tbuckley/cabot-search huggingface dataset:
BlastFrost: fast querying of 100,000s of bacterial genomes in Bifrost graphs
Authors: Nina Luhmann, Guillaume Holley, Mark Achtman
Journal: Genome biology (2021)

Abstract BlastFrost is a highly efficient method for querying 100,000s of genome assemblies, building on Bifrost, a dynamic data structure for compacted and colored de Bruijn graphs. BlastFrost queries a Bifrost data structure for sequences of interest and extracts local subgraphs, enabling the identification of the presence or absence of individual genes or single nucleotide sequence variants. We show two examples using Salmonella genomes: finding within minutes the presence of genes in the SPI-2 pathogenicity island in a collection of 926 genomes and identifying single nucleotide polymorphisms associated with fluoroquinolone resistance in three genes among 190,209 genomes. BlastFrost is available at https://github.com/nluhmann/BlastFrost/tree/master/data .
MO01.15 Nitric Oxide Lung Cancer Active Vaccination
Authors: H. Confino, S. Yarkoni, M. Goldshtein, E. Dekel, O. Lerner, S. Puyesky, S. Lisi, R. Kalaora, P. Golden, A. Avniel, I. Wolf
Journal: Journal of Thoracic Oncology (2021)
Abstract 17910: Are Characteristics of Hospitals Associated With Outcome in Resuscitated Patients? Insights From the Paris Sudden Death Expertise Center
Authors: Richard Chocron, Wulfran Bougouin, Frankie Beganton, Eloi Marijon, Xavier Jouven, Alain Cariou, Florence Dumas
Journal: Circulation (2016)

Background: Since the quality of post-cardiac arrest (PCA) care may influence the outcome, the triage strategy deserves evaluation that integrates characteristics of receiving hospitals. Hypothesis...
Electrohydraulic lithotripsy for the treatment of stone impacted in a lumen-apposing metal stent in a patient with endoscopic cholecystoduodenostomy
Authors: Edson Guzmán-Calderón, Belén Martínez-Moreno, Juan A. Casellas, José Ramón Aparicio
Journal: Endoscopy (2021)

An 89-year-old woman presented to our department having experienced acute cholecystitis a few weeks previously. Her comorbidities, chronic kidney disease, and congestive heart failure meant she was not a suitable candidate for surgery. She underwent EUS-guided gallbladder drainage, which was performed without complications. During this procedure, a 10-mm × 10-mm lumen-apposing metal stent (LAMS) (Hot Axios; Boston Scientific) was implanted for gallbladder drainage. A few days later, the patient complained of right-upper quadrant abdominal pain and fever, and a new acute cholecystitis episode was diagnosed.
Abstract 16181: Pacemaker Dependence Following Transcatheter Aortic Valve Replacement: A Retrospective Cohort Study
Authors: Michael I Brener, John Wells, Shagnik Ray, Matthew J Czarny, Jon R Resar, Rani K Hasan
Journal: Circulation (2018)

Introduction: Conduction abnormalities (CAs) necessitating permanent pacemaker (PPM) implantation after transcatheter aortic valve replacement (TAVR) are common. It is unknown whether these CAs per...
A guttural cough
Authors: Kathryn McCarthy, Shoba Philips
Journal: BMJ (2021)

A man in his 50s presented to his general practitioner with a four month history of persistent, guttural cough. The cough prevented him from completing sentences. He was a non-smoker and had no other symptoms. Chest examination by his GP was normal.

At a GP follow-up one month later the patient described increasing breathlessness and tiredness. Haemoglobin was measured at 122 g/L (normal adult male range 130-180 g/L)1 and chest radiography showed clear lungs and pleural spaces.

During this time, the patient attended a National Bowel Scope screening programme for a flexible sigmoidoscopy. This was reported as “all clear.” He had no gastrointestinal symptoms.

Two months later, the patient was still unable to speak in full sentences and requested a respiratory consultation. Chest radiography was reported as normal and a computed tomography scan was requested (see fig 1). Haemoglobin was measured at 96 g/L.1



Fig 1 
Computed tomography scan of the chest …
New Year’s Resolutions – A Different Perspective
Authors: Margaret Tempero
Journal: Journal of the National Comprehensive Cancer Network (2021)

A fter a typical year, January usually finds us reflecting on bad habits.We resolve to lose weight, exercise more, be more productive or more efficient, spend more time with family, and so forth.But 2020 was not a typical year.With a pandemic raging, we also saw horrifying examples of social injustice, a nation divided along political lines, weather extremes, and deadly firestorms.The year ended with a Presidential election that was contentious and uncomfortable, even long after voting had ceased.Consequently, as I look forward to 2021, I'm struck by what all of this has taught us or led us to adopt that we should resolve to retain.So, I invite you all to join me in making the following commitments:
The Use of Rifaximin in Patients With Cirrhosis
Authors: Paolo Caraceni, Victor Vargas, Elsa Solà, Carlo Alessandria, Koos de Wit, Jonel Trebicka, Paolo Angeli, Rajeshwar P. Mookerjee, François Durand, Elisa Pose, Aleksander Krag, Jasmohan S. Bajaj, Ulrich Beuers, Pere Ginès
Journal: Hepatology (2021)

Rifaximin is an oral nonsystemic antibiotic with minimal gastrointestinal absorption and broad‐spectrum antibacterial activity covering both gram‐positive and gram‐negative organisms. Rifaximin is currently used worldwide in patients with cirrhosis for preventing recurrent HE because its efficacy and safety have been proven by large randomized clinical trials. In the last decade, experimental and clinical evidence suggest that rifaximin could have other beneficial effects on the course of cirrhosis by modulating the gut microbiome and affecting the gut‐liver axis, which in turn can interfere with major events of the pathophysiological cascade underlying decompensated cirrhosis, such as systemic inflammatory syndrome, portal hypertension, and bacterial infections. However, the use of rifaximin for prevention or treatment of other complications, including spontaneous bacterial peritonitis or other bacterial infections, is not accepted because evidence by clinical trials is still very weak. The present review deals in the first part with the potential impact of rifaximin on pathogenic mechanisms in liver diseases, whereas in the second part, its clinical effects are critically discussed. It clearly emerges that, because of its potential activity on multiple pathogenic events, the efficacy of rifaximin in the prevention or management of complications other than HE deserves to be investigated extensively. The results of double‐blinded, adequately powered randomized clinical trials assessing the effect of rifaximin, alone or in combination with other drugs, on hard clinical endpoints, such as decompensation of cirrhosis, acute‐on‐chronic liver failure, and mortality, are therefore eagerly awaited.
Spain will become the sixth country worldwide to allow euthanasia and assisted suicide
Authors: Aser García Rada
Journal: BMJ (2021)

Euthanasia and assisted suicide will be legal in Spain once the country’s Senate ratifies an historical bill passed on 17 December by the Congress of Deputies, the nation’s lower house of parliament.

Following the forecasted ratification, next spring Spain will become the sixth country worldwide to acknowledge the right to an assisted death, after the Netherlands, Belgium, Luxembourg, Canada, and New Zealand. Switzerland permits assisted suicide for “unselfish reasons.”1 Several US states also allow assisted dying.

After decades of social debate and four previous failed attempts, the bill was passed with cross party support from leftist and conservative parliamentarians.

The bill, promoted by the Spanish Socialist Workers’ Party (PSOE)—ruling under a coalition with the …
Hepatic NOD2 promotes hepatocarcinogenesis via a RIP2-mediated proinflammatory response and a novel nuclear autophagy-mediated DNA damage mechanism
Authors: Yi Zhou, Liang Hu, Wenqing Tang, Dongping Li, Lijie Ma, Hongchun Liu, Shuncai Zhang, Xiaojie Zhang, Ling Dong, Xizhong Shen, She Chen, Ruyi Xue, Si Zhang
Journal: Journal of Hematology & Oncology (2021)

Abstract Background Key hepatic molecules linking gut dysbiosis and hepatocarcinogenesis remain largely unknown. Gut-derived gut microbiota contains pathogen-associated molecular patterns (PAMPs) that may circulate into the liver and, consequently, be recognized by hepatic pattern recognition receptors (PRRs). NOD2, a general intracellular PRR, recognizes muramyl dipeptide (MDP), present in both gram (+) and gram (−) bacteria. Here, we investigated the role of NOD2 as a molecular sensor translating gut dysbiosis signaling into hepatocarcinogenesis. Methods NOD2 expression was measured in clinical hepatocellular carcinoma (HCC) samples using qPCR (80 pairs), western blotting (30 pairs) and immunostaining (141 pairs). The role of NOD2 in hepatocarcinogenesis was examined in the hepatocyte-specific Nod2 -knockout ( Nod2 △hep ), Rip2 -knockout ( Rip2 △hep ), Lamin A/C -knockout ( Lamn △hep ) and Rip2 / Lamin A/C double-knockout ( Rip2/Lamn △hep ) mice models of diethylnitrosamine (DEN)/CCl 4 -induced HCC. Results NOD2 was upregulated and activated in HCC samples, and high NOD2 expression correlated with poor prognosis in HCC patients. Hepatic NOD2 deletion in vivo decreased DEN/CCl 4 -induced HCC by reducing the inflammatory response, DNA damage and genomic instability. NOD2 activation increased liver inflammation via RIP2-dependent activation of the MAPK, NF-κB and STAT3 pathways. Notably, a novel RIP2-independent mechanism was discovered, whereby NOD2 activation induces the nuclear autophagy pathway. We showed that NOD2 undergoes nuclear transport and directly binds to a component of nuclear laminae, lamin A/C, to promote its protein degradation, leading to impaired DNA damage repair and increased genomic instability. Conclusions We reveal a novel bridge, bacterial sensor NOD2, linking gut-derived microbial metabolites to hepatocarcinogenesis via induction of the inflammatory response and nuclear autophagy. Thus, we propose hepatic NOD2 as a promising therapeutic target against HCC.
The Revision of the Code.
Authors: None Harmony
Journal: JAMA (1894)

<h3>To the Editor:</h3> —Please allow a member to refute a misstatement which seems to have been purposely made by your voluminous, vituperative and dogmatic correspondent, "A Conservative Member," in his last—the tirade against the committee on revision of theAssociation'sConstitution and Code (April 21 issue). He asserts, "they were not authorized to transmogrify the Code," and that they have "greatly exceeded their instructions," etc. Now, one who attended the Detroit meeting, should know that this committee was doubly instructed to do just what it has done. The committee's announcement of their instructions and plan of work, in the Nov. 19, 1892Journalcontains an imperfectly condensed statement of the two sets of resolutions which were unanimously passed by theAssociationat two different days' sessions. Both of these sets of resolutions were offered in sympathy and harmony with President Marcy's wise and liberal recommendations contained in his admirable address,
Covid-19: Use lateral flow tests in schools to find cases, urges Independent SAGE
Authors: Matthew Limb
Journal: BMJ (2021)

<h3>Abstract</h3> Tendons are composed of a heterogeneous cell environment, with <i>Scleraxis</i>-lineage (<i>Scx</i><sup><i>Lin</i></sup>) cells being the predominant population. Although <i>Scx</i><sup><i>Lin</i></sup> cells are required for maintenance of tendon homeostasis, their functions during tendon healing are unknown. To this end, we first characterized the spatiotemporal dynamics of <i>Scx</i><sup><i>Lin</i></sup> cells during tendon healing, and identified that the overall <i>Scx</i><sup><i>Lin</i></sup> pool continuously expands up to early remodeling healing phase. To better define the function of <i>Scx</i><sup><i>Lin</i></sup> cells during the late proliferative phase of healing, we inducibly depleted <i>Scx</i><sup><i>Lin</i></sup> cells from day 14-18 post-surgery using the Scx-Cre; Rosa-DTR mouse model, with local administration of diphtheria toxin inducing apoptosis of <i>Scx</i><sup><i>Lin</i></sup> cells in the healing tendon. At D28 post-surgery, <i>Scx</i><sup><i>Lin</i></sup> cell depleted tendons (DTR) had substantial impairments in structure and function, relative to WT, demonstrating the importance of <i>Scx</i><sup><i>Lin</i></sup> cells during tendon healing. Next, bulk RNAseq was utilized to identify the underlying mechanisms that were impaired with depletion and revealed that <i>Scx</i><sup><i>Lin</i></sup> depletion induced molecular and morphological stagnation of the healing process at D28. However, this stagnation was transient, such that by D56 tendon mechanics in DTR were not significantly different than wildtype repairs. Collectively, these data offer fundamental knowledge on the dynamics and roles of <i>Scx</i><sup><i>Lin</i></sup> cells during tendon healing.
STOML2 potentiates metastasis of hepatocellular carcinoma by promoting PINK1-mediated mitophagy and regulates sensitivity to lenvatinib
Authors: Yahui Zheng, Chong Huang, Lu Lu, Kangkang Yu, Jing Zhao, Mingquan Chen, Lu Liu, Qingfeng Sun, Zhifei Lin, Jianming Zheng, Jinhong Chen, Jubo Zhang
Journal: Journal of Hematology & Oncology (2021)

Abstract Background Dysregulation of both mitochondrial biogenesis and mitophagy is critical to sustain oncogenic signaling pathways. However, the mechanism of mitophagy in promoting hepatocellular carcinoma (HCC) progression remains poorly understood. In this study, we investigated the clinical significance and biological involvement of mitochondrial inner membrane protein STOML2 in HCC. Methods STOML2 was identified by gene expression profiles of HCC tissues and was measured in tissue microarray and cell lines. Gain/loss-of-function experiment was applied to study the biological function of STOML2 in HCC. Flow cytometry, Western blotting, laser confocal microscopy, transmission electron microscopy, and co-immunoprecipitation were used to detect and analyze mitophagy. ChIP and luciferase reporter assay were conducted to evaluate the relationship between STOML2 and HIF-1α. The sensitivity to lenvatinib was assessed in HCC both in vitro and in vivo. Results Increased expression of STOML2 was found in HCC compared with paired peritumoral tissues. It was more significant in HCC with metastasis and correlated with worse overall survival and higher probability of recurrence after hepatectomy. Upregulation of STOML2 accelerated HCC cells colony formation, migration and invasion. Mechanically, TCGA dataset-based analysis showed enrichment of autophagy-related pathways in STOML2 highly-expressed HCC. Next, STOML2 was demonstrated to interact and stabilize PINK1 under cellular stress, amplify PINK1-Parkin-mediated mitophagy and then promote HCC growth and metastasis. Most interestingly, HIF-1α was upregulated and transcriptionally increased STOML2 expression in HCC cells under the treatment of lenvatinib. Furthermore, higher sensitivity to lenvatinib was found in HCC cells when STOML2 was downregulated. Combination therapy with lenvatinib and mitophagy inhibitor hydroxychloroquine obtained best efficacy. Conclusions Our findings suggested that STOML2 could amplify mitophagy through interacting and stabilizing PINK1, which promote HCC metastasis and modulate the response of HCC to lenvatinib. Combinations of pharmacologic inhibitors that concurrently block both angiogenesis and mitophagy may serve as an effective treatment for HCC.
Microbial and metabolic features associated with outcome of infliximab therapy in pediatric Crohn’s disease
Authors: Yizhong Wang, Xuefeng Gao, Xinyue Zhang, Fangfei Xiao, Hui Hu, Xiaolu Li, Fang Dong, Mingming Sun, Yongmei Xiao, Ting Ge, Dan Li, Guangjun Yu, Zhanju Liu, Ting Zhang
Journal: Gut Microbes (2021)

Gut microbial dysbiosis and altered metabonomics have been implicated in the pathogenesis of Crohn's disease (CD). The aim of our study was to characterize the gut microbiome structure and metabolic activities in pediatric CD patients with different clinical outcomes after infliximab (IFX) therapy. Fecal samples were collected from 20 healthy children and 29 newly diagnosed pediatric CD patients. 16S rRNA/ITS2 gene sequencing and targeted metabolomics analysis were applied to profile the gut bacterial microbiome, mycobiome, and metabolome, respectively. Pediatric CD patients exhibited lower relative abundances of short-chain fatty acids (SCFAs)-producing bacteria including Faecalibacterium, Clostridium clusters IV and XIVb, Roseburia, and Ruminococcus, which were correlated with reduced fecal levels of SCFAs. Decreased unconjugated bile acids (BAs) pool size and a lower unconjugated/conjugated BAs ratio were associated with reduced relative abundances of Bifidobacterium and Clostridium clusters IV and XIVb which contain bile salt hydrolases (BSH) genes. IFX treatment enriched the BSH-producing bacteria in CD subjects, which may explain a decreased level of conjugated BAs and an increase in unconjugated BAs as well as the unconjugated/conjugated BAs ratio. Furthermore, a sustained response (SR) of IFX therapy was associated with higher abundances of Methylobacterium, Sphingomonas, Staphylococcus, and Streptococcus, and higher fecal concentrations of amino acids, including L-aspartic acid, linoleic acid, and L-lactic acid at baseline. Our study suggests that the effects of IFX might be partially mediated by enriching bacteria taxa that producing SCFAs and BSH thereby inhibiting inflammation and restoring the BA metabolism. Some fecal bacteria and metabolites may be predictive of outcomes of IFX therapy for pediatric CD patients.
Follicular Lymphoma–associated BTK Mutations are Inactivating Resulting in Augmented AKT Activation
Authors: Nan Hu, Fangyang Wang, Tianyu Sun, Zhengfan Xu, Jing Zhang, Denzil Bernard, Shilin Xu, Shaomeng Wang, Mark Kaminski, Suma Devata, Tycel Phillips, Sami N. Malek
Journal: Clinical Cancer Research (2021)

On the basis of the recent discovery of mutations in Bruton tyrosine kinase (BTK) in follicular lymphoma, we studied their functional properties.We identified novel somatic BTK mutations in 7% of a combined total of 139 follicular lymphoma and 11 transformed follicular lymphoma cases, none of which had received prior treatment with B-cell receptor (BCR) targeted drugs. We reconstituted wild-type (WT) and mutant BTK into various engineered lymphoma cell lines. We measured BCR-induced signal transduction events in engineered cell lines and primary human follicular lymphoma B cells.We uncovered that all BTK mutants destabilized the BTK protein and some created BTK kinase-dead mutants. The phospholipase C gamma 2 (PLCγ2) is a substrate of BTK but the BTK mutants did not alter PLCγ2 phosphorylation. Instead, we discovered that BTK mutants induced an exaggerated AKT phosphorylation phenotype in anti-Ig-treated recombinant lymphoma cell lines. The short hairpin RNA-mediated knockdown of BTK expression in primary human nonmalignant lymph node-derived B cells resulted in strong anti-Ig-induced AKT activation, as did the degradation of BTK protein in cell lines using ibrutinib-based proteolysis targeting chimera. Finally, through analyses of primary human follicular lymphoma B cells carrying WT or mutant BTK, we detected elevated AKT phosphorylation following surface Ig crosslinking in all follicular lymphoma B cells, including all BTK-mutant follicular lymphoma. The augmented AKT phosphorylation following BCR crosslinking could be abrogated by pretreatment with a PI3Kδ inhibitor.Altogether, our data uncover novel unexpected properties of follicular lymphoma-associated BTK mutations with direct implications for targeted therapy development in follicular lymphoma.See related commentary by Afaghani and Taylor, p. 2123.
T resident helper cells promote humoral responses in the lung
Authors: Nivedya Swarnalekha, David Schreiner, Ludivine C. Litzler, Saadia Iftikhar, Daniel Kirchmeier, Marco Künzli, Young Min Son, Jie Sun, Etori Aguiar Moreira, Carolyn G. King
Journal: Science Immunology (2021)

Analysis of CD4 + T cell heterogeneity in the lung uncovers a Bcl6-dependent subset that supports mucosal antibody production.
The NHS is a tough place to work for all of us
Authors: Graham Smith
Journal: BMJ (2021)

McLachlan and Fleming make valid points about the struggles of medical training.1 But they are wrong to blame the “in my dayers” for “telling current trainees that they will never be as good as those who have gone before them.” We sympathise with current trainees, as many of the changes resulting from the reduction in hours have removed the support mechanisms that kept us sane—working in firms, living together in …
NTPDase8 protects mice from intestinal inflammation by limiting P2Y<sub>6</sub> receptor activation: identification of a new pathway of inflammation for the potential treatment of IBD
Authors: Mabrouka Salem, Joanna Lecka, Julie Pelletier, Danielle Gomes Marconato, Aline Dumas, Luc Vallières, Gaetan Brochu, Bernard Robaye, Christian Jobin, Jean Sévigny
Journal: Gut (2021)

Objective Nucleotides are danger signals that activate inflammatory responses via binding P2 receptors. The nucleoside triphosphate diphosphohydrolase-8 (NTPDase8) is an ectonucleotidase that hydrolyses P2 receptor ligands. We investigated the role of NTPDase8 in intestinal inflammation. Design We generated NTPDase8-deficient ( Entpd8 –/– ) mice to define the role of NTPDase8 in the dextran sodium sulfate (DSS) colitis model. To assess inflammation, colons were collected and analysed by histopathology, reverse transcriptase-quantitative real-time PCR (RT-qPCR) and immunohistochemistry. P2 receptor expression was analysed by RT-qPCR on primary intestinal epithelium and NTPDase8 activity by histochemistry. The role of intestinal P2Y 6 receptors was assessed by bone marrow transplantation experiments and with a P2Y 6 receptor antagonist. Results NTPDase8 is the dominant enzyme responsible for the hydrolysis of nucleotides in the lumen of the colon. Compared with wild-type (WT) control mice, the colon of Entpd8 –/– mice treated with DSS displayed significantly more histological damage, immune cell infiltration, apoptosis and increased expression of several proinflammatory cytokines. P2Y 6 was the dominant P2Y receptor expressed at the mRNA level by the colonic epithelia. Irradiated P2ry6 –/– mice transplanted with WT bone marrow were fully protected from DSS-induced intestinal inflammation. In agreement, the daily intrarectal injection of a P2Y 6 antagonist protected mice from DSS-induced intestinal inflammation in a dose-dependent manner. Finally, human intestinal epithelial cells express NTPDase8 and P2Y 6 similarly as in mice. Conclusion NTPDase8 protects the intestine from inflammation most probably by limiting the activation of P2Y 6 receptors in colonic epithelial cells. This may provide a novel therapeutic strategy for the treatment of inflammatory bowel disease.