tbuckley/cabot-search huggingface dataset:
Abstract A57: GPCRs as potential therapeutic targets in pancreatic cancer-associated fibroblasts
Authors: Shu Zhou, Thalia McCann, Randall French, Andrew Lowy, Paul Insel
Journal: Cancer Research (2015)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense fibrotic stromal matrix, composed of activated fibroblasts/stellate cells, inflammatory cells and other cell types. This unique tumor microenvironment has been increasingly recognized as a key mediator of PDAC progression and drug resistance. Thus, targeting the tumor stroma may be a novel therapeutic approach for PDAC. We hypothesized that G protein-coupled receptors (GPCRs) expressed by pancreatic cancer-associated fibroblasts (CAFs) may be potential therapeutic targets for PDAC. To begin to test this hypothesis, we used an unbiased GPCRomic array approach to identify and quantify the GPCRs expressed by pancreatic CAFs. We found 104 GPCRs, whose expression was shared in CAFs obtained from the primary tumors of five patients. Among those GPCRs, 35 had at least two-fold higher expression in the CAFs compared to normal pancreatic fibroblasts and included GPCRs that link to each of the major classes of G proteins. RT-PCR analysis of the 10 most up-regulated GPCRs correlated well (r2=0.82) with the data from the GPCR array. We conclude that: 1) GPCRomic array analysis can identify and quantify the profile of GPCRs expressed by pancreatic CAFs; 2) the CAF-expressed profile differs from that of normal pancreatic fibroblasts and 3) GPCRs expressed by CAFs may have functional roles and be novel therapeutic targets for PDAC. Citation Format: Shu Zhou, Thalia McCann, Randall French, Andrew Lowy, Paul Insel. GPCRs as potential therapeutic targets in pancreatic cancer-associated fibroblasts. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A57.
A preliminary investigation of the effectiveness of high visibility enforcement programs using naturalistic driving study data: A grouped random parameters approach
Authors: Sarvani Sonduru Pantangi, Grigorios Fountas, Md Tawfiq Sarwar, Panagiotis Ch. Anastasopoulos, Alan Blatt, Kevin Majka, John Pierowicz, Satish B. Mohan
Journal: Analytic Methods in Accident Research (2019)
Predicting Bleeding Risk to Guide Aspirin Use for the Primary Prevention of Cardiovascular Disease
Authors: Vanessa Selak, Rod Jackson, Katrina Poppe, Billy Wu, Matire Harwood, Corina Grey, Romana Pylypchuk, Suneela Mehta, Andrew Kerr, Sue Wells
Journal: Annals of Internal Medicine (2019)

Background: Many prognostic models for cardiovascular risk can be used to estimate aspirin's absolute benefits, but few bleeding risk models are available to estimate its likely harms. Objective: To develop prognostic bleeding risk models among persons in whom aspirin might be considered for the primary prevention of cardiovascular disease (CVD). Design: Prospective cohort study. Setting: New Zealand primary care. Participants: The study cohort comprised 385 191 persons aged 30 to 79 years whose CVD risk was assessed between 2007 and 2016. Those with indications for or contraindications to aspirin and those who were already receiving antiplatelet or anticoagulant therapy were excluded. Measurements: For each sex, Cox proportional hazards models were developed to predict major bleeding risk; participants were censored at the earliest of the date on which they first met an exclusion criterion, date of death, or study end date (30 June 2017). The main models included the following predictors: demographic characteristics (age, ethnicity, and socioeconomic deprivation), clinical measurements (systolic blood pressure and ratio of total–high-density lipoprotein cholesterol), family history of premature CVD, medical history (smoking, diabetes, bleeding, peptic ulcer disease, cancer, chronic liver disease, chronic pancreatitis, or alcohol-related conditions), and medication use (nonsteroidal anti-inflammatory agents, corticosteroids, and selective serotonin reuptake inhibitors). Results: During 1 619 846 person-years of follow-up, 4442 persons had major bleeding events (of which 313 [7%] were fatal). The main models predicted a median 5-year bleeding risk of 1.0% (interquartile range, 0.8% to 1.5%) in women and 1.1% (interquartile range, 0.7% to 1.6%) in men. Plots of predicted-against-observed event rates showed good calibration throughout the risk range. Limitation: Hemoglobin level, platelet count, and body mass index were excluded from the main models because of high numbers of missing values, and the models were not externally validated in non–New Zealand populations. Conclusion: Prognostic bleeding risk models were developed that can be used to estimate the absolute bleeding harms of aspirin among persons in whom aspirin is being considered for the primary prevention of CVD. Primary Funding Source: The Health Research Council of New Zealand.
Abstract 370: Wt1 Influences Regenerative Angiogenic Function of the Vascular Endothelium
Authors: Robert Ogley, Richard McGregor, Nick Hastie, Patrick Hadoke
Journal: Circulation Research (2017)

Ischaemia causes irreversible tissue damage in cardiovascular disease. Since regenerative angiogenesis (new blood vessel formation from existing vasculature) fails to consistently induce sufficient reperfusion to facilitate repair, a targeted approach to manipulating angiogenesis is clinically desirable. The Wilms’ tumour suppressor (Wt1) is a transcription factor which regulates numerous genes and cellular processes, including many intrinsic to angiogenesis. We hypothesise that Wt1 influences the angiogenic function of endothelial cells. Wt1 was identified in endothelial and non-endothelial cells comprising vessel outgrowths generated by cultured aortic rings from Wt1-GFP reporter mice. Inducible deletion of Wt-1 from the endothelium (VE-Wt1 KO) significantly delayed angiogenesis in this assay (p&lt;0.05 relative to Cre and vehicle controls, n=5-8). In vivo , Wt-1 expression was evident in vascular endothelial cells and perivascular cells of the hindlimb as early as 3 days following femoral artery ligation to induce ischaemia. Less expression was detected by day 28. VE-Wt1 KO had no effect on hindlimb reperfusion (laser Doppler; days 0-28) or on vessel density (day 28). Similarly, VE-Wt1 KO had no effect on vessel density (histology, immunohistochemistry) or expression of angiogenic factors (qRT-PCR) in sponges inserted beneath the skin of mice (20 days). To further understand the role of Wt1 in angiogenesis, transcriptomic analysis was performed for RNA expression in Wt1 + and Wt1 - cells isolated (FACs) from sponges 7 and 21 days after implantation in Wt1-GFP mice. Wt1 + cells exhibited higher expression of genes involved in a number of processes relevant to tissue repair, including vasculature development (D7: p=10 -7.43 , D21: p=10 -3.47 , n=3) and angiogenesis (D7: p=10 -3.90 , D21: p=10 -4.74 , n=3). These results show that deletion of endothelial Wt-1 delays, rather than permanently inhibiting, angiogenesis: suggesting a more complex mechanism of action than reported previously. Transcriptomic data suggest that expression in endothelial cells (and other cells in the endothelial lineage) contributes to tissue repair in ischaemia. This work has improved our understanding of the regulatory role of Wt1 in angiogenesis.
Targeting PI3K-Gamma in Non-Hodgkin Lymphoma
Authors: David A. Fruman
Journal: Journal of Clinical Oncology (2019)

Article Tools UNDERSTANDING THE PATHWAY Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES DYNAMO: A Phase II Study of Duvelisib (IPI-145) in Patients With Refractory Indolent Non-Hodgkin Lymphoma. February 11, 2019 ARTICLE CITATION DOI: 10.1200/JCO.19.00215 Journal of Clinical Oncology - published online before print February 27, 2019 PMID: 30811291 Targeting PI3K-Gamma in Non-Hodgkin Lymphoma David A. Fruman, PhD1xDavid A. FrumanSearch for articles by this author Show More 1University of California, Irvine, Irvine, CA https://doi.org/10.1200/JCO.19.00215 First Page Full Text PDF Figures and Tables © 2019 by American Society of Clinical Oncology Companion DYNAMO: A Phase II Study of Duvelisib (IPI-145) in Patients With Refractory Indolent Non-Hodgkin Lymphoma
A Case of Intramuscular Cryptococcosis Mimicking a Malignant Tumor on FDG PET/CT
Authors: Ling Wang, Xiangwu Zheng, Jie Lin, Kun Tang
Journal: Clinical Nuclear Medicine (2019)

Intramuscular cryptococcosis is extremely rare. In this case, a 76-year-old man with history of acute myeloid leukemia presented a painful mass in the right upper arm. FDG PET/CT demonstrated a low-density irregular-shaped mass in the triceps muscle of the right upper arm with adjacent bone erosion. The lesion presented with significantly increased activity with an SUVmax of 23.4, which could be misdiagnosed as a malignant tumor. The lesion was confirmed as cryptococcosis by periodic acid-Schiff stain and culture of biopsied specimen. Because cryptococcal infection is treatable, it is important to increase awareness of this hypermetabolic benign lesion in the unusual location.
Health Care Utilization in Transplanted Versus Non-Transplanted Sickle Cell Disease Patients
Authors: Santosh L. Saraf, Krishna Ghimire, Pritesh Patel, Karen Sweiss, John G. Quigley, Irum Khan, David Peace, Michel Gowhari, Shivi Jain, John P. Galvin, Robert E. Molokie, Victor R. Gordeuk, Damiano Rondelli
Journal: Blood (2018)
Xpert MTB/RIF Ultra improved the diagnosis of paucibacillary tuberculosis: A prospective cohort study
Authors: Guirong Wang, Shuqi Wang, Guanglu Jiang, Xinting Yang, Mailing Huang, Fengmin Huo, Yifeng Ma, Guangming Dai, Weimin Li, Xiaoyou Chen, Hairong Huang
Journal: Journal of Infection (2019)
Analysis of time-to-treatment discontinuation of targeted therapy, immunotherapy, and chemotherapy in clinical trials of patients with non-small-cell lung cancer
Authors: G.M. Blumenthal, Y. Gong, K. Kehl, P. Mishra-Kalyani, K.B. Goldberg, S. Khozin, P.G. Kluetz, G.R. Oxnard, R. Pazdur
Journal: Annals of Oncology (2019)
Progress Toward Poliomyelitis Eradication — Pakistan, January 2017–September 2018
Authors: Christopher Hsu, Abdirahman Mahamud, Muhammad Safdar, Joanna Nikulin, Jaume Jorba, Kelley Bullard, John Agbor, Milhia Kader, Salmaan Sharif, Jamal Ahmed, Derek Ehrhardt
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Among the three wild poliovirus (WPV) serotypes, only WPV type 1 (WPV1) has been reported in polio cases or detected from environmental surveillance globally since 2012. Pakistan remains one of only three countries worldwide (the others are Afghanistan and Nigeria) that has never had interrupted WPV1 transmission. This report documents Pakistan's activities and progress toward polio eradication during January 2017-September 2018 and updates previous reports (1,2). In 2017, Pakistan reported eight WPV1 cases, a 60% decrease from 20 cases in 2016. As of September 18, 2018, four cases had been reported, compared with five cases at that time in 2017. Nonetheless, in 2018, WPV1 continues to be isolated regularly from environmental surveillance sites, primarily in the core reservoir areas of Karachi, Quetta, and Peshawar, signifying persistent transmission. Strategies to increase childhood immunity have included an intense schedule of supplemental immunization activities (SIAs), expanding and refining deployment of community-based vaccination implemented by community health workers recruited from the local community in reservoir areas, and strategic placement of permanent transit points where vaccination is provided to mobile populations. Interruption of WPV1 transmission will require further programmatic improvements throughout the country with a focus on specific underperforming subdistricts in reservoir areas.
Plant-based sterols and stanols in health &amp; disease: “Consequences of human development in a plant-based environment?”
Authors: J. Plat, S. Baumgartner, T. Vanmierlo, D. Lütjohann, K.L. Calkins, D.G. Burrin, G. Guthrie, C. Thijs, A.A. Te Velde, A.C.E. Vreugdenhil, R. Sverdlov, J. Garssen, K. Wouters, E.A. Trautwein, T.G. Wolfs, C. van Gorp, M.T. Mulder, N.P. Riksen, A.K. Groen, R.P. Mensink
Journal: Progress in Lipid Research (2019)

Dietary plant sterols and stanols as present in our diet and in functional foods are well-known for their inhibitory effects on intestinal cholesterol absorption, which translates into lower low-density lipoprotein cholesterol concentrations. However, emerging evidence suggests that plant sterols and stanols have numerous additional health effects, which are largely unnoticed in the current scientific literature. Therefore, in this review we pose the intriguing question "What would have occurred if plant sterols and stanols had been discovered and embraced by disciplines such as immunology, hepatology, pulmonology or gastroenterology before being positioned as cholesterol-lowering molecules?" What would then have been the main benefits and fields of application of plant sterols and stanols today? We here discuss potential effects ranging from its presence and function intrauterine and in breast milk towards a potential role in the development of non-alcoholic steatohepatitis (NASH), cardiovascular disease (CVD), inflammatory bowel diseases (IBD) and allergic asthma. Interestingly, effects clearly depend on the route of entrance as observed in intestinal-failure associated liver disease (IFALD) during parenteral nutrition regimens. It is only until recently that effects beyond lowering of cholesterol concentrations are being explored systematically. Thus, there is a clear need to understand the full health effects of plant sterols and stanols.
A blood dendritic cell vaccine for acute myeloid leukemia expands anti-tumour T cell responses at remission
Authors: Derek N. J. Hart, Jennifer L. Hsu, Christian E. Bryant, Michael S. Papadimitrious, Benjamin Kong, Robin E. Gasiorowski, Daniel W. Orellana, Helen M. McGuire, Barbara Fazekas de St Groth, Douglas E. Joshua, Phoebe Joy Ho, Stephen R. Larsen, Harry J. Iland, John Gibson, Georgina J. Clark, Phillip D. Fromm
Journal: Blood (2017)
Mertk Inhibition Promotes Anti-Leukemia Immunity By Reversing T Cell Suppression Via the PD-1 Axis
Authors: Alisa Lee-Sherick, Kristen Jacobsen, Curtis J. Henry, Rebecca Parker, Xiaodong Wang, Stephen V Frye, H. Shelton Earp, Deborah DeRyckere, Douglas K Graham
Journal: Blood (2018)
Detection of genomic alterations in breast cancer (BC) patients with paired plasma and tumour specimens
Authors: Y.S. Yap, D. Ho, R.C.-H. Ng, C.H.-T. Chan, A.S.-G. Lee, I.B.-H. Tan, S.B.H. Ng
Journal: Annals of Oncology (2019)

Background: There is increasing interest in the use of circulating tumour DNA (ctDNA) to identify targetable genomic alterations for therapy selection. However, the feasibility of next generation sequencing on ctDNA in BC patients with varying disease burden merits further investigation. Methods: The cohort of 35 BC patients included 30 metastatic cases with paired primary and metastatic specimens in addition to plasma taken prior to commencement of a new line of palliative systemic therapy (all subtypes), + 5 patients (3 stage III, 2 stage II) about to commence neoadjuvant systemic therapy. DNA from tumour, buffy coat and plasma was sequenced on a 77-gene capture panel customised for BC. Matched tumour/normal samples were processed to discover somatic alterations using a standard GATK pipeline. Plasma samples were processed using unique molecular identifiers to identify potential alterations at low frequency. Results: Among the entire cohort, 74% (26/35) of patients had mutation(s) in at least 1 gene detected from ctDNA: 60% (3/5) for the neoadjuvant cases, 77% (23/30) for the metastatic cases. The most frequently mutated genes from ctDNA analysis were TP53 (17/35; 49%) and PIK3CA (8/35; 23%), with HER2, HER3, JAK2, NF1, MAGI3 and TSC2 mutations observed in 2 patients each (6%). There was no obvious correlation between detection of ctDNA mutation and disease burden, serum CA-15.3 tumour marker or circulating tumour cell levels using a microfluidic platform. Out of 35 patients, 21(60.0%) had ≥1 concordant mutation via both ctDNA and tumour genotyping. Concordance between the plasma and primary and/or metastatic lesions was observed for 59% (39/66) of the mutations detected in ctDNA. Among the metastatic cases, 14/37(38%) of the concordant mutations were shared between the plasma, primary and metastatic specimens, while 5(14%) were shared between the plasma and the primary only, and 18/37(49%) shared between the plasma and metastatic lesions only. Conclusions: Detection of genomic alterations from ctDNA is feasible in BC patients, but concordance of mutations in ctDNA is better with the metastatic than the primary lesion. This is likely due to suboptimal quality of DNA from archived tissue, and spatial, temporal heterogeneity. Legal entity responsible for the study: National Cancer Centre Singapore and Genome Institute of Singapore. Funding: SingHealth Foundation. Disclosure: Y.S. Yap: Personal financial interests, honoraria for consultancy and talks, travel support: AstraZeneca, Eisai, Lilly, Novartis, Pfizer, Roche. All other authors have declared no conflicts of interest.
Satisfaction with a digitally-enabled telephone health coaching intervention for people with non-diabetic hyperglycaemia
Authors: Peter Coventry, Peter Bower, Amy Blakemore, Elizabeth Baker, Mark Hann, Jinshuo Li, Angela Paisley, Martin Gibson
Journal: npj Digital Medicine (2019)

International evidence shows that lifestyle interventions can effectively reduce the risk of developing diabetes in people with non-diabetic hyperglycaemia (NDH). A candidate intervention that has potential to be rolled out at population level is health coaching. Digital interventions offer the means to potentially enhance user satisfaction with health coaching and improve efficiencies. We used a randomised controlled trial to test whether a digitally-enabled health coaching intervention that included an online dashboard and telephone health coaching improved user satisfaction and cost-efficiencies compared with a telephone only health coaching intervention. The primary outcome was satisfaction measured by Client Satisfaction Questionnaire (CSQ-8). 103 participants with NDH were allocated to the telephone coaching only intervention and 106 participants with NDH were allocated to the digital and telephone coaching intervention. In an intention-to-treat analysis satisfaction was higher in participants allocated to the digital and telephone coaching intervention than those allocated to the telephone only intervention, but the difference was not significant. There were no significant differences between the groups on secondary outcomes (HbA1c, BMI, activation, depression, self-management, health status). From a service commissioning perspective the mean incremental cost of the digitally-enabled intervention was £236 ($332; €270). Call times, including administration, were longer for participants allocated to the digitally-enabled intervention. The results show that user satisfaction with digitally-enabled intervention is broadly equivalent with that of telephone delivered interventions in the context of routinely delivered diabetes prevention programmes. There is scope for future work that assesses how economies of scale can be achieved at larger user bases.
A Machine Learning Method for Detecting Autocorrelation of Evolutionary Rates in Large Phylogenies
Authors: Qiqing Tao, Koichiro Tamura, Fabia U. Battistuzzi, Sudhir Kumar
Journal: Molecular Biology and Evolution (2019)

Abstract New species arise from pre-existing species and inherit similar genomes and environments. This predicts greater similarity of the tempo of molecular evolution between direct ancestors and descendants, resulting in autocorrelation of evolutionary rates in the tree of life. Surprisingly, molecular sequence data have not confirmed this expectation, possibly because available methods lack the power to detect autocorrelated rates. Here, we present a machine learning method, CorrTest, to detect the presence of rate autocorrelation in large phylogenies. CorrTest is computationally efficient and performs better than the available state-of-the-art method. Application of CorrTest reveals extensive rate autocorrelation in DNA and amino acid sequence evolution of mammals, birds, insects, metazoans, plants, fungi, parasitic protozoans, and prokaryotes. Therefore, rate autocorrelation is a common phenomenon throughout the tree of life. These findings suggest concordance between molecular and nonmolecular evolutionary patterns, and they will foster unbiased and precise dating of the tree of life.
P113/O17 Human lymph node stromal cells express self-antigens targeted by anti-citrullinated protein antybodies: role for tolerance induction in rheumathoid arthritis
Authors: C Grasso, JS Hähnlein, R Nadafi, TA De Jong, TH Ramwadhdoebe, JF Semmelink, DM Gerlag, PP Tak, RE Mebius, M Safy, M Maas, AI Catrina, H Wähämaa, LGM Van Baarsen
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Student for a master or a PhD. <h3>Introduction</h3> In rheumatoid arthritis (RA) the cause for loss of tolerance and anti–citrullinated protein antibody (ACPA) production remains unidentified. Mouse studies showed that peripheral tolerance can be maintained through presentation of peripheral tissue antigens (PTAs) by lymph node stromal cells (LNSCs). We hypothesize that deregulation of peripheral tolerance mechanisms mediated by LNSCs might underlie pathogenesis of RA. Here we investigated the expression of PTAs, citrullinated proteins and immunomodulatory molecules by human LNSCs during health and autoimmunity. <h3>Methods</h3> LN tissue sections and LNSCs were prepared from freshly collected lymph node needle biopsies obtained from 24 patients with RA, 23 individuals positive for autoantibodies but without clinical apparent disease (RA-risk group) and 14 seronegative healthy controls. Expression of PADI enzymes, citrullinated proteins, DEAF1, AIRE and PTAs was investigated at mRNA and protein level. Expression of immunomodulatory molecules in LNSCs was assessed after stimulation with IFNγ (n=15). <h3>Results</h3> Citrinullated proteins, targeted by ACPA, were found in human LN tissue as well as in cultured LNSCs. In addition, we observed the expression of transcription factors AIRE and DEAF1 as well as disease-related PTAs in LNSCs with some PTAs showing a distinct expression pattern in autoimmune LNSCs compared to healthy controls. TGF-β was constitutively expressed by LNSCs while CD86 or IL-10 were not detected. Upon IFNγ stimulation LNSCs upregulated MHC class II, co-stimulatory molecules CD40 and CD80 as well as T cell negative regulators CD274, NOS2 and IDO. Overall, no clear differences between donor groups were observed for these markers with exception of a slightly lower induction of CD40 and NOS2 in RA LNSCs. <h3>Conclusions</h3> We present for the first time that human LNSCs express several PTAs and the transcription factors AIRE and DEAF1, driving PTA expression. Additionally, human LNSCs express molecules involved in citrullination, antigen presentation and immunomodulation. Moreover, antigens targeted by ACPAs are present in LN tissue and LNSCs. These data suggest that LNSCs have the machinery to regulate peripheral tolerance. <h3>Disclosure of Interest</h3> None declared.
IL-7 Activates a STAT5/PIM1 Axis to Promote T-Cell Acute Lymphoblastic Leukemia Proliferation and Viability in a Bcl-2-Independent Manner
Authors: Ribeiro Daniel, Alice Melão, Ruben van Boxtel, Cristina Santos, Ana Silva, Milene C Silva, Bruno António Cardoso, Paul J. Coffer, Joao Barata
Journal: Blood (2018)