a multicenter, randomized phase II trial, trastuzumab (T), a humanized-mAb targeting Her2/Neu, in combination with carboplatin/paclitaxel (C/P), is recognized as an alternative in treating advanced/recurrent HER2/Neu-positive USC. We report the updated survival analysis of NCT01367002. Patients and Methods: Eligible patients had stage III to IV or recurrent disease. Participants were randomized 1:1 to receive C/P for six cycles ± T followed by maintenance T until progression or toxicity. Progression-free survival (PFS) was the primary endpoint; overall survival (OS) and toxicity were secondary endpoints. Results: Sixty-one patients were randomized. After a median-follow-up of 25.9 months, 43 progressions and 38 deaths occurred among 58 evaluable patients. Updated median-PFS continued to favor the T-arm, with medians of 8.0 months versus 12.9 months in the control and T-arms (HR = 0.46; 90% CI, 0.28–0.76; P = 0.005). Median-PFS was 9.3 months versus 17.7 months among 41 patients with stage III to IV disease undergoing primary treatment (HR = 0.44; 90% CI, 0.23–0.83; P = 0.015), and 7.0 months versus 9.2 months among 17 patients with recurrent disease (HR = 0.12; 90% CI, 0.03–0.48; P = 0.004). OS was higher in the T compared with the control arm, with medians of 29.6 months versus 24.4 months (HR = 0.58; 90% CI, 0.34–0.99; P = 0.046). The benefit was most notable in those with stage III to IV disease, with survival median not reached in the T-arm versus 24.4 months in the control arm (HR = 0.49; 90% CI, 0.25–0.97; P = 0.041). Toxicity was not different between arms. Conclusions: Addition of T to C/P increased PFS and OS in women with advanced/recurrent HER2/Neu-positive USC, with the greatest benefit seen for the treatment of stage III to IV disease.
Repurposing anthelmintic agents to eradicate resistant leukemia
Authors: Caterina Mezzatesta, Liridon Abduli, Anna Guinot, Cornelia Eckert, Denis Schewe, Marketa Zaliova, Luciana Vinti, Blerim Marovca, Yi-Chien Tsai, Silvia Jenni, Julia Aguade-Gorgorio, Arend von Stackelberg, Martin Schrappe, Franco Locatelli, Martin Stanulla, Gunnar Cario, Jean-Pierre Bourquin, Beat C. Bornhauser
Journal: Blood Cancer Journal (2020)

Abstract Despite rapid progress in genomic profiling in acute lymphoblastic leukemia (ALL), identification of actionable targets and prediction of response to drugs remains challenging. To identify specific vulnerabilities in ALL, we performed a drug screen using primary human ALL samples cultured in a model of the bone marrow microenvironment combined with high content image analysis. Among the 2487 FDA-approved compounds tested, anthelmintic agents of the class of macrocyclic lactones exhibited potent anti-leukemia activity, similar to the already known anti-leukemia agents currently used in induction chemotherapy. Ex vivo validation in 55 primary ALL samples of both precursor B cell and T-ALL including refractory relapse cases confirmed strong anti-leukemia activity with IC 50 values in the low micromolar range. Anthelmintic agents increased intracellular chloride levels in primary leukemia cells, inducing mitochondrial outer membrane depolarization and cell death. Supporting the notion that simultaneously targeting cell death machineries at different angles may enhance the cell death response, combination of anthelmintic agents with the BCL-2 antagonist navitoclax or with the chemotherapeutic agent dexamethasone showed synergistic activity in primary ALL. These data reveal anti-leukemia activity of anthelmintic agents and support exploiting drug repurposing strategies to identify so far unrecognized anti-cancer agents with potential to eradicate even refractory leukemia.
Association of Statin Use With Disability-Free Survival and Cardiovascular Disease Among Healthy Older Adults
Authors: Zhen Zhou, Richard Ofori-Asenso, Andrea J. Curtis, Monique Breslin, Rory Wolfe, John J. McNeil, Anne M. Murray, Michael E. Ernst, Christopher M. Reid, Jessica E. Lockery, Robyn L. Woods, Andrew M. Tonkin, Mark R. Nelson
Journal: Journal of the American College of Cardiology (2020)
Abstract 14424: Quantifying Mitochondrial Injury With Varying Duration of Ischemia: Implications for Donation After Circulatory Death Organ Transplantation
Authors: Qun Chen, Oluwatoyin Akande, Stefano Toldo, Edward J Lesnefsky, Mohammed Quader
Journal: Circulation (2019)

Introduction: Heart transplantation, a lifesaving option for patients with advanced heart failure is limited do to available donor hearts, which at present are procured from Brain Death Donors (DBD...
Mesenteric Volvulus from Jejunal Diverticulosis
Authors: Wan-Yu Hung, Cheng-Yen Huang
Journal: New England Journal of Medicine (2020)

A 75-year-old man presented with abdominal pain and vomiting, and imaging showed a “whirl sign” suggestive of midgut volvulus. Jejunal diverticula were identified during surgery.
Centralization of High-risk Surgery in the US
Authors: Kyle H. Sheetz, Nader N. Massarweh
Journal: JAMA (2020)

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Health Effects of Asian Dust: A Systematic Review and Meta-Analysis
Authors: Masahiro Hashizume, Yoonhee Kim, Chris Fook Sheng Ng, Yeonseung Chung, Lina Madaniyazi, Michelle L. Bell, Yue Leon Guo, Haidong Kan, Yasushi Honda, Seung-Muk Yi, Ho Kim, Yuji Nishiwaki
Journal: Environmental Health Perspectives (2020)

BACKGROUND: Potential adverse health effects of Asian dust exposure have been reported, but systematic reviews and quantitative syntheses are lacking.OBJECTIVE: We reviewed epidemiologic studies that assessed the risk of mortality, hospital admissions, and symptoms/dysfunction associated with exposure to Asian dust.METHODS: We performed a systematic search of PubMed and Web of Science to identify studies that reported the association between Asian dust exposure and human health outcomes.We conducted separate meta-analyses using a random-effects model for mortality and hospital admissions for a specific health outcome and assessed pooled estimates for each lag when at least three studies were available for a specific lag.RESULTS: We identified 89 studies that met our inclusion criteria for the systematic review, and 21 studies were included in the meta-analysis.The pooled estimates (percentage changes) of mortality from circulatory and respiratory causes for Asian dust days vs. non-Asian dust days were 2.33% [95% confidence interval (CI): 0.76, 3.93] increase at lag 0 and 3.99% (95% CI: 0.08, 8.06) increase at lag 3, respectively.The increased risk for hospital admissions for respiratory disease, asthma, and pneumonia peaked at lag 3 by 8.85% (95% CI: 0.80, 17.55), 14.55% (95% CI: 6.74, 22.94), and 8.51% (95% CI: 2.89, 14.44), respectively.Seven of 12 studies reported reduced peak expiratory flow, and 16 of 21 studies reported increased respiratory symptoms associated with Asian dust exposure.There were substantial variations between the studies in definitions of Asian dust, study designs, model specifications, and confounder controls.DISCUSSION: We found evidence of increased mortality and hospital admissions for circulatory and respiratory events.However, the number of studies included in the meta-analysis was not large and further evidences are merited to strengthen our conclusions.Standardized protocols for epidemiological studies would facilitate interstudy comparisons.
Comparative Genomics Reveals Evolution of a Beak Morphology Locus in a High-Altitude Songbird
Authors: Yalin Cheng, Matthew J Miller, Dezhi Zhang, Gang Song, Chenxi Jia, Yanhua Qu, Fumin Lei
Journal: Molecular Biology and Evolution (2020)

The Ground Tit (Pseudopodoces humilis) has lived on the Qinghai-Tibet Plateau for ∼5.7 My and has the highest altitudinal distribution among all parids. This species has evolved an elongated beak in response to long-term selection imposed by ground-foraging and cavity-nesting habits, yet the genetic basis for beak elongation remains unknown. Here, we perform genome-wide analyses across 14 parid species and identify 25 highly divergent genomic regions that are significantly associated with beak length, finding seven candidate genes involved in bone morphogenesis and remolding. Neutrality tests indicate that a model allowing for a selective sweep in the highly conserved COL27A1 gene best explains variation in beak length. We also identify two nonsynonymous fixed mutations in the collagen domain that are predicted to be functionally deleterious yet may have facilitated beak elongation. Our study provides evidence of adaptive alleles in COL27A1 with major effects on beak elongation of Ps. humilis.