tbuckley/cabot-search huggingface dataset:
Efficacy and Toxicity Analysis of Capecitabine and Temozolomide in Neuroendocrine Neoplasms
Authors: Taymeyah Al-Toubah, Eleonora Pelle, Tiffany Valone, Mintallah Haider, Jonathan R. Strosberg
Journal: Journal of the National Comprehensive Cancer Network (2021)

The capecitabine/temozolomide (CAPTEM) regimen has significant activity in advanced neuroendocrine tumors (NETs). Questions exist regarding activity in pancreatic versus nonpancreatic NETs, risk of opportunistic infections, long-term myelotoxicity, and safety of prolonged treatment duration. Analysis of large patient cohorts is needed for the evaluation of rare toxicities and assessment of risk factors.We conducted a retrospective study of all patients with advanced NETs seen at Moffitt Cancer Center between January 2008 and June 2019 who received treatment with CAPTEM.A total of 462 patients were eligible. The objective radiographic response rate was 46%, and the disease control rate was 81%. Median progression-free survival (PFS) was 18 months (95% CI, 14.0-21.9 months) and median overall survival was 51 months (95% CI, 42.8-59.2 months): 62 months in well-differentiated NETs versus 14 months in poorly differentiated neuroendocrine carcinomas (P<.0001). Patients with primary pancreatic tumors had the highest partial response rates and longest median PFS. Incidences of grade 4 thrombocytopenia and neutropenia were 7% and 3%, respectively, and substantially higher in women than men (P=.02 and P=.004, respectively). Only 1 case (0.2%) of suspected Pneumocystis pneumonia (PCP) was observed in a patient receiving corticosteroids. Three patients developed myelodysplastic disease, all of whom had received prior peptide receptor radiotherapy (PRRT). There were no acute treatment-related deaths; 1 patient died 2 months after a thrombocytopenic bleed.The CAPTEM regimen is exceptionally safe. Efficacy is particularly robust in well-differentiated pancreatic NETs. Severe myelotoxicity is rare; the risk of grade 4 cytopenias is significantly increased in women, and therefore sex-based dosing should be considered. There were no cases of myelodysplastic syndromes, except among patients who had received PRRT, a known risk factor. The risk of PCP is negligible.
Pan-Sarbecovirus Neutralizing Antibodies in BNT162b2-Immunized SARS-CoV-1 Survivors
Authors: Chee-Wah Tan, Wan-Ni Chia, Barnaby E Young, Feng Zhu, Beng-Lee Lim, Wan-Rong Sia, Tun-Linn Thein, Mark I-C Chen, Yee-Sin Leo, David C Lye, Lin-Fa Wang
Journal: New England Journal of Medicine (2021)

SummaryEmerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern pose a challenge to the effectiveness of current vaccines. A vaccine that could prevent infection caused by known and future variants of concern as well as infection with pre-emergent sarbecoviruses (i.e., those with potential to cause disease in humans in the future) would be ideal. Here we provide data showing that potent cross-clade pan-sarbecovirus neutralizing antibodies are induced in survivors of severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) infection who have been immunized with the BNT162b2 messenger RNA (mRNA) vaccine. The antibodies are high-level and broad-spectrum, capable of neutralizing not only known variants of concern but also sarbecoviruses that have been identified in bats and pangolins and that have the potential to cause human infection. These findings show the feasibility of a pan-sarbecovirus vaccine strategy. (Funded by the Singapore National Research Foundation and National Medical Research Council.)Download a PDF of the Research Summary. Quick Take Protective Effects of Covid-19 Vaccines in SARS-CoV-1 Survivors 2m 24s
P-69 Intensive follow-up program and oncological outcomes of 278 biliary tract cancer patients after curative intent surgery: A single-center retrospective experience
Authors: A. Rizzo, G. Frega, A. Palloni, A. Piemontese, A. Di Federico, A. Ricci, R. Carloni, F. Fabbri, M. Novelli, S. Tavolari, M. Di Marco, M. Ravaioli, G. Brandi
Journal: Annals of Oncology (2021)
Population Health and Human Rights
Authors: Julio Frenk, Octavio Gómez-Dantés
Journal: New England Journal of Medicine (2021)

Interview with Dr. Octavio Gómez-Dantés on translating the concept of human rights into health benefits for populations. (08:54)Download The way a society protects and promotes human rights shapes public policies, determines the distribution of resources and access to services, and ultimately affects population health. Scholarship and action on human rights have been foundational to the public health field.
Covid-19: UK cases continue to rise amid warnings of impact of schools reopening
Authors: Gareth Iacobucci
Journal: BMJ (2021)

The numbers of covid cases, hospitalisations, and deaths are continuing to rise across the UK, the latest figures have shown. In England, 200 705 people tested positive for covid-19 in the week to 18 August, up 5% on the previous week and the highest figure since the week to 21 July, figures published by NHS Test and Trace on 26 August showed.1

In Scotland—where schools have restarted after the summer holidays—a record 5021 daily cases were recorded on 25 August.2 “Undoubtedly the gathering of people together in schools will have fuelled that to some extent, and you can see that in the proportion of younger people who are testing positive,” said John Swinney, Scotland’s deputy first …
Evolutionary Profile for (Host and Viral) MLKL Indicates Its Activities as a Battlefront for Extensive Counteradaptation
Authors: Suzette N Palmer, Sruthi Chappidi, Chelsea Pinkham, Dustin C Hancks
Journal: Molecular Biology and Evolution (2021)

Pathogen infection triggers host innate defenses which may result in the activation of regulated cell death (RCD) pathways such as apoptosis. Given a vital role in immunity, apoptotic effectors are often counteracted by pathogen-encoded antagonists. Mounting evidence indicates that programmed necrosis, which is mediated by the RIPK3/MLKL axis and termed necroptosis, evolved as a countermeasure to pathogen-mediated inhibition of apoptosis. Yet, it is unclear whether components of this emerging RCD pathway display signatures associated with pathogen conflict that are rare in combination but common to key host defense factors, namely, rapid evolution, viral homolog (virolog), and cytokine induction. We leveraged evolutionary sequence analysis that examines rates of amino acid replacement, which revealed: 1) strong and recurrent signatures of positive selection for primate and bat RIPK3 and MLKL, and 2) elevated rates of amino acid substitution on multiple RIPK3/MLKL surfaces suggestive of past antagonism with multiple, distinct pathogen-encoded inhibitors. Furthermore, our phylogenomics analysis across poxvirus genomes illuminated volatile patterns of evolution for a recently described MLKL viral homolog. Specifically, poxviral MLKLs have undergone numerous gene replacements mediated by duplication and deletion events. In addition, MLKL protein expression is stimulated by interferons in human and mouse cells. Thus, MLKL displays all three hallmarks of pivotal immune factors of which only a handful of factors like OAS1 exhibit. These data support the hypothesis that over evolutionary time MLKL functions-which may include execution of necroptosis-have served as a major determinant of infection outcomes despite gene loss in some host genomes.
MERTK on mononuclear phagocytes regulates T cell antigen recognition at autoimmune and tumor sites
Authors: Robin S. Lindsay, Jennifer C. Whitesell, Kristen E. Dew, Erika Rodriguez, Adam M. Sandor, Dayna Tracy, Seth F. Yannacone, Brittany N. Basta, Jordan Jacobelli, Rachel S. Friedman
Journal: The Journal of Experimental Medicine (2021)

Understanding mechanisms of immune regulation is key to developing immunotherapies for autoimmunity and cancer. We examined the role of mononuclear phagocytes during peripheral T cell regulation in type 1 diabetes and melanoma. MERTK expression and activity in mononuclear phagocytes in the pancreatic islets promoted islet T cell regulation, resulting in reduced sensitivity of T cell scanning for cognate antigen in prediabetic islets. MERTK-dependent regulation led to reduced T cell activation and effector function at the disease site in islets and prevented rapid progression of type 1 diabetes. In human islets, MERTK-expressing cells were increased in remaining insulin-containing islets of type 1 diabetic patients, suggesting that MERTK protects islets from autoimmune destruction. MERTK also regulated T cell arrest in melanoma tumors. These data indicate that MERTK signaling in mononuclear phagocytes drives T cell regulation at inflammatory disease sites in peripheral tissues through a mechanism that reduces the sensitivity of scanning for antigen leading to reduced responsiveness to antigen.
Pure drug nano-assemblies: A facile carrier-free nanoplatform for efficient cancer therapy
Authors: Shuwen Fu, Guanting Li, Wenli Zang, Xinyu Zhou, Kexin Shi, Yinglei Zhai
Journal: Acta Pharmaceutica Sinica B (2021)

Nanoparticulate drug delivery systems (Nano-DDSs) have emerged as possible solution to the obstacles of anticancer drug delivery. However, the clinical outcomes and translation are restricted by several drawbacks, such as low drug loading, premature drug leakage and carrier-related toxicity. Recently, pure drug nano-assemblies (PDNAs), fabricated by the self-assembly or co-assembly of pure drug molecules, have attracted considerable attention. Their facile and reproducible preparation technique helps to remove the bottleneck of nanomedicines including quality control, scale-up production and clinical translation. Acting as both carriers and cargos, the carrier-free PDNAs have an ultra-high or even 100% drug loading. In addition, combination therapies based on PDNAs could possibly address the most intractable problems in cancer treatment, such as tumor metastasis and drug resistance. In the present review, the latest development of PDNAs for cancer treatment is overviewed. First, PDNAs are classified according to the composition of drug molecules, and the assembly mechanisms are discussed. Furthermore, the co-delivery of PDNAs for combination therapies is summarized, with special focus on the improvement of therapeutic outcomes. Finally, future prospects and challenges of PDNAs for efficient cancer therapy are spotlighted.
26202 Antineoplastic therapy after discontinuation of sonidegib 200 mg in patients with advanced basal cell carcinoma: Results from the 42-month, randomized, double-blind BOLT study
Authors: Ralf Gutzmer, Alexander Guminski, Peter Foley, Anne Lynn S. Chang, Karl Lewis, Nicholas Squittieri, Carmen Loquai
Journal: Journal of the American Academy of Dermatology (2021)
X-CNV: genome-wide prediction of the pathogenicity of copy number variations
Authors: Li Zhang, Jingru Shi, Jian Ouyang, Riquan Zhang, Yiran Tao, Dongsheng Yuan, Chengkai Lv, Ruiyuan Wang, Baitang Ning, Ruth Roberts, Weida Tong, Zhichao Liu, Tieliu Shi
Journal: Genome Medicine (2021)

Abstract Background Gene copy number variations (CNVs) contribute to genetic diversity and disease prevalence across populations. Substantial efforts have been made to decipher the relationship between CNVs and pathogenesis but with limited success. Results We have developed a novel computational framework X-CNV ( www.unimd.org/XCNV ), to predict the pathogenicity of CNVs by integrating more than 30 informative features such as allele frequency (AF), CNV length, CNV type, and some deleterious scores. Notably, over 14 million CNVs across various ethnic groups, covering nearly 93% of the human genome, were unified to calculate the AF. X-CNV, which yielded area under curve (AUC) values of 0.96 and 0.94 in training and validation sets, was demonstrated to outperform other available tools in terms of CNV pathogenicity prediction. A meta-voting prediction (MVP) score was developed to quantitively measure the pathogenic effect, which is based on the probabilistic value generated from the XGBoost algorithm. The proposed MVP score demonstrated a high discriminative power in determining pathogenetic CNVs for inherited traits/diseases in different ethnic groups. Conclusions The ability of the X-CNV framework to quantitatively prioritize functional, deleterious, and disease-causing CNV on a genome-wide basis outperformed current CNV-annotation tools and will have broad utility in population genetics, disease-association studies, and diagnostic screening.
27066 Angiosarcoma of the scalp and paraneoplastic encephalopathy: Multidisciplinary approach to diagnosis and treatment
Authors: Joohee Han, Noah Goldfarb, Jonathan Koffel, Zhiyi Sha, Keith Skubitz, H. Brent Clark, Maria Hordinsky, Monica Rani, Elisabeth Hurliman
Journal: Journal of the American Academy of Dermatology (2021)
Profiteering from vaccine inequity: a crime against humanity?
Authors: Fatima Hassan, Gavin Yamey, Kamran Abbasi
Journal: BMJ (2021)

Early in the pandemic, Pfizer announced an intention to profit from its covid-19 vaccine. 1 In the first three months of 2021, Pfizer's vaccine brought in $3.5bn (£2.5bn; €3bn) in revenue and hundreds of millions in profit. 2 Other companies are also making exceptional profits from covid-19.Moderna, which received public funding to develop its covid-19 vaccine, will earn several billion dollars from vaccine sales. 3 Even Astra Zeneca, with its acclaimed "non-profit" model, will receive billions in revenue and is free to raise the price once itconsiders the pandemic to be over.
ALT neuroblastoma chemoresistance due to telomere dysfunction–induced ATM activation is reversible with ATM inhibitor AZD0156
Authors: Balakrishna Koneru, Ahsan Farooqi, Thinh H. Nguyen, Wan Hsi Chen, Ashly Hindle, Cody Eslinger, Monish Ram Makena, Trevor A. Burrow, Joanne Wilson, Aaron Smith, Venkatesh Pilla Reddy, Elaine Cadogan, Stephen T. Durant, C. Patrick Reynolds
Journal: Science Translational Medicine (2021)

ATM activation at telomeres confers chemoresistance in ALT neuroblastoma and is reversible in preclinical models by ATM knockdown or inhibition.
Cardiac Magnetic Resonance Assessment of Response to Cardiac Resynchronization Therapy and Programming Strategies
Authors: Xu Gao, Mohamad Abdi, Daniel A Auger, Changyu Sun, Christopher A Hanson, Austin A Robinson, Christopher Schumann, Pim J Oomen, Sarah Ratcliffe, Rohit Malhotra, Andrew Darby, Oliver J Monfredi, J Michael Mangrum, Pamela Mason, Sula Mazimba, Jeffrey W Holmes, Christopher M Kramer, Frederick H Epstein, Michael Salerno, Kenneth C Bilchick
Journal: JACC. Cardiovascular imaging (2021)
Effects of exercise training in people with non-small cell lung cancer before lung resection: a systematic review and meta-analysis
Authors: Francis-Edouard Gravier, Pauline Smondack, Guillaume Prieur, Clement Medrinal, Yann Combret, Jean-François Muir, Jean-Marc Baste, Antoine Cuvelier, Fairuz Boujibar, Tristan Bonnevie
Journal: Thorax (2021)

Introduction Exercise training before lung resection for non-small cell lung cancer is believed to decrease postoperative complications (POC) by improving cardiorespiratory fitness. However, this intervention lacks a strong evidence base. Aim To assess the effectiveness of preoperative exercise training compared with usual care on POC and other secondary outcomes in patients with scheduled lung resection. Methods A systematic search of randomised trials was conducted by two authors. Meta-analysis was performed, and the effect of exercise training was estimated by risk ratios (RR) and mean differences, with their CIs. Clinical usefulness was estimated according to minimal important difference values (MID). Results Fourteen studies involving 791 participants were included. Compared with usual care, exercise training reduced overall POC (10 studies, 617 participants, RR 0.58, 95% CI 0.45 to 0.75) and clinically relevant POC (4 studies, 302 participants, Clavien-Dindo score ≥2 RR 0.42, 95% CI 0.25 to 0.69). The estimate of the effect of exercise training on mortality was very imprecise (6 studies, 456 participants, RR 0.66, 95% CI 0.20 to 2.22). The main risks of bias were a lack of participant blinding and selective reporting. Exercise training appeared to improve exercise capacity, pulmonary function and also quality of life and depression, although the clinical usefulness of the changes was unclear. The quality of the evidence was graded for each outcome. Conclusion Preoperative exercise training leads to a worthwhile reduction in postoperative complications. These estimates were both accurate and large enough to make recommendations for clinical practice.
Targeted T cell receptor gene editing provides predictable T cell product function for immunotherapy
Authors: Thomas R. Müller, Sebastian Jarosch, Monika Hammel, Justin Leube, Simon Grassmann, Bettina Bernard, Manuel Effenberger, Immanuel Andrä, M. Zeeshan Chaudhry, Theresa Käuferle, Antje Malo, Luka Cicin-Sain, Peter Steinberger, Tobias Feuchtinger, Ulrike Protzer, Kathrin Schumann, Michael Neuenhahn, Kilian Schober, Dirk H. Busch
Journal: Cell Reports Medicine (2021)

Adoptive transfer of T cells expressing a transgenic T cell receptor (TCR) has the potential to revolutionize immunotherapy of infectious diseases and cancer. However, the generation of defined TCR-transgenic T cell medicinal products with predictable in vivo function still poses a major challenge and limits broader and more successful application of this "living drug." Here, by studying 51 different TCRs, we show that conventional genetic engineering by viral transduction leads to variable TCR expression and functionality as a result of variable transgene copy numbers and untargeted transgene integration. In contrast, CRISPR/Cas9-mediated TCR replacement enables defined, targeted TCR transgene insertion into the TCR gene locus. Thereby, T cell products display more homogeneous TCR expression similar to physiological T cells. Importantly, increased T cell product homogeneity after targeted TCR gene editing correlates with predictable in vivo T cell responses, which represents a crucial aspect for clinical application in adoptive T cell immunotherapy.
Genesis, evolution and host species distribution of influenza A (H10N3) virus in China
Authors: Ruyi Gao, Huafen Zheng, Kaituo Liu, Zhuxing Ji, Miao Cai, Min Gu, Jiao Hu, Xiaowen Liu, Shunlin Hu, Xiaoquan Wang, Xiufan Liu
Journal: Journal of Infection (2021)
Genomic evidence consistent with antagonistic pleiotropy may help explain the evolutionary maintenance of same-sex sexual behaviour in humans
Authors: Brendan P. Zietsch, Morgan J. Sidari, Abdel Abdellaoui, Robert Maier, Niklas Långström, Shengru Guo, Gary W. Beecham, Eden R. Martin, Alan R. Sanders, Karin J. H. Verweij
Journal: Nature Human Behaviour (2021)
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Authors: Zachary Holcomb, Sadaf Hussain, Jennifer Huang, Sophia Delano
Journal: JAMA Dermatology (2021)

Megan Arthur, MD; Nicole M. Fett, MD, MSCE; Emile Latour, MS; Heidi Jacobe, MD; Elaine Kunzler, MD; Stephanie Florez-Pollack, MD; Jacob Houser, BS; Shivani Sharma, BA; Smriti Prasad, BSA; Alisa Femia, MD; Marleigh J. Stern, MD; Lisa K. Pappas-Taffer, MD; Rebecca Gaffney, MD; Anthony P. Fernandez, MD, PhD; Daniel Knabel, MD; Adela Rambi Cardones, MD, MHSc; Nicole Leung, MD; Anne Laumann, MBChB; Jeong Min Yu, MD; Jeffrey Zhao, BA; Ruth Ann Vleugels, MD, MPH; Elizabeth Tkachenko, BS; Kelly Lo, BS
Patient and general public attitudes towards clinical artificial intelligence: a mixed methods systematic review
Authors: Albert T Young, Dominic Amara, Abhishek Bhattacharya, Maria L Wei
Journal: The Lancet Digital Health (2021)

Artificial intelligence (AI) promises to change health care, with some studies showing proof of concept of a provider-level performance in various medical specialties. However, there are many barriers to implementing AI, including patient acceptance and understanding of AI. Patients' attitudes toward AI are not well understood. We systematically reviewed the literature on patient and general public attitudes toward clinical AI (either hypothetical or realised), including quantitative, qualitative, and mixed methods original research articles. We searched biomedical and computational databases from Jan 1, 2000, to Sept 28, 2020, and screened 2590 articles, 23 of which met our inclusion criteria. Studies were heterogeneous regarding the study population, study design, and the field and type of AI under study. Six (26%) studies assessed currently available or soon-to-be available AI tools, whereas 17 (74%) assessed hypothetical or broadly defined AI. The quality of the methods of these studies was mixed, with a frequent issue of selection bias. Overall, patients and the general public conveyed positive attitudes toward AI but had many reservations and preferred human supervision. We summarise our findings in six themes: AI concept, AI acceptability, AI relationship with humans, AI development and implementation, AI strengths and benefits, and AI weaknesses and risks. We suggest guidance for future studies, with the goal of supporting the safe, equitable, and patient-centred implementation of clinical AI.
Cross-sectional associations of tau protein biomarkers with semantic and episodic memory in older adults without dementia: A systematic review and meta-analysis
Authors: Teuntje A.D. Pelgrim, Magdalena Beran, Emma L. Twait, Mirjam I. Geerlings, Jet M.J. Vonk
Journal: Ageing Research Reviews (2021)

Pathological tau is suggested to play a role in cognitive deterioration in the preclinical phase of Alzheimer's disease. We investigated cross-sectional associations of tau burden with episodic and semantic memory performance in older adults without dementia. A systematic search in MEDLINE (via PubMed), PsychINFO, and Embase resulted in 24 eligible studies for meta-analysis. Tau burden was assessed using CSF, PET, or histopathological measures. All studies evaluated associations of tau with episodic memory: weighted effect sizes were -0.46 (95 % CI [-0.73; -0.20], p < .001) for episodic composite scores, -0.19 ([-0.36; -0.03], p = .024) for delayed word list recall, and -0.05 ([-0.14; 0.04], p = .257) for logical memory. Fourteen studies evaluated associations of tau with semantic memory: weighted effect sizes were -0.28 ([-0.52; -0.04], p = .023) for semantic composite scores, -0.06 ([-0.16; 0.03], p = .194) for semantic fluency, and 0.06 ([-0.06; 0.18], p = .319) for picture naming. Our findings indicate that tau burden related to both episodic and semantic memory impairment in older individuals without a diagnosis of mild cognitive impairment or manifest dementia, with episodic composite scores showing the strongest association with tau burden. Future potential lies in developing more sensitive scores to detect this subtle cognitive impairment, which could contribute to early identification of individuals in the preclinical phase of Alzheimer's disease, thereby improving early diagnosis and timely intervention.
Pharmacokinetics and pharmacogenetics of liposomal cytarabine in AML patients treated with CPX-351
Authors: Mélanie Donnette, Mourad Hamimed, Joseph Ciccolini, Yael Berda-Haddad, Elise Kaspi, Geoffroy Venton, Bruno Lacarelle, Regis Costello, L'’Houcine Ouafik, Laure Farnault, Raphaelle Fanciullino
Journal: Journal of Controlled Release (2021)
25997 Safety of tildrakizumab 100 mg and 200 mg through 5 years of exposure in reSURFACE 1
Authors: Pablo Fernández-Peñas, Akihiko Asahina, Atsuyuki Igarashi, Jayme Heim, Alan Mendelsohn, Stephen Rozzo, Neal Bhatia
Journal: Journal of the American Academy of Dermatology (2021)
25748 Ixekizumab sustained complete clearance, itch resolution, and improved quality of life for moderate-to-severe psoriasis patients who achieved rapid, high skin clearance
Authors: David Rosmarin, Melinda Gooderham, Laura Ferris, Kyoungah See, Eric Wolf, Russel Burge, Missy McKean-Matthews, Kristian Reich
Journal: Journal of the American Academy of Dermatology (2021)