tbuckley/cabot-search huggingface dataset:
Development of a Clinical Decision Support System for Severity Risk Prediction and Triage of COVID-19 Patients at Hospital Admission: an International Multicenter Study
Authors: Guangyao Wu, Pei Yang, Yuanliang Xie, Henry C. Woodruff, Xiangang Rao, Julien Guiot, Anne-Noelle Frix, Renaud Louis, Michel Moutschen, Jiawei Li, Jing Li, Chenggong Yan, Dan Du, Shengchao Zhao, Yi Ding, Bin Liu, Wenwu Sun, Fabrizio Albarello, Alessandra D'Abramo, Vincenzo Schininà, Emanuele Nicastri, Mariaelena Occhipinti, Giovanni Barisione, Emanuela Barisione, Iva Halilaj, Pierre Lovinfosse, Xiang Wang, Jianlin Wu, Philippe Lambin
Journal: European Respiratory Journal (2020)

Background The outbreak of coronavirus disease 2019 (COVID-19) has globally strained medical resources and caused significant mortality. Objective To develop and validate a machine-learning model based on clinical features for severity risk assessment and triage for COVID-19 patients at hospital admission. Method 725 patients were used to train and validate the model. This included a retrospective cohort from Wuhan, China of 299 hospitalised COVID-19 patients from 23 December 2019 to 13 February 2020, and five cohorts with 426 patients from eight centres in China, Italy and Belgium from 20 February 2020 to 21 March 2020. The main outcome was the onset of severe or critical illness during hospitalisation. Model performances were quantified using the area under the receiver operating characteristic curve (AUC) and metrics derived from the confusion matrix. Results In the retrospective cohort, the median age was 50 years and 137 (45.8%) were male. In the five test cohorts, the median age was 62 years and 236 (55.4%) were male. The model was prospectively validated on five cohorts yielding AUCs ranging from 0.84 to 0.93, with accuracies ranging from 74.4% to 87.5%, sensitivities ranging from 75.0% to 96.9%, and specificities ranging from 55.0% to 88.0%, most of which performed better than the pneumonia severity index. The cut-off values of the low-, medium- and high-risk probabilities were 0.21 and 0.80. The online calculators can be found at www.covid19risk.ai . Conclusion The machine-learning model, nomogram and online calculator might be useful to access the onset of severe and critical illness among COVID-19 patients and triage at hospital admission.
An Oxidation‐Enhanced Magnetic Resonance Imaging Probe for Visual and Specific Detection of Singlet Oxygen Generated in Photodynamic Cancer Therapy In Vivo
Authors: Kai Deng, Bo Wu, Cai‐Xia Wang, Qian Wang, Hui Yu, Jia‐Mi Li, Kun‐Heng Li, Hong‐Yang Zhao, Shi‐Wen Huang
Journal: Advanced Healthcare Materials (2020)

Abstract Singlet oxygen is regarded as the primary cytotoxic agent in cancer photodynamic therapy (PDT). Despite the advances in optical methods to image singlet oxygen, it remains a challenge for in vivo application due to the limited tissue penetration depth of light. Up to date, no singlet oxygen‐specific magnetic resonance imaging (MRI) probe has been reported. Herein, a T 2 ‐weighted MRI probe is reported to visually detect singlet oxygen generated in PDT in vitro and in vivo. The MRI probe Ce6/Fe 3 O 4 ‐M is constructed by co‐encapsulation of photosensitizer Ce6 and Fe 3 O 4 nanoparticles in mPEG 2000 ‐TK‐C 16 micelles. Thioketal (TK) linker in the probe is highly sensitive to singlet oxygen, but lowly sensitive to other reactive oxygen species (ROS) existing in physiological and pathological environments. Singlet oxygen, generated with light irradiation, triggers the cleavage of TK, which leads to loss of surface polyethylene glycol, increment of the hydrophobicity, and aggregation of Fe 3 O 4 nanoparticles. Subsequently, negatively enhanced T 2 ‐weighted MRI signal is obtained for visual detection of singlet oxygen in the solution, cancer cells, and in vivo. This oxidation responsive MRI probe is expected to hold great promise in evaluating the ability of photosensitizers to generate singlet oxygen and in predicting the therapeutic efficacies of PDT in vivo.
Microenvironmentally-driven Plasticity of CD44 isoform expression determines Engraftment and Stem-like Phenotype in CRC cell lines
Authors: Thiemo F. Dinger, Oleg Chen, Claudia Dittfeld, Lydia Hetze, Melanie Hüther, Marit Wondrak, Steffen Löck, Wolfgang Eicheler, Georg Breier, Leoni A. Kunz-Schughart
Journal: Theranostics (2020)

Theranostic biomarkers for putative cancer stem-like cells (CSC) in colorectal cancer (CRC) are of particular interest in translational research to develop patient-individualized treatment strategies. Surface proteins still under debate are CD44 and CD133. The structural and functional diversity of these antigens, as well as their plasticity, has only just begun to be understood. Our study aimed to gain novel insight into the plasticity of CD133/CD44, thereby proving the hypothesis of marker-associated tumorigenic and non-tumorigenic phenotypes to be environmentally driven. Methods: CD133/CD44 profiles of 20 CRC cell lines were monitored; three models with distinct surface patterns in vitro were systematically examined. CD133/CD44 subpopulations were isolated by FACS and analyzed upon in vitro growth and/or in limiting dilution engraftment studies. The experimental setup included biomarker analyses on the protein (flow cytometry, Western blotting, immunofluorescence) and mRNA levels (RT-/qPCR) as well as CD44 gene sequencing. Results: In general, we found that (i) the in vitro CD133/CD44 pattern never determined engraftment and (ii) the CD133/CD44 population distributions harmonized under in vivo conditions. The LS1034 cell line appeared as a unique model due to its de novo in vivo presentation of CD44. CD44v8-10 was identified as main transcript, which was stronger expressed in primary human CRC than in normal colon tissues. Biomarker pattern of LS1034 cells in vivo reflected secondary engraftment: the tumorigenic potential was highest in CD133+/CD44+, intermediate in CD133+/CD44- and entirely lost in CD133-/CD44- subfractions. Both CD44+ and CD44- LS1034 cells gave rise to tumorigenic and non-tumorigenic progeny and were convertible - but only as long as they expressed CD133 in vivo. The highly tumorigenic CD133+/CD44(v8-10)+ LS1034 cells were localized in well-oxygenated perivascular but not hypoxic regions. From a multitude of putative modulators, only the direct interaction with stromal fibroblasts triggered an essential, in vivo-like enhancement of CD44v8-10 presentation in vitro. Conclusion: Environmental conditions modulate CD133/CD44 phenotypes and tumorigenic potential of CRC subpopulations. The identification of fibroblasts as drivers of cancer-specific CD44 expression profile and plasticity sheds light on the limitation of per se dynamic surface antigens as biomarkers. It can also explain the location of putative CD133/CD44-positive CRC CSC in the perivascular niche, which is likely to comprise cancer-associated fibroblasts. The LS1034 in vitro/in vivo model is a valuable tool to unravel the mechanism of stromal-induced CD44v8-10 expression and identify further therapeutically relevant, mutual interrelations between microenvironment and tumorigenic phenotype.
Constructing an automatic diagnosis and severity-classification model for acromegaly using facial photographs by deep learning
Authors: Yanguo Kong, Xiangyi Kong, Cheng He, Changsong Liu, Liting Wang, Lijuan Su, Jun Gao, Qi Guo, Ran Cheng
Journal: Journal of Hematology & Oncology (2020)

Abstract Due to acromegaly’s insidious onset and slow progression, its diagnosis is usually delayed, thus causing severe complications and treatment difficulty. A convenient screening method is imperative. Based on our previous work, we herein developed a new automatic diagnosis and severity-classification model for acromegaly using facial photographs by deep learning on the data of 2148 photographs at different severity levels. Each photograph was given a score reflecting its severity (range 1~3). Our developed model achieved a prediction accuracy of 90.7% on the internal test dataset and outperformed the performance of ten junior internal medicine physicians (89.0%). The prospect of applying this model to real clinical practices is promising due to its potential health economic benefits.
Gaseous sulfur trioxide induced controllable sulfonation promoting biomineralization and osseointegration of polyetheretherketone implants
Authors: Teng Wan, Zixue Jiao, Min Guo, Zongliang Wang, Yizao Wan, Kaili Lin, Qinyi Liu, Peibiao Zhang
Journal: Bioactive Materials (2020)

Fabricating a desired porous structure on the surface of biomedical polyetheretherketone (PEEK) implants for enhancing biological functions is crucial and difficult due to its inherent chemical inertness. In this study, a porous surface of PEEK implants was fabricated by controllable sulfonation using gaseous sulfur trioxide (SO3) for different time (5, 15, 30, 60 and 90 min). Micro-topological structure was generated on the surface of sulfonated PEEK implants preserving original mechanical properties. The protein absorption capacity and apatite forming ability was thus improved by the morphological and elemental change with higher degree of sulfonation. In combination of the appropriate micromorphology and bioactive sulfonate components, the cell adhesion, migration, proliferation and extracellular matrix secretion were obviously enhanced by the SPEEK-15 samples which were sulfonated for 15 min. Finding from this study revealed that controllable sulfonation by gaseous SO3 would be an extraordinarily strategy for improving osseointegration of PEEK implants by adjusting the microstructure and chemical composition while maintaining excellent mechanical properties.
Potential use of corneal confocal microscopy in the diagnosis of Parkinson’s disease associated neuropathy
Authors: Ning-Ning Che, Hong-Qi Yang
Journal: Translational Neurodegeneration (2020)

Parkinson's disease (PD) is a chronic, progressive neurodegenerative disease affecting about 2-3% of population above the age of 65. In recent years, Parkinson's research has mainly focused on motor and non-motor symptoms while there are limited studies on neurodegeneration which is associated with balance problems and increased incidence of falls. Corneal confocal microscopy (CCM) is a real-time, non-invasive, in vivo ophthalmic imaging technique for quantifying nerve damage in peripheral neuropathies and central neurodegenerative disorders. CCM has shown significantly lower corneal nerve fiber density (CNFD) in patients with PD compared to healthy controls. Reduced CNFD is associated with decreased intraepidermal nerve fiber density in PD. This review provides an overview of the ability of CCM to detect nerve damage associated with PD.
Essential Amino Acids—Essential in Arterial Thrombosis
Authors: Zachary T. Hilt, Craig N. Morrell
Journal: Circulation (2020)

Article, see p 49A proper balanced diet is a mainstay of guidance to improving quality of life and reducing comorbidities from diet-related obesity and diabetes mellitus.Balanced nutritional intake affects the ability of fundamental molecular functions to continue within our cells.Essential amino acids (EAA), such as the branched-chain amino acids (BCAA) leucine, isoleucine, and valine, cannot be synthesized by the human body in meaningful amounts and instead must be taken in from external food sources.BCAA have been described to have 3 major roles: (1) serve as a building block for protein synthesis, (2) act as a source of energy, and (3) regulate cell growth and autophagy. 1Despite the term "essential," as we are increasingly appreciating across multiple disciplines of science, too much of any good thing can turn into a bad thing.BCAA are popular as an exercise supplement, because it is believed that increased levels of these 3 amino acids promotes building of muscle mass after exercise. 2However, the usefulness of BCAA supplementation is marked by conflicting evidence of its utility. 2 Pathologically, cross-sectional studies have shown positive associations of circulating BCAA with cardiovascular risk, hypertension, metabolic dysregulation, and insulin resistance.Infusions of healthy individuals with essential amino acids led to insulin release without driving its clearance from the blood. 3It is unsurprising that longitudinal studies of BCAA have linked them to metabolic syndrome and type 2 diabetes mellitus.Cross-sectional studies have reported positive correlations between increased circulating BCAAs and cardiovascular risk, hypertension, metabolic dysregulation, and insulin resistance. 1 However, all of these studies have reported associations between increased levels of BCAAs and disease risk, yet few studies have revealed direct mechanisms by which BCAAs can drive disease progression.In this issue of Circulation, Xu et al describe a novel role for BCAA catabolism in driving platelet activation and promoting cardiovascular disease. 4The authors use complementary approaches including ex vivo human clinical samples, in vivo mouse models, in vitro cell culture, and analytical chemistry techniques to demonstrate that elevated levels of BCAAs and their downstream catabolites lead to hyperactive platelets and subsequent risk of arterial thrombosis.Ingestion of BCAAs by human subjects led to an increase in relative levels of leucine, isoleucine, and valine inside platelets.These platelets manifested a corresponding increase in agonist-induced activation, granule release, aggregation, and spreading.Thrombin-induced αIIbβ3 activation determined by PAC1 (pituitary adenylate cyclase-activating polypeptide type 1 receptor) binding to human platelets increased with BCAA ingestion, suggesting that BCAAs increase αIIbβ3-mediated outside-in signaling.
Comparative effectiveness of biological medicines in rheumatoid arthritis: systematic review and network meta-analysis including aggregate results from reanalysed individual patient data
Authors: Kirsten Janke, Katharina Biester, Dietmar Krause, Bernd Richter, Christoph Schürmann, Katharina Hirsch, Helmut Hörn, Michaela Florina Kerekes, Petra Kohlepp, Beate Wieseler
Journal: BMJ (2020)

Abstract Objective To assess the comparative effectiveness of biological medicines in rheumatoid arthritis in sufficiently similar patient populations, based on the current definitions of key outcomes. Design Systematic review and network meta-analysis including aggregate results from reanalysed individual patient data. Data sources Clinical study reports and aggregate results from reanalyses of individual patient data on key outcomes for rheumatoid arthritis provided by study sponsors for studies conducted up to 2017, and several databases and registries from inception up to February 2017. Eligibility criteria for selecting studies Randomised controlled trials investigating patient relevant outcomes in adults with rheumatoid arthritis treated with biological medicines in combination with methotrexate after methotrexate failure for at least 24 weeks. Results 45 eligible trials were identified. Combining data from clinical study reports and aggregate results from reanalyses of individual patient data allowed extensive analyses yielding sufficiently similar populations and homogeneous study results for network meta-analyses, including up to 35 studies on eight biological medicines combined with methotrexate. These analyses showed few statistically significant differences between the combination treatments. For example, anakinra showed less benefit than almost all the other seven biological medicines regarding clinical remission or low disease activity (clinical disease activity index ≤2.8 or ≤10, respectively) and certolizumab pegol showed more harm than the other seven biological medicines regarding serious adverse events or infections. Some outcomes had very wide 95% confidence intervals, potentially implying unidentified differences between the eight biological medicines, but wide 95% confidence intervals were less prominent for low disease activity, serious adverse events, and infections. Owing to a lack of head-to-head trials, results were mainly based on indirect comparisons with a limited number of studies, and recently approved Janus kinase inhibitors could not be included. Conclusions For patients with rheumatoid arthritis after methotrexate failure, only minor differences in benefits and harms were seen between biological medicines in combination with methotrexate. However, the analysis was hampered by a lack of long term direct comparisons. The substantial information gain achieved by the reanalysis of individual patient data calls for the routine availability of individual patient data.
Covid-19: Lack of testing in Brazil is a “major failure,” says MSF
Authors: Jacqui Thornton
Journal: BMJ (2020)

Brazil is ignoring the evidence by failing to take the necessary public health measures to tackle the coronavirus pandemic, according to the humanitarian organisation Medecins Sans Frontieres (MSF). It said that case detection through testing was a “major failure” in the country.

As of 1 July, World Health Organization figures show that Brazil had 1 368 195 confirmed cases and 58 314 deaths from covid-19—the highest in the world after the US.1

MSF said that a lack of tests and inadequate testing was not helping the authorities prepare for the crisis or give its people the right message about the need for caution and social distancing.

The non-governmental organisation earlier reported that testing is being rolled out at an incredibly slow pace in Brazil, with 7500 tests per million people, which …
Cancer-Associated Point Mutations in the<i>DLC1</i>Tumor Suppressor and Other<i>Rho-GAPs</i>Occur Frequently and Are Associated with Decreased Function
Authors: Dunrui Wang, Xiaolan Qian, Beatriz Sanchez-Solana, Brajendra K. Tripathi, Marian E. Durkin, Douglas R. Lowy
Journal: Cancer Research (2020)

In advanced cancer, the RHOA GTPase is often active together with reduced expression of genes encoding Rho-specific GTPase-accelerating proteins (Rho-GAP), which negatively regulate RHOA and related GTPases. Here we used the The Cancer Genome Atlas dataset to examine 12 tumor types (including colon, breast, prostate, pancreas, lung adenocarcinoma, and squamous cell carcinoma) for the frequency of codon mutations of 10 Rho-GAP and experimentally tested biochemical and biological consequences for cancer-associated mutants that arose in the DLC1 tumor suppressor gene. DLC1 was the Rho-GAP gene mutated most frequently, with 5%-8% of tumors in five of the tumor types evaluated having DLC1 missense mutations. Furthermore, 20%-26% of the tumors in four of these five tumor types harbored missense mutations in at least one of the 10 Rho-GAPs. Experimental analysis of the DLC1 mutants indicated 7 of 9 mutants whose lesions were located in the Rho-GAP domain were deficient for Rho-GAP activity and for suppressing cell migration and anchorage-independent growth. Analysis of a DLC1 linker region mutant and a START domain mutant showed each was deficient for suppressing migration and growth in agar, but their Rho-GAP activity was similar to that of wild-type DLC1. Compared with the wild-type, the linker region mutant bound 14-3-3 proteins less efficiently, while the START domain mutant displayed reduced binding to Caveolin-1. Thus, mutation of Rho-GAP genes occurs frequently in some cancer types and the majority of cancer-associated DLC1 mutants evaluated were deficient biologically, with various mechanisms contributing to their reduced activity. SIGNIFICANCE: These findings indicate that point mutation of Rho-GAP genes is unexpectedly frequent in several cancer types, with DLC1 mutants exhibiting reduced function by various mechanisms.
TGF-β causes Docetaxel resistance in Prostate Cancer via the induction of Bcl-2 by acetylated KLF5 and Protein Stabilization
Authors: Yixiang Li, Baotong Zhang, Lingwei Xiang, Siyuan Xia, Omer Kucuk, Xingming Deng, Lawrence H. Boise, Jin-Tang Dong
Journal: Theranostics (2020)

Prostate cancer is the second leading cause of cancer-related death in the United States.As a first line treatment for hormone-refractory prostate cancer, docetaxel (DTX) treatment leads to suboptimal effect since almost all patients eventually develop DTX resistance.In this study, we investigated whether and how TGF-β affects DTX resistance of prostate cancer.Methods: Cytotoxicity of DTX in DU 145 and PC-3 cells was measured by CCK-8 and Matrigel colony formation assays.Resistance to DTX in DU 145 cells was examined in a xenograft tumorigenesis model.A luciferase reporter system was used to determine transcriptional activities.Gene expression was analyzed by RT-qPCR and Western blotting.Results: We found that KLF5 is indispensable in TGF-β-induced DTX resistance.Moreover, KLF5 acetylation at lysine 369 mediates DTX resistance in vitro and in vivo.We showed that the TGF-β/acetylated KLF5 signaling axis activates Bcl-2 expression transcriptionally.Furthermore, DTX-induced Bcl-2 degradation depends on a proteasome pathway, and TGF-β inhibits DTX-induced Bcl-2 ubiquitination.Conclusion: Our study demonstrated that the TGF-β-acetylated KLF5-Bcl-2 signaling axis mediates DTX resistance in prostate cancer and blockade of this pathway could provide clinical insights into chemoresistance of prostate cancer.
Resilience and Burnout Among Physicians and the General US Working Population
Authors: Colin P. West, Liselotte N. Dyrbye, Christine Sinsky, Mickey Trockel, Michael Tutty, Laurence Nedelec, Lindsey E. Carlasare, Tait D. Shanafelt
Journal: JAMA Network Open (2020)

<h3>Importance</h3> The prevalence of physician burnout is well documented, and resilience training has been proposed as an option to support physician well-being. However, the resilience of physicians compared with that of the US working population is not established, and the association between resilience and physician burnout is not well understood. <h3>Objectives</h3> To evaluate resilience among physicians and US workers, and to determine the association between resilience and burnout among US physicians. <h3>Design, Setting, and Participants</h3> A cross-sectional national survey study of 5445 US physicians and a probability-based sample of 5198 individuals in the US working population was conducted between October 12, 2017, and March 15, 2018. <h3>Main Outcomes and Measures</h3> Resilience was measured using the 2-item Connor-Davidson Resilience Scale (total scores range from 0-8; higher scores indicate greater resilience); burnout was measured using the full Maslach Burnout Inventory with overall burnout indicated by a score of at least 27 on the 0 to 54 emotional exhaustion subscale and/or at least 10 on the depersonalization subscale (higher scores indicate greater burnout). <h3>Results</h3> Of 30 456 physicians who received an invitation to participate, 5445 (17.9%) completed surveys (2995 men [62.1%]; median [IQR] age of 53 [42-62] years). In multivariable analysis, mean (SD) resilience scores were higher among physicians than the general employed population (6.49 [1.30] vs 6.25 [1.37]; adjusted mean difference, 0.25 points; 95% CI, 0.19-0.32;<i>P</i> &lt; .001). Among physicians, resilience was associated with burnout. Physicians without overall burnout had higher mean (SD) resilience scores than physicians with burnout (6.82 [1.15] vs 6.13 [1.36]; adjusted mean difference, 0.68 points, 95% CI, 0.61-0.76;<i>P</i> &lt; .001). Each 1-point increase in resilience score was associated with 36% lower odds of overall burnout (odds ratio, 0.64; 95% CI, 0.60-0.67;<i>P</i> &lt; .001). However, 392 of 1350 physicians (29%) with the highest possible resilience score had burnout. <h3>Conclusions and Relevance</h3> The findings of this national survey study suggest that physicians exhibited higher levels of resilience than the general working population in the US. Resilience was inversely associated with burnout symptoms, but burnout rates were substantial even among the most resilient physicians. Additional solutions, including efforts to address system issues in the clinical care environment, are needed to reduce burnout and promote physician well-being.