tbuckley/cabot-search huggingface dataset:
A targeting black phosphorus nanoparticle based immune cells nano-regulator for photodynamic/photothermal and photo-immunotherapy
Authors: Xiaoge Zhang, Junjie Tang, Chao Li, Yao Lu, Lili Cheng, Jie Liu
Journal: Bioactive Materials (2020)

Photo-immunotherapy is a novel therapeutic approach against malignant tumors with minimal invasiveness. Herein, a targeting multifunctional black phosphorus (BP) nanoparticle, modified by PEGylated hyaluronic acid (HA), was designed for photothermal/photodynamic/photo-immunotherapy. In vitro and in vivo assays indicated that HA-BP nanoparticles possess excellent biocompatibility, stability, and sufficient therapeutic efficacy in the combined therapy of photothermal therapy (PTT) and photodynamic therapy (PDT) for cancer therapy. Moreover, the results of in vitro showed that HA-BP down-regulated the expression of CD206 (M2 macrophage marker) by 42.3% and up-regulated the ratio of CD86（M1 macrophage marker）by 59.6%, indicating that HA-BP nanoparticles have functions in remodeling tumor associated macrophages (TAMs) phenotype (from pro-tumor M2 TAMs to anti-tumor M1 macrophages). Fluorescence (FL) and photoacoustic (PA) multimodal imaging confirmed the selective accumulation of HA-BP in tumor site via both CD44+ mediated active targeting and passive EPR effect. In vitro and in vivo studies suggested that the combined therapy of PDT, PTT and immunotherapy using HA-BP could not only significantly inhibit original tumor but also induce immunogenic cell death (ICD) and release Damage-associated molecular patterns (DAMPs), which could induce maturation of dendritic cells (DCs) and activate effector cells that robustly evoke the antitumor immune responses for cancer treatment. This study expands the biomedical application of BP nanoparticles and displays the potential of modified BP as a multifunctional therapeutic platform for the future cancer therapy.
Computerized image analysis of blood vessels within mucosal defects for the prediction of delayed bleeding following colonic endoscopic mucosal resection: a pilot study
Authors: Yonatan Shaleve, Edmond Sabo, Michael J. Bourke, Amir Klein
Journal: Endoscopy (2020)

Abstract Background Clinically significant post-endoscopic bleeding (CSPEB) is a common complication following colonic endoscopic mucosal resection (EMR). Current prediction tools are clinical and do not use the appearance of the post-EMR mucosal defect. We aimed to predict CSPEB by analyzing blood vessel morphology within the post-EMR mucosal defect. Methods 43 patients with CSPEB were matched to 43 non-bleeders for clinical variables associated with CSPEB. Computerized image analysis quantified the morphologic characteristics of the blood vessels in the defect. Variables were measured in relation to the mucosal defect area. Multivariate analysis and a neural network (NNET) were used as prediction models. Results The CSPEB group vessels had larger maximum diameter (113.07 vs. 69.03; P &lt; 0.001), larger minimum radius (5.09 vs. 3.28; P = 0.002), larger perimeter value (337.82 vs. 193.86; P &lt; 0.001), larger vessel length-of-outline (351.83 vs. 220.68; P = 0.002), and larger fractal dimension (1.11 vs. 1.10; P = 0.005) compared with non-bleeders. Discriminant analysis yielded 86 % sensitivity and 76.7 % specificity and an NNET classifier yielded 100 % sensitivity and 76.9 % specificity for identifying patients at risk. Conclusions Blood vessel morphology in the post-EMR defect can be used to predict bleeding following colonic EMR.
THU0021 Defective rap1 activation in synovial fluid t lymphocytes from patients with rheumatoid arthritis
Authors: PH Remans, KA Reedquist, SI Gringhuis, FC Breedveld, JM Van laar, CL Verweij
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Rap1 is a small G-protein, member of the Ras GTPase family. Rap1 has been linked to T cell anergy and it is suggested that Rap1 has the potential to inhibit Ras-mediated oncogenic or growth promoting activity. Synovial fluid (SF) T cells from patients with rheumatoid arthritis (RA) display a defective phosphorylation pattern of several pivotal signalling proteins and severe hyporesponsiveness upon antigenic stimulation. Our previous data showed that the hyporesponsive state of the SF T cells in RA correlates with markers of oxidative stress and replenishment of the intracellular level of the anti-oxidant (GSH) by treatment of cells with N-acetyl-cysteine (NAC) seems to partly restore the observed signalling defects. <h3>Objectives</h3> To determine Rap1 activation and its correlation with oxidative stress in T cells from healthy controls compared to peripheral blood (PB) and SF T cells isolated from patients with RA. <h3>Methods</h3> T cells from healthy donors and PB and SF from RA patients were isolated and 5 min after stimulation with either CD3 antibodies or PMA+ionomycine, whole cell lysates were prepared in Ral lysis buffer. GTP-bound Rap1 was precipitated using the bacterial expressed fusion protein GST-RalGDS and detected by ECL Western blotting. In whole cell lysates, total Rap1, RapGAP and Spa1 were detected by ECL western blotting as well. <h3>Results</h3> Our data show that in T cells isolated from healthy controls, Rap1 activation was sensitive to redox balance alterations. Upregulation of intracellular GSH by incubation with 10 mM NAC for 48 h resulted in diminished Rap1 activation, while depletion of GSH by pre-incubation with 200mM BSO resulted in increased Rap1 activation. We also observed that treatment of T cells with H2O2 led to the rapid activation of Rap1. Despite an environment of oxidative stress in the inflamed joints of RA patients, we found that in SF T cells Rap1 was present in its inactive GDP-bound state. Furthermore, while the PB T cells of RA patients could be normally activated, Rap1 remained inactive in SF T cells upon stimulation. The defective Rap1 activation was not due to increased levels of the Rap1 GTPase activating proteins RapGAP or spa1. While restoration of the intracellular redox balance seems to reverse the hypo responsiveness of the SF T cells, this had no effect on the defective rap1 activation. <h3>Conclusion</h3> Rap1 activation is defective in SF T cells from RA patients, and cannot be restored by the replenishment of GSH with NAC. This defective activation is not due to increased levels of the Rap1 GTPase activating proteins RapGAP or Spa1.
Renin-angiotensin aldosterone inhibitor use at hospital discharge among patients with moderate to severe acute kidney injury and its association with recurrent acute kidney injury and mortality
Authors: Edward D. Siew, Sharidan K. Parr, Khaled Abdel-Kader, Amy M. Perkins, Robert A. Greevy, Andrew J. Vincz, Jason Denton, Otis D. Wilson, Adriana M. Hung, T. Alp Ikizler, Cassianne Robinson-Cohen, Michael E. Matheny
Journal: Kidney International (2020)
Refined Stratification Based on Baseline Concomitant Mutations and Longitudinal Circulating Tumor DNA Monitoring in Advanced EGFR-Mutant Lung Adenocarcinoma Under Gefitinib Treatment
Authors: Jianchun Duan, JiaChen Xu, Zhijie Wang, Hua Bai, Ying Cheng, Tongtong An, Hongjun Gao, Kai Wang, Qing Zhou, Yanping Hu, Yong Song, Cuimin Ding, Feng Peng, Li Liang, Yi Hu, Cheng Huang, Caicun Zhou, Yuankai Shi, Jiefei Han, Di Wang, Yanhua Tian, Zhenlin Yang, Li Zhang, Shaokun Chuai, Junyi Ye, Guanshan Zhu, Junhui Zhao, Yi-long Wu, Jie Wang
Journal: Journal of Thoracic Oncology (2020)
Myxosporea (Myxozoa, Cnidaria) Lack DNA Cytosine Methylation
Authors: Ryan Kyger, Agusto Luzuriaga-Neira, Thomas Layman, Tatiana Orli Milkewitz Sandberg, Devika Singh, Dorothée Huchon, Sateesh Peri, Stephen D Atkinson, Jerri L Bartholomew, Soojin V Yi, David Alvarez-Ponce
Journal: Molecular Biology and Evolution (2020)

DNA cytosine methylation is central to many biological processes, including regulation of gene expression, cellular differentiation, and development. This DNA modification is conserved across animals, having been found in representatives of sponges, ctenophores, cnidarians, and bilaterians, and with very few known instances of secondary loss in animals. Myxozoans are a group of microscopic, obligate endoparasitic cnidarians that have lost many genes over the course of their evolution from free-living ancestors. Here, we investigated the evolution of the key enzymes involved in DNA cytosine methylation in 29 cnidarians and found that these enzymes were lost in an ancestor of Myxosporea (the most speciose class of Myxozoa). Additionally, using whole-genome bisulfite sequencing, we confirmed that the genomes of two distant species of myxosporeans, Ceratonova shasta and Henneguya salminicola, completely lack DNA cytosine methylation. Our results add a notable and novel taxonomic group, the Myxosporea, to the very short list of animal taxa lacking DNA cytosine methylation, further illuminating the complex evolutionary history of this epigenetic regulatory mechanism.
E-cigarettes are safer than smoking but not without risks, concludes toxicity review
Authors: Jacqui Wise
Journal: BMJ (2020)

Electronic cigarettes are significantly less harmful than smoking but are not risk-free, a report from the Committee on Toxicity of Chemicals in Food, Consumer Products, and the Environment (COT) has concluded.1

COT, which is made up of independent experts, was commissioned to produce a report by the Department of Health and Social Care and Public Health England to review electronic nicotine delivery systems and devices that use an e-liquid that does not contain any nicotine.

In 2015 a review commissioned by Public Health England, which concluded that e-cigarettes were 95% less harmful than tobacco, led to widespread criticism with many questioning the evidence and the authors’ conflicts of interest.234 The COT report did not give any overall …
Helen Salisbury: Stewardship of resources
Authors: Helen Salisbury
Journal: BMJ (2020)

All doctors will remember being quizzed about a proposed list of investigations, being fixed by the beady eye of their superior and asked, "And how will that change your management of this patient?"Our training taught us to be logical and, above all, to avoid waste.I'd like to think that the patient's time and comfort were part of the equation, but mostly it
SYTL4 downregulates microtubule stability and confers paclitaxel resistance in triple-negative breast cancer
Authors: Xi-Yu Liu, Wang Jiang, Ding Ma, Li-Ping Ge, Yun-Song Yang, Zong-Chao Gou, Xiao-En Xu, Zhi-Ming Shao, Yi-Zhou Jiang
Journal: Theranostics (2020)

Background: Taxanes are frontline chemotherapeutic drugs for patients with triple-negative breast cancer (TNBC); however, chemoresistance reduces their effectiveness. We hypothesized that the molecular profiling of tumor samples before and after neoadjuvant chemotherapy (NAC) would help identify genes associated with drug resistance. Methods: We sequenced 10 samples by RNA-seq from 8 NAC patients with TNBC: 3 patients with a pathologic complete response (pCR) and the other 5 with non-pCR. Differentially expressed genes that predicted chemotherapy response were selected for in vitro functional screening via a small-scale siRNAs pool. The clinical and functional significance of the gene of interest in TNBC was further investigated in vitro and in vivo, and biochemical assays and imaging analysis were applied to study the mechanisms. Results: Synaptotagmin-like 4 (SYTL4), a Rab effector in vesicle transport, was identified as a leading functional candidate. High SYTL4 expression indicated a poor prognosis in multiple TNBC cohorts, specifically in taxane-treated TNBCs. SYTL4 was identified as a novel chemoresistant gene as validated in TNBC cells, a mouse model and patient-derived organoids. Mechanistically, downregulating SYTL4 stabilized the microtubule network and slowed down microtubule growth rate. Furthermore, SYTL4 colocalized with microtubules and interacted with microtubules through its middle region containing the linker and C2A domain. Finally, we found that SYTL4 was able to bind microtubules and inhibit the in vitro microtubule polymerization. Conclusion: SYTL4 is a novel chemoresistant gene in TNBC and its upregulation indicates poor prognosis in taxane-treated TNBC. Further, SYTL4 directly binds microtubules and decreases microtubule stability.
Regardless of Age, Obesity and Hypertension Increase Risks With COVID-19
Authors: Mitchell H. Katz
Journal: JAMA Internal Medicine (2020)

Jonathan W. Cunningham, MD; Muthiah Vaduganathan, MD, MPH; Brian L. Claggett, PhD; Karola S. Jering, MD; Ankeet S. Bhatt, MD, MBA; Ning Rosenthal, MD, MPH, PhD; Scott D. Solomon, MD
AB0175 INNOVATIVE PREPARATION OF CURCUMIN NANOPARTICLES TO IMPROVE ANTI-INFLAMMATORY EFFECT IN RHEUMATIC DISEASE
Authors: A. Soltani, N. Abdolahi, Y. Ghanbari
Journal: Annals of the Rheumatic Diseases (2020)

Background: Curcumin (Cur) as a natural compound can be used in the wide spectrum of healthy functions and pharmacological activities [1-4]. It shows great promise for medication of various pro-inflammatory chronic illnesses [5]. In this study, we evaluate the ability of poly(lactide-co-glycolide)(PLGA) and different grads of PVA (polyvinyl alcohol) and lecithin as a drug delivery system for poorly soluble Cur Objectives: The goal of this study was to prepare and characterize Cur encapsulated PLGA and different grads of PVA and lecithin as an efficient nanocarrier for improve anti-inflammatory effect in rheumatic disease Methods: The PLGA nanospheres were formulated and then characterized for percent yield, encapsulation efficiency, surface morphology, and in vitro drug release profiles. At first, 6 mg of Cur was added to the organic phase including 24 mg of polymer dissolved in 5 mL of dichloromethane to constitute 1:4 (drug-to-polymer) ratios. Then, a mixture of PVA-lecithin (at about 5 cc) was added to maintain the stability of double emulsion droplets. The emulsion was continuously stirred at 300 rpm for 24 hours (at temperature of 37.5 ˚C) to evaporate the solvent, leaving behind the colloidal suspension of the drug-encapsulated nanoparticle in aqueous phase. The encapsulation of Cur into PLGA was characterized by Fourier transform infrared spectroscopy (FT-IR) and Transmission electron microscopy (TEM). Results: Our studies achieved the successful formation of smooth surface and spherical shape Cur encapsulated into PLGA nanoparticles by the TEM image confirmed. The particle size distribution demonstrated a range of 30 nm to 100 nm, with the mean particle size being 45 nm. FTIR study implies successful loading of Cur into the nanoparticles. We show high drug-loading efficiency about 98 ± 0.5% for 6% of Cur weight in total ingredients weight of PLGA (w/w). It was also seen that a slower sustained release of 10% CUR in 48 hours is observed with biocompatible PLGA in phosphate buffered saline (pH = 7.4). The MTT assay of the Cur-PLGA exhibited no cytotoxic effect on Normal mouse fibroblast cells (L-929) cell line. IC50 of Cur -PLGA increased 99.5% against Cur nanoparticles (33.57 ±0.62 µM) (P &lt; 0.05). Conclusion: In this study, we constructed a novel preparation of curcumin nanoparticles with PLGA and different grads of PVA (polyvinyl alcohol) and lecithin to improve the bioavailability of CUR and PLGA exhibited no cytotoxic effect on L-929 cell line References: In this study, we constructed a novel preparation of curcumin nanoparticles with PLGA and different grads of PVA (polyvinyl alcohol) and lecithin to improve the bioavailability of CUR and PLGA exhibited no cytotoxic effect on L-929 cell line Disclosure of Interests: None declared
All medical students will sit the same exam from 2025
Authors: Callum Phillips
Journal: BMJ (2020)

A single entry test for UK and international graduates1 who wish to practise medicine in the UK will be developed by the General Medical Council together with medical schools and fully implemented by 2024-25, the GMC has said.

The national medical licensing assessment will comprise an applied knowledge test (AKT) and a clinical and professional skills assessment (CPSA). The GMC has said that the standardised assessment will guarantee foundation year doctors have met the required proficiency for safe practice of medicine before being …
Development and Validation of SDBeasy Score as a Predictor of Behavioral Outcomes in Childhood
Authors: Charmaine van Eeden, Sukhpreet K. Tamana, Indra Narang, Nevin Hammam, Joyce Chikuma, Diana L. Lefebvre, Meghan B. Azad, Theo J. Moraes, Padmaja Subbarao, Allan B. Becker, Stuart E. Turvey, Malcolm R. Sears, Carmen Rasmussen, Jacqueline Pei, Piushkumar J. Mandhane
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: There are limited tools to identify which children are at greatest risk for developing sleep-disordered breathing (SDB)-associated behavioral morbidity.Objectives: To examine associations between age of onset and duration of parent-reported symptoms of SDB and behavioral problems at the age of 5 years.Methods: Data were collected and analyses were completed for participants in the CHILD (Canadian Healthy Infant Longitudinal Development) cohort at the Edmonton and Toronto sites. We generated an SDBeasy score on the basis of the age of onset and duration of SDB symptoms as reported by parents completing the Pediatric Sleep Questionnaire. Using CHILD-Edmonton data, we completed multivariate linear regression to determine whether the SDBeasy score was associated with behavioral problems at the age 5 years of age as assessed by using the Child Behavior Checklist (CBCL). We then validated the SDBeasy score using CHILD-Toronto data.Measurements and Main Results: At the 5-year visit, 581 of 716 (81%) CHILD-Edmonton participants still enrolled had CBCL data. Of the 581 children with data, 77% (446 of 581) had an SDBeasy score of 0 (never had SDB symptoms), whereas 20 of 581 children (3.4%) had persistent SDB symptoms from infancy through 5 years of age (SDBeasy score of 24). Children had a 0.35-point-higher CBCL total behavioral score at 5 years for each 1-point increase in their SDBeasy score (95% confidence interval, 0.24-0. 5; P < 0.01). We found consistent results among CHILD-Toronto participants; children had a 0.26-point-higher CBCL total behavioral score at 5 years for each 1-point increase in their SDBeasy score (95% confidence interval, 0.08-0.44; P = 0.005).Conclusions: The SDBeasy score, based on the Pediatric Sleep Questionnaire, enables identification of children with higher behavioral-problem scores.
Melatonin overcomes MCR-mediated colistin resistance in Gram-negative pathogens
Authors: Yuan Liu, Yuqian Jia, Kangni Yang, Ziwen Tong, Jingru Shi, Ruichao Li, Xia Xiao, Wenkai Ren, Rüdiger Hardeland, Russel J. Reiter, Zhiqiang Wang
Journal: Theranostics (2020)

Background: Emergence, prevalence and widely spread of plasmid-mediated colistin resistance in Enterobacteriaceae strongly impairs the clinical efficacy of colistin against life-threatening bacterial infections. Combinations of antibiotics and FDA-approved non-antibiotic agents represent a promising means to address the widespread emergence of antibiotic-resistant pathogens. Methods: Herein, we investigated the synergistic activity between melatonin and antibiotics against MCR (mobilized colistin resistance)-positive Gram-negative pathogens through checkerboard assay and time-killing curve. Molecular mechanisms underlying its mode of action were elucidated. Finally, we assessed the in vivo efficacy of melatonin in combination with colistin against drug-resistant Gram-negative bacteria. Results: Melatonin, which has been approved for treating sleep disturbances and circadian disorders, substantially potentiates the activity of three antibiotics, particularly colistin, against MCR-expressing pathogens without enhancing its toxicity. This is evidence that the combination of colistin with melatonin enhances bacterial outer membrane permeability, promotes oxidative damage and inhibits the effect of efflux pumps. In three animal models infected by mcr-1-carrying E. coli, melatonin dramatically rescues colistin efficacy. Conclusion: Our findings revealed that melatonin serves as a promising colistin adjuvant against MCR-positive Gram-negative pathogens.
Effects of DPP-4 Inhibitor Linagliptin Versus Sulfonylurea Glimepiride as Add-on to Metformin on Renal Physiology in Overweight Patients With Type 2 Diabetes (RENALIS): A Randomized, Double-Blind Trial
Authors: Marcel H.A. Muskiet, Lennart Tonneijck, Mark M. Smits, Mark H.H. Kramer, D. Margriet Ouwens, Bolette Hartmann, Jens J. Holst, Daan J. Touw, A.H. Jan Danser, Jaap A. Joles, Daniël H. van Raalte
Journal: Diabetes Care (2020)

OBJECTIVE To compare effects of the dipeptidyl peptidase 4 (DPP-4) inhibitor linagliptin with those of a sulfonylurea on renal physiology in metformin-treated patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS In this double-blind randomized trial, 46 overweight T2DM patients without renal impairment received once-daily linagliptin (5 mg) or glimepiride (1 mg) for 8 weeks. Fasting glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippuric acid clearances. Fractional excretions, urinary damage markers, and circulating DPP-4 substrates (among others, glucagon-like peptide 1 and stromal cell–derived factor-1α [SDF-1α]) were measured. RESULTS HbA1c reductions were similar with linagliptin (–0.45 ± 0.09%) and glimepiride (–0.65 ± 0.10%) after 8 weeks (P = 0.101). Linagliptin versus glimepiride did not affect GFR, ERPF, estimated intrarenal hemodynamics, or damage markers. Only linagliptin increased fractional excretion (FE) of sodium (FENa) and potassium, without affecting FE of lithium. Linagliptin-induced change in FENa correlated with SDF-1α (R = 0.660) but not with other DPP-4 substrates. CONCLUSIONS Linagliptin does not affect fasting renal hemodynamics compared with glimepiride in T2DM patients. DPP-4 inhibition promotes modest natriuresis, possibly mediated by SDF-1α, likely distal to the macula densa.
Challenges in Prediction and Diagnosis of Alcohol Withdrawal Syndrome and Wernicke Encephalopathy
Authors: Gian Pietro Sechi, M. Margherita Sechi
Journal: JAMA Internal Medicine (2020)

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Increased Odds of Death for Patients with Interstitial Lung Disease and COVID-19: A Case–Control Study
Authors: Anthony J. Esposito, Aravind A. Menon, Auyon J. Ghosh, Rachel K. Putman, Laura E. Fredenburgh, Souheil Y. El-Chemaly, Hilary J. Goldberg, Rebecca M. Baron, Gary M. Hunninghake, Tracy J. Doyle
Journal: American Journal of Respiratory and Critical Care Medicine (2020)