tbuckley/cabot-search huggingface dataset:
Triclocarban, Triclosan, Bromochlorophene, Chlorophene, and Climbazole Effects on Nuclear Receptors: An <i>in Silico</i> and <i>in Vitro</i> Study
Authors: Maša Kenda, Nataša Karas Kuželički, Mitsuru Iida, Hiroyuki Kojima, Marija Sollner Dolenc
Journal: Environmental Health Perspectives (2020)

Endocrine-disrupting chemicals can interfere with hormonal homeostasis and have adverse effects for both humans and the environment. Their identification is increasingly difficult due to lack of adequate toxicological tests. This difficulty is particularly problematic for cosmetic ingredients, because
Microbiota Effects on Carcinogenesis: Initiation, Promotion, and Progression
Authors: Lacey R. Lopez, Rachel M. Bleich, Janelle C. Arthur
Journal: Annual Review of Medicine (2020)

Carcinogenesis is a multistep process by which normal cells acquire genetic and epigenetic changes that result in cancer. In combination with host genetic susceptibility and environmental exposures, a prominent procarcinogenic role for the microbiota has recently emerged. In colorectal cancer (CRC), three nefarious microbes have been consistently linked to cancer development: (a) Colibactin-producing Escherichia coli initiates carcinogenic DNA damage, (b) enterotoxigenic Bacteroides fragilis promotes tumorigenesis via toxin-induced cell proliferation and tumor-promoting inflammation, and (c) Fusobacterium nucleatum enhances CRC progression through two adhesins, Fap2 and FadA, that promote proliferation and antitumor immune evasion and may contribute to metastases. Herein, we use these three prominent microbes to discuss the experimental evidence linking microbial activities to carcinogenesis and the specific mechanisms driving this stepwise process. Precisely defining mechanisms by which the microbiota impacts carcinogenesis at each stage is essential for developing microbiota-targeted strategies for the diagnosis, prognosis, and treatment of cancer.
MTOR suppresses autophagy-mediated production of IL25 in allergic airway inflammation
Authors: Wen Li, Yinfang Wu, Yun Zhao, Zhouyang Li, Haixia Chen, Lingling Dong, Huiwen Liu, Min Zhang, Yanping Wu, Jiesen Zhou, Juan Xiong, Yue Hu, Wen Hua, Bin Zhang, Minzhi Qiu, Qing-ling Zhang, Chunhua Wei, Mingchun Wen, Jing Han, Xiaobo Zhou, Weiliang Qiu, Fugui Yan, Huaqiong Huang, Songmin Ying, Augustine M K Choi, Huahao Shen, Zhihua Chen
Journal: Thorax (2020)

Introduction Airway epithelial cells are recognised as an essential controller for the initiation and perpetuation of asthmatic inflammation, yet the detailed mechanisms remain largely unknown. This study aims to investigate the roles and mechanisms of the mechanistic target of rapamycin (MTOR)–autophagy axis in airway epithelial injury in asthma. Methods We examined the MTOR–autophagy signalling in airway epithelium from asthmatic patients or allergic mice induced by ovalbumin or house dust mites, or in human bronchial epithelial (HBE) cells. Furthermore, mice with specific MTOR knockdown in airway epithelium and autophagy-related lc3b -/- mice were used for allergic models. Results MTOR activity was decreased, while autophagy was elevated, in airway epithelium from asthmatic patients or allergic mice, or in HBE cells treated with IL33 or IL13. These changes were associated with upstream tuberous sclerosis protein 2 signalling. Specific MTOR knockdown in mouse bronchial epithelium augmented, while LC3B deletion diminished allergen-induced airway inflammation and mucus hyperproduction. The worsened inflammation caused by MTOR deficiency was also ameliorated in lc3b -/- mice. Mechanistically, autophagy was induced later than the emergence of allergen-initiated inflammation, particularly IL33 expression. MTOR deficiency increased, while knocking out of LC3B abolished the production of IL25 and the eventual airway inflammation on allergen challenge. Blocking IL25 markedly attenuated the exacerbated airway inflammation in MTOR-deficiency mice. Conclusion Collectively, these results demonstrate that allergen-initiated inflammation suppresses MTOR and induces autophagy in airway epithelial cells, which results in the production of certain proallergic cytokines such as IL25, further promoting the type 2 response and eventually perpetuating airway inflammation in asthma.
Disruption of retinoid homeostasis induces RBP4 overproduction in diabetes: O-GlcNAcylation involved
Authors: Shyi-Jang Shin, Chao-Hung Chen, Wen-Chen Kuo, Hua-Chen Chan, Hsiu-Chuan Chan, Kun-Der Lin, Liang-Yin Ke
Journal: Metabolism (2020)
Donor-derived CD19 CAR-T cell therapy of relapse of CD19-positive B-ALL post allotransplant
Authors: Cheng Zhang, Xiao-Qi Wang, Rong-Li Zhang, Fang Liu, Yi Wang, Zhi-Ling Yan, Yong-Ping Song, Ting Yang, Ping Li, Zhen Wang, Ying-Ying Ma, Lei Gao, Yao Liu, Li Gao, Pei-Yan Kong, Jun Liu, Xu Tan, Jiang F. Zhong, Yu-Qing Chen, Ai-Bin Liang, Jin-Hua Ren, Zhen-Yu Li, Jiang Cao, Quan-Li Gao, Jian Zhou, Ying Gao, Ding Zhang, Fang-Yi Fan, Ming-Zhe Han, Robert Peter Gale, Xi Zhang
Journal: Leukemia (2020)

Abstract Safety and efficacy of allogeneic anti-CD19 chimeric antigen receptor T cells (CAR-T cells) in persons with CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) relapsing after an allotransplant remain unclear. Forty-three subjects with B-ALL relapsing post allotransplant received CAR-T cells were analyzed. 34 (79%; 95% confidence interval [CI]: 66, 92%) achieved complete histological remission (CR). Cytokine release syndrome (CRS) occurred in 38 (88%; 78, 98%) and was ≥grade-3 in 7. Two subjects died from multiorgan failure and CRS. Nine subjects (21%; 8, 34%) developed ≤grade-2 immune effector cell-associated neurotoxicity syndrome (ICANS). Two subjects developed ≤grade-2 acute graft- versus -host disease (G v HD). 1-year event-free survival (EFS) and survival was 43% (25, 62%). In 32 subjects with a complete histological remission without a second transplant, 1-year cumulative incidence of relapse was 41% (25, 62%) and 1-year EFS and survival, 59% (37, 81%). Therapy of B-ALL subjects relapsing post transplant with donor-derived CAR-T cells is safe and effective but associated with a high rate of CRS. Outcomes seem comparable to those achieved with alternative therapies but data from a randomized trial are lacking.
THU0024 Effects of c-reactive protein on monocyte activation
Authors: KJ Woollard, CJ Loryman, GD Kitas, HR Griffiths
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> FcgammaIIa (CD32) has been identified as the functional high affinity CRP receptor on leukocytes (monocytes and neutrophils). Studies on the effects of CRP on neutrophils show that receptor activation signals to downstream functional changes in phagocytosis, cytokine release and generation of reactive oxygen species. The effects of CRP on monocytes which are key players in rheumatoid chronic inflammation, have not been studied. <h3>Objectives</h3> To investigate the phenotypic and functional consequences of CRP on peripheral blood monocytes <i>in vitro</i>. <h3>Methods</h3> Peripheral whole bloods (PWB) from consenting individuals, with or without RA (ARA criteria), were collected into citrate and kept on ice. Mononuclear cells (MNC) and monocytes (MON) were isolated by differential centrifugation using lymphoprep and Dynal negative isolation kit respectively, using sigmacoted tubes to minimise artefactual activation. Cells were exposed to CRP from 0–200 microg for up to 30 min at 37°C and analysed for (a) CD11b and CD32 expression by flow cytometry (PWB and MNC); (b) adhesion to LPS-activated human umbilical vein endothelial cells (MON) and (c) release of reactive oxygen species (MON). <h3>Results</h3> CD14<sup>+</sup>ve rheumatoid monocytes expressed more than double the level of CD11b (8.644 + 0.57), compared with those from healthy controls (4.17 + 0.4), p = 0.0043. There was little difference in CD32 expression. Exposure of PWB and MNC's from normal healthy subjects to increasing concentrations of CRP led to a dose dependent increase in CD11b expression from 5.7 + 0.1 to 12 + 0.6 at 200 microg CRP (p &lt; 0.01); this was not enhanced by LPS (500 ng/ml). However, not all normals were responders to CRP: 46% of subjects (n = 13) showed no change in CD11b levels. Monocyte adhesion to HUVECs as determined using BCECF loaded cells relative to U937 monocytes, significantly altered following treatment with CRP for 30 mins at 37°C. Release of superoxide anion (MON) was elicited by 200 but not 20 microg CRP, as determined by cytochrome C reduction. <h3>Conclusion</h3> CRP can effect monocyte activation <i>ex vivo</i>, and induce phenotypic changes similar to those observed in rheumatoid patients. The variation in response from normal subjects may reflect different CD32 genotypes. A single nucleotide polymorphism in FcgammaRIIa which encodes histidine or arginine at position 131, strongly influences both IgG2a and CRP binding<sup>1</sup> and may identify individuals with functionally discrete responses to CRP. Allele specific response to CRP may be important in monocyte activation and extravasation during rheumatoid arthritis and complicating vascular disease. <h3>Reference</h3> Stein MP. C-reactive protein binding to Fc gamma RIIa on human monocytes and neutrophils is allele specific. J Clin Invest. 2000;105:369–76
Evaluation of four final irrigation protocols for cleaning root canal walls
Authors: Qiang Li, Qian Zhang, Xiaoying Zou, Lin Yue
Journal: International Journal of Oral Science (2020)

Abstract The aim of this study was to compare the efficiency of four final irrigation protocols in smear layer removal and bacterial inhibition in root canal systems. Thirty roots inoculated with Enterococcus faecalis were prepared with ProTaper Universal files. The teeth were disinfected by conventional needle irrigation, sonic agitation using the EndoActivator device, passive ultrasonic irrigation, or an M3 Max file. Teeth with no root canal preparation served as blank controls for the establishment of the infection baseline. Teeth with preparation but no final irrigation served as a post-instrumentation baseline. After the final irrigation, the teeth were sectioned in half. One half of each tooth was examined by scanning electron microscopy (SEM) to assess smear layer removal using a five-point scale. The other half was examined by confocal laser scanning microscopy (CLSM) using the LIVE/DEAD BackLight bacterial viability kit to evaluate the depth of bacterial survival in dentinal tubules. SEM analysis revealed no significant difference in smear layer removal throughout the whole canal among the EA, PUI, and M3 Max groups ( P &gt; 0.05). CLSM revealed that PUI achieved the greatest bacterial inhibition depth in the coronal ((174.27 ± 31.63) μm), middle ((160.94 ± 37.77) μm), and apical ((119.53 ± 28.49) μm) thirds of the canal (all P &lt; 0.05 vs. other groups). According to this comprehensive SEM and CLSM evaluation, PUI appears to have the best infection control ability in root canal systems.
Endoscopic ultrasound-guided gastrojejunal anastomosis followed by retrograde colonoscope-assisted metal stenting of the bile duct
Authors: Artur Raiter, Katarzyna M. Pawlak, Katarzyna Kozłowska-Petriczko, Jan Petriczko, Anna Wiechowska-Kozłowska
Journal: Endoscopy (2020)

Over the past decades, the secondary mechanical obstruction of the upper gastrointestinal (GI) tract caused by pancreatic head tumors has been treated with a standard surgical approach. The recent development of minimally invasive techniques like transluminal interventions guided by endoscopic ultrasound (EUS) has opened up new modalities for some patients [1] [2].
SARS-CoV-2–specific antibody rearrangements in prepandemic immune repertoires of risk cohorts and patients with COVID-19
Authors: Lisa Paschold, Donjete Simnica, Edith Willscher, Maria J.G.T. Vehreschild, Jochen Dutzmann, Daniel G. Sedding, Christoph Schultheiß, Mascha Binder
Journal: Journal of Clinical Investigation (2020)

A considerable fraction of B cells recognize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with germline-encoded elements of their B cell receptor, resulting in the production of neutralizing and nonneutralizing antibodies. We found that antibody sequences from different discovery cohorts shared biochemical properties and could be retrieved across validation cohorts, confirming the stereotyped character of this naive response in coronavirus disease 2019 (COVID-19). While neutralizing antibody sequences were found independently of disease severity, in line with serological data, individual nonneutralizing antibody sequences were associated with fatal clinical courses, suggesting detrimental effects of these antibodies. We mined 200 immune repertoires from healthy individuals and 500 repertoires from patients with blood or solid cancers - all acquired prior to the pandemic - for SARS-CoV-2 antibody sequences. While the largely unmutated B cell rearrangements occurred in a substantial fraction of immune repertoires from young and healthy individuals, these sequences were less likely to be found in individuals over 60 years of age and in those with cancer. This reflects B cell repertoire restriction in aging and cancer, and may to a certain extent explain the different clinical courses of COVID-19 observed in these risk groups. Future studies will have to address if this stereotyped B cell response to SARS-CoV-2 emerging from unmutated antibody rearrangements will create long-lived memory.
11 Haemostatic radiotherapy in gastro-oesophageal cancer: referral patterns and treatment efficacy
Authors: G Walls, R Turkington, C Harrison
Journal: Gut (2017)

Background  Haemorrhage from unresectable gastric and oesophageal malignancies reduces quality of life, shortens survival, and is associated with considerable burden for blood banks.  Aim  The purpose of this study was to evaluate the outcomes of radiotherapy (RT) in achieving haemostasis, and to describe referral patterns to the Clinical Oncology team.  Method  Retrospective analysis of all patients with gastro-oesophageal cancer that received RT with haemostatic intention from 2013–2016 in Northern Ireland. Only patients who required packed red cell transfusions were included. Study endpoints included improvement in haemoglobin (Hb) and transfusion requirement.  Results  Haemostatic RT was used in 25 cases (13 oesophagus; 12 stomach). Mean age of patients was 77 years (44–89). Mean Hb nadir in the period from first Hb drop to RT was 64 g/L (36–99). Endoscopic intervention was performed in 3 cases (1 Haemospray and clip; 2 Haemospray only). Mean time from diagnosis to first evidence of haemorrhage was 4.5 months (0-12). Mean time from first Hb decrease to radiotherapy referral was 13 weeks (1–45). There was a statistically significant increase in the mean Hb following radiotherapy (87 g/dl to 103 g/dl; p  Conclusions  Radiotherapy is an effective treatment for haemorrhage associated with gastro-oesophageal malignancy and referrals to Clinical Oncology should be considered early.
Ten years of fertility treatment experience and reproductive options in transgender men
Authors: Isabelle Stuyver, Sara Somers, Veerle Provoost, Katrien Wierckx, Hans Verstraelen, Elia Wyverkens, Lien Van Glabeke, Guy T’Sjoen, Ann Buysse, Guido Pennings, Petra De Sutter
Journal: International Journal of Transgender Health (2020)

Up to 2018, the Belgian law stated that transgender people who wanted to change their legal sex had to undergo physical gender affirming treatment. This included gonadectomy to a medically possible and justified extent, which entailed that they had to accept the fact that they could no longer reproduce. However, research has shown that many transgender people desire to have children.(1) to describe a cohort of transgender men and their respective cisgender female partners, to share our experiences with their request for donor conception, and to evaluate their disclosure intentions to the child, (2) to explore how the couples approach current and future reproductive options.This mixed method study presents data from a retrospective analysis of patient records and from a qualitative interview study. The couples were selected from the group of transgender men who - together with their respective cisgender female partners - applied for sperm donation at Ghent University Hospital between 2002 and 2012.Forty-seven transgender men with a cisgender female partner requested treatment with anonymous donor sperm for a first child as a couple. Forty-one requests were accepted for treatment. We found that most couples requesting treatment intended to disclose the use of donor sperm to their future child (n = 34) while 24 couples were planning to inform the child about the parent's transgender identity. The six couples we interviewed saw donor conception as the preferred route to become parents. Adoption was seen as less obvious. The couples' attitudes toward stem cell-derived gametes reflected the significance of the genetic link with the child for both parents.Not all participants in our study were aware of their reproductive options. To be able to make a well-informed decision, transgender people should be counseled about all options at the time of transition.
Endoscopic stag beetle knife treatment for symptomatic Zenker’s diverticulum
Authors: Epifanio Silvino do Monte, Edson Ide, Vitor Massaro Takamatsu Sagae, Igor Braga Ribeiro, Mateus Pereira Funari, Pedro Victor Aniz Gomes de Oliveira, Eduardo Guimarães Hourneaux de Moura
Journal: Endoscopy (2020)

Zenker’s diverticulum is a pulsion diverticulum that develops through Killian’s triangle, an area of weakness of the posterior hypopharynx. The reported prevalence of Zenker’s diverticulum is between 0.01 % and 0.11 %, and it is typically seen in middle-aged and older male patients in their seventh or eighth decade of life [1]. Diagnosis is based on clinical symptoms such as dysphagia, the predominant symptom in 80 % to 90 % of patients. The diagnosis of Zenker’s diverticulum is made on a barium swallow examination. Upper endoscopy is not required to confirm the diagnosis but is recommended to exclude malignancy [2].
Conserved anti-inflammatory effects and sensing of butyrate in zebrafish
Authors: Pradeep Manuneedhi Cholan, Alvin Han, Brad R Woodie, Maxinne Watchon, Angela RM Kurz, Angela S Laird, Warwick J Britton, Lihua Ye, Zachary C Holmes, Jessica R McCann, Lawrence A David, John F Rawls, Stefan H Oehlers
Journal: Gut Microbes (2020)

Short-chain fatty acids (SCFAs) are produced by microbial fermentation of dietary fiber in the gut. Butyrate is a particularly important SCFA with anti-inflammatory properties and is generally present at lower levels in inflammatory diseases associated with gut microbiota dysbiosis in mammals. We aimed to determine if SCFAs are produced by the zebrafish microbiome and if SCFAs exert conserved effects on zebrafish immunity as an example of the non-mammalian vertebrate immune system. We demonstrate that bacterial communities from adult zebrafish intestines synthesize all three main SCFA in vitro, although SCFA were below our detectable limits in zebrafish intestines in vivo. Immersion in butyrate, but not acetate or propionate, reduced the recruitment of neutrophils and M1-type pro-inflammatory macrophages to wounds. We found conservation of butyrate sensing by neutrophils via orthologs of the hydroxycarboxylic acid receptor 1 (hcar1) gene. Neutrophils from Hcar1-depleted embryos were no longer responsive to the anti-inflammatory effects of butyrate, while macrophage sensitivity to butyrate was independent of Hcar1. Our data demonstrate conservation of anti-inflammatory butyrate effects and identify the presence of a conserved molecular receptor in fish.
A multistate model of survival prediction and event monitoring in prefibrotic myelofibrosis
Authors: Alessandra Carobbio, Paola Guglielmelli, Elisa Rumi, Chiara Cavalloni, Valerio De Stefano, Silvia Betti, Alessandro Rambaldi, Maria Chiara Finazzi, Juergen Thiele, Alessandro M. Vannucchi, Ayalew Tefferi, Tiziano Barbui
Journal: Blood Cancer Journal (2020)

Abstract Among 382 patients with WHO-defined prefibrotic myelofibrosis (pre-PMF) followed for a median of 6.9 years, fibrotic or leukemic transformation or death accounts for 15, 7, and 27% of cases, respectively. A multistate model was applied to analyze survival data taking into account intermediate states that are part of the clinical course of pre-PMF, including overt PMF and acute myeloid leukemia (AML). Within this multistate framework, multivariable models disclosed older age (&gt;65 years) and leukocytosis (&gt;15 × 10 9 /L) as predictors of death and leukemic transformation. The risk factors for fibrotic progression included anemia and grade 1 bone marrow fibrosis. The outcome was further affected by high molecular risk (HMR) but not driver mutations. Direct transition to overt PMF, AML, or death occurred in 15.2, 4.7, and 17.3% of patients, respectively. The risk of AML was the highest in the first 5 years (7%), but leveled off thereafter. Conversely, the probability of death from overt PMF or AML increased more rapidly over time, especially when compared to death in the pre-PMF state without disease progression. The probability of being alive with pre-PMF status decreased to 70 and 30% at 10 and 20 years, respectively. This study highlights the aspects of the clinical course and estimates of disease progression in pre-PMF.
Trial of Upadacitinib or Abatacept in Rheumatoid Arthritis
Authors: Andrea Rubbert-Roth, Jeffrey Enejosa, Aileen L. Pangan, Boulos Haraoui, Maureen Rischmueller, Nasser Khan, Ying Zhang, Naomi Martin, Ricardo M. Xavier
Journal: New England Journal of Medicine (2020)

Upadacitinib is an oral selective Janus kinase inhibitor to treat rheumatoid arthritis. The efficacy and safety of upadacitinib as compared with abatacept, a T-cell costimulation modulator, in patients with rheumatoid arthritis refractory to biologic disease-modifying antirheumatic drugs (DMARDs) are unclear.
Impact of spleen size and splenectomy on outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis: A retrospective analysis by the chronic malignancies working party on behalf of European society for blood and marrow transplantation (EBMT)
Authors: Nicola Polverelli, Katya Mauff, Nicolaus Kröger, Marie Robin, Dietrich Beelen, David Beauvais, Patrice Chevallier, Mohamad Mohty, Jakob Passweg, Marie Thérèse Rubio, Johan Maertens, Jürgen Finke, Martin Bornhäuser, Radovan Vrhovac, Grzegorz Helbig, Jean‐Baptiste Mear, Luca Castagna, Péter Reményi, Emanuele Angelucci, Dimitrios Karakasis, Jose Rifòn, Tiarlan Sirait, Domenico Russo, Liesbeth de Wreede, Tomasz Czerw, Juan Carlos Hernández‐Boluda, Patrick Hayden, Donal McLornan, Ibrahim Yakoub‐Agha
Journal: American Journal of Hematology (2020)

Abstract The role of spleen size and splenectomy for the prediction of post‐allogeneic hematopoietic stem cell transplant (allo‐HCT) outcome in myelofibrosis remains under debate. In EBMT registry, we identified a cohort of 1195 myelofibrosis patients transplanted between 2000‐2017 after either fludarabine‐busulfan or fludarabine‐melphalan regimens. Overall, splenectomy was performed in 202 (16.9%) patients and its use decreased over time (28.3% in 2000‐2009 vs 14.1% in 2010‐2017 period). By multivariate analysis, splenectomy was associated with less NRM (HR 0.64, 95% CI 0.44‐0.93, P = .018) but increased risk of relapse (HR 1.43, 95% CI 1.01‐2.02, P = .042), with no significant impact on OS (HR 0.86, 95% CI 0.67‐1.12, P = .274). However, in subset analysis comparing the impact of splenectomy vs specific spleen sizes, for patients with progressive disease, an improved survival was seen in splenectomised subjects compared to those patients with a palpable spleen length ≥ 15 cm (HR 0.44, 95% CI 0.28‐0.69, P &lt; .001), caused by a significant reduction in NRM (HR 0.26, 95% CI 0.14‐0.49, P &lt; .001), without significantly increased relapse risk (HR 1.47, 95% CI 0.87‐2.49, P = .147). Overall, despite the possible biases typical of retrospective cohorts, this study highlights the potential detrimental effect of massive splenomegaly in transplant outcome and supports the role of splenectomy for myelofibrosis patients with progressive disease and large splenomegaly.