tbuckley/cabot-search huggingface dataset:
Gut microbial bile acid metabolite skews macrophage polarization and contributes to high-fat diet-induced colonic inflammation
Authors: Lingyu Wang, Zizhen Gong, Xiuyuan Zhang, Fangxinxing Zhu, Yuchen Liu, Chaozhi Jin, Xixi Du, Congfeng Xu, Yingwei Chen, Wei Cai, Chunyan Tian, Jin Wu
Journal: Gut Microbes (2020)

High-fat diet (HFD) leads to systemic low-grade inflammation, which has been involved in the pathogenesis of diverse metabolic and inflammatory diseases. Colon is thought to be the first organ suffering from inflammation under HFD conditions due to the pro-inflammatory macrophages infiltration, however, the mechanisms concerning the induction of pro-inflammatory phenotype of colonic macrophages remains unclear. In this study, we show that HFD increased the percentage of gram-positive bacteria, especially genus Clostridium, and resulted in the significant increment of fecal deoxycholic acid (DCA), a gut microbial metabolite produced by bacteria mainly restricted to genus Clostridium. Notably, reducing gram-positive bacteria with vancomycin diminished fecal DCA and profoundly alleviated pro-inflammatory macrophage infiltration in colon, whereas DCA-supplemented feedings to vancomycin-treated mice provoked obvious pro-inflammatory macrophage infiltration and colonic inflammation. Meanwhile, intra-peritoneal administration of DCA also elicited considerable recruitment of macrophages with pro-inflammatory phenotype. Mechanistically, DCA dose-dependently promoted M1 macrophage polarization and pro-inflammatory cytokines production at least partially through toll-like receptor 2 (TLR2) transactivated by M2 muscarinic acetylcholine receptor (M2-mAchR)/Src pathway. In addition, M2-mAchR mediated increase of TLR2 transcription was mainly achieved via targeting AP-1 transcription factor. Moreover, NF-κB/ERK/JNK signalings downstream of TLR2 are involved in the DCA-induced macrophage polarization. In conclusion, our findings revealed that high level DCA induced by HFD may serve as an initiator to activate macrophages and drive colonic inflammation, thus offer a mechanistic basis that modulation of gut microbiota or intervening specific bile acid receptor signaling could be potential therapeutic approaches for HFD-related inflammatory diseases.
A Crazy Cause of Dyspnea
Authors: Amy Leigh Miller, Scott Schissel, Bruce D. Levy, Joseph Loscalzo
Journal: New England Journal of Medicine (2011)

An 18-year-old black woman with a history of asthma presented with fever, ear pain, and dull discomfort on the right side of the chest that was unchanged with movement or inspiration. A radiograph revealed air-space opacities in both lungs.
Brentuximab vedotin plus nivolumab as first-line therapy in older or chemotherapy-ineligible patients with Hodgkin lymphoma (ACCRU): a multicentre, single-arm, phase 2 trial
Authors: Bruce D Cheson, Nancy L Bartlett, Betsy LaPlant, Hun J Lee, Ranjana J Advani, Beth Christian, Catherine S Diefenbach, Tatyana A Feldman, Stephen M Ansell
Journal: The Lancet Haematology (2020)
Program Components and Results From an Organized Colorectal Cancer Screening Program Using Annual Fecal Immunochemical Testing
Authors: Kevin Selby, Christopher D. Jensen, Theodore R. Levin, Jeffrey K. Lee, Joanne E. Schottinger, Wei K. Zhao, Douglas A. Corley, Chyke A. Doubeni
Journal: Clinical Gastroenterology and Hepatology (2020)

Programmatic colorectal cancer (CRC) screening increases uptake, but the design and resources utilized for such models are not well known. We characterized program components and participation at each step in a large program that used mailed fecal immunochemical testing (FIT) with opportunistic colonoscopy.Mixed-methods with site visits and retrospective cohort analysis of 51-75-year-old adults during 2017 in the Kaiser Permanente Northern California integrated health system.Among 1,023,415 screening-eligible individuals, 405,963 (40%) were up to date with screening at baseline, and 507,401 of the 617,452 not up-to-date were mailed a FIT kit. Of the entire cohort (n = 1,023,415), 206,481 (20%) completed FIT within 28 days of mailing, another 61,644 (6%) after a robocall at week 4, and 40,438 others (4%) after a mailed reminder letter at week 6. There were over 800,000 medical record screening alerts generated and about 295,000 FIT kits distributed during patient office visits. About 100,000 FIT kits were ordered during direct-to-patient calls by medical assistants and 111,377 people (11%) completed FIT outside of the automated outreach period. Another 13,560 (1.3%) completed a colonoscopy, sigmoidoscopy, or fecal occult blood test unrelated to FIT. Cumulatively, 839,463 (82%) of those eligible were up to date with screening at the end of the year and 12,091 of 14,450 patients (83.7%) with positive FIT had diagnostic colonoscopy.The >82% screening participation achieved in this program resulted from a combination of prior endoscopy (40%), large initial response to mailed FIT kits (20%), followed by smaller responses to automated reminders (10%) and personal contact (12%).
Therapy Approved for Rare Neurological Autoimmune Disorder
Authors: Rebecca Voelker
Journal: JAMA (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Dolutegravir-based and low-dose efavirenz-based regimen for the initial treatment of HIV-1 infection (NAMSAL): week 96 results from a two-group, multicentre, randomised, open label, phase 3 non-inferiority trial in Cameroon
Authors: Alexandra Calmy, Tamara Tovar Sanchez, Charles Kouanfack, Mireille Mpoudi-Etame, Sandrine Leroy, Ségolène Perrineau, Martial Lantche Wandji, Darius Tetsa Tata, Pierette Omgba Bassega, Thérèse Abong Bwenda, Marie Varloteaux, Marcel Tongo, Eitel Mpoudi-Ngolé, Alice Montoyo, Noémie Mercier, Vincent LeMoing, Martine Peeters, Jacques Reynes, Eric Delaporte, A Calmy, T Tovar Sanchez, C Kouanfack, M Mpoudi-Etame, S Leroy, S Perrineau, M Lantche-Wandji, D Tetsa-Tata, P Omgba-Bassega, T Abong-Bwenda, M Varloteaux, M Tongo, E Mpoudi-Ngolé, A Montoyo, N Mercier, V LeMoing, M Peeters, J Reynes, E Delaporte, A Ayouba, A Agholeng, C Butel, A Cournil, S Eymard-Duvernay, B Granouillac, S Izard, A Lacroix, L Serrano, N Vidal, PJ Fouda, R Mougnoutou, J Olinga, V Omgba, SC Tchokonte-Ngandé, B Ymele, CD Epoupa-Mpacko, M Fotso, R Moukoko, T Nké, A Akamba, S Lekelem, SB Tongo-Fotack, S Ngono, M Tanga, E Ebong, G Edoul-Mbesse, M Tongo, L Ciaffi, S Koulla-Shiro, G Manirakiza, ED Mimbé, S Boyer, M Bousmah, G Maradan, ML Nishimwe, B Spire, MP Lê, G Peytavin, A Diallo, I Fournier, C Rekacewicz, C Perez Casas
Journal: The Lancet HIV (2020)
Abstract 13962: Precision Pharmacological Treatment for Obstructive Hypertrophic Cardiomyopathy With Mavacamten: One-Year Results From PIONEER-OLE
Authors: Stephen B Heitner, Steven Lester, Andrew Wang, Sheila M Hegde, Liang Fang, Ganesh Balaratnam, Amy J Sehnert, Daniel Jacoby
Journal: Circulation (2019)

Introduction: Despite the well-established need for disease-specific pharmacological therapies in hypertrophic cardiomyopathy (HCM), there has been little success to date. Mavacamten (Mava), a targ...
Morbidity and mortality associated with prescription cannabinoid drug use in COPD
Authors: Nicholas T Vozoris, Priscila Pequeno, Ping Li, Peter C Austin, Anne L Stephenson, Denis E O'Donnell, Sudeep S Gill, Andrea S Gershon, Paula A Rochon
Journal: Thorax (2020)

Introduction Respiratory-related morbidity and mortality were evaluated in relation to incident prescription oral synthetic cannabinoid (nabilone, dronabinol) use among older adults with chronic obstructive pulmonary disease (COPD). Methods This was a retrospective, population-based, data-linkage cohort study, analysing health administrative data from Ontario, Canada, from 2006 to 2016. We identified individuals aged 66 years and older with COPD, using a highly specific, validated algorithm, excluding individuals with malignancy and those receiving palliative care (n=185 876 after exclusions). An equivalent number (2106 in each group) of new cannabinoid users (defined as individuals dispensed either nabilone or dronabinol, with no dispensing for either drug in the year previous) and controls (defined as new users of a non-cannabinoid drug) were matched on 36 relevant covariates, using propensity scoring methods. Cox proportional hazard regression was used. Results Rate of hospitalisation for COPD or pneumonia was not significantly different between new cannabinoid users and controls (HR 0.87; 95% CI 0.61–1.24). However, significantly higher rates of all-cause mortality occurred among new cannabinoid users compared with controls (HR 1.64; 95% CI 1.14–2.39). Individuals receiving higher-dose cannabinoids relative to controls were observed to experience both increased rates of hospitalisation for COPD and pneumonia (HR 2.78; 95% CI 1.17–7.09) and all-cause mortality (HR 3.31; 95% CI 1.30–9.51). Conclusions New cannabinoid use was associated with elevated rates of adverse outcomes among older adults with COPD. Although further research is needed to confirm these observations, our findings should be considered in decisions to use cannabinoids among older adults with COPD.
Covid-19: public messaging on vaccination must heed warnings from confused face mask messaging
Authors: Simon E Kolstoe
Journal: BMJ (2020)

One reason face coverings have become a contentious issue is the medical community’s failure to make clear why people are being asked to wear them.1

At the beginning of the pandemic, people were “panic buying” products including toilet roll, so it made sense not to promote the buying of medical masks by the public, especially as the medical community was experiencing shortages of …
Influenza infection fortifies local lymph nodes to promote lung-resident heterosubtypic immunity
Authors: Daniel H. Paik, Donna L. Farber
Journal: The Journal of Experimental Medicine (2020)

Influenza infection generates tissue-resident memory T cells (TRMs) that are maintained in the lung and can mediate protective immunity to heterologous influenza strains, but the precise mechanisms of local T cell–mediated protection are not well understood. In a murine heterosubtypic influenza challenge model, we demonstrate that protective lung T cell responses derive from both in situ activation of TRMs and the enhanced generation of effector T cells from the local lung draining mediastinal lymph nodes (medLNs). Primary infection fortified the medLNs with an increased number of conventional dendritic cells (cDCs) that mediate enhanced priming of T cells, including those specific for newly encountered epitopes; cDC depletion during the recall response diminished medLN T cell generation and heterosubtypic immunity. Our study shows that during a protective recall response, cDCs in a fortified LN environment enhance the breadth, generation, and tissue migration of effector T cells to augment lung TRM responses.
Biallelic Pathogenic GFRA1 Variants Cause Autosomal Recessive Bilateral Renal Agenesis
Authors: Veronica Arora, Suliman Khan, Ayman W. El-Hattab, Ratna Dua Puri, Maria Eugenia Rocha, Rijad Merdzanic, Omid Paknia, Christian Beetz, Arndt Rolfs, Aida M. Bertoli-Avella, Peter Bauer, Ishwar C. Verma
Journal: Journal of the American Society of Nephrology (2020)

Significance Statement Bilateral renal agenesis (BRA) represents the most severe form of congenital anomalies of the kidney and the urinary tract. Currently, only three genes are known to cause nonsyndromic BRA in humans. The rarity and the high mortality of BRA make it challenging to identify additional loci. Genome sequencing identified a novel causal association of GFRA1 variants with BRA in humans. Two homozygous, putative, loss-of-function variants (p.Arg226* and p.Thr432Profs*) were found in index cases with BRA from two unrelated consanguineous families by prioritizing homozygous variants and conducting a dedicated database search. These findings have implications for early genetic diagnosis and genetic counseling for families with BRA. Background Congenital anomalies of the kidney and urinary tract (CAKUT) are one of the most common malformations identified in the fetal stage. Bilateral renal agenesis (BRA) represents the most severe and fatal form of CAKUT. Only three genes have been confirmed to have a causal role in humans ( ITGA8 , GREB1L , and FGF20 ). Methods Genome sequencing within a diagnostic setting and combined data repository analysis identified a novel gene. Results Two patients presented with BRA, detected during the prenatal period, without additional recognizable malformations. They had parental consanguinity and similarly affected, deceased siblings, suggesting autosomal recessive inheritance. Evaluation of homozygous regions in patient 1 identified a novel, nonsense variant in GFRA1 (NM_001348097.1:c.676C&gt;T, p.[Arg226*]). We identified 184 patients in our repository with renal agenesis and analyzed their exome/genome data. Of these 184 samples, 36 were from patients who presented with isolated renal agenesis. Two of them had loss-of-function variants in GFRA1 . The second patient was homozygous for a frameshift variant (NM_001348097.1:c.1294delA, p.[Thr432Profs*13]). The GFRA1 gene encodes a receptor on the Wolffian duct that regulates ureteric bud outgrowth in the development of a functional renal system, and has a putative role in the pathogenesis of Hirschsprung disease. Conclusions These findings strongly support the causal role of GFRA1 -inactivating variants for an autosomal recessive, nonsyndromic form of BRA. This knowledge will enable early genetic diagnosis and better genetic counseling for families with BRA.
IL-22–induced cell extrusion and IL-18–induced cell death prevent and cure rotavirus infection
Authors: Zhan Zhang, Jun Zou, Zhenda Shi, Benyue Zhang, Lucie Etienne-Mesmin, Yanling Wang, Xuyan Shi, Feng Shao, Benoit Chassaing, Andrew T. Gewirtz
Journal: Science Immunology (2020)

Bacterial flagellin can elicit production of TLR5-mediated IL-22 and NLRC4-mediated IL-18 cytokines that act in concert to cure and prevent rotavirus (RV) infection. This study investigated the mechanism by which these cytokines act to impede RV. Although IL-18 and IL-22 induce each other's expression, we found that IL-18 and IL-22 both impeded RV independently of one another and did so by distinct mechanisms that involved activation of their cognate receptors in intestinal epithelial cells (IEC). IL-22 drove IEC proliferation and migration toward villus tips, which resulted in increased extrusion of highly differentiated IEC that serve as the site of RV replication. In contrast, IL-18 induced cell death of RV-infected IEC thus directly interrupting the RV replication cycle, resulting in spewing of incompetent virus into the intestinal lumen and causing a rapid drop in the number of RV-infected IEC. Together, these actions resulted in rapid and complete expulsion of RV, even in hosts with severely compromised immune systems. These results suggest that a cocktail of IL-18 and IL-22 might be a means of treating viral infections that preferentially target short-lived epithelial cells.
Abstract A06: Differential response to autophagy in primary versus melanoma cells
Authors: Lauren C. Morehead, Alan J. Tackett, Isabelle R. Miousse
Journal: Cancer Research (2020)

Abstract Autophagy is a cellular recycling mechanism triggered by nutrient scarcity. Upregulation of autophagy is associated with lifespan extension, DNA repair, and improved cancer immune recognition. Cancer cells can also utilize this mechanism to cope with nutrient-limited conditions. Chloroquine, an inhibitor of autophagy, has shown promising results alone and in combination with other anticancer agents in various types of cancer. However, several promoters of autophagy have also been shown to display potent anticancer properties. To better understand the relationship between autophagy and cancer, we tested promoters and inhibitors of autophagy in a metastatic melanoma cell line (B16F10) and compared the results with primary human dermal fibroblasts (HDF). After 48h, all tested promoters and inhibitors of autophagy decreased the number of live cells in the B16F10 melanoma cell line compared to untreated controls. In primary cells, promotion of autophagy with methionine restriction (25 μM versus 100 μM in control), complete methionine replacement with homocysteine, and 50 μM of the polyamine spermidine did not affect the number of live cells. Sulforaphane (10 μM) and serum starvation significantly decreased the number of live primary cells. Inhibition of autophagy with 6.25 μM chloroquine did not affect primary cell numbers, while there was a significant decrease in cell numbers associated with a dose of 10 μM of chloroquine and 0.1 μM bafilomycin A1. Cell numbers remained unaffected by longer incubations (96h with replenishment after 48h) of HDF cells with methionine restriction, replacement of methionine with homocysteine, and 6.25 μM chloroquine. These data suggest that cancer cells are more sensitive to both promotion and inhibition of autophagy than primary cells. Interesting compound-specific differences were noted in primary cells. Ongoing preclinical studies evaluate the potential of modulating autophagy as an adjuvant cancer therapy for immune checkpoint inhibitors in metastatic melanoma. Citation Format: Lauren C. Morehead, Alan J. Tackett, Isabelle R. Miousse. Differential response to autophagy in primary versus melanoma cells [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A06.
Ionotropic Receptors as a Driving Force behind Human Synapse Establishment
Authors: Lucas Henriques Viscardi, Danilo Oliveira Imparato, Maria Cátira Bortolini, Rodrigo Juliani Siqueira Dalmolin
Journal: Molecular Biology and Evolution (2020)

The origin of nervous systems is a main theme in biology and its mechanisms are largely underlied by synaptic neurotransmission. One problem to explain synapse establishment is that synaptic orthologs are present in multiple aneural organisms. We questioned how the interactions among these elements evolved and to what extent it relates to our understanding of the nervous systems complexity. We identified the human neurotransmission gene network based on genes present in GABAergic, glutamatergic, serotonergic, dopaminergic, and cholinergic systems. The network comprises 321 human genes, 83 of which act exclusively in the nervous system. We reconstructed the evolutionary scenario of synapse emergence by looking for synaptic orthologs in 476 eukaryotes. The Human-Cnidaria common ancestor displayed a massive emergence of neuroexclusive genes, mainly ionotropic receptors, which might have been crucial to the evolution of synapses. Very few synaptic genes had their origin after the Human-Cnidaria common ancestor. We also identified a higher abundance of synaptic proteins in vertebrates, which suggests an increase in the synaptic network complexity of those organisms.
Recent advances in the role of the adenosinergic system in coronary artery disease
Authors: Franck Paganelli, Marine Gaudry, Jean Ruf, Régis Guieu
Journal: Cardiovascular Research (2020)

Abstract Adenosine is an endogenous nucleoside that plays a major role in the physiology and physiopathology of the coronary artery system, mainly by activating its A2A receptors (A2AR). Adenosine is released by myocardial, endothelial, and immune cells during hypoxia, ischaemia, or inflammation, each condition being present in coronary artery disease (CAD). While activation of A2AR improves coronary blood circulation and leads to anti-inflammatory effects, down-regulation of A2AR has many deleterious effects during CAD. A decrease in the level and/or activity of A2AR leads to: (i) lack of vasodilation, which decreases blood flow, leading to a decrease in myocardial oxygenation and tissue hypoxia; (ii) an increase in the immune response, favouring inflammation; and (iii) platelet aggregation, which therefore participates, in part, in the formation of a fibrin-platelet thrombus after the rupture or erosion of the plaque, leading to the occurrence of acute coronary syndrome. Inflammation contributes to the development of atherosclerosis, leading to myocardial ischaemia, which in turn leads to tissue hypoxia. Therefore, a vicious circle is created that maintains and aggravates CAD. In some cases, studying the adenosinergic profile can help assess the severity of CAD. In fact, inducible ischaemia in CAD patients, as assessed by exercise stress test or fractional flow reserve, is associated with the presence of a reserve of A2AR called spare receptors. The purpose of this review is to present emerging experimental evidence supporting the existence of this adaptive adenosinergic response to ischaemia or inflammation in CAD. We believe that we have achieved a breakthrough in the understanding and modelling of spare A2AR, based upon a new concept allowing for a new and non-invasive CAD management.
Disease Course and Outcomes of COVID-19 Among Hospitalized Patients With Gastrointestinal Manifestations
Authors: Monika Laszkowska, Adam S. Faye, Judith Kim, Han Truong, Elisabeth R. Silver, Myles Ingram, Benjamin May, Benjamin Ascherman, Logan Bartram, Jason Zucker, Magdalena E. Sobieszczyk, Julian A. Abrams, Benjamin Lebwohl, Daniel E. Freedberg, Chin Hur
Journal: Clinical Gastroenterology and Hepatology (2020)

Background & AimsOur understanding of outcomes and disease time course of COVID-19 in patients with gastrointestinal (GI) symptoms remains limited. In this study we characterize the disease course and severity of COVID-19 among hospitalized patients with gastrointestinal manifestations in a large, diverse cohort from the Unites States.MethodsThis retrospective study evaluated hospitalized individuals with COVID-19 between March 11 and April 28, 2020 at two affiliated hospitals in New York City. We evaluated the association between GI symptoms and death, and also explored disease duration, from symptom onset to death or discharge.ResultsOf 2804 patients hospitalized with COVID-19, the 1,084 (38.7%) patients with GI symptoms were younger (aOR for age ≥75, 0.59; 95% CI, 0.45-0.77) and had more co-morbidities (aOR for modified Charlson comorbidity score ≥2, 1.22; 95% CI, 1.01-1.48) compared to those without GI symptoms. Individuals with GI symptoms had better outcomes, with a lower likelihood of intubation (aHR, 0.66; 95% CI, 0.55-0.79) and death (aHR, 0.71; 95% CI, 0.59-0.87), after adjusting for clinical factors. These patients had a longer median disease course from symptom onset to discharge (13.8 vs 10.8 days, log-rank p = .048; among 769 survivors with available symptom onset time), which was driven by longer time from symptom onset to hospitalization (7.4 vs 5.4 days, log-rank P < .01).ConclusionHospitalized patients with GI manifestations of COVID-19 have a reduced risk of intubation and death, but may have a longer overall disease course driven by duration of symptoms prior to hospitalization.