tbuckley/cabot-search huggingface dataset:
Abstract #4216: A role for c-Src in EGFR-induced upregulation of HIF-1\#945;
Authors: Matthew Herynk, Tina Cascone, Li Xu, John Heymach
Journal: Cancer Research (2009)

Non-small cell lung cancer (NSCLC) is the leading cause of cancer related deaths in the United States and worldwide. Receptor tyrosine kinase (RTK) signaling through Epidermal Growth Factor Receptor (EGFR) has been shown to play a key role in the development and progression of NSCLC. Two activating mutations within EGFR, L858R and del19, have been demonstrated to lead to oncogene addiction and have also been shown to confer sensitivity to targeted EGFR inhibitors (e.g. erlotinib and gefitinib). Earlier work has demonstrated a crucial role for the EGFR downstream effector c-Src in the upregulation of Vascular Endothelial Growth Factor (VEGF), a HIF-1\#945; regulated gene. We have identified a correlation between mutant EGFR and elevated HIF-1\#945; protein levels. Thus, we hypothesized that c-Src may be a critical downstream effector of mutant EGFR and may have a central role in the upregulation of HIF-1\#945; signaling by activated EGFR. NSCLC cell lines were treated with erlotinib to demonstrate a role for mutant EGFR in the upregulation of HIF-1\#945; and subsequently VEGF protein levels. HCC827 NSCLC cells, expressing the EGFR sensitizing mutant, had significantly reduced HIF-1\#945; protein levels and VEGF secretion when treated with the EGFR inhibitor, whereas, A549 cells, expressing the wild-type EGFR, were minimally effected by erlotinib treatment, compared their respective untreated controls. Furthermore, transient transfection with del19 EGFR led to increased VEGF promoter activity as demonstrated by a luciferase assay. These data demonstrate a central role for mutant EGFR signaling in the upregulation of HIF-1\#945; protein levels and VEGF secretion. Hence, signaling through mutant EGFR uncouples the normal regulation of HIF-1\#945; from hypoxia leading to aberrant expression of the angiogenic growth factor, VEGF. To identify critical signaling pathways potentially involved in the EGFR-induced up-regulation of HIF-1\#945;, multiple inhibitors were utilized. Inhibition of Mek did not affect HIF-1\#945; protein levels compared to controls, whereas inhibition of phosphotidylinositol-3-kinase (PI3K) led to a 50% reduction in HIF-1\#945; protein levels versus untreated cells. The Src family inhibitor PP2 led to a complete reduction of HIF-1\#945; protein, and similar results were seen with erlotinib. Moreover, erlotinib and PP2 led to a partial reduction of HIF-2\#945; protein levels. Collectively, our data demonstrate that NSCLC cells expressing activating mutations in EGFR have elevated HIF-1\#945; protein levels and that the c-Src signaling pathway may play a central role in the uncoupling of HIF-1\#945; signaling from hypoxia-induced regulation.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4216.
FDG PET/CT Findings of Unsuspected Pulmonary Epithelioid Angiosarcoma Manifested as a Brain Metastasis
Authors: Gui-Xiong Zhang, Yongjiang Zheng, Wen-Shan Huang, Min Yang, Jie-Hua Xu
Journal: Clinical Nuclear Medicine (2019)

Abstract A 42-year-old man presented paroxysmal sharp pain in the right side of the head. Head CT showed a lesion in the right frontal lobe. MRI of the head suggested the possibility of metastasis. FDG PET/CT showed increased uptake corresponding to lesions in the right frontal lobe of the brain, the left upper lobe of lung, and the left adrenal gland, respectively. Cerebral and pulmonary lesions were both resected. Histopathology confirmed that both lesions are primary epithelioid angiosarcomas.
Challenges in modelling the proportion of undiagnosed HIV infections in Sweden
Authors: Emmi Andersson, Fumiyo Nakagawa, Ard van Sighem, Maria Axelsson, Andrew N Phillips, Anders Sönnerborg, Jan Albert
Journal: Eurosurveillance (2019)

BackgroundSweden has a low HIV prevalence. However, among new HIV diagnoses in 2016, the proportion of late presenters and migrants was high (59% and 81%, respectively). This poses challenges in estimating the proportion of undiagnosed persons living with HIV (PLHIV).AimTo estimate the proportion of undiagnosed PLHIV in Sweden comparing two models with different demands on data availability and modelling expertise.MethodsAn individual-based stochastic simulation model of HIV positive populations (SSOPHIE) and the incidence method of the European Centre for Disease Prevention and Control (ECDC) HIV Modelling Tool were applied to clinical, surveillance and migration data from Sweden 1980-2016.ResultsSSOPHIE estimated that the proportion of undiagnosed PLHIV in 2013 was 26% (n = 2,100; 90% plausibility range (PR): 900-5,000) for all PLHIV, 17% (n = 600; 90% PR: 100-2,000) for men who have sex with men (MSM), 35% in male (n = 300; 90% PR: 200-700) and 34% in female (n = 400; 90% PR: 200-800) migrants from sub-Saharan Africa (SSA). The estimates for the ECDC model in 2013 were 21% (n = 2,013; 95% confidence interval (CI): 1,831-2,189) for all PLHIV, 15% (n = 369; 95% CI: 299-434) for MSM and 21% (n = 530; 95% CI: 436-632) for migrants from SSA.ConclusionsThe proportion of undiagnosed PLHIV in Sweden is uncertain. SSOPHIE estimates had wide PR. The ECDC model estimates were unreliable because migration was not accounted for. Better migration data and estimation methods are required to obtain reliable estimates of proportions of undiagnosed PLHIV in similar settings.
Association of Diabetic Retinopathy and Diabetic Kidney Disease With All-Cause and Cardiovascular Mortality in a Multiethnic Asian Population
Authors: Charumathi Sabanayagam, Miao Li Chee, Riswana Banu, Ching-Yu Cheng, Su Chi Lim, E. Shyong Tai, Thomas Coffman, Tien Y. Wong
Journal: JAMA Network Open (2019)

<h3>Importance</h3> The association of diabetic microvascular complications such as diabetic retinopathy (DR) and diabetic kidney disease (DKD) with mortality in populations is not clear. <h3>Objective</h3> To examine the association of DR and DKD separately and jointly with all-cause and cardiovascular disease (CVD) mortality in a multiethnic Asian population. <h3>Design, Setting, and Participants</h3> A population-based cohort study was conducted including 2964 adults between the ages of 40 and 80 years with diabetes who participated in the Singapore Epidemiology of Eye Diseases study (baseline, 2004-2011). Data analysis was performed from January to May 2018. <h3>Exposures</h3> Diabetic retinopathy ascertained from retinal photographs and DKD from estimated glomerular filtration rate. <h3>Main Outcomes and Measures</h3> All-cause and CVD mortality obtained by linkage with the National Registry of Births and Deaths until May 2017. <h3>Results</h3> Of the 2964 adults (mean [SD] age, 61.8 [10.0] years; 1464 [49.4%] female; 592 Chinese, 1052 Malay, and 1320 Indian), 29.9% of the participants had DR, while 20.7% had DKD. Over a median (interquartile range) follow-up of 8.8 (7.2-11.0) years, 610 deaths occurred (20.6%), of which 267 (9.0%) were due to CVD. In separate models, the multivariable hazard ratios for all-cause and CVD mortality were 1.54 (95% CI, 1.24-1.91) and 1.74 (95% CI, 1.27-2.40), respectively, for DR and 2.04 (95% CI, 1.64-2.56) and 2.29 (95% CI, 1.64-3.19), respectively, for DKD. In models including both DR and DKD, the subgroup with DKD alone (27.1% and 12.6%) followed by DR alone (6.5% and 5.2%) contributed substantially to the excess risk of all-cause and CVD mortality. Compared with those with no DR and DKD, the hazard ratios of all-cause and CVD mortality were 1.89 (95% CI, 1.40-2.57) and 2.26 (95% CI, 1.42-3.61), respectively, for DKD alone and 1.38 (95% CI, 1.03-1.86) and 1.64 (95% CI, 1.06-2.56), respectively, for DR alone. Hazard ratios for all-cause and CVD mortality were 2.76 (95% CI, 2.05-3.72) and 3.41 (95% CI, 2.19-5.32), respectively, for those with both DKD and DR. The relative excess risk associated with the interaction was 0.49 (95% CI, −0.29 to 1.27;<i>P</i> = .20) for all-cause mortality and 0.51 (95% CI, −0.83 to 1.85;<i>P</i> = .50) for CVD mortality. <h3>Conclusions and Relevance</h3> These results suggest that risks of all-cause and CVD mortality were significantly higher in those with DKD and DR, but DKD was more strongly associated with excess risk. The findings underscore the importance of early identification and close monitoring and management of patients with DR and DKD to reduce the risk of death.
Indoxyl Sulfate and p-Cresyl Sulfate Promote Vascular Calcification and Associate with Glucose Intolerance
Authors: Britt Opdebeeck, Stuart Maudsley, Abdelkrim Azmi, Annelies De Maré, Wout De Leger, Bjorn Meijers, Anja Verhulst, Pieter Evenepoel, Patrick C. D’Haese, Ellen Neven
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Vascular calcification contributes to high cardiovascular mortality in patients with CKD. Although research findings have suggested an association between the uremic toxins indoxyl sulfate and p-cresyl sulfate and cardiovascular disease, direct evidence has been lacking. In this study, the authors demonstrate in a rat model of CKD that continuous exposure to indoxyl sulfate or p-cresyl sulfate promotes moderate to severe calcification in the aorta and peripheral vessels. Activation of inflammation and coagulation pathways in the arterial wall plays a pivotal role in toxin-induced calcification and strongly associates with hyperglycemia and insulin resistance. These findings provide etiologic evidence for indoxyl sulfate and p-cresyl sulfate as major contributors to vascular calcification and suggest new avenues for identifying novel therapeutic targets to prevent or treat calcification in the vessel wall of patients with CKD. Background Protein-bound uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (PCS) have been associated with cardiovascular morbidity and mortality in patients with CKD. However, direct evidence for a role of these toxins in CKD-related vascular calcification has not been reported. Methods To study early and late vascular alterations by toxin exposure, we exposed CKD rats to vehicle, IS (150 mg/kg per day), or PCS (150 mg/kg per day) for either 4 days (short-term exposure) or 7 weeks (long-term exposure). We also performed unbiased proteomic analyses of arterial samples coupled to functional bioinformatic annotation analyses to investigate molecular signaling events associated with toxin-mediated arterial calcification. Results Long-term exposure to either toxin at serum levels similar to those experienced by patients with CKD significantly increased calcification in the aorta and peripheral arteries. Our analyses revealed an association between calcification events, acute-phase response signaling, and coagulation and glucometabolic signaling pathways, whereas escape from toxin-induced calcification was linked with liver X receptors and farnesoid X/liver X receptor signaling pathways. Additional metabolic linkage to these pathways revealed that IS and PCS exposure engendered a prodiabetic state evidenced by elevated resting glucose and reduced GLUT1 expression. Short-term exposure to IS and PCS (before calcification had been established) showed activation of inflammation and coagulation signaling pathways in the aorta, demonstrating that these signaling pathways are causally implicated in toxin-induced arterial calcification. Conclusions In CKD, both IS and PCS directly promote vascular calcification via activation of inflammation and coagulation pathways and were strongly associated with impaired glucose homeostasis.
Significantly lower annual rates of neoplastic progression in short- compared to long-segment non-dysplastic Barrett’s esophagus: a systematic review and meta-analysis
Authors: Viveksandeep Thoguluva Chandrasekar, Nour Hamade, Madhav Desai, Tarun Rai, Venkata Subhash Gorrepati, Ramprasad Jegadeesan, Anjana Sathyamurthy, Prateek Sharma
Journal: Endoscopy (2019)

Abstract Background Although shorter lengths of Barrett’s esophagus (BE) have been associated with a lower risk of neoplastic progression, precise estimates have varied, especially for non-dysplastic BE (NDBE) only. Therefore, current US guidelines do not provide specific recommendations on surveillance intervals based on BE length. We performed a systematic review and meta-analysis of the published literature to examine neoplastic progression rates of NDBE based on BE length. Methods PubMed, Cochrane, Google Scholar, and Embase were comprehensively searched. Studies reporting progression rates in patients with NDBE and &gt; 1 year of follow-up were included. The number of patients progressing to esophageal adenocarcinoma (EAC) and high grade dysplasia (HGD)/EAC in individual studies and the mean follow-up were recorded to derive person-years of follow-up. Pooled rates of progression to EAC and HGD/EAC based on BE length (&lt; 3 cm vs. ≥ 3 cm) were calculated. Results Of the 486 initial studies identified, 10 met the inclusion/exclusion criteria. These included a total of 4097 NDBE patients; 1979 with short-segment BE (SSBE; 10 773 person-years of follow-up) and 2118 with long-segment BE (LSBE; 12 868 person-years). The annual rates of progression to EAC were significantly lower for SSBE compared with LSBE: 0.06 % (95 % confidence interval 0.01 % – 0.10 %) vs. 0.31 % (0.21 % – 0.40 %), respectively; odds ratio (OR) 0.25 (0.11 – 0.56); P &lt; 0.001, as were the rates for the combined endpoint (HGD/EAC): 0.24 % (0.09 % – 0.32 %) vs. 0.76 % (0.43 % – 0.89 %), respectively; OR 0.35 (0.21 – 0.58); P &lt; 0.001. There was no significant heterogeneity among studies. Conclusion The results demonstrate significantly lower rates of neoplastic progression in NDBE patients with SSBE compared with LSBE. BE length can easily be used for risk stratification purposes for NDBE patients undergoing surveillance endoscopy and consideration should be given to tailoring surveillance intervals based on BE length in future US guidelines.
Abstract 15431: Clinical Outcomes of Patients With Myocardial Infarction With Non-Obstructive Coronaries (MINOCA)
Authors: Sivabaskari Pasupathy, Rosanna Tavella, Srisankavi Sivasankar, Christopher Zeitz, Matthew Worthley, Ajay Sinhal, Margaret Arstall, John Beltrame
Journal: Circulation (2018)

Introduction: Patients with Troponin positive Non-Obstructive Coronary Arteries (TpNOCA) warrant further investigation to elucidate the ischemic or non-ischemic cause of the suspected acute myocard...
Targeting High Mobility Group Box-1 (HMGB1) Promotes Cell Death in Myelodysplastic Syndrome
Authors: Angel Y.F. Kam, Sadhna O. Piryani, Chad M. McCall, Hee Su Park, David A. Rizzieri, Phuong L. Doan
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Myelodysplastic syndrome (MDS) is associated with a dysregulated innate immune system. The purpose of this study was to determine whether modulation of the innate immune system via high mobility group box-1 (HMGB1) could reduce cell viability in MDS. Experimental Design: We quantified HMGB1 in an MDS cell line MDS-L and in primary MDS cells compared with nonmalignant hematopoietic cells. We performed loss-of-function studies of HMGB1 using pooled siRNAs and a small-molecule inhibitor sivelestat compared with standard chemotherapy. We measured levels of engraftment of MDS-L cells in NOD-scidIL2Rgnull (NSG) mice following treatment with sivelestat. Mechanistically, we interrogated cell survival pathways and 45 targets within the NFκB pathway using both protein analysis and a proteome profiler array. Results: We discovered that HMGB1 had increased expression in both MDS-L cells and in primary CD34+ MDS cells compared with healthy CD34+ hematopoietic cells. Sivelestat impaired MDS cell expansion, increased cellular death, and spared healthy hematopoietic cells. MDS-L marrow engraftment is reduced significantly at 17 weeks following treatment with sivelestat compared with control mice. Treatment of CD34+ MDS cells with sivelestat and azacitidine or decitabine was additive to increase apoptotic cell death compared with chemotherapy alone. Sivelestat promoted apoptosis with increased expression of PUMA, activated caspase 3, and increased DNA double-strand breaks. Inhibition of HMGB1 reduced levels of Toll-like receptors (TLR) and suppressed activation of NFκB in MDS-L cells. Conclusions: Inhibition of HMGB1 could promote MDS cell death and alter innate immune responses via suppression of NFκB pathways.
A randomised controlled trial of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDITOF-MS) versus conventional microbiological methods for identifying pathogens: Impact on optimal antimicrobial therapy of invasive bacterial and fungal infections in Vietnam
Authors: Behzad Nadjm, Vu Quoc Dat, James I. Campbell, Vu Tien Viet Dung, Alessandro Torre, Nguyen Thi Cam Tu, Ninh Thi Thanh Van, Dao Tuyet Trinh, Nguyen Phu Huong Lan, Nguyen Vu Trung, Nguyen Thi Thuy Hang, Le Thi Hoi, Stephen Baker, Marcel Wolbers, Nguyen Van Vinh Chau, Nguyen Van Kinh, Guy E. Thwaites, H. Rogier van Doorn, Heiman F.L. Wertheim
Journal: Journal of Infection (2019)

We assessed the impact of MALDITOF-MS on the timeliness of optimal antimicrobial therapy through a parallel-arm randomised controlled trial in two hospitals in Vietnam.We recruited patients with a pathogen (bacterial or fungal) cultured from a normally sterile sample. Samples were randomly assigned (1:1) to identification by MALDITOF-MS or conventional diagnostics. The primary outcome was the proportion on optimal antimicrobial therapy within 24 h of positive culture, determined by a blinded independent review committee. Trial registered at ClinicalTrials.gov (NCT02306330).Among 1005 randomised patients, pathogens were isolated from 628 (326 intervention, 302 control), with 377 excluded as likely contaminants or discharged/died before positive culture. Most isolates were cultured from blood (421/628, 67.0%). The proportion receiving optimal antimicrobial therapy within 24 h (the primary outcome) or 48 h of growth was not significantly different between MALDITOF-MS and control arms (135/326, 41.4% vs 120/302, 39.7%; Adjusted Odds ration (AOR) 1.17, p = 0.40 and 151/326, 46.3% vs 141/302, 46.7%; AOR 1.05 p = 0.79, respectively).MALDITOF-MS, in the absence of an antimicrobial stewardship programme, did not improve the proportion on optimal antimicrobial therapy at 24 or 48 h after first growth in a lower-middle income setting with high rates of antibiotic resistance.
Cognitive impairment in Asian patients with heart failure: prevalence, biomarkers, clinical correlates, and outcomes
Authors: YanHong Dong, Shuan Yong Teo, Kathleen Kang, Melissa Tan, Lieng Hsi Ling, Poh Shuan Daniel Yeo, David Sim, Fazlur Jaufeerally, Kui Toh Gerard Leong, Hean Yee Ong, Dinna Soon, Sheldon Lee, Seet Yoong Loh, Ru San Tan, Siew Pang Chan, Arthur Mark Richards, Carolyn Su Ping Lam
Journal: European Journal of Heart Failure (2019)
National Institute for Health and Care Excellence, social values and healthcare priority setting
Authors: Peter Littlejohns, Kalipso Chalkidou, Anthony J Culyer, Albert Weale, Annette Rid, Katharina Kieslich, Clare Coultas, Catherine Max, Jill Manthorpe, Benedict Rumbold, Victoria Charlton, Helen Roberts, Ruth Faden, James Wilson, Carleigh Krubiner, Polly Mitchell, Gry Wester, Jennifer A Whitty, Selena Knight
Journal: Journal of the Royal Society of Medicine (2019)

On 1 April 2019, the National Institute for Health and Care Excellence was 20 years old. This is an anniversary worth noting, if for no other reason than how remarkable it is for a National Health Service quango (quasi-autonomous non-governmental organisation) to be still standing two decades after its inception. There are more reasons for marking and celebrating the National Institute for Health and Care Excellence’s 20-year run. In the intervening years, the Institute has done much to advance the health of the UK population. It has achieved an international reputation for robust and fair healthcare prioritisation that is widely viewed as setting the global standard. The National Institute for Health and Care Excellence built this reputation not only through the rigorous development and application of scientific methods to guide its work but also through its efforts to articulate the underpinning social and ethical values that provide its decisions with robust justification. The National Institute for Health and Care Excellence’s reputation also rests on its commitment to transparency, accountability and inclusiveness in facilitating public and patient input in its deliberations.
CHD1 Loss Alters AR Binding at Lineage-Specific Enhancers and Modulates Distinct Transcriptional Programs to Drive Prostate Tumorigenesis
Authors: Michael A. Augello, Deli Liu, Lesa D. Deonarine, Brian D. Robinson, Dennis Huang, Suzan Stelloo, Mirjam Blattner, Ashley S. Doane, Elissa W.P. Wong, Yu Chen, Mark A. Rubin, Himisha Beltran, Olivier Elemento, Andries M. Bergman, Wilbert Zwart, Andrea Sboner, Noah Dephoure, Christopher E. Barbieri
Journal: Cancer Cell (2019)
Biomedical Applications of DNA‐Based Molecular Devices
Authors: Shaoli Liu, Qiao Jiang, Yuanning Wang, Baoquan Ding
Journal: Advanced Healthcare Materials (2019)

Abstract Strict Watson–Crick base pairing and availability by automated synthesis have allowed deoxyribonucleic acid (DNA) molecules to be used as engineerable building blocks for constructing versatile nanostructures. In recent decades, with the development of DNA nanotechnology, a range of DNA‐based dynamic molecular devices with sophisticated nanostructures have been designed and constructed. Featuring programmability and biocompatibility, the applications of DNA‐based nanodevices have been extensively focused on the interfaces of biological systems. This review summarizes the recent progress in the design of DNA devices exhibiting programmable functions for biomedical applications. In vitro and in vivo applications of DNA‐based nanodevices in cellular imaging and systemic drug delivery are highlighted. The challenges and open opportunities are also discussed.
Introduction: <i>ARPH</i> Approach to Controversial Issues
Authors: Jonathan E. Fielding, Ross C. Brownson, Lawrence W. Green
Journal: Annual Review of Public Health (2019)

The difference in difference (DID) design is a quasi-experimental research design that researchers often use to study causal relationships in public health settings where randomized controlled trials (RCTs) are infeasible or unethical. However, causal ...Read More