tbuckley/cabot-search huggingface dataset:
Scaffolds Functionalized with Matrix from Induced Pluripotent Stem Cell Fibroblasts for Diabetic Wound Healing
Authors: Francesco Santarella, Rukmani Sridharan, Milica Marinkovic, Ronaldo Jose Farias Correa Do Amaral, Brenton Cavanagh, Avi Smith, Olga Kashpur, Behzad Gerami‐Naini, Jonathan A. Garlick, Fergal J. O'Brien, Cathal J. Kearney
Journal: Advanced Healthcare Materials (2020)

Abstract Diabetic foot ulcers (DFUs) are chronic wounds, with 20% of cases resulting in amputation, despite intervention. A recently approved tissue engineering product—a cell‐free collagen‐glycosaminoglycan (GAG) scaffold—demonstrates 50% success, motivating its functionalization with extracellular matrix (ECM). Induced pluripotent stem cell (iPSC) technology reprograms somatic cells into an embryonic‐like state. Recent findings describe how iPSCs‐derived fibroblasts (“post‐iPSF”) are proangiogenic, produce more ECM than their somatic precursors (“pre‐iPSF”), and their ECM has characteristics of foetal ECM (a wound regeneration advantage, as fetuses heal scar‐free). ECM production is 45% higher from post‐iPSF and has favorable components (e.g., Collagen I and III, and fibronectin). Herein, a freeze‐dried scaffold using ECM grown by post‐iPSF cells (Post‐iPSF Coll) is developed and tested vs precursors ECM‐activated scaffolds (Pre‐iPSF Coll). When seeded with healthy or DFU fibroblasts, both ECM‐derived scaffolds have more diverse ECM and more robust immune responses to cues. Post‐iPSF‐Coll had higher GAG, higher cell content, higher Vascular Endothelial Growth Factor (VEGF) in DFUs, and higher Interleukin‐1‐receptor antagonist (IL‐1ra) vs. pre‐iPSF Coll. This work constitutes the first step in exploiting ECM from iPSF for tissue engineering scaffolds.
Covid-19: Ministers urged to waive £993 visa bill for “stranded” doctors who had exams cancelled
Authors: Abi Rimmer
Journal: BMJ (2020)

Medical bodies have urged the home secretary to extend the visas of around 200 doctors who were left stranded in the UK when the General Medical Council postponed its exams because of the covid-19 pandemic.

The BMA wrote a letter to Priti Patel which was co-signed by the British Association of Physicians of Indian Origin (BAPIO), the Association of Pakistani Physicians of Northern Europe, the Nepalese Doctors Association, the Medical Association of Nigerians Across Great Britain, and the British International Doctors’ Association.

The letter said that more than 3000 doctors were waiting to take their second Professional and Linguistic Assessments Board (PLAB 2) test—the final assessment needed before overseas doctors are granted licence to practise in the UK. …
Efficacy and safety of topical resorcinol 15% as long‐term treatment of mild‐to‐moderate hidradenitis suppurativa: a valid alternative to clindamycin in the panorama of antibiotic resistance
Authors: E. Molinelli, V. Brisigotti, O. Simonetti, A. Campanati, C. Sapigni, G.M. D’Agostino, A. Giacchetti, C. Cota, A. Offidani
Journal: British Journal of Dermatology (2020)

Hidradenitis suppurativa (HS) is a chronic inflammatory disease that affects the hair follicle in the apocrine gland-bearing regions. Although HS is not primarily caused by bacterial infection, antibiotics represent the first line treatment in the management of HS primarily for their anti-inflammatory properties, with additional contributions via antimicrobial and immunomodulatory effects.
Involvement of the M-CSF/IL-34/CSF-1R pathway in malignant pleural mesothelioma
Authors: Thibaut Blondy, Sènan Mickael d'Almeida, Tina Briolay, Julie Tabiasco, Clément Meiller, Anne-Laure Chéné, Laurent Cellerin, Sophie Deshayes, Yves Delneste, Jean-François Fonteneau, Nicolas Boisgerault, Jaafar Bennouna, Marc Grégoire, Didier Jean, Christophe Blanquart
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer related to asbestos exposure. The tumor microenvironment content, particularly the presence of macrophages, was described as crucial for the development of the disease. This work aimed at studying the involvement of the M-CSF (CSF-1)/IL-34/CSF-1R pathway in the formation of macrophages in MPM, using samples from patients. Methods Pleural effusions (PEs), frozen tumors, primary MPM cells and MPM cell lines used in this study belong to biocollections associated with clinical databases. Cytokine expressions were studied using real-time PCR and ELISA. The Cancer Genome Atlas database was used to confirm our results on an independent cohort. An original three-dimensional (3D) coculture model including MPM cells, monocytes from healthy donors and a tumor antigen-specific cytotoxic CD8 T cell clone was used. Results We observed that high interleukin (IL)-34 levels in PE were significantly associated with a shorter survival of patients. In tumors, expression of CSF1 was correlated with ‘M2-like macrophages’ markers, whereas this was not the case with IL34 expression, suggesting two distinct modes of action of these cytokines. Expression of IL34 was higher in MPM cells compared with primary mesothelial cells. Particularly, high expression of IL34 was observed in MPM cells with an alteration of CDKN2A . Finally, using 3D coculture model, we demonstrated the direct involvement of MPM cells in the formation of immunosuppressive macrophages, through activation of the colony stimulating factor-1 receptor (CSF1-R) pathway, causing the inhibition of cytotoxicity of tumor antigen-specific CD8 + T cells. Conclusions The M-CSF/IL-34/CSF-1R pathway seems strongly implicated in MPM and could constitute a therapeutic target to act on immunosuppression and to support immunotherapeutic strategies.
Requirement for LIM kinases in acute myeloid leukemia
Authors: Patrizia Jensen, Michela Carlet, Richard F. Schlenk, Andrea Weber, Jana Kress, Ines Brunner, Mikołaj Słabicki, Gregor Grill, Simon Weisemann, Ya-Yun Cheng, Irmela Jeremias, Claudia Scholl, Stefan Fröhling
Journal: Leukemia (2020)
Household finished flooring and soil-transmitted helminth and Giardia infections among children in rural Bangladesh and Kenya: a prospective cohort study
Authors: Jade Benjamin-Chung, Yoshika S Crider, Andrew Mertens, Ayse Ercumen, Amy J Pickering, Audrie Lin, Lauren Steinbaum, Jenna Swarthout, Mahbubur Rahman, Sarker M Parvez, Rashidul Haque, Sammy M Njenga, Jimmy Kihara, Clair Null, Stephen P Luby, John M Colford, Benjamin F Arnold
Journal: The Lancet Global Health (2021)

BackgroundSoil-transmitted helminths and Giardia duodenalis are responsible for a large burden of disease globally. In low-resource settings, household finished floors (eg, concrete floors) might reduce transmission of soil-transmitted helminths and G duodenalis.MethodsIn a prospective cohort of children nested within two randomised trials in rural Bangladesh and Kenya, we estimated associations between household finished flooring and soil-transmitted helminths and G duodenalis prevalence. In 2015–16, we collected stool samples from children aged 2–16 years in rural Bangladesh and Kenya. We detected soil-transmitted helminth infection using quantitative PCR (qPCR; Bangladesh n=2800; Kenya n=3094), and G duodenalis using qPCR in Bangladesh (n=6894) and ELISA in Kenya (n=8899). We estimated adjusted prevalence ratios (aPRs) using log-linear models adjusted for potential confounders.Findings7187 (92·2%) of 7795 children in Bangladesh and 9077 (93·7%) of 9686 children in Kenya provided stool specimens that were analysed by qPCR. At enrolment, 691 (10%) households in Bangladesh and 471 (5%) households in Kenya had finished floors. In both countries, household finished flooring was associated with lower Ascaris lumbricoides prevalence (Bangladesh aPR 0·33, 95% CI 0·14–0·78; Kenya 0·62, 0·39–0·98) and any soil-transmitted helminths (Bangladesh 0·73, 0·52–1·01; Kenya 0·57, 0·37–0·88). Household finished floors were also associated with lower Necator americanus prevalence in Bangladesh (0·52, 0·29–0·94) and G duodenalis prevalence in both countries (Bangladesh 0·78, 0·64–0·95; Kenya 0·82, 0·70–0·97).InterpretationIn low-resource settings, living in households with finished floors over a 2-year period was associated with lower prevalence of G duodenalis and some soil-transmitted helminths in children.FundingBill & Melinda Gates Foundation and Task Force for Global Health.
Immune modulation via T regulatory cell enhancement: Disease‐modifying therapies for autoimmunity and their potential for chronic allergic and inflammatory diseases—An EAACI position paper of the Task Force on Immunopharmacology (TIPCO)
Authors: Franziska Roth‐Walter, Ian M. Adcock, Cristina Benito‐Villalvilla, Rodolfo Bianchini, Leif Bjermer, Onur Boyman, Gaetano Caramori, Luigi Cari, Kian Fan Chung, Zuzana Diamant, Ibon Eguiluz‐Gracia, Edward F. Knol, Antonios Kolios, Francesca Levi‐Schaffer, Giuseppe Nocentini, Oscar Palomares, Frank Redegeld, Betty Van Esch, Cristiana Stellato
Journal: Allergy (2020)

Abstract Therapeutic advances using targeted biologicals and small‐molecule drugs have achieved significant success in the treatment of chronic allergic, autoimmune, and inflammatory diseases particularly for some patients with severe, treatment‐resistant forms. This has been aided by improved identification of disease phenotypes. Despite these achievements, not all severe forms of chronic inflammatory and autoimmune diseases are successfully targeted, and current treatment options, besides allergen immunotherapy for selected allergic diseases, fail to change the disease course. T cell–based therapies aim to cure diseases through the selective induction of appropriate immune responses following the delivery of engineered, specific cytotoxic, or regulatory T cells (Tregs). Adoptive cell therapies (ACT) with genetically engineered T cells have revolutionized the oncology field, bringing curative treatment for leukemia and lymphoma, while therapies exploiting the suppressive functions of Tregs have been developed in nononcological settings, such as in transplantation and autoimmune diseases. ACT with Tregs are also being considered in nononcological settings such as cardiovascular disease, obesity, and chronic inflammatory disorders. After describing the general features of T cell–based approaches and current applications in autoimmune diseases, this position paper reviews the experimental models testing or supporting T cell–based approaches, especially Treg‐based approaches, in severe IgE‐mediated responses and chronic respiratory airway diseases, such as severe asthma and COPD. Along with an assessment of challenges and unmet needs facing the application of ACT in these settings, this article underscores the potential of ACT to offer curative options for patients with severe or treatment‐resistant forms of these immune‐driven disorders.
Combination treatment with radiotherapy and a novel oxidative phosphorylation inhibitor overcomes PD-1 resistance and enhances antitumor immunity
Authors: Dawei Chen, Hampartsoum B Barsoumian, Grant Fischer, Liangpeng Yang, Vivek Verma, Ahmed I Younes, Yun Hu, Fatemeh Masropour, Katherine Klein, Christopher Vellano, Joseph Marszalek, Michael Davies, Maria Angelica Cortez, James Welsh
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Despite outstanding responses to anti-PD-1 agents in a subset of non-small cell lung cancer (NSCLC) patients, approximately 80% of patients fail to have prolonged favorable response. Recent studies show that tumor cell oxidative metabolism is a barrier to PD-1 immunotherapy and radiotherapy could overcome PD-1 resistance, so it is urgent to determine if combination treatment with radiotherapy and a novel oxidative phosphorylation (OXPHOS) inhibitor (IACS-010759) is an effective strategy against PD-1 resistance in NSCLC. Methods The antitumor effect of this combinational treatment was evaluated in vitro and in vivo. For in vivo experiments, we treated 129Sv/Ev mice with anti-PD1-sensitive and anti-PD1-resistant 344SQ NSCLC adenocarcinoma xenografts with oral IACS-010759 combined with radiotherapy (XRT). In vitro experiments included PCR, seahorse bioenergetic profiling, flow cytometry phenotyping, and clonogenic survival assay. Results In the current study, we found that our PD-1-resistant model utilized OXPHOS to a significantly greater extent than the PD-1-sensitive model and XRT increased OXPHOS in vitro and in vivo. Thus, we explored the effect of the novel OXPHOS inhibitor IACS-010759 on PD-1-resistant NSCLC in an effort to overcome XRT-induced immunosuppression and maximize response to PD-1. Additionally, combined XRT and IACS-010759 promoted antitumor effects in the PD-1-resistant model, but not in the sensitive model. After elucidation of the most optimal dose/fractionation scheme of XRT with IACS-010759, the combinatorial therapy with this regimen did not increase the abscopal antitumor effect, although IACS-010549 did not decrease CD45+, CD4+, and CD8+ immune cells. Finally, triple therapy with IACS-010759, XRT, and anti-PD-1 promoted abscopal responses and prolonged survival time. Conclusion OXPHOS inhibition as part of a combinatorial regimen with XRT is a promising strategy to address PD-1-resistant NSCLC, and this combination is being tested clinically.
Incidence and significance of venous thromboembolism in critically ill pulmonary tuberculosis patients
Authors: Angela Lau, Wendy Sligl, Ken Sun, James Barrie, Richard Long
Journal: European Respiratory Journal (2020)

<b>Venous thromboembolism (VTE) is common in critically ill pulmonary tuberculosis (PTB) patients despite thromboprophylaxis. Clinicians need to be aware of the association between PTB, VTE and critical illness as it has management and outcome implications.</b>https://bit.ly/2Ns7JWZ
Publisher Correction: Early-onset colorectal cancer: initial clues and current views
Authors: Lorne J. Hofseth, James R. Hebert, Anindya Chanda, Hexin Chen, Bryan L. Love, Maria M. Pena, E. Angela Murphy, Mathew Sajish, Amit Sheth, Phillip J. Buckhaults, Franklin G. Berger
Journal: Nature Reviews Gastroenterology & Hepatology (2020)
Diagnostic strategies for SARS-CoV-2 infection and interpretation of microbiological results
Authors: G. Caruana, A. Croxatto, A.T. Coste, O. Opota, F. Lamoth, K. Jaton, G. Greub
Journal: Clinical Microbiology and Infection (2020)

BackgroundTo face the current COVID-19 pandemic, diagnostic tools are essential. It is recommended to use real-time RT-PCR for RNA viruses in order (a) to perform a rapid and accurate diagnostic, (b) to guide patient care and management and (c) to guide epidemiological strategies. Further studies are warranted to define the role of serological diagnosis and a possible correlation between serological response and prognosis.ObjectivesThe aim was to guide clinical microbiologists in the use of these diagnostic tests and clinicians in the interpretation of their results.SourcesA search of literature was performed through PubMed and Google Scholar using the keywords SARS-CoV-2, SARS-CoV-2 molecular diagnosis, SARS-CoV-2 immune response, SARS-CoV-2 serology/antibody testing, coronavirus diagnosis.ContentThe present review discusses performances, limitations and use of current and future diagnostic tests for SARS-CoV-2.ImplicationsReal-time RT-PCR remains the reference method for diagnosis of SARS-CoV-2 infection. On the other hand, notwithstanding its varying sensitivity according to the time of infection, serology represents a valid asset (a) to try to solve possible discrepancies between a highly suggestive clinical and radiological presentation and negative RT-PCR, (b) to solve discrepancies between different PCR assays and (c) for epidemiological purposes.
TPL2 enforces RAS-induced inflammatory signaling and is activated by point mutations
Authors: Paarth B. Dodhiawala, Namrata Khurana, Daoxiang Zhang, Yi Cheng, Lin Li, Qing Wei, Kuljeet Seehra, Hongmei Jiang, Patrick M. Grierson, Andrea Wang-Gillam, Kian-Huat Lim
Journal: Journal of Clinical Investigation (2020)

NF-κB transcription factors, driven by the IRAK/IKK cascade, confer treatment resistance in pancreatic ductal adenocarcinoma (PDAC), a cancer characterized by near-universal KRAS mutation. Through reverse-phase protein array and RNA sequencing we discovered that IRAK4 also contributes substantially to MAPK activation in KRAS-mutant PDAC. IRAK4 ablation completely blocked RAS-induced transformation of human and murine cells. Mechanistically, expression of mutant KRAS stimulated an inflammatory, autocrine IL-1β signaling loop that activated IRAK4 and the MAPK pathway. Downstream of IRAK4, we uncovered TPL2 (also known as MAP3K8 or COT) as the essential kinase that propels both MAPK and NF-κB cascades. Inhibition of TPL2 blocked both MAPK and NF-κB signaling, and suppressed KRAS-mutant cell growth. To counter chemotherapy-induced genotoxic stress, PDAC cells upregulated TLR9, which activated prosurvival IRAK4/TPL2 signaling. Accordingly, a TPL2 inhibitor synergized with chemotherapy to curb PDAC growth in vivo. Finally, from TCGA we characterized 2 MAP3K8 point mutations that hyperactivate MAPK and NF-κB cascades by impeding TPL2 protein degradation. Cancer cell lines naturally harboring these MAP3K8 mutations are strikingly sensitive to TPL2 inhibition, underscoring the need to identify these potentially targetable mutations in patients. Overall, our study establishes TPL2 as a promising therapeutic target in RAS- and MAP3K8-mutant cancers and strongly prompts development of TPL2 inhibitors for preclinical and clinical studies.
FRI0153 ULTRA HIGH-RESOLUTION ULTRASOUND (UHFUS) OF LABIAL SALIVARY GLANDS: POTENTIAL APPLICATIONS IN PRIMARY SJÖGREN’S SYNDROME
Authors: C. Baldini, F. Ferro, R. Izzetti, S. Vitali, S. Fonzetti, G. Governato, G. Aringhieri, E. Elefante, M. Mosca, V. Donati, D. Caramella
Journal: Annals of the Rheumatic Diseases (2020)

Background: Major salivary gland ultrasonography has an established role in diagnosis and assessment of pSS. Nowadays, however, interest is also growing in last-generation ultra high resolution ultrasound (UHFUS) transducers, which can produce frequencies up to 70 MHz and achieve tissue resolution up to 30 μm, opening up new possibilities for the study labial salivary glands (LSG). Objectives: To investigate the usefulness of UHFUS in LSG ultrasound-guided biopsy and preoperative planning. Methods: Consecutive patients undergoing a LSG for clinically suspected pSS were included in this study from January 2018 to December 2019. UHFUS of LSG was performed by using VEVO MD, equipped with a 70 MHz probe, scanning first the central compartment of the inferior lip, and then both peripheral compartments. The following parameters were evaluated: distribution of the glands, parenchymal inhomogeneity (score 0-3, from normal to evident), and fibrosis. UHFUS imaging was used to help locate the LSG for the US-guided biopsy. The same expert pathologist calculated the surface area of gland sections examined, the LSG focus score (FS), the number of foci and evaluated the presence of ectopic germinal centers (GCs). Consecutive patients that had undergone a traditional LSG biopsy from December 2016 to December 2017 were included as controls. Results: We included a total of 249 patients with suspected pSS: 137 undergoing the UHFUS-guided LSGs and 112 the traditional LSG biopsy procedure. No demographic differences were observed between the two groups. No differences were also observed in the distribution of the final diagnosis. A diagnosis of pSS according the ACR 2016 criteria was made in 60/137 (43.8%) and 36/112 (32.1%) patients, respectively whereas a diagnosis of no-SS sicca was made in 44/137 (32.1%) and in 43/112 (38.4%) patients; the remaining diagnosis included secondary SS (4/137, 3% and 9/112, 8%) and undifferentiated connective tissue disease (UCTD) (29/137, 21.2%, and 24/112, 21.4%). With respect to no-SS sicca controls and UCTD patients, pSS patients presented higher UHFUS inhomogeneity scores in both central and peripheral labial compartments (p=0.001). There were no complications from the HUFUS-guided LSG biopsy. The mean glandular surface area obtained was significantly higher than the area obtained by traditional LSG biopsy procedure (7.4 ±4.0 mm 2 vs 6.3±3.7 mm 2 , p=0.02) thus facilitating the assessment of the FS. Interestingly, the latter showed a good correlation with the UHFUS inhomogeneity (r=0.509**, p=0.000). Conclusion: UHFUS of LSG appeared feasible and sensitive in pSS, potentially offering unique advantages in LSG ultrasound-guided biopsy. Disclosure of Interests: None declared
Evaluation of the Merits and Limitations of Evidence-Based Medicine—Reply
Authors: Arash Mostaghimi, Adewole Adamson, John Barbieri
Journal: JAMA Dermatology (2020)

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Lack of Handwashing Access: A Widespread Deficiency in the Age of COVID-19
Authors: Charles W. Schmidt
Journal: Environmental Health Perspectives (2020)

Handwashing is a basic and critically important component of sanitation.Lack of access to proper facilities contributed to hundreds of thousands of deaths in 2017 from diarrheal diseases and lower respiratory infections. 12That means scaling up handwashing access to address COVID-19 can have long-term benefits by preventing other diseases.