tbuckley/cabot-search huggingface dataset:
Juxtacrine Signaling Inhibits Antitumor Immunity by Upregulating PD-L1 Expression
Authors: Wen-Hao Yang, Jong-Ho Cha, Weiya Xia, Heng-Huan Lee, Li-Chuan Chan, Ying-Nai Wang, Jennifer L. Hsu, Guoxin Ren, Mien-Chie Hung
Journal: Cancer Research (2018)

Programmed death-ligand 1 (PD-L1) is a well-known immune checkpoint protein that helps cancer cells evade immune response. Anti-PD-L1 immune therapy has been approved for the treatment of several advanced human cancers. Therefore, further understanding of the regulatory mechanisms of PD-L1 is critical to improve PD-L1-targeting immunotherapy. Recent studies indicated that contact-dependent pathways may regulate anticancer immunity, highlighting the importance of cell contact-induced signaling in cancer immunity. Here, we show that tumor cell contact upregulates PD-L1 expression and reduces T-cell-mediated cell killing through the membrane receptor tyrosine kinase ephrin receptor A10 (EphA10), which is not expressed in normal tissues except testis and is known to mediate cell contact-dependent juxtacrine signaling. Knockout of EphA10 in tumor cells increased T-cell-mediated antitumor immunity in syngeneic mouse models. EphA10 expression also correlated positively with PD-L1 in human breast tumor tissues. Together, our data reveal that in addition to paracrine/autocrine signaling, cell contact-mediated juxtacrine signaling also promotes PD-L1 expression, implying that tumor cells may escape immune surveillance via this mechanism and that targeting EphA10 to boost antitumor immunity may be a new immune checkpoint blockade strategy for female patients with breast cancer.Significance: Regulation of PD-L1 expression by cell contact-mediated signaling promotes immune escape in breast cancer and may lead to the development of an immunotherapy with less adverse effects in female patients. Cancer Res; 78(14); 3761-8. ©2018 AACR.
Whole Lung Lavage Therapy Of Pulmonary Alveolar ProteINOSis: A Global Survey Of Current Practices And Procedures
Authors: I. Campo, M. Luisetti, M. Griese, B. C. Trapnell, F. Bonella, J. C. Grutters, K. Nakata, C. H. M. van Moorsel, U. Costabel, V. Cottin, T. Ichiwata, Y. Inoue, A. Braschi, G. Bonizzoni, G. A. Iotti, C. Tinelli, G. Rodi
Journal: American Journal of Respiratory and Critical Care Medicine (2016)
Smad3 suppresses Nrf2-mediated expression of GCLC.
Authors: Andrei V. Bakin, Konjeti R. Sekhar, Cammie Rinehart, Michael J. Meredith, Carlos L. Arteaga, Michael L. Freeman
Journal: Cancer Research (2004)

3491   Transforming growth factor-beta (TGF-β) regulates cell proliferation and differentiation. TGF-β signaling occurs through transmembrane serine-threonine kinase type II and type I receptors. Smad2 and Smad3 transcription factors activated by type I receptor and common Smad4 translocate to the nucleus to regulate transcription of target genes. In cDNA microarray studies in mouse mammary epithelial NMuMG cells, we identified new target genes suppressed by TGF-β including Gstp2, Gsta4, Gstm1, catalase, and glutamate cysteine ligase. These genes are regulated by the Nuclear Factor-Erythroid 2p45 related transcription factor Nrf2 (Chan and Kwong Biochim. Biophys. Acta 1517: 19-26, 2002; Kwak et al, Mol. Med. 2: 135-145, 2001;Chanas et al., Biochem. J. 356(A2): 405-410, 2002) which binds to antioxidant response elements (AREs) as a heterodimer and participates in the regulation of Phase II gene expression, a component of cancer chemoprevention. (Ramos-Gomez et al. Proc. Natl. Acad. Sci. USA 98:3410-3415, 2001). GCLC, the catalytic subunit of glutamate cysteine ligase (GCL) was used as a molecular surrogate to determine if TGF-β signaling could suppress Nrf2-regulated gene expression. NMuMG cells were transiently co-transfected with either a GCLC Lux or an ARE/GCLC Lux reporter and vectors expressing Nrf2 or Smad3E (a constitutively active Smad3 molecule). Exposure to TGF-β or Smad3E suppressed activity of both Lux reporters and was shown to be dependent upon Nrf2 binding to the ARE as mutation of the GCLC–ARE site abrogated Lux activity. TGF-mediated suppression, however, could be inhibited by forced expression of Nrf2; this could be reversed by co-transfection of Smad3E. GMSAs coupled with immunoprecipitation immunoblotting experiments demonstrated that Smad3 associated with Nrf2 in an off DNA reaction. c-Jun was shown to participate in ARE-dependent expression of GCLC, as demonstrated by the ability of His tagged c-Jun to immunoprecipitate Nrf2, loss of GCLC Lux reporter activity in mouse embryonic fibroblasts containing a targeted disruption of c-Jun, and the ability of forced expression of c-Jun in HepG2 cells to induce ARE-dependent GCLC reporter activity in an ARE-dependent fashion. Similar to the results obtained with Nrf2, induction of GCLC Lux activity by co-transfection of c-Jun was reversed by forced expression of Smad3E. Wild type and Smad3 null dermal mouse fibroblasts were transfected with the GCLC Lux reporter. Loss of Smad3 expression enhanced basal GCLC Lux reporter activity while reconstitution of Smad 3 into the null cells reduced GCLC Lux activity to the level observed in Smad3 +/+ cells. Similar results occurred when cells were exposed to TGFβ. These data suggest that TGF-β suppresses Nrf2-mediated gene expression via Smad signaling.
Abstract 19233: C-myb Regulates Microrna143 and Microrna145 Gene Expression in Embryonic and Adult Vascular Smooth Muscle Cells
Authors: Mark Chandy, Masayoshi Ishida, Eric Shikatani, Omar El-Mouranyi, Talat Alfrooze, Mansoor Husain
Journal: Circulation (2016)

Background:  MicroRNAs (miR) are small non-coding RNAs. The bicistronic miR-143/145 gene determines cell fate of cardiomyocytes, vascular smooth muscle cells (VSMC) and endothelial cells. The regulation of miR-143/145 remains unclear. Transcription factor c-Myb controls proliferation and differentiation of hematopoiesis progenitors and VSMC.   Hypothesis:  c-Myb regulates miR-143/145 expression in VSMC proliferation and differentiation.   Methods & Results:  Flow cytometry of d3.75 mouse embryoid bodies (EBs) was used to isolate SMC progenitors with surface markers VEGFR2 (V) and PDGFRα (P). In  c-myb  knockout EB, V + /P -  and V-/P+ progenitor cells had low expression of miR-143/145 suggesting a role for c-Myb in their regulation. Primary carotid VSMC isolated from mice with diminished expression of c-Myb (LoxP) treated with TGFβ have reduced expression of miR-143 and miR-145. Sequence alignment identified c-Myb-binding sites (MBS) in the promoter of the miR-143/145 gene. ChIP assays in EBs and adult VSMC revealed c-Myb binding to MBS. Using site-directed mutagenesis in a promoter-reporter construct, we identified MBS mediate transcriptional regulation of miR-143/145 in VSMC. Immunoblots were used to test whether c-Myb regulated a known target of miR-143, the ETS domain-containing protein-1 (Elk-1). Increased levels of c-Myb inversely correlated with Elk-1, suggesting c-Myb represses Elk-1. This effect was abrogated by miR-143 antagomir, and enhanced by miR-143 mimic.   Conclusion:  c-Myb regulates miR-143/145 expression in differentiating embryonic SMC progenitors and TGFβ-stimulated adult VSMC via MBS in the miR-143/145 promoter.
Oncological outcome of laparoscopically assisted pancreatoduodenectomy for ductal adenocarcinoma in a retrospective cohort study
Authors: Simon Kuesters, Sophia Chikhladze, Frank Makowiec, Olivia Sick, Stefan Fichtner-Feigl, Ulrich T. Hopt, Uwe A. Wittel
Journal: International Journal of Surgery (2018)
Abstract 12311: Platelet Force Measurements are Predictive of Triage Category and Blood Transfusion After Trauma
Authors: Nathan J White, Lucas Ting, Esther B Lim, Ari Karchin, Xu Wang, Annie O Smith, Diana Chien, Tessa C Rue, Nathan Sniadecki
Journal: Circulation (2015)

Introduction: Platelets rapidly adhere, aggregate and contract forcefully at wound sites to initiate hemostasis. This process, known as primary hemostasis, is a critical component of clot formation after trauma. However, the clinical value of monitoring primary hemostasis after trauma remains unknown. This pilot study aimed to identify the potential clinical value of monitoring primary hemostasis after trauma by measuring platelet forces. Methods: Blood was sampled from Emergency Department trauma patients at a U.S. Level I trauma center. Primary hemostasis was measured as contractile force generated by platelet micro-aggregates formed within a microfluidic device. Citrated blood was flowed through a microfluidic channel at high shear rate for 15 seconds, causing platelet aggregates to rapidly form, activate, and contract at collagen-coated micro-force sensors. The maximum platelet force generated over five minutes was recorded in nanonewtons (nN). ANOVA was used to compare platelet force for each trauma triage category: Healthy non-trauma control vs. Modified vs. Full trauma team activation. Logistic regression was used to identify the association of platelet force with the need for any blood product transfusion within 24 hours of hospitalization. Results: N=28 trauma patients and N=7 healthy control subjects were included in this pilot analysis of an ongoing cross-sectional observational study. Of the trauma subjects 7/28 (25%) met Full trauma team activation criteria, and 7/28 (25%) required a blood-product transfusion. Mean (SD) platelet force was 227(63) nN for healthy controls, 157(48) nN for Modified, and 126(35) nN for Full trauma team activations (ANOVA, p=0.004). Platelet forces were 164 (45) nN for non-transfused vs. 112(20) nN for transfused subjects (t-test, p=0.008). The platelet force unit Odds Ratio for blood product transfusion was 0.965 (95%CI= 0.936, 0.996), indicating that the odds of receiving a transfusion was decreased significantly by 3.5% for every one nN increase of platelet force. Conclusions: Directly measuring primary hemostasis using platelet forces may enhance trauma triage and predict the need for blood product transfusion after trauma.
大疱性表皮松解研究流程成果评分工具(iscorEB)的可靠性和有效性
Authors: A.L. Bruckner, D.L. Fairclough, J.A. Feinstein, I. Lara-Corrales, A.W. Lucky, J. Tolar, E. Pope
Journal: British Journal of Dermatology (2018)

大疱性表皮松解(EB)是一种罕见的基因性发疱病,影响皮肤,甚至是内部器官。在研究中准确估算此类复杂疾病的严重性非常困难。我们研发了一项工具,被称为大疱性表皮松解研究流程成果评分工具(instrument for scoring clinical outcomes of research for Epidermolysis Bullosa, iscorEB),用于从医生和患者角度评估疾病严重性。在本文中,我们提到的数据来自于加拿大和美国的2家机构对iscorEB的测试。三十一名患者以及六名不同医学背景的医生参与了研究,以体现评分对于评估疾病严重性的一致性和有效性。我们发现,医生之间以及医生和患者之间有很好的一致性。我们还证明了iscorEB能够区分轻度、中度和重度疾病患者以及亚型EB。
Decellularized and matured esophageal scaffold for circumferential esophagus replacement: Proof of concept in a pig model
Authors: Guillaume Luc, Guillaume Charles, Caroline Gronnier, Magali Cabau, Charlotte Kalisky, Mallory Meulle, Reine Bareille, Samantha Roques, Lionel Couraud, Johanna Rannou, Laurence Bordenave, Denis Collet, Marlène Durand
Journal: Biomaterials (2018)
Abstract 16167: Stellate Ganglion Blockade and Bilateral Cardiac Sympathetic Denervation in Patients With Life-Threatening Ventricular Arrhythmias
Authors: Ricardo Cardona Guarache, Luis Velazco, Anthony Cassano, Antonio Abbate, Kenneth A Ellenbogen, Jayanthi Koneru
Journal: Circulation (2016)

Introduction: Autonomic modulation is an increasingly recognized strategy to treat ventricular tachycardia (VT) or ventricular fibrillation (VF) refractory to beta-blockers, antiarrhythmic drugs an...
Abstract 24024: Utilizing Telemedicine to Construct Population-Based STEMI Systems of care in Developing Countries
Authors: Sameer Mehta, Roberto Botelho, Francisco Fernandez, Sunil Agarwal, Marco Perin, Rodolfo Cardoso, Cesar Dusilek, Marco A Gamba, Juan C Perez-Alva, Mario Torres, Daniel Rodriguez
Journal: Circulation (2017)

Background: Major disparities exist between developed and developing countries in the outcomes of patients presenting with Acute Myocardial Infarction (AMI). Telemedicine has emerged as a powerful, cost-efficient, and scalable tool. Whether telemedicine can improve AMI results remains unclear. Methods: We incorporated a hub and spoke strategy for Latin America Telemedicine Infarct Network (LATIN) to expand access to care in regions in Brazil, Colombia, and Mexico that lacked AMI care. Small clinics and primary care health centers in remote areas (spokes) were strategically connected to hubs that could perform 24/7 primary PCI. Experts at 3 central sites in Uberlandia, Sao Paulo, and Bogota, provided urgent EKG diagnosis and tele-consultation for the entire LATIN network by triggering ambulance dispatch and implementing standardized AMI protocols. Results: A total of 257 LATIN centers (Brazil 95, Colombia 113, Mexico 49) were networked using similar telemedicine protocols. In Colombia, LATIN coverage was established to cover 31% of the nation’s 48 million population. With this expanded geographic reach, 4.694 (1.2%) of the 401,095 screened patients were diagnosed as having STEMI. A total of 2,041 (43.5%) STEMI were urgently reperfused. Primary PCI was performed in the majority of patients - 1,578 (77.3%) that were referred for urgent perfusion. The major reasons for non-treatment included insurance denials, lack of ICU beds and chest pain &gt;12 hours. Time to Telemedicine Diagnosis (TTD) was 5.1 minutes, and tele-ECG accuracy was 98%. D2B time for the cohort was 53 minutes, but chest pain to treatment time was &gt;6 hours. Overall, in-hospital mortality was 5.8%. Conclusions: LATIN demonstrates the feasibility of creating a population based and telemedicine-guided AMI management strategy that can hugely expand access to reperfusion strategies. Telemedicine has important public health implications as a global approach to urgent AMI care in developing countries.
Clinical Trials in Idiopathic Pulmonary Fibrosis in the “Posttreatment Era”
Authors: Kevin F. Gibson, Daniel J. Kass
Journal: JAMA (2018)

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Reevaluating the Evidence for Blood Pressure Targets in Type 2 Diabetes
Authors: Julio A. Lamprea-Montealegre, Ian H. de Boer
Journal: Diabetes Care (2018)

There is general consensus that treating adults with type 2 diabetes mellitus (T2DM) and hypertension to a target blood pressure (BP) of <140/90 mmHg helps prevent cardiovascular disease (CVD). Whether more intensive BP control should be routinely targeted remains a matter of debate. While the American Diabetes Association (ADA) BP guidelines recommend an individualized assessment to consider different treatment goals, the American College of Cardiology/American Heart Association BP guidelines recommend a BP target of <130/80 mmHg for most individuals with hypertension, including those with T2DM (1–3).

In large part, these discrepant recommendations reflect the divergent results of the Action to Control Cardiovascular Risk in Diabetes-BP trial (ACCORD-BP) among people with T2DM and the Systolic Blood Pressure Intervention Trial (SPRINT), which excluded people with diabetes (4,5). Both trials evaluated the effect of intensive compared with standard BP treatment targets (<120 vs. <140 mmHg systolic) on a composite CVD end point of nonfatal myocardial infarction or stroke or death from cardiovascular causes. SPRINT also included unstable angina and acute heart failure in its composite end point. While ACCORD-BP did not show a significant benefit from the intervention (hazard ratio [HR] 0.88; 95% CI 0.73–1.06), SPRINT found a significant 25% relative risk reduction on the primary end point favoring intensive therapy (0.75; 0.64–0.89).

Why did ACCORD-BP and SPRINT arrive at divergent conclusions? Recent secondary analyses provide new insights into potential reasons, including differences in trial design, populations studied, approach to BP lowering, trial end points, and statistical power or chance findings.

While SPRINT used a parallel group study design, ACCORD-BP used …
Ingestible roasted barley for contrast-enhanced photoacoustic imaging in animal and human subjects
Authors: Depeng Wang, Dong Hyeun Lee, Haoyuan Huang, Tri Vu, Rachel Su Ann Lim, Nikhila Nyayapathi, Upendra Chitgupi, Maggie Liu, Jumin Geng, Jun Xia, Jonathan F. Lovell
Journal: Biomaterials (2018)
Age-Related Racial Disparity in Suicide Rates Among US Youths From 2001 Through 2015
Authors: Jeffrey A. Bridge, Lisa M. Horowitz, Cynthia A. Fontanella, Arielle H. Sheftall, Joel Greenhouse, Kelly J. Kelleher, John V. Campo
Journal: JAMA Pediatrics (2018)

This study compares age-specific rates of suicide between black and white youths using data from the Web-based Injury Statistics Query and Reporting System (WISQARS) of the Centers for Disease Control and Prevention.
Nitric Oxide–Releasing Macromolecular Scaffolds for Antibacterial Applications
Authors: Lei Yang, Evan S. Feura, Mona Jasmine R. Ahonen, Mark H. Schoenfisch
Journal: Advanced Healthcare Materials (2018)

Exogenous nitric oxide (NO) represents an attractive antibacterial agent because of its ability to both disperse and directly kill bacterial biofilms while avoiding resistance. Due to the challenges associated with administering gaseous NO, NO-releasing macromolecular scaffolds are developed to facilitate NO delivery. This progress report describes the rational design and application of NO-releasing macromolecular scaffolds as antibacterial therapeutics. Special consideration is given to the role of the physicochemical properties of the NO storage vehicles on antibacterial or anti-biofilm activity.
Abstract B06: A SOX9+ bile duct progenitor as a cell of origin of hepatocellular carcinoma
Authors: Patrick Viatour
Journal: Cancer Research (2018)

Abstract Hepatocellular carcinoma (HCC) is the most frequent form of liver cancer and its associated mortality is increasing. Most HCC patients are diagnosed at an advanced stage of the disease, which is not eligible for curative surgery and for which efficient drugs remain elusive. Consequently, the prognosis of these patients is particularly poor, begging for a revolution in our therapeutic approach of the disease. Our in-depth understanding of HCC etiology suggests that patients at risk could be regularly screened for the early detection and treatment of nascent neoplastic lesions. This strategy requires a detailed knowledge of the early events that initiate HCC since their nature shapes the features of the developing lesions. However, the identity of cells that can serve as a cell of origin for HCC as well as the molecular events that transform them remain unknown, hampering the development of an early-intervention strategy. To address this important gap in our knowledge, we have taken advantage of a tractable model of HCC initiated upon Rb family loss of function, which is an almost universal event in cancer and particularly in HCC. The Cre/Lox-mediated inactivation of Rb family genes in distinct liver cell populations (cholangiocytes, hepatocytes, and various populations of bipotential and committed progenitors) reveals that most tested cell types, while displaying aberrant cell cycle activity, are resistant to transformation upon Rb pathway alteration. However, Rb family inactivation in Sox9-expressing bile duct progenitor cells initiates HCC that recapitulates the human disease. Interestingly, these committed cholangiocyte progenitors rapidly lose their canonical markers to adopt markers that are specific of the hepatocyte lineage, suggesting that Rb gene family inactivation potentiates their cellular plasticity. Importantly, analysis of human HCC array reveals that expansion of Sox9-expressing cells is a common feature of premalignant lesions and early-stage HCC. Despite its almost universal alteration in cancer, our mouse genetic approach demonstrates that only rare cell populations are susceptible to transformation upon Rb pathway inactivation. In addition, our data show that a cholangiocyte-restricted progenitor population can serve as the cell of origin for a hepatocyte-based type of cancer. This model will enable us to deconstruct the molecular mechanisms that initiate and drive early HCC development and ultimately allow us to shift the clinical management of the disease towards its early steps. Citation Format: Patrick Viatour. A SOX9+ bile duct progenitor as a cell of origin of hepatocellular carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B06.
Prostate screening could rise again after new US cancer data
Authors: Owen Dyer
Journal: BMJ (2018)

After falling for two decades, prostate cancer mortality in the United States has levelled out since a government taskforce recommended against routine prostate specific antigen (PSA) screening, an annual report has shown.1

The findings on prostate cancer are the most striking conclusions of this year’s survey of cancer trends from cancer registrars and researchers from the Centers for Disease Control and Prevention, the National Cancer Institute, and the American Cancer Society. They were laid out in a separate article, alongside a broader report on the status of malignant disease, in the journal Cancer .2

The data are sure to reignite debate over the wisdom of recommendations from the US Preventive Services Task Force (USPSTF) that have discouraged routine screening of …