tbuckley/cabot-search huggingface dataset:
Erratum: Corrigendum: Gut microbiome–derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease
Authors: Nathan D Mathewson, Robert Jenq, Anna V Mathew, Mark Koenigsknecht, Alan Hanash, Tomomi Toubai, Katherine Oravecz-Wilson, Shin-Rong Wu, Yaping Sun, Corinne Rossi, Hideaki Fujiwara, Jaeman Byun, Yusuke Shono, Caroline Lindemans, Marco Calafiore, Thomas C Schmidt, Kenya Honda, Vincent B Young, Subramaniam Pennathur, Marcel van den Brink, Pavan Reddy
Journal: Nature Immunology (2016)
Covid-19: Antibody tests will not be rolled out in UK until at least May, MPs hear
Authors: Gareth Iacobucci
Journal: BMJ (2020)

Antibody tests to determine whether someone has had covid-19 will not be available until at least May, the government’s national testing coordinator has said. John Newton, Public Health England’s director of health improvement, said that none of the tests tried so far had been accurate enough.

The government has set itself a target to carry out 100 000 covid-19 tests a day by the end of April, through a “five pillar” policy including a big increase in capacity for polymerase chain reaction (PCR) swab tests that detect the presence of the virus, alongside rolling out antibody testing.1

But Newton, appointed last week to oversee this increase, told MPs on …
Stimuli-responsive nanocarriers for drug delivery, tumor imaging, therapy and theranostics
Authors: Peng Mi
Journal: Theranostics (2020)

In recent years, much progress has been motivated in stimuli-responsive nanocarriers, which could response to the intrinsic physicochemical and pathological factors in diseased regions to increase the specificity of drug delivery. Currently, numerous nanocarriers have been engineered with physicochemical changes in responding to external stimuli, such as ultrasound, thermal, light and magnetic field, as well as internal stimuli, including pH, redox potential, hypoxia and enzyme, etc. Nanocarriers could respond to stimuli in tumor microenvironments or inside cancer cells for on-demanded drug delivery and accumulation, controlled drug release, activation of bioactive compounds, probes and targeting ligands, as well as size, charge and conformation conversion, etc., leading to sensing and signaling, overcoming multidrug resistance, accurate diagnosis and precision therapy. This review has summarized the general strategies of developing stimuli-responsive nanocarriers and recent advances, presented their applications in drug delivery, tumor imaging, therapy and theranostics, illustrated the progress of clinical translation and made prospects.
Availability of Statistical Code From Studies Using Medicare Data in General Medical Journals
Authors: Jennie DeBlanc, Bradley Kay, Jessica Lehrich, Neil Kamdar, Thomas S. Valley, John Z. Ayanian, Brahmajee K. Nallamothu
Journal: JAMA Internal Medicine (2020)

ratings agreed at one extreme and the third system assigned the hospital a rating at the opposite extreme.Discussion | We found for most hospitals the 3 rating systems did not fully agree on the hospital's mortality performance for a particular condition, but there was generally moderate agreement in the ratings.3][4] While our data set included more than 3000 hospitals for each condition, only certain types of hospitals were included in our analysis.Free-standing pediatric hospitals, federal hospitals, and prospective payment systemexempt cancer hospitals were not included in the analysis.If there are differences in how the rating systems assess the mortality performance of the excluded hospitals, this could result in a level of agreement different from what we found in our particular data set.In addition, our analysis was based on a single snapshot of data from June 2017.If we were to repeat the analysis with a different data snapshot, we could possibly find different results.Our study did not assess the methods used by each rating system, so we cannot draw conclusions about which rating system did the best job of correctly identifying high-performing and lowperforming hospitals; we simply compared the agreement and disagreement of the public ratings.As mortality reflects a singular objective construct, one step might be for the mortality rating systems to come together to identify best practices and work to produce a single rating so that stakeholders can center on one truth.
Protein Kinase C-δ Mediates Kidney Tubular Injury in Cold Storage–Associated Kidney Transplantation
Authors: Jiefu Zhu, Gang Zhang, Zhixia Song, Xiaohong Xiang, Shaoqun Shu, Zhiwen Liu, Danyi Yang, Qingqing Wei, Zheng Dong
Journal: Journal of the American Society of Nephrology (2020)

Kidney injury associated with cold storage is a determinant of delayed graft function and the long-term outcome of transplanted kidneys, but the underlying mechanism remains elusive. We previously reported a role of protein kinase C-δ (PKCδ) in renal tubular injury during cisplatin nephrotoxicity and albumin-associated kidney injury, but whether PKCδ is involved in ischemic or transplantation-associated kidney injury is unknown.To investigate PKCδ's potential role in injury during cold storage-associated transplantation, we incubated rat kidney proximal tubule cells in University of Wisconsin (UW) solution at 4°C for cold storage, returning them to normal culture medium at 37°C for rewarming. We also stored kidneys from donor mice in cold UW solution for various durations, followed by transplantation into syngeneic recipient mice.We observed PKCδ activation in both in vitro and in vivo models of cold-storage rewarming or transplantation. In the mouse model, PKCδ was activated and accumulated in mitochondria, where it mediated phosphorylation of a mitochondrial fission protein, dynamin-related protein 1 (Drp1), at serine 616. Drp1 activation resulted in mitochondrial fission or fragmentation, accompanied by mitochondrial damage and tubular cell death. Deficiency of PKCδ in donor kidney ameliorated Drp1 phosphorylation, mitochondrial damage, tubular cell death, and kidney injury during cold storage-associated transplantation. PKCδ deficiency also improved the repair and function of the renal graft as a life-supporting kidney. An inhibitor of PKCδ, δV1-1, protected kidneys against cold storage-associated transplantation injury.These results indicate that PKCδ is a key mediator of mitochondrial damage and renal tubular injury in cold storage-associated transplantation and may be an effective therapeutic target for improving renal transplant outcomes.
Digestive findings that do not require endoscopic surveillance – Reducing the burden of care: European Society of Gastrointestinal Endoscopy (ESGE) Position Statement
Authors: Enrique Rodríguez-de-Santiago, Leonardo Frazzoni, Lorenzo Fuccio, Jeanin E van Hooft, Thierry Ponchon, Cesare Hassan, Mário Dinis-Ribeiro
Journal: Endoscopy (2020)

Summary of Statements With the aim of reducing the overall burden of care, ESGE recommends against surveillance of a series of conditions. Namely: ESGE recommends against surveillance of individuals with the following: an inlet esophageal patch; Los Angeles (LA) grade A or B erosive esophagitis; or &lt; 1 cm columnar-lined esophagus. ESGE recommends against surveillance of those with intestinal metaplasia limited to the antrum unless additional risk factors are present, such as persistent Helicobacter pylori infection, incomplete metaplasia, or a family history of gastric cancer; or for fundic gland polyps in the absence of suspicious endoscopic features or hereditary syndromes. ESGE recommends against surveillance of gastrointestinal leiomyomas, lipomas, and antral pancreatic rests, provided that these lesions have typical ultrasonographic features. ESGE recommends against routine endoscopic surveillance in duodenal peptic ulcer, unless symptoms persist despite adequate therapy. ESGE suggests against surveillance of confirmed pancreatic serous cystic neoplasms. ESGE recommends against endoscopic surveillance for patients with hyperplastic polyps in the rectosigmoid, with 1 – 4 adenomas &lt; 10 mm with low-grade dysplasia, or with a serrated polyp &lt; 10 mm without dysplasia. ESGE recommends against surveillance of gastrointestinal conditions in individuals over 80 years old who have less than 10 years of life expectancy and poor general health status.
Leaving no one behind: Where are 2.6 million stillbirths?
Authors: Susannah H Leisher, Mary Kinney, Hannah Blencowe, Jessica Sexton, Paul Cassidy, Lauren Christiansen-Lindquist, Rakhi Dandona, Miranda Davies, Adrienne Gordon, Clea Harmer, Kapila Jayaratne, Fleurisca Korteweg, Maryam Mozooni, Sara Nam, Daniel Nuzum, Paula Quigley, Claire Claire Storey, Debbie Haine Vijayvergiya, Lindsey Wimmer, Luc de Bernis, Vicki Flenady, J. Frederik Frøen, Alexander Heazell, Joy E Lawn
Journal: BMJ (2020)
The Spectrum of Neurologic Disease in the Severe Acute Respiratory Syndrome Coronavirus 2 Pandemic Infection
Authors: Samuel J. Pleasure, Ari J. Green, S. Andrew Josephson
Journal: JAMA Neurology (2020)

Ling Mao; Huijuan Jin; Mengdie Wang; Yu Hu; Shengcai Chen; Quanwei He; Jiang Chang; Candong Hong; Yifan Zhou; David Wang; Xiaoping Miao; Yanan Li, MD, PhD; Bo Hu, MD, PhD
Proinflammatory P2Y14 receptor inhibition protects against ischemic acute kidney injury in mice
Authors: Maria Agustina Battistone, Alexandra C. Mendelsohn, Raul German Spallanzani, Andrew S. Allegretti, Rachel N. Liberman, Juliana Sesma, Sahir Kalim, Susan M. Wall, Joseph V. Bonventre, Eduardo R. Lazarowski, Dennis Brown, Sylvie Breton
Journal: Journal of Clinical Investigation (2020)

Ischemic acute kidney injury (AKI), a complication that frequently occurs in hospital settings, is often associated with hemodynamic compromise, sepsis, cardiac surgery, or exposure to nephrotoxins. Here, using a murine renal ischemia/reperfusion injury (IRI) model, we show that intercalated cells (ICs) rapidly adopted a proinflammatory phenotype after IRI. Wwe demonstrate that during the early phase of AKI either blockade of the proinflammatory P2Y14 receptor located on the apical membrane of ICs or ablation of the gene encoding the P2Y14 receptor in ICs (a) inhibited IRI-induced increase of chemokine expression in ICs, (b) reduced neutrophil and monocyte renal infiltration, (c) reduced the extent of kidney dysfunction, and (d) attenuated proximal tubule damage. These observations indicate that the P2Y14 receptor participates in the very first inflammatory steps associated with ischemic AKI. In addition, we show that the concentration of the P2Y14 receptor ligand UDP-glucose (UDP-Glc) was higher in urine samples from intensive care unit patients who developed AKI compared with patients without AKI. In particular, we observed a strong correlation between UDP-Glc concentration and the development of AKI in cardiac surgery patients. Our study identifies the UDP-Glc/P2Y14 receptor axis as a potential target for the prevention and/or attenuation of ischemic AKI.
Mental Health and Psychosocial Problems of Medical Health Workers during the COVID-19 Epidemic in China
Authors: Wen-rui Zhang, Kun Wang, Lu Yin, Wen-feng Zhao, Qing Xue, Mao Peng, Bao-quan Min, Qing Tian, Hai-xia Leng, Jia-lin Du, Hong Chang, Yuan Yang, Wei Li, Fang-fang Shangguan, Tian-yi Yan, Hui-qing Dong, Ying Han, Yu-ping Wang, Fiammetta Cosci, Hong-xing Wang
Journal: Psychotherapy and Psychosomatics (2020)

&lt;b&gt;&lt;i&gt;Objective:&lt;/i&gt;&lt;/b&gt; We explored whether medical health workers had more psychosocial problems than nonmedical health workers during the COVID-19 outbreak. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; An online survey was run from February 19 to March 6, 2020; a total of 2,182 Chinese subjects participated. Mental health variables were assessed via the Insomnia Severity Index (ISI), the Symptom Check List-revised (SCL-90-R), and the Patient Health Questionnaire-4 (PHQ-4), which included a 2-item anxiety scale and a 2-item depression scale (PHQ-2). &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Compared with nonmedical health workers (&lt;i&gt;n&lt;/i&gt; = 1,255), medical health workers (&lt;i&gt;n&lt;/i&gt; = 927) had a higher prevalence of insomnia (38.4 vs. 30.5%, &lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.01), anxiety (13.0 vs. 8.5%, &lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.01), depression (12.2 vs. 9.5%; &lt;i&gt;p&lt;/i&gt;&amp;#x3c; 0.04), somatization (1.6 vs. 0.4%; &lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.01), and obsessive-compulsive symptoms (5.3 vs. 2.2%; &lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.01). They also had higher total scores of ISI, GAD-2, PHQ-2, and SCL-90-R obsessive-compulsive symptoms (&lt;i&gt;p&lt;/i&gt; ≤ 0.01). Among medical health workers, having organic disease was an independent factor for insomnia, anxiety, depression, somatization, and obsessive-compulsive symptoms (&lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.05 or 0.01). Living in rural areas, being female, and being at risk of contact with COVID-19 patients were the most common risk factors for insomnia, anxiety, obsessive-compulsive symptoms, and depression (&lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.01 or 0.05). Among nonmedical health workers, having organic disease was a risk factor for insomnia, depression, and obsessive-compulsive symptoms (&lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.01 or 0.05). &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; During the COVID-19 outbreak, medical health workers had psychosocial problems and risk factors for developing them. They were in need of attention and recovery programs.
Gut-resident CX3CR1 <sup>hi</sup> macrophages induce tertiary lymphoid structures and IgA response in situ
Authors: Balázs Koscsó, Sravya Kurapati, Richard R. Rodrigues, Jelena Nedjic, Kavitha Gowda, Changsik Shin, Chetna Soni, Azree Zaffran Ashraf, Indira Purushothaman, Maryknoll Palisoc, Sulei Xu, Haoyu Sun, Sathi Babu Chodisetti, Eugene Lin, Matthias Mack, Yuka Imamura Kawasawa, Pingnian He, Ziaur S. M. Rahman, Iannis Aifantis, Natalia Shulzhenko, Andrey Morgun, Milena Bogunovic
Journal: Science Immunology (2020)

Gut-resident CX3CR1 hi macrophages drive formation of tertiary lymphoid structures that initiate IgA responses to Salmonella infection.
Golgi-Localized PAQR4 Mediates Antiapoptotic Ceramidase Activity in Breast Cancer
Authors: Line Pedersen, Pouda Panahandeh, Muntequa I. Siraji, Stian Knappskog, Per Eystein Lønning, Ruth Gordillo, Philipp E. Scherer, Anders Molven, Knut Teigen, Nils Halberg
Journal: Cancer Research (2020)

Abstract The metabolic network of sphingolipids plays important roles in cancer biology. Prominent sphingolipids include ceramides and sphingosine-1-phosphate that regulate multiple aspects of growth, apoptosis, and cellular signaling. Although a significant number of enzymatic regulators of the sphingolipid pathway have been described in detail, many remained poorly characterized. Here we applied a patient-derived systemic approach to identify and molecularly define progestin and adipoQ receptor family member IV (PAQR4) as a Golgi-localized ceramidase. PAQR4 was approximately 5-fold upregulated in breast cancer compared with matched control tissue and its overexpression correlated with disease-specific survival rates in breast cancer. Induction of PAQR4 in breast tumors was found to be subtype-independent and correlated with increased ceramidase activity. These findings establish PAQR4 as Golgi-localized ceramidase required for cellular growth in breast cancer. Significance: Induction of and cellular dependency on de novo sphingolipid synthesis via PAQR4 highlights a central vulnerability in breast cancer that may serve as a viable therapeutic target.
Depletion of Vasohibin 1 Speeds Contraction and Relaxation in Failing Human Cardiomyocytes
Authors: Christina Yingxian Chen, Alexander K. Salomon, Matthew A. Caporizzo, Sam Curry, Neil A. Kelly, Kenneth Bedi, Alexey I. Bogush, Elisabeth Krämer, Saskia Schlossarek, Philip Janiak, Marie-Jo Moutin, Lucie Carrier, Kenneth B. Margulies, Benjamin L. Prosser
Journal: Circulation Research (2020)

Rationale: Impaired myocardial relaxation is an intractable feature of several heart failure (HF) causes. In human HF, detyrosinated microtubules stiffen cardiomyocytes and impair relaxation. Yet the identity of detyrosinating enzymes have remained ambiguous, hindering mechanistic study and therapeutic development. Objective: We aimed to determine if the recently identified complex of VASH1/2 (vasohibin 1/2) and SVBP (small vasohibin binding protein) is an active detyrosinase in cardiomyocytes and if genetic inhibition of VASH-SVBP is sufficient to lower stiffness and improve contractility in HF. Methods and Results: Transcriptional profiling revealed that VASH1 transcript is &gt;10-fold more abundant than VASH2 in human hearts. Using short hairpin RNAs (shRNAs) against VASH1 , VASH2 , and SVBP , we showed that both VASH1- and VASH2-SVBP complexes function as tubulin carboxypeptidases in cardiomyocytes, with a predominant role for VASH1. We also generated a catalytically dead version of the tyrosinating enzyme TTL (TTL-E331Q) to separate the microtubule depolymerizing effects of TTL from its enzymatic activity. Assays of microtubule stability revealed that both TTL and TTL-E331Q depolymerize microtubules, while VASH1 and SVBP depletion reduce detyrosination independent of depolymerization. We next probed effects on human cardiomyocyte contractility. Contractile kinetics were slowed in HF, with dramatically slowed relaxation in cardiomyocytes from patients with HF with preserved ejection fraction. Knockdown of VASH1 conferred subtle kinetic improvements in nonfailing cardiomyocytes, while markedly improving kinetics in failing cardiomyocytes. Further, TTL, but not TTL-E331Q, robustly sped relaxation. Simultaneous measurements of calcium transients and contractility demonstrated that VASH1 depletion speeds kinetics independent from alterations to calcium cycling. Finally, atomic force microscopy confirmed that VASH1 depletion reduces the stiffness of failing human cardiomyocytes. Conclusions: VASH-SVBP complexes are active tubulin carboxypeptidases in cardiomyocytes. Inhibition of VASH1 or activation of TTL is sufficient to lower stiffness and speed relaxation in cardiomyocytes from patients with HF, supporting further pursuit of detyrosination as a therapeutic target for diastolic dysfunction.
Randomized Double-Blind Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer
Authors: Matthew D. Galsky, Amir Mortazavi, Matthew I. Milowsky, Saby George, Sumati Gupta, Mark T. Fleming, Long H. Dang, Daniel M. Geynisman, Radhika Walling, Robert S. Alter, Mohamad Kassar, Jue Wang, Shilpa Gupta, Nancy Davis, Joel Picus, George Philips, David I. Quinn, G. Kenneth Haines, Noah M. Hahn, Qianqian Zhao, Menggang Yu, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2020)

Platinum-based chemotherapy for first-line treatment of metastatic urothelial cancer is typically administered for a fixed duration followed by observation until progression. "Switch maintenance" therapy with PD-1 blockade at the time of chemotherapy cessation may be attractive for mechanistic and pragmatic reasons.Patients with metastatic urothelial cancer achieving at least stable disease on first-line platinum-based chemotherapy were enrolled. Patients were randomly assigned double-blind 1:1 to switch maintenance pembrolizumab 200 mg intravenously once every 3 weeks versus placebo for up to 24 months. Patients with disease progression on placebo could cross over to pembrolizumab. The primary objective was to determine the progression-free survival. Secondary objectives included determining overall survival as well as treatment outcomes according to PD-L1 combined positive score (CPS).Between December 2015 and November 2018, 108 patients were randomly assigned to pembrolizumab (n = 55) or placebo (n = 53). The objective response rate was 23% with pembrolizumab and 10% with placebo. Treatment-emergent grade 3-4 adverse events occurred in 59% receiving pembrolizumab and 38% of patients receiving placebo. Progression-free survival was significantly longer with maintenance pembrolizumab versus placebo (5.4 months [95% CI, 3.1 to 7.3 months] v 3.0 months [95% CI; 2.7 to 5.5 months]; hazard ratio, 0.65; log-rank P = .04; maximum efficiency robust test P = .039). Median overall survival was 22 months (95% CI, 12.9 months to not reached) with pembrolizumab and 18.7 months (95% CI, 11.4 months to not reached) with placebo. There was no significant interaction between PD-L1 CPS ≥ 10 and treatment arm for progression-free survival or overall survival.Switch maintenance pembrolizumab leads to additional objective responses in patients achieving at least stable disease with first-line platinum-based chemotherapy and prolongs progression-free survival in patients with metastatic urothelial cancer.
Gain-of-Function Genetic Alterations of G9a Drive Oncogenesis
Authors: Shinichiro Kato, Qing Yu Weng, Megan L. Insco, Kevin Y. Chen, Sathya Muralidhar, Joanna Pozniak, Joey Mark S. Diaz, Yotam Drier, Nhu Nguyen, Jennifer A. Lo, Ellen van Rooijen, Lajos V. Kemeny, Yao Zhan, Yang Feng, Whitney Silkworth, C. Thomas Powell, Brian B. Liau, Yan Xiong, Jian Jin, Julia Newton-Bishop, Leonard I. Zon, Bradley E. Bernstein, David E. Fisher
Journal: Cancer Discovery (2020)

Epigenetic regulators, when genomically altered, may become driver oncogenes that mediate otherwise unexplained pro-oncogenic changes lacking a clear genetic stimulus, such as activation of the WNT/β-catenin pathway in melanoma. This study identifies previously unrecognized recurrent activating mutations in the G9a histone methyltransferase gene, as well as G9a genomic copy gains in approximately 26% of human melanomas, which collectively drive tumor growth and an immunologically sterile microenvironment beyond melanoma. Furthermore, the WNT pathway is identified as a key tumorigenic target of G9a gain-of-function, via suppression of the WNT antagonist DKK1. Importantly, genetic or pharmacologic suppression of mutated or amplified G9a using multiple in vitro and in vivo models demonstrates that G9a is a druggable target for therapeutic intervention in melanoma and other cancers harboring G9a genomic aberrations. SIGNIFICANCE: Oncogenic G9a abnormalities drive tumorigenesis and the "cold" immune microenvironment by activating WNT signaling through DKK1 repression. These results reveal a key druggable mechanism for tumor development and identify strategies to restore "hot" tumor immune microenvironments.This article is highlighted in the In This Issue feature, p. 890.