tbuckley/cabot-search huggingface dataset:
IL-27 induces LL-37/CRAMP expression from intestinal epithelial cells: implications for immunotherapy of <i>Clostridioides difficile</i> infection
Authors: Banglao Xu, Xianan Wu, Yi Gong, Ju Cao
Journal: Gut Microbes (2021)

Clostridioides difficile infection is currently the leading cause of nosocomial antibiotic-associated diarrhea and pseudomembranous colitis worldwide. Cathelicidins, a major group of natural antimicrobial peptides, have antimicrobial and immunomodulatory activities in Clostridioides difficile infection. Here, we have shown that cytokine IL-27 induced human cathelicidin antimicrobial peptide (LL-37) expression in primary human colonic epithelial cells. IL-27 receptor-deficient mice had impaired expression of cathelicidin-related antimicrobial peptide (CRAMP, mouse homolog for human LL-37) after Clostridioides difficile infection, and restoration of CRAMP improved Clostridium difficile clearance and reduced mortality in IL-27 receptor-deficient mice after Clostridioides difficile challenge. In clinical samples from 119 patients with Clostridioides difficile infection, elevated levels of IL-27 were positively correlated with LL-37 in the sera and stools. These findings suggest that IL-27 may be involved in host immunity against Clostridioides difficile infection via induction of LL-37/CRAMP. Therefore, IL-27-LL-37 axis may be a valuable pathway in the development of immune-based therapy.
A SHHecret target of relapsed medulloblastoma: Astrocytes
Authors: Zulekha A. Qadeer, William A. Weiss
Journal: The Journal of Experimental Medicine (2021)

In this issue of JEM, Guo et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20202350) examine the importance of tumor-derived astrocytes in SHH-medulloblastoma recurrence. They show that tumor cells transdifferentiate to tumor-derived astrocytes via bone morphogenetic proteins and Sox9, which excitingly can be targeted by BMP inhibitors.
KDM5ヒストンデメチラーゼ活性は細胞トランスクリプトームの不均一性を治療抵抗性に関連付ける【JST・京大機械翻訳】
Authors: Hinohara Kunihiko, Wu Hua-Jun, Vigneau Sebastien, O McDonald Thomas, J Igarashi Kyomi, N Yamamoto Kimiyo, Madsen Thomas, Fassl Anne, B Egri Shawn, Papanastasiou Malvina, Ding Lina, Peluffo Guillermo, Cohen Ofir, C Kales Stephen, Lal-Nag Madhu, Rai Ganesha, J Maloney David, Jadhav Ajit, Simeonov Anton, Wagle Nikhil, Brown Myles, Meissner Alexander, Sicinski Piotr, D Jaffe Jacob, Jeselsohn Rinath, A Gimelbrant Alexander, Michor Franziska, Polyak Kornelia
Journal: Cancer Cell (2018)
Correction: <i>Dickkopf 1 impairs the tumor response to PD-1 blockade by inactivating CD8+ T cells in deficient mismatch repair colorectal cancer</i>
Authors: Michael A Curran, Casey R Ager, Philip Jones, Akash Boda, Kimal Rajapakshe, Spencer Thomas Lea, Maria Emilia Di Francesco, Priyamvada Jayaprakash, Ravaen B Slay, Brittany Morrow, Rishika Prasad, Meghan A Dean, Colm R Duffy, Cristian Coarfa
Journal: Journal for ImmunoTherapy of Cancer (2021)
Characterization of human FDCs reveals regulation of T cells and antigen presentation to B cells
Authors: Balthasar A. Heesters, Kyah van Megesen, Ilhan Tomris, Robert P. de Vries, Giuliana Magri, Hergen Spits
Journal: The Journal of Experimental Medicine (2021)

Stromal-derived follicular dendritic cells (FDCs) are essential for germinal centers (GCs), the site where B cells maturate their antibodies. FDCs present native antigen to B cells and maintain a CXCL13 gradient to form the B cell follicle. Yet despite their essential role, the transcriptome of human FDCs remains undefined. Using single-cell RNA sequencing and microarray, we provided the transcriptome of these enigmatic cells as a comprehensive resource. Key genes were validated by flow cytometry and microscopy. Surprisingly, marginal reticular cells (MRCs) rather than FDCs expressed B cell activating factor (BAFF). Furthermore, we found that human FDCs expressed TLR4 and can alter antigen availability in response to pathogen-associated molecular patterns (PAMPs). High expression of PD-L1 and PD-L2 on FDCs activated PD1 on T cells. In addition, we found expression of genes related to T cell regulation, such as HLA-DRA, CD40, and others. These data suggest intimate contact between human FDCs and T cells.
Association of COVID-19 Mitigation Measures With Changes in Cardiorespiratory Fitness and Body Mass Index Among Children Aged 7 to 10 Years in Austria
Authors: Gerald Jarnig, Johannes Jaunig, Mireille N. M. van Poppel
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Previous studies have shown reductions in self-reported physical activity levels in children associated with implementation of COVID-19 mitigation measures, and data on objectively assessed health parameters are limited. <h3>Objective</h3> To examine the association of COVID-19 mitigation measures with changes in cardiorespiratory fitness (CRF) measures and body mass index (BMI) among primary schoolchildren. <h3>Design, Setting, and Participants</h3> This cohort study included children aged 7 to 10 years from 12 randomly selected primary schools in urban and rural districts of Klagenfurt, Austria. Baseline CRF and BMI measurements were obtained in September 2019 before COVID-19 mitigation measures were implemented, and follow-up measurements were obtained in June and September 2020. <h3>Exposures</h3> COVID-19 mitigation measures. <h3>Main Outcomes and Measures</h3> Cardiorespiratory fitness was measured with a 6-minute endurance run test. Height and weight were objectively measured. Standard deviation scores were calculated for CRF and BMI. Changes over time were analyzed using analyses of variance. Secondary analyses were performed for subgroups stratified by sex. <h3>Results</h3> A total of 764 children (383 girls [50.1%]) aged 7 to 10 years had all measurements completed. From September 2019 to September 2020, CRF SD scores changed by −1.06 (95% CI, −1.13 to −1.00), with a similar decrease in both boys and girls. Body mass index SD scores had increased by 0.12 (95% CI, 0.06-0.16) in June 2020 and by 0.16 (95% CI, 0.12-0.20) in September 2020 compared with September 2019. The increase in BMI SD scores (from September 2019 to September 2020) was greater among boys (0.23; 95% CI, 0.18-0.29) than among girls (0.09; 95% CI, 0.04-0.15). During the 1-year period, the percentage of children with overweight or obesity increased from 20.3% (155 children) to 24.1% (184 children) (difference, 3.8% [29 children]). <h3>Conclusions and Relevance</h3> In this cohort study of children in Austria, COVID-19 mitigation measures were associated with decreases in CRF measures and increases in BMI. The findings suggest that collaborative efforts are needed to reverse these changes in children's health to prevent long-term negative health outcomes.
Clinical Importance of Left Atrial Infiltration in Cardiac Transthyretin Amyloidosis
Authors: Francesco Bandera, Raffaele Martone, Liza Chacko, Sharmananthan Ganesananthan, Janet A. Gilbertson, Markella Ponticos, Thirusha Lane, Ana Martinez-Naharro, Carol Whelan, Cristina Quarta, Dorota Rowczenio, Rishi Patel, Yousuf Razvi, Helen Lachmann, Ashutosh Wechelakar, James Brown, Daniel Knight, James Moon, Aviva Petrie, Francesco Cappelli, Marco Guazzi, Luciano Potena, Claudio Rapezzi, Ornella Leone, Philip N. Hawkins, Julian D. Gillmore, Marianna Fontana
Journal: JACC. Cardiovascular imaging (2021)

The aim of this study was to characterize left atrial (LA) pathology in explanted hearts with transthyretin amyloid cardiomyopathy (ATTR-CM); LA mechanics using echocardiographic speckle-tracking in a large cohort of patients with ATTR-CM; and to study the association with mortality.The clinical significance of LA involvement in ATTR-CM is of great clinical interest.Congo red staining and immunohistochemistry was performed to assess the presence, type, and extent of amyloid and associated changes in 5 explanted ATTR-CM atria. Echo speckle tracking was used to assess LA reservoir, conduit, contractile function, and stiffness in 906 patients with ATTR-CM (551 wild-type (wt)-ATTR-CM; 93 T60A-ATTR-CM; 241 V122I-ATTR-CM; 21 other).There was extensive ATTR amyloid infiltration in the 5 atria, with loss of normal architecture, vessels remodeling, capillary disruption, and subendocardial fibrosis. Echo speckle tracking in 906 patients with ATTR-CM demonstrated increased atrial stiffness (median [25th-75th quartile] 1.83 [1.15-2.92]) that remained independently associated with prognosis after adjusting for known predictors (lnLA stiff: HR: 1.23; 95% CI: 1.03-1.49; P = 0.029). There was substantial impairment of the 3 phasic functional atrial components (reservoir 8.86% [5.94%-12.97%]; conduit 6.5% [4.53%-9.28%]; contraction function 4.0% [2.29%-6.56%]). Atrial contraction was absent in 22.1% of patients whose electrocardiograms showed sinus rhythm (SR) "atrial electromechanical dissociation" (AEMD). AEMD was associated with poorer prognosis compared with patients with SR and effective mechanical contraction (P = 0.0018). AEMD conferred a similar prognosis to patients in atrial fibrillation.The phenotype of ATTR-CM includes significant infiltration of the atrial walls, with progressive loss of atrial function and increased stiffness, which is a strong independent predictor of mortality. AEMD emerged as a distinctive phenotype identifying patients in SR with poor prognosis.
Autophagy receptor CCDC50 tunes the STING-mediated interferon response in viral infections and autoimmune diseases
Authors: Panpan Hou, Yuxin Lin, Zibo Li, Ruiqing Lu, Yicheng Wang, Tian Tian, Penghui Jia, Xi Zhang, Liu Cao, Zhongwei Zhou, Chunmei Li, Jieruo Gu, Deyin Guo
Journal: Cellular and Molecular Immunology (2021)
Disseminated intravascular coagulation and its immune mechanisms
Authors: Narcis I. Popescu, Cristina Lupu, Florea Lupu
Journal: Blood (2021)

Disseminated intravascular coagulation (DIC) is a syndrome triggered by infectious and noninfectious pathologies characterized by excessive generation of thrombin within the vasculature and widespread proteolytic conversion of fibrinogen. Despite diverse clinical manifestations ranging from thrombo-occlusive damage to bleeding diathesis, DIC etiology commonly involves excessive activation of blood coagulation and overlapping dysregulation of anticoagulants and fibrinolysis. Initiation of blood coagulation follows intravascular expression of tissue factor or activation of the contact pathway in response to pathogen-associated or host-derived, damage-associated molecular patterns. The process is further amplified through inflammatory and immunothrombotic mechanisms. Consumption of anticoagulants and disruption of endothelial homeostasis lower the regulatory control and disseminate microvascular thrombosis. Clinical DIC development in patients is associated with worsening morbidities and increased mortality, regardless of the underlying pathology; therefore, timely recognition of DIC is critical for reducing the pathologic burden. Due to the diversity of triggers and pathogenic mechanisms leading to DIC, diagnosis is based on algorithms that quantify hemostatic imbalance, thrombocytopenia, and fibrinogen conversion. Because current diagnosis primarily assesses overt consumptive coagulopathies, there is a critical need for better recognition of nonovert DIC and/or pre-DIC states. Therapeutic strategies for patients with DIC involve resolution of the eliciting triggers and supportive care for the hemostatic imbalance. Despite medical care, mortality in patients with DIC remains high, and new strategies, tailored to the underlying pathologic mechanisms, are needed.
Trends in Prevalence of Type 1 and Type 2 Diabetes in Children and Adolescents in the US, 2001-2017
Authors: Jean M. Lawrence, Jasmin Divers, Scott Isom, Sharon Saydah, Giuseppina Imperatore, Catherine Pihoker, Santica M. Marcovina, Elizabeth J. Mayer-Davis, Richard F. Hamman, Lawrence Dolan, Dana Dabelea, David J. Pettitt, Angela D. Liese
Journal: JAMA (2021)

<h3>Importance</h3> Changes in the prevalence of youth-onset diabetes have previously been observed. <h3>Objective</h3> To estimate changes in prevalence of type 1 and type 2 diabetes in youths in the US from 2001 to 2017. <h3>Design, Setting, and Participants</h3> In this cross-sectional observational study, individuals younger than 20 years with physician-diagnosed diabetes were enumerated from 6 areas in the US (4 geographic areas, 1 health plan, and select American Indian reservations) for 2001, 2009, and 2017. <h3>Exposures</h3> Calendar year. <h3>Main Outcomes and Measures</h3> Estimated prevalence of physician-diagnosed type 1 and type 2 diabetes overall and by race and ethnicity, age, and sex. <h3>Results</h3> Among youths 19 years or younger, 4958 of 3.35 million had type 1 diabetes in 2001, 6672 of 3.46 million had type 1 diabetes in 2009, and 7759 of 3.61 million had type 1 diabetes in 2017; among those aged 10 to 19 years, 588 of 1.73 million had type 2 diabetes in 2001, 814 of 1.85 million had type 2 diabetes in 2009, and 1230 of 1.85 million had type 2 diabetes in 2017. The estimated type 1 diabetes prevalence per 1000 youths for those 19 years or younger increased significantly from 1.48 (95% CI, 1.44-1.52) in 2001 to 1.93 (95% CI, 1.88-1.98) in 2009 to 2.15 (95% CI, 2.10-2.20) in 2017, an absolute increase of 0.67 per 1000 youths (95%, CI, 0.64-0.70) and a 45.1% (95% CI, 40.0%-50.4%) relative increase over 16 years. The greatest absolute increases were observed among non-Hispanic White (0.93 per 1000 youths [95% CI, 0.88-0.98]) and non-Hispanic Black (0.89 per 1000 youths [95% CI, 0.88-0.98]) youths. The estimated type 2 diabetes prevalence per 1000 youths aged 10 to 19 years increased significantly from 0.34 (95% CI, 0.31-0.37) in 2001 to 0.46 (95% CI, 0.43-0.49) in 2009 to 0.67 (95% CI, 0.63-0.70) in 2017, an absolute increase of 0.32 per 1000 youths (95% CI, 0.30-0.35) and a 95.3% (95% CI, 77.0%-115.4%) relative increase over 16 years. The greatest absolute increases were observed among non-Hispanic Black (0.85 per 1000 youths [95% CI, 0.74-0.97]) and Hispanic (0.57 per 1000 youths [95% CI, 0.51-0.64]) youths. <h3>Conclusions and Relevance</h3> In 6 areas of the US from 2001 to 2017, the estimated prevalence of diabetes among children and adolescents increased for both type 1 and type 2 diabetes.
The prevalence of mental disorders among homeless people in high-income countries: An updated systematic review and meta-regression analysis
Authors: Stefan Gutwinski, Stefanie Schreiter, Karl Deutscher, Seena Fazel
Journal: PLoS Medicine (2021)

Background Homelessness continues to be a pressing public health concern in many countries, and mental disorders in homeless persons contribute to their high rates of morbidity and mortality. Many primary studies have estimated prevalence rates for mental disorders in homeless individuals. We conducted a systematic review and meta-analysis of studies on the prevalence of any mental disorder and major psychiatric diagnoses in clearly defined homeless populations in any high-income country. Methods and findings We systematically searched for observational studies that estimated prevalence rates of mental disorders in samples of homeless individuals, using Medline, Embase, PsycInfo, and Google Scholar. We updated a previous systematic review and meta-analysis conducted in 2007, and searched until 1 April 2021. Studies were included if they sampled exclusively homeless persons, diagnosed mental disorders by standardized criteria using validated methods, provided point or up to 12-month prevalence rates, and were conducted in high-income countries. We identified 39 publications with a total of 8,049 participants. Study quality was assessed using the JBI critical appraisal tool for prevalence studies and a risk of bias tool. Random effects meta-analyses of prevalence rates were conducted, and heterogeneity was assessed by meta-regression analyses. The mean prevalence of any current mental disorder was estimated at 76.2% (95% CI 64.0% to 86.6%). The most common diagnostic categories were alcohol use disorders, at 36.7% (95% CI 27.7% to 46.2%), and drug use disorders, at 21.7% (95% CI 13.1% to 31.7%), followed by schizophrenia spectrum disorders (12.4% [95% CI 9.5% to 15.7%]) and major depression (12.6% [95% CI 8.0% to 18.2%]). We found substantial heterogeneity in prevalence rates between studies, which was partially explained by sampling method, study location, and the sex distribution of participants. Limitations included lack of information on certain subpopulations (e.g., women and immigrants) and unmet healthcare needs. Conclusions Public health and policy interventions to improve the health of homeless persons should consider the pattern and extent of psychiatric morbidity. Our findings suggest that the burden of psychiatric morbidity in homeless persons is substantial, and should lead to regular reviews of how healthcare services assess, treat, and follow up homeless people. The high burden of substance use disorders and schizophrenia spectrum disorders need particular attention in service development. This systematic review and meta-analysis has been registered with PROSPERO (CRD42018085216). Trial registration PROSPERO CRD42018085216 .
Impact of the COVID-19 pandemic on incidence, time of diagnosis and delivery of healthcare among paediatric oncology patients in Germany in 2020: Evidence from the German Childhood Cancer Registry and a qualitative survey
Authors: Friederike Erdmann, Maike Wellbrock, Claudia Trübenbach, Claudia Spix, Martin Schrappe, Joachim Schüz, Desiree Grabow, Michael Eichinger
Journal: The Lancet Regional Health - Europe (2021)

The indirect impact of the COVID-19 pandemic on cancer care and timely diagnosis is of increasing concern. We investigated the impact of the COVID-19 pandemic on incidence, time of diagnosis and delivery of healthcare among paediatric oncology patients in Germany in 2020. We analysed incident paediatric cancer cases diagnosed in 0- to 17-year olds in Germany in 2020 using data of the German Childhood Cancer Registry. Absolute numbers and age-standardised incidence rates (ASR) in 2020 were compared to the previous five years (2015–2019). Moreover, we conducted a survey with open-ended questions, gathering perceptions of the diagnostic process and healthcare delivery for paediatric oncology patients during the COVID-19 pandemic. More or similar numbers of paediatric cancer patients were newly diagnosed each month throughout 2020 in comparison to the previous five years. The estimated ASRs showed markedly higher incidence rates, overall and across diagnostic groups, in 2020 compared to 2015-2019. Results from the qualitative survey indicated that diagnostic processes, timeliness of diagnosis, and delivery of treatment were hardly affected during the COVID-19 pandemic. However, psychosocial supportive care and non-urgent appointments were considerably reduced during the lockdown periods. We found no indications of severe adverse effects of the COVID-19 pandemic on diagnosis and delivery of healthcare among children with cancer in Germany. The underlying reasons of the increase in incidence rates remain speculative. Continued close monitoring of incidence patterns may shed light on the underlying reasons of the present increase and contribute to understanding disease aetiology. None
Garcinia cambogia, Either Alone or in Combination With Green Tea, Causes Moderate to Severe Liver Injury
Authors: Raj Vuppalanchi, Herbert L. Bonkovsky, Jawad Ahmad, Huiman Barnhart, Francisco Durazo, Robert J. Fontana, Jiezhun Gu, Ikhlas Khan, David E. Kleiner, Christopher Koh, Don C. Rockey, Elizabeth J. Phillips, Yi-Ju Li, Jose Serrano, Andrew Stolz, Hans L. Tillmann, Leonard B. Seeff, Jay H. Hoofnagle, Victor J. Navarro
Journal: Clinical Gastroenterology and Hepatology (2021)
SELP Asp603Asn and severe thrombosis in COVID-19 males
Authors: Chiara Fallerini, Sergio Daga, Elisa Benetti, Nicola Picchiotti, Kristina Zguro, Francesca Catapano, Virginia Baroni, Simone Lanini, Alessandro Bucalossi, Giuseppe Marotta, Francesca Colombo, Margherita Baldassarri, Francesca Fava, Giada Beligni, Laura Di Sarno, Diana Alaverdian, Maria Palmieri, Susanna Croci, Andrea M. Isidori, Simone Furini, Elisa Frullanti, Alessandra Renieri, Francesca Mari
Journal: Journal of Hematology & Oncology (2021)

Abstract Thromboembolism is a frequent cause of severity and mortality in COVID-19. However, the etiology of this phenomenon is not well understood. A cohort of 1186 subjects, from the GEN-COVID consortium, infected by SARS-CoV-2 with different severity was stratified by sex and adjusted by age. Then, common coding variants from whole exome sequencing were mined by LASSO logistic regression. The homozygosity of the cell adhesion molecule P-selectin gene ( SELP) rs6127 (c.1807G &gt; A; p.Asp603Asn) which has been already associated with thrombotic risk is found to be associated with severity in the male subcohort of 513 subjects (odds ratio = 2.27, 95% Confidence Interval 1.54–3.36). As the SELP gene is downregulated by testosterone, the odd ratio is increased in males older than 50 (OR 2.42, 95% CI 1.53–3.82). Asn/Asn homozygotes have increased D-dimers values especially when associated with poly Q ≥ 23 in the androgen receptor (OR 3.26, 95% CI 1.41–7.52). These results provide a rationale for the repurposing of antibodies against P-selectin as adjuvant therapy in rs6127 male homozygotes especially if older than 50 or with an impaired androgen receptor.
O-13 Gut microbiome to predict survival time in advanced gastric cancer treated with nivolumab: The DELIVER trial (JACCRO GC-08)
Authors: Y. Sunakawa, R. Matoba, E. Inoue, Y. Sakamoto, R. Kawabata, A. Ishiguro, Y. Akamaru, Y. Kito, M. Takahashi, J. Matsuyama, H. Yabusaki, A. Makiyama, T. Suzuki, M. Tsuda, H. Yasui, J. Hihara, A. Takeno, H. Kawakami, K. Muro, T. Nakajima, W. Ichikawa, M. Fujii
Journal: Annals of Oncology (2021)
Partnering With the Faith-Based Community to Address Disparities in COVID-19 Vaccination Rates and Outcomes Among US Black and Latino Populations
Authors: Anthony Evans, Joseph Webster, Glenn Flores
Journal: JAMA (2021)

This Viewpoint discusses the low rates at which Black and Latino individuals in the US are being vaccinated against COVID-19 and how the National Black Church Initiative plans to address gaps in vaccination as well as other health care disparities.
Bird evolution by insulin resistance
Authors: Takumi Satoh
Journal: Trends in Endocrinology and Metabolism (2021)

Drift of oxygen concentrations in the atmosphere was one of the main drivers of the evolution of vertebrates. The drop in oxygen concentrations at the Permian-Triassic (PT) boundary may have been the biggest challenge to vertebrates. This hypoxic condition forced theropods to lose certain genes to maximize their efficiency of oxygen usage. Recent studies show that omentin and insulin-sensitive glucose transporter 4 (GLUT4) are missing in the bird genome. Since these gene products play essential roles in maintaining insulin sensitivity, this loss forced theropods to become insulin resistant. Insulin resistance may have been the key to allowing theropods to become hyperathletic under hypoxic conditions and to outcompete mammals during the Triassic period. A second challenge was the gradual increase in oxygen concentrations during the late Jurassic, Cretaceous, and Tertiary periods when reactive oxygen species (ROS) leakage from mitochondria became a problem. Since the simplest solution was the expansion of body size, some theropods became bigger to reduce ROS leakage per volume. Another solution was the development of a constitutively active countermeasure against ROS. A recent study shows that Neoaves have constitutively active nuclear factor erythroid 2-related factor 2 (NRF2) due to deletion of the C-terminal part of the KEAP1 protein, thus allowing Neoaves to express antioxidant enzymes to overcome ROS leakage.