tbuckley/cabot-search huggingface dataset:
β2M Signals Monocytes Through Non-Canonical TGFβ Receptor Signal Transduction
Authors: Zachary T. Hilt, Preeti Maurya, Laura Tesoro, Daphne N. Pariser, Sara K. Ture, Simon J. Cleary, Mark R. Looney, Kathleen E. McGrath, Craig N. Morrell
Journal: Circulation Research (2021)

Circulating monocytes can have proinflammatory or proreparative phenotypes. The endogenous signaling molecules and pathways that regulate monocyte polarization in vivo are poorly understood. We have shown that platelet-derived β2M (β-2 microglobulin) and TGF-β (transforming growth factor β) have opposing effects on monocytes by inducing inflammatory and reparative phenotypes, respectively, but each bind and signal through the same receptor. We now define the signaling pathways involved.To determine the molecular mechanisms and signal transduction pathways by which β2M and TGF-β regulate monocyte responses both in vitro and in vivo.Wild-type- (WT) and platelet-specific β2M knockout mice were treated intravenously with either β2M or TGF-β to increase plasma concentrations to those in cardiovascular diseases. Elevated plasma β2M increased proinflammatory monocytes, while increased plasma TGFβ increased proreparative monocytes. TGF-βR (TGF-β receptor) inhibition blunted monocyte responses to both β2M and TGF-β in vivo. Using imaging flow cytometry, we found that β2M decreased monocyte SMAD2/3 nuclear localization, while TGF-β promoted SMAD nuclear translocation but decreased noncanonical/inflammatory (JNK [jun kinase] and NF-κB [nuclear factor-κB] nuclear localization). This was confirmed in vitro using both imaging flow cytometry and immunoblots. β2M, but not TGF-β, promoted ubiquitination of SMAD3 and SMAD4, that inhibited their nuclear trafficking. Inhibition of ubiquitin ligase activity blocked noncanonical SMAD-independent monocyte signaling and skewed monocytes towards a proreparative monocyte response.Our findings indicate that elevated plasma β2M and TGF-β dichotomously polarize monocytes. Furthermore, these immune molecules share a common receptor but induce SMAD-dependent canonical signaling (TGF-β) versus noncanonical SMAD-independent signaling (β2M) in a ubiquitin ligase dependent manner. This work has broad implications as β2M is increased in several inflammatory conditions, while TGF-β is increased in fibrotic diseases. Graphic Abstract: A graphic abstract is available for this article.
Circulating tumor DNA methylation as markers for early detection of pancreatic ductal adenocarcinoma (PDAC).
Authors: Xiaoding Liu, Shiwei Guo, Chengcheng Ma, Yatong Li, Xiaoqian Liu, Zhiwen Zhang, Lianyuan Yu, Menghua Dai, Shuo Shen, Huanwen M. Wu, Zhixi Su, Qiye He, Rui Liu, Jin Gang, Zhiyong Liang
Journal: Journal of Clinical Oncology (2021)

395 Background: PDAC is a cancer of high mortality and low survival. Its early detection is critical due to symptoms often occur only at advanced stages. However there is no reliable screening tool to identify high-risk patients. ctDNA methylation has recently emerged as a promising new target to differentiate PDAC plasma from normal plasma for its early detection. Methods: Reduced representation bisulfite sequencing libraries were made in 46 PDAC tissues, 30 para-PDAC tissues and 20 PDAC plasmas to screen PDAC-specific markers, which was done by quantifying and comparing methylation levels of genomic regions and individual CpG sites between those groups. Markers were validated in plasma samples from 84 PDAC patients and 64 normal controls to propose a blood classifier. The best-performing markers were developed into a targeted sequencing panel, which was tested on a larger collection of plasma samples from patients of a variety of pancreatic diseases to build and validate a PDAC-predicting model. Results: We profiled genome-wide methylation patterns of tissues samples to identify 171 PDAC-specific markers. We reiterated training and cross-validating PDAC classification models using SVM method, and achieved an average sensitivity of 86% and specificity of 88%. To prove the feasibility of a non-invasive detection in plasma, a targeted methylation assay using those markers was tested on PDAC and normal plasmas, and yielded an average sensitivity of 68.4% and a specificity of 85.8%. We refined the panel by selecting the most discriminatory markers and built the version II of the panel, which was named PANcreatic Cancer Detection Assay, or PANDA, for a more efficient target capture, which was validated in an independent cohort of plasma samples that included 94 PDAC cases, 25 chronic pancreatitis (CP) cases and 80 normal samples from multiple centers. The PANDA achieved an AUC of 0.906 when classifying PDAC from normal, and an AUC of 0.882 when separating PDAC from CPs, both of which are more accurate than CA19-9, the conventional blood marker for PDAC. We further integrated test subjects’ age and their CA19-9 level as features into the PANDA model, which further elevated their AUC to 0.882 and 0.933 when classifying PDAC plasma from either CP plasma or normal plasma, respectively. Conclusions: We have developed PANDA, an NGS based target assay covering PDAC-specific DNA methylation targets by screening and validation on PDAC tissues and plasmas. Combined with age and CA19-9 blood level, PANDA has shown encouraging results to classify PDAC plasma from non-malignant diseases, demonstrating its potential to be optimized into non-invasive diagnostics for blood-based early PDAC screening.
Primary Central Nervous System Lymphoma Revealed by 68Ga-FAPI and 18F-FDG PET/CT
Authors: Ying Zhang, Jiawei Cai, Zefang Lin, Shaobo Yao, Weibing Miao
Journal: Clinical Nuclear Medicine (2021)

A 67-year-old woman presented with left limb weakness, facial paralysis, and unsteady gait for 1 month. Brain MRI detected a mass in the right frontal lobe with prominent peritumoral edema, suggesting a malignant brain tumor. In 18F-FDG PET/CT, the mass was very FDG avid, and 68Ga-FAPI PET/CT showed the mass had heterogeneously mild to moderate increased uptake of the tracer. Histopathological examination after surgical resection of the mass confirmed the diagnosis of diffuse large B-cell lymphoma. The current case indicated the existence of fibrosis in the lymphoma lesion to some extent.
Outcomes of a Noninferiority Randomised Controlled Trial of Surgery for Men with Urodynamic Stress Incontinence After Prostate Surgery (MASTER)
Authors: Paul Abrams, Lynda D. Constable, David Cooper, Graeme MacLennan, Marcus J. Drake, Chris Harding, Anthony Mundy, Kirsty McCormack, Alison McDonald, John Norrie, Craig Ramsay, Rebecca Smith, Nikki Cotterill, Mary Kilonzo, Cathryn Glazener
Journal: European Urology (2021)

Stress urinary incontinence (SUI) is common after radical prostatectomy and likely to persist despite conservative treatment. The sling is an emerging operation for persistent SUI, but randomised controlled trial (RCT) comparison with the established artificial urinary sphincter (AUS) is lacking.To compare the outcomes of surgery in men with bothersome urodynamic SUI after prostate surgery.A noninferiority RCT was conducted among men with bothersome urodynamic SUI from 27 UK centres. Blinding was not possible due the surgeries.Participants were randomly assigned (1:1) to the male transobturator sling (n = 190) or the AUS (n = 190) group.The primary outcome was patient-reported SUI 12 mo after randomisation, collected from postal questionnaire using a composite outcome from two items in validated International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form questionnaire (ICIQ-UI SF). Noninferiority margin was 15%, thought to be of acceptable lower effectiveness, in return for reduced adverse events (AEs) and easier operation, for the sling. Secondary outcomes were operative and postoperative details, patient-reported measures, and AEs, up to 12 mo after surgery.A total of 380 participants were included. At 12 mo after randomisation, incontinence rates were 134/154 (87.0%) for male sling versus 133/158 (84.2%) for AUS (difference 3.6% [95% confidence interval {CI} -11.6 to 4.6], pNI = 0.003), showing noninferiority. Incontinence symptoms (ICIQ-UI SF) reduced from scores of 16.1 and 16.4 at baseline to 8.7 and 7.5 for male sling and AUS, respectively (mean difference 1.4 [95% CI 0.2-2.6], p = 0.02). Serious AEs (SAEs) were few: n = 6 and n = 13 for male sling and AUS (one man had three SAEs), respectively. Quality of life scores improved, and satisfaction was high in both groups. All other secondary outcomes that show statistically significant differences favour the AUS.Using a strict definition, urinary incontinence rates remained high, with no evidence of difference between male sling and AUS. Symptoms and quality of life improved significantly in both groups, and men were generally satisfied with both procedures. Overall, secondary and post hoc analyses were in favour of AUS.Urinary incontinence after prostatectomy has considerable effect on men's quality of life. MASTER shows that if surgery is needed, both surgical options result in fewer symptoms and high satisfaction, despite most men not being completely dry. However, most other results indicate that men having an artificial urinary sphincter have better outcomes than those who have a sling.
Estimating the health impact of vaccination against ten pathogens in 98 low-income and middle-income countries from 2000 to 2030: a modelling study
Authors: Xiang Li, Christinah Mukandavire, Zulma M Cucunubá, Susy Echeverria Londono, Kaja Abbas, Hannah E Clapham, Mark Jit, Hope L Johnson, Timos Papadopoulos, Emilia Vynnycky, Marc Brisson, Emily D Carter, Andrew Clark, Margaret J de Villiers, Kirsten Eilertson, Matthew J Ferrari, Ivane Gamkrelidze, Katy A M Gaythorpe, Nicholas C Grassly, Timothy B Hallett, Wes Hinsley, Michael L Jackson, Kévin Jean, Andromachi Karachaliou, Petra Klepac, Justin Lessler, Xi Li, Sean M Moore, Shevanthi Nayagam, Duy Manh Nguyen, Homie Razavi, Devin Razavi-Shearer, Stephen Resch, Colin Sanderson, Steven Sweet, Stephen Sy, Yvonne Tam, Hira Tanvir, Quan Minh Tran, Caroline L Trotter, Shaun Truelove, Kevin van Zandvoort, Stéphane Verguet, Neff Walker, Amy Winter, Kim Woodruff, Neil M Ferguson, Tini Garske
Journal: The Lancet (2021)
Pulmonary MTBVAC vaccination induces immune signatures previously correlated with prevention of tuberculosis infection
Authors: Karin Dijkman, Nacho Aguilo, Charelle Boot, Sam O. Hofman, Claudia C. Sombroek, Richard A.W. Vervenne, Clemens H.M. Kocken, Dessislava Marinova, Jelle Thole, Esteban Rodríguez, Michel P.M. Vierboom, Krista G. Haanstra, Eugenia Puentes, Carlos Martin, Frank A.W. Verreck
Journal: Cell Reports Medicine (2021)

To fight tuberculosis, better vaccination strategies are needed. Live attenuated Mycobacterium tuberculosis-derived vaccine, MTBVAC, is a promising candidate in the pipeline, proven to be safe and immunogenic in humans so far. Independent studies have shown that pulmonary mucosal delivery of Bacillus Calmette-Guérin (BCG), the only tuberculosis (TB) vaccine available today, confers superior protection over standard intradermal immunization. Here we demonstrate that mucosal MTBVAC is well tolerated, eliciting polyfunctional T helper type 17 cells, interleukin-10, and immunoglobulins in the airway and yielding a broader antigenic profile than BCG in rhesus macaques. Beyond our previous work, we show that local immunoglobulins, induced by MTBVAC and BCG, bind to M. tuberculosis and enhance pathogen uptake. Furthermore, after pulmonary vaccination, but not M. tuberculosis infection, local T cells expressed high levels of mucosal homing and tissue residency markers. Our data show that pulmonary MTBVAC administration has the potential to enhance its efficacy and justifies further exploration of mucosal vaccination strategies in preclinical efficacy studies.
AB0617 OPTICAL COHERENCE TOMOGRAPHY IN THE ASSESSMENT OF SKIN FIBROSIS IN SYSTEMIC SCLEROSIS: A CROSS-SECTIONAL STUDY
Authors: D. Temiz Karadağ, O. Gundogdu, G. Lettieri, M. C. Padula, A. Padula, F. Del Galdo, S. D’angelo, G. Abignano
Journal: Annals of the Rheumatic Diseases (2020)

Background: Previous studies have shown that Optical Coherence Tomography (OCT) is a reliable biomarker of skin fibrosis and significantly correlates with the severity of the skin involvement in Systemic Sclerosis (SSc) 1,2 . Objectives: Aim of this cross-sectional study was to evaluate the performance of skin OCT to discriminate between SSc and healthy controls (HC) and to compare results with the current gold standard, the modified Rodnan skin score (mRss), in a different SSc study cohort. Methods: Dorsal forearm skin of consecutive diffuse cutaneous SSc (dcSSc) patients and matched-HC was scanned by an investigator blinded to the clinical data using Vivosight scanner (Michelson Diagnostics, Kent, UK). Minimum Optical Density (MinOD), Maximum OD (MaxOD) and OD at 300 micron-depth (OD300) were measured. Clinical involvement was assessed by a blinded operator using the mRss and results were compared with imaging data. Statistical analysis was performed using GraphPad Prism software V.7.0. Results: A total of 88 OCT images were obtained from 22 dcSSc patients [20 Female, mean age 49 (±11) years, 12 with &lt; 5 years disease duration) and 22 HC (20 Female, mean age 50.7 (±6.7) years]. All OCT measures (MinOD, MaxOD and OD300) were significantly lower in SSc patients than in HC (p=0.011, p&lt;0.0001, p&lt;0.0001 respectively). MaxOD and OD300 were significantly different between the four groups (0-3) of patients based on the mRss at the site of analysis (p=0.035, p=0.001 respectively). Skin OCT showed a good performance in discriminating SSc skin vs HC (overall AUC 0.72, 0.8 and 0.89 for MinOD, MaxOD and OD300 respectively). Conclusion: These results confirm in a cohort different from those of the previous studies that skin OCT is able to reflect the severity of skin involvement in SSc. Longitudinal studies are needed to validate its potential as surrogate outcome measure of skin fibrosis in SSc patients. References: [1]Abignano G et al. Ann Rheum Dis 2013; 2. Pires NSM et al. Ann Rheum Dis 2018. Disclosure of Interests: None declared
Optimizing expression quantitative trait locus mapping workflows for single-cell studies
Authors: Anna S. E. Cuomo, Giordano Alvari, Christina B. Azodi, Davis J. McCarthy, Marc Jan Bonder
Journal: Genome biology (2021)

Abstract Background Single-cell RNA sequencing (scRNA-seq) has enabled the unbiased, high-throughput quantification of gene expression specific to cell types and states. With the cost of scRNA-seq decreasing and techniques for sample multiplexing improving, population-scale scRNA-seq, and thus single-cell expression quantitative trait locus (sc-eQTL) mapping, is increasingly feasible. Mapping of sc-eQTL provides additional resolution to study the regulatory role of common genetic variants on gene expression across a plethora of cell types and states and promises to improve our understanding of genetic regulation across tissues in both health and disease. Results While previously established methods for bulk eQTL mapping can, in principle, be applied to sc-eQTL mapping, there are a number of open questions about how best to process scRNA-seq data and adapt bulk methods to optimize sc-eQTL mapping. Here, we evaluate the role of different normalization and aggregation strategies, covariate adjustment techniques, and multiple testing correction methods to establish best practice guidelines. We use both real and simulated datasets across single-cell technologies to systematically assess the impact of these different statistical approaches. Conclusion We provide recommendations for future single-cell eQTL studies that can yield up to twice as many eQTL discoveries as default approaches ported from bulk studies.
SAT0047 Purine metabolism and antioxidant system in osteoarthritis
Authors: AB Zborovsky, MY Stazharov, VF Martemyanov, SA Bedina, EE Mozgovaya, TP Chernykh
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Till now there are few of information on a Purine metabolism (PM) and Antioxidant system (AS) condition of blood of osteoarthritis (OA) patients. <h3>Objectives</h3> To study the enzymatic profile of PM and AS in blood of OA patients. <h3>Methods</h3> The activities of Xanthine Oxidase (XO), Xanthine dehydrogenase (XDG), 5'-Nucleotidase (5'-NT), Adenosindesa-minase (ADA), Guanindesaminase (Guanase), Superoxid-dismutase (SOD), Glutathion reductase (GP), the contents of Uric acid (UA) were measured with Spectrophotometer. XDG, ADA, SOD isoenzymes were examined with method of electrophoresis in agarose gel and obtained enzymograms were evaluated at Densitometry. <h3>Results</h3> 44 patients with OA and 30 healthy controls (HC) were under observation. The mean age of patients – 53 ± 2.6 years. The mean duration of disease – 10.2 ± 2.7 years. We revealed the increase of XO, ADA, Guanasa, SOD, GP, GR activity, XDG-2, SOD-1 isoensymes, contents of UA in OA patients with synovitis in comparison with HC. The increase of XDG, SOD, GP activity, SOD-1 isoensymes were observed in OA patients without synovitis in comparison with HC and the decrease of UA, XDG-2 isoenzymes, also the increase of XDG, GP activity were revealed in comparison with OA patients with synovitis. <h3>Conclusion</h3> PM and AS are essentially changed in OA. These changes depended on the clinical form of OA. The enzyme indices can be used for early activity of disease diagnostic and differentiation of OA clinical form.
Electronic health record alerts for acute kidney injury: multicenter, randomized clinical trial
Authors: F Perry Wilson, Melissa Martin, Yu Yamamoto, Caitlin Partridge, Erica Moreira, Tanima Arora, Aditya Biswas, Harold Feldman, Amit X Garg, Jason H Greenberg, Monique Hinchcliff, Stephen Latham, Fan Li, Haiqun Lin, Sherry G Mansour, Dennis G Moledina, Paul M Palevsky, Chirag R Parikh, Michael Simonov, Jeffrey Testani, Ugochukwu Ugwuowo
Journal: BMJ (2021)

Abstract Objective To determine whether electronic health record alerts for acute kidney injury would improve patient outcomes of mortality, dialysis, and progression of acute kidney injury. Design Double blinded, multicenter, parallel, randomized controlled trial. Setting Six hospitals (four teaching and two non-teaching) in the Yale New Haven Health System in Connecticut and Rhode Island, US, ranging from small community hospitals to large tertiary care centers. Participants 6030 adult inpatients with acute kidney injury, as defined by the Kidney Disease: Improving Global Outcomes (KDIGO) creatinine criteria. Interventions An electronic health record based “pop-up” alert for acute kidney injury with an associated acute kidney injury order set upon provider opening of the patient’s medical record. Main outcome measures A composite of progression of acute kidney injury, receipt of dialysis, or death within 14 days of randomization. Prespecified secondary outcomes included outcomes at each hospital and frequency of various care practices for acute kidney injury. Results 6030 patients were randomized over 22 months. The primary outcome occurred in 653 (21.3%) of 3059 patients with an alert and in 622 (20.9%) of 2971 patients receiving usual care (relative risk 1.02, 95% confidence interval 0.93 to 1.13, P=0.67). Analysis by each hospital showed worse outcomes in the two non-teaching hospitals (n=765, 13%), where alerts were associated with a higher risk of the primary outcome (relative risk 1.49, 95% confidence interval 1.12 to 1.98, P=0.006). More deaths occurred at these centers (15.6% in the alert group v 8.6% in the usual care group, P=0.003). Certain acute kidney injury care practices were increased in the alert group but did not appear to mediate these outcomes. Conclusions Alerts did not reduce the risk of our primary outcome among patients in hospital with acute kidney injury. The heterogeneity of effect across clinical centers should lead to a re-evaluation of existing alerting systems for acute kidney injury. Trial registration ClinicalTrials.gov NCT02753751 .
Impact of tumor location on effectiveness of first-line 5-FU-based palliative doublet chemotherapy in patients with metastatic gastroesophageal cancer.
Authors: Suleyman Yasin Goksu, Rodrigo Alterio, Elizabeth McGehee, Muhammad Shaalan Beg, Syed Mohammad Ali Kazmi, Matthew R. Porembka, Sam C. Wang, Nina Niu Sanford, David H. Wang, Aravind Sanjeevaiah
Journal: Journal of Clinical Oncology (2021)

240 Background: While gastroesophageal cancers with different primary tumor locations can have distinct molecular characteristics and clinical outcomes, the efficacy of palliative chemotherapy in tumors with different locations is unknown. Using primary tumor location as a surrogate for molecular subtype, we investigated the differential efficacy of first-line doublet chemotherapy in metastatic gastroesophageal adenocarcinomas. Methods: We performed a retrospective review of patients with metastatic gastroesophageal adenocarcinoma who received first-line palliative chemotherapy at the University of Texas Southwestern Medical Center and the Dallas County Safety Net Parkland Hospital diagnosed between 2011-2019. Cases were identified using cancer registries. We categorized the tumor location as proximal or distal based on endoscopy and imaging studies. Disease response was assessed on the first staging scan and classified as ‘disease shrinkage, stability, or progression.’ Overall and progression-free survival were evaluated using Kaplan-Meier and Cox proportional hazards methods. Results: 99 patients were identified; 58.6% had proximal tumors. Patients with proximal tumors were more likely to be white (38% vs. 13%, p = 0.008) and older with age ≥ 50 years (71% vs. 51%, p = 0.04) and less likely to have peritoneal metastasis (48% vs. 78%, p = 0.003) than distal tumors. Patients with proximal tumors had a higher disease shrinkage than patients with distal tumors (53% vs. 21%, p = 0.004). Patients with proximal tumors also had better overall survival (median 12.5 vs. 8.7 months) and progression-free survival in response to 5-FU based chemotherapy (median 5 vs. 4 months) compared to patients with distal tumors, but this was not statistically significant. On multivariable analysis, tumor location was not independently predictive of progression-free survival after adjusting for age, gender, presence of signet rings, diffuse, intestinal histology, and peritoneal metastasis (HR 1.22 95% CI 0.74-2.00), but pretreatment albumin was (HR 0.63 95% CI 0.43-0.94). Conclusions: Proximal gastroesophageal cancers have a better clinical response to first-line 5FU containing chemotherapy than distal cancers. Currently, there is no platform to determine molecular subgroups that is commercially available. Until testing for this becomes available, differences in response rates to palliative chemotherapy in gastroesophageal cancers with different anatomical locations should be recognized and studied further.