tbuckley/cabot-search huggingface dataset:
Cytomegalovirus Infection–Enhanced Cardiac Allograft Vasculopathy Is Abolished by DHPG Prophylaxis in the Rat
Authors: KarlLemström, RoopeSihvola, CathrienBruggeman, PekkaHäyry, PetriKoskinen
Journal: Circulation (1997)

Background A wealth of clinical and experimental evidence exists for cytomegalovirus (CMV) infection as an accelerating factor in the development of cardiac allograft vasculopathy. In this study, the impact of 9-(1,3-dihydroxy-2-propoxymethyl) guanine (DHPG) on rat CMV infection–enhanced cardiac allograft vasculopathy is investigated. Methods and Results Heterotopic rat cardiac allografts were performed from the DA to the WF rat strain, and the recipients were immunosuppressed with cyclosporine A 2 mg·kg−1·d−1 SC for a period of 90 days until the end of experiment. Two groups of recipients were infected intraperitoneally with 105 plaque-forming units of rat CMV, whereas one group was left noninfected and used as controls. One group of rat CMV–infected rats was treated with DHPG with an initial dose of 20 mg/kg IP and a maintenance dose of 10 mg/kg IP twice a day from 1 day before transplantation to 30 days after transplantation. Compared with noninfected rats, rat CMV infection was associated with a signi...
Improvement of Alveolar–Capillary Membrane Diffusing Capacity With Enalapril in Chronic Heart Failure and Counteracting Effect of Aspirin
Authors: MarcoGuazzi, GiancarloMarenzi, MarinaAlimento, MauroContini, PiergiuseppeAgostoni
Journal: Circulation (1997)

Background KII ACE, the enzyme that converts angiotensin I and inactivates bradykinin, is highly concentrated in the lungs; its blockade reduces exposure to angiotensin II and enhances exposure to prostaglandins generated by local kinin hyperconcentration. Our hypothesis is that ACE inhibitors improve pulmonary function in chronic heart failure (CHF) by readjusting lung vessel tone and permeability or alveolar–capillary membrane diffusion. Methods and Results In 16 CHF patients and 16 normal volunteers or mild untreated hypertensives, pulmonary function and exercise tests with respiratory gas analysis were assessed on placebo, enalapril (10 mg BID), enalapril plus aspirin (325 mg/d), or aspirin, in random order and double blind, for 15 days each. In CHF, enalapril increased pulmonary carbon monoxide diffusion (DLCO), oxygen consumption (Vo2), and exercise tolerance and reduced the ratio of dead space to tidal volume (Vd/Vt) and the ventilatory equivalent for carbon dioxide production Ve/Vco2). On enala...
International Multicentre Validation and Transferability of the SIMULATE Ureterorenoscopy Training Curriculum
Authors: A. Aydin, K. Ahmed, N. Raison, T. Abe, A.S. Gözen, T. Knoll, F. Moltzahn, A. Skolarikos, A. Lantz, B. Chew, G. Thalmann, N. Shinohara, J. Rassweiler, G. Zeng, M.S. Khan, P. Dasgupta
Journal: International Journal of Surgery (2018)
Abstract A19: Establishment of in vitro and in vivo models of inflammatory myofibroblastic tumor
Authors: Jinhan (Angela) Xie, Emily V. A. Mould, Ashleigh Fordham, Andrew J. Gifford, Toby Trahair, Karen L. Mackenzie
Journal: Clinical Cancer Research (2018)

Abstract Inflammatory myofibroblastic tumors (IMTs) are sarcomas of soft tissue that most commonly arise in children, adolescents, and young adults. If not cured by surgery, IMT has a high propensity for local recurrence as multifocal nodules, and may rapidly progress to fatal disease. Anaplastic Lymphoma Kinase (ALK) driven tumorigenesis is implicated in approximately 50% of IMT cases. IMT patients with ALK rearrangement have been reported to respond to the ALK inhibitor, crizotinib, but with the possibility of relapse with resistant disease. The second-generation ALK inhibitor ceritinib showed improved specificity and potency toward crizotinib-resistant tumors; however, resistant disease may still emerge. Thus, there is an urgent need for identifying alternative treatment options for ALK-driven IMT. In this study, we utilized fresh malignant ascites collected from a 9-year-old boy (IMT-1) with epithelioid inflammatory myofibroblastic sarcoma (eIMS), at diagnosis (IMT-1A) and third relapse (IMT-1D) to establish the in vitro cell culture and in vivo orthotopic patient-derived xenograft (PDX) model. Primary cell cultures were successfully established from both samples with confirmed ALK rearrangement. The PDX was established by intraperitoneal injection of cultured IMT-1D cells into nonobese diabetic severe combined immune-deficient mice with IL-2 receptor gamma chain deficiency (NSG) mice. Within 6-8 weeks of inoculation, 100% of the mice became moribund due to robust multifocal intraperitoneal tumors that grew in close association with abdominal organs, including the pancreas and small bowel. The xenograft recapitulated both morphologic and immunohistochemical features of the tumor within the patient. Positive immunohistochemical staining for ALK in a characteristic perinuclear membrane pattern and ALK gene rearrangement were also demonstrated in tumor cells cultured from peritoneal fluid of the xenografted mice. Our in vitro cultures and in vivo PDX models provide a valuable opportunity to undertake a detailed characterization of ALK-driven IMT at diagnosis and following ceritinib failure. They are ideal models for preclinical evaluation of new therapeutic approaches to the treatment of ALK-driven IMT. Citation Format: Jinhan (Angela) Xie, Emily V. A. Mould, Ashleigh Fordham, Andrew J. Gifford, Toby Trahair, Karen L. Mackenzie. Establishment of in vitro and in vivo models of inflammatory myofibroblastic tumor [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr A19.
Abstract 1284: How can you interpret gene lists from -omics experiments
Authors: Jeffrey V. Wong, Augustin Luna, Emek Demir, Igor Rodchenkov, Özgün Babur, Chris Sander, Gary D. Bader
Journal: Cancer Research (2018)

Abstract Understanding the mechanisms responsible for a cellular behaviour often begins with observations of genes and gene products. Depending on the type of experiment, the number of resulting genes can be small, but increasingly, researchers are faced with many thousands of measurements, as in the case of transcriptomic or protein-DNA binding observations. Here, we describe ways to pair experimental results consisting of one or more genes with analysis tools with the overall aim being to make results more biologically interpretable. In certain cases, experimental approaches such as screens for essential genes can generate one or a few ‘genes of interest' and there is a desire to understand their relationship to one another as well as discover links to additional, interesting genes. To this end, ‘GeneMANIA' is a web tool that accepts gene names and returns a network visualization of related genes based on similarity in expression, localization, protein domains and those involved in physical interactions. Likewise, ‘PCViz' is a web tool that displays a network of interactions drawn from Pathway Commons, a web resource for pathway and interaction knowledge. In cases where experiments generate a lengthy list of genes, for instance, transcriptomic measurements, there is a desire to understand their relevance to a phenotype of interest. Pathway enrichment analysis methods aim to summarize gene lists as pathways, which have a closer link to cell function. An online ‘Guide' by Pathway Commons includes workflows that illustrate how to chain together software tools to identify pathways from the corresponding gene-level data then organize and summarize the pathway-level results in an interactive visualization known as an Enrichment Map. For those wishing to drill-down to individual pathways, Pathway Commons offers a set of web apps, including ‘Search' that enables users to query by keyword and visualize ranked search results. Ongoing development of web apps aims to enhance the accessibility to pathways and integrate support for analysis and visualization of experimental data. The full complement of data, tools and resources offered by Pathway Commons in support of pathway analysis are described. Citation Format: Jeffrey V. Wong, Augustin Luna, Emek Demir, Igor Rodchenkov, Özgün Babur, Chris Sander, Gary D. Bader. How can you interpret gene lists from -omics experiments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1284.
Abstract 710: CD73 inhibitors (CD73i) reverse the AMP/adenosine-mediated impairment of immune effector cell activation by immune checkpoint inhibitors (ICI)
Authors: Annette Becker, Nell Narasappa, Fangfang Yin, Kristen Zhang, Daniel DiRenzo, Timothy Park, Jaroslaw Kalisiak, Ken Lawson, Jenna Jeffrey, Jay P. Powers, Ulrike Schindler, Matthew J. Walters, Joanne B. Tan
Journal: Cancer Research (2018)

Abstract INTRODUCTION: CD73 catalyzes the extracellular generation of adenosine (ADO) from adenosine monophosphate (AMP). ADO suppresses immune responses, including those of T cells, NK cells and dendritic cells through activation of A2aR and A2bR receptors. Exhausted T cells and NK cells express high levels of several immune checkpoint proteins, including PD-1 and TIGIT. We present here preclinical data on the ability of CD73i to reverse effector cell suppression from exposure to ADO even in the presence of ICI. METHODS: CD73i effects in a monotherapeutic setting were assessed by CD3/CD28/CD2 T cell stimulation and cytolytic assays. Combinatorial settings were assessed using mixed lymphocyte reactions (MLRs). In vivo effects of CD73i + ICI were determined using syngeneic tumor models. RESULTS: CD73 is expressed across a wide range of tumor types, including those with limited response to anti-PD-1 therapy. CD73i completely rescued AMP-mediated inhibition of T cell proliferation and effector function as well as NK cell cytolytic function. AMP abrogated the enhanced allogeneic CD4+ T cell activation and IFN-γ production mediated by blocking PD-1/PD-L1 and TIGIT, an effect that was reversed by CD73i. Mechanistically, addition of AMP in MLRs repressed expression of activation markers and immune checkpoint proteins. Thus, activation of the adenosinergic pathway may limit the efficacy of ICI. TCGA data from anti-PD-1-treated melanoma patients identified CD73 expression as a negative prognostic factor. Finally, co-administration of a CD73i with an anti-PD-1 mAb resulted in significant reduction of tumor volume associated with increases in immune cell infiltration. CONCLUSIONS: CD73 inhibition, alone or in combination with anti-PD-1 and anti-TIGIT antibodies, translates into potent enhancement of immune cell activation in a variety of studies. These data provide a rationale for CD73i + ICI combinations. Citation Format: Annette Becker, Nell Narasappa, Fangfang Yin, Kristen Zhang, Daniel DiRenzo, Timothy Park, Jaroslaw Kalisiak, Ken Lawson, Jenna Jeffrey, Jay P. Powers, Ulrike Schindler, Matthew J. Walters, Joanne B. Tan. CD73 inhibitors (CD73i) reverse the AMP/adenosine-mediated impairment of immune effector cell activation by immune checkpoint inhibitors (ICI) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 710.
Plasma Adiponectin, Body Mass Index, and Mortality in Patients With Chronic Heart Failure
Authors: CarolineKistorp, JensFaber, SørenGalatius, FinnGustafsson, JanFrystyk, AllanFlyvbjerg, PerHildebrandt
Journal: Circulation (2005)

Background— Recent studies have suggested that higher body mass index (BMI) is associated with improved prognosis in chronic heart failure (CHF). The adipocytokine adiponectin is inversely associated with BMI, and in healthy subjects, low adiponectin is a predictor of mortality. In a prospective study, we therefore evaluated the association between plasma adiponectin levels and mortality among patients with CHF. Methods and Results— In 195 CHF patients (age 69.3±10.2 years, BMI 27.3±5.2 kg/m2, left ventricular ejection fraction 30±8.9%, mean±SD), plasma adiponectin and N-terminal pro brain natriuretic peptide (NT-proBNP) were measured at baseline. Adiponectin was positively associated with NT-proBNP (β=0.47, P<0.001), and both biomarkers were negatively associated with BMI (β=−0.43, P<0.001 for adiponectin and β=−0.38, P<0.001 for NT-proBNP, respectively) During a median follow-up of 2.6 years, 46 (23.5%) of the patients died. After adjustment for clinical variables associated with CHF severity (age, syst...
Impairment of Heart Rate Recovery After Peak Exercise Predicts Poor Outcome After Pediatric Heart Transplantation
Authors: AlessandroGiardini, MatthewFenton, GrahamDerrick, MichaelBurch
Journal: Circulation (2013)

Background—A blunted heart rate recovery (HRR) from peak exercise is associated with adverse outcome in adults with ischemic heart disease. We assessed HRR after pediatric heart transplantation (HTx) and its prognostic use. Methods and Results—Between 2004 and 2010 we performed 360 maximal exercise tests (median, 2 tests/patient; range, 1–7) in 128 children (66 men; age at test, 14±3 years) who received HTx (age, 8.5±5.1 years) because of cardiomyopathy (66%) or congenital heart defects (34%). The change in heart rate from peak exercise to 1 minute of recovery was measured as HRR and was expressed as Z score calculated from reference data obtained in 160 healthy children. HRR was impaired soon after HTx (average in first 2 years Z=−1.9±3.5) but improved afterward (Z=+0.52/y), such that HRR Z score normalized in most patients by 6 years after HTx (average, 0.6±1.8). A subsequent decline in HRR Z score was noted from 6 years after HTx (rate of Z=−0.11/y). After 27±15 months from the most recent exercise tes...
Reliability of a consensus-based ultrasound definition and scoring for enthesitis in spondyloarthritis and psoriatic arthritis: an OMERACT US initiative
Authors: Peter V Balint, Lene Terslev, Philippe Aegerter, George Arthur Willem Bruyn, Isabelle Chary-Valckenaere, Frederique Gandjbakhch, Annamaria Iagnocco, Sandrine Jousse-Joulin, Ingrid Möller, Esperanza Naredo, Wolfgang A Schmidt, Richard J Wakefield, Maria-Antonietta D’Agostino
Journal: Annals of the Rheumatic Diseases (2018)

To evaluate the reliability of consensus-based ultrasound (US) definitions of elementary components of enthesitis in spondyloarthritis (SpA) and psoriatic arthritis (PsA) and to evaluate which of them had the highest contribution to defining and scoring enthesitis.Eleven sonographers evaluated 40 entheses from five patients with SpA/PsA at four bilateral sites. Nine US elementary lesions were binary-scored: hypoechogenicity, thickened insertion, enthesophytes, calcifications, erosions, bone irregularities, bursitis and Doppler signal inside and around enthesis. Kappa statistics were used to evaluate reliability. Sonographers were also asked to state which lesions can be considered as inflammatory or structural and should be included in the final definition of enthesitis. Only the lesions, scored as present in at least 75% of the entheses considered as having an enthesitis, were included in the final definition.The prevalence of detected lesions was quite low except for enthesophytes (55%) and bone irregularities (54%). Reliability ranged from poor to good (the lowest for thickened enthesis (kappa 0.1 (95% CI 0 to 0.7)) and the highest for enthesophytes (kappa 0.6 (95% CI 0.5 to 0.7)). When adjusted for low prevalence, kappa values increased for all lesions, with the best result observed for detecting Doppler signal at insertion (0.9) and for bursitis (0.8). The US components included in the final definition were hypoechogenicity, increased thickness at enthesis, erosions and calcifications/enthesophytes and Doppler signal at insertion.By using a consensus-based stepwise approach, a final reliable US score and definition of enthesitis in SpA/PsA were produced. Further studies are sought for implementing this score in clinical trials and practice.
Abstract 2736: Preclinical pharmacologic and pharmacodynamic studies of a novel and potent IDO1 inhibitor D-0751
Authors: Yaolin Wang, Zhe Shi, Zixing Han, Zhenwu Wang, Yueheng Jiang, Xing Dai
Journal: Cancer Research (2018)

Abstract Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that catalyzes the degradation of the essential amino acid L-tryptophan to kynurenine. It plays an important role in the initial and rate-limiting step in the breakdown of tryptophan. It has been reported that IDO1, an enzyme induced by IFN-gamma, is one of the central regulators of immune responses in various physiologic and pathologic settings and the enzyme is frequently expressed in cancers. Kynurenine produced by IDO1 suppresses T-cell function in the tumor microenvironment, resulting in tumor cell evasion from immune cells. IDO1 inhibitors, such as epacadostat and BMS-986205, have shown preliminary clinical therapeutic response in melanoma and other solid tumors when combined with anti-PD-1 antibody. Here, we report the discovery of a novel and selective IDO1 inhibitor with potent activity in various cell-based assays. Our lead molecule D-0751 inhibits IDO1 activity in HeLa cell and human whole blood assay with IC50 of 0.6 nM and 13 nM, respectively. It activates the human T-cell activity in a HeLa co-culture study with EC50 at 9 nM. D-0751 is optimized to have good PK profile in rodent, dog and monkey as well as slow clearance when incubated with human hepatocyte. Pharmacodynamic (PD) effect has been observed in mouse models (blood and tumor samples) as well as in dog (blood samples) with efficient kynurenine reduction observed at optimal dose level. Taken together, these results support the advancement of D-0751 as a clinical candidate in combination with anti-PD-1/L1 antibody in various solid tumor indications. Citation Format: Yaolin Wang, Zhe Shi, Zixing Han, Zhenwu Wang, Yueheng Jiang, Xing Dai. Preclinical pharmacologic and pharmacodynamic studies of a novel and potent IDO1 inhibitor D-0751 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2736.
Delayed Fluorescence: Maximizing Aggregation of Organic Fluorophores to Prolong Fluorescence Lifetime for Two‐Photon Fluorescence Lifetime Imaging (Adv. Healthcare Mater. 15/2018)
Authors: Wenbo Hu, Lihong Guo, Lei Bai, Xiaofei Miao, Yun Ni, Qi Wang, Hui Zhao, Meng Xie, Lin Li, Xiaomei Lu, Wei Huang, Quli Fan
Journal: Advanced Healthcare Materials (2018)

In article number 1800299, Lin Li, Wei Huang, Quli Fan, and co-workers, report a simple approach to fabricate a water-soluble organic semiconducting nanoparticle for in vivo two-photon fluorescence lifetime imaging. The as-prepared nanoparticles not only have strong two-photon absorption but also exhibit an ultra-long, yet oxygen-inert, fluorescence lifetime.
Abstract 12575: Right Ventricular Dysfunction Plays an Important Role in Predicting Non-Response to Tolvaptan Treatment in Patients With Heart Failure With Reduced Ejection Fraction With Chronic Kidney Disease
Authors: Noriaki Iwahashi, Masaomi Gohbara, Shunsuke Kataoka, Eiichi Akiyama, Nobuhiko Maejima, Kengo Tsukahara, Kiyoshi Hibi, Masami Kosuge, Toshiaki Ebina, Satoshi Umemura, Kazuo Kimura
Journal: Circulation (2014)

Background: Tolvaptan (TLV), a newly-developed vasopressin type 2 receptor antagonist, has a unique feature of diuresis, but the response to this drug can be unpredictable especially in patients with heart failure(HF) with renal dysfunction. This retrospective study used a novel speckle tracking echocardiography to examine the predictability of TLV effectiveness in patients with HF. RV function was estimated by TAPSE and RV strain in this study. Methods: In total, 56 consecutive patients admitted for acute decompensated HF were enrolled (Age72±14 years, 29male). Their ejection fractions were uniformly reduced (HFrEF, LVEF &lt;35%) and CKD stage 3B, 4, 5 (GFR &lt;45ml/min/1.73m2). They were administered TLV at 7.5-15 mg/day for one week. Non-response to TLV was defined as no evidence of a 1 kg decrease in body weight (BW) during the week following TLV treatment. Blood sampling and echocardiography, including strain imaging, were performed just prior to starting TLV. Vivid q and Echo PAC PC (GE, Norway) were used for echocardiographic analyses including strain. We analyzed LV function by lobal longitudinal strain (GLS) and RV systolic function by 2D speckle strain from the 4ch view. Results: Although 46 patients decreased their BW by more than 1kg (Responders; ΔBW= 5.1±0.7kg), 10 patients were non-responders (ΔBW=0.5±0.4kg). Responders achieved the improvements of the symptoms (edema/ congestion). Logistic regression analysis showed that RV dysfunction (RV strain, TAPSE) was the significant predictor for non-responders. On the other hand, eGFR was not significant predictor for non-response to TLV in this population. Conclusions: RV dysfunction may be an important predictor of the effectiveness of TLV in patients with HFrEF with CKD. In particular, RV strain was useful was the useful predictor.
Abstract 4023: Gap junctions contribute to anchorage-independent clustering of breast cancer cells
Authors: Fabien Gava, Lise Rigal, Odile Mondesert, Elise Pesce, Bernard Ducommun, Valérie Lobjois
Journal: Cancer Research (2018)

Abstract Purpose: Cancer cell cluster formation is a key process involved during primary tumor growth, metastatic cells dissemination and secondary tumor evolution. We previously reported that cell-cell adhesion proteins such as E-Cadherin and desmosomal proteins are involved in cell aggregation independently of cell migration or matrix adhesion (Saias et al. 2015). Here we investigate the involvement of gap junction intercellular communication (GJIC) during anchorage-independent clustering of MCF7 breast adenocarcinoma cells. Experimental Design: Live cell imaging and image processing was used to evaluate MCF7 clustering in the presence of pharmacological inhibitors and to perform a LOPAC® small bioactive compound library screening. Flow cytometry was performed to monitor calcein transfer assay and to evaluate GJIC. Results: We first demonstrate that functional GJIC are established in the early phase of aggregation. We next show that pharmacological inhibition of GJIC using Tonabersat and Meclofenamate both reduces calcein transfer and delays clustering of MCF7 cells. We found that treatment with Latrunculin A, an actin cytoskeleton-disrupting agent, inhibits MCF7 clustering and impairs calcein transfer. In a screen for inhibitors of cell aggregation using a small-compound chemical library we identified Brefeldin A, an inhibitor of vesicular trafficking, and showed that it also impairs calcein transfer. Conclusion: Our results demonstrate that GJIC are involved at the earliest stages of the anchorage-independent clustering process. They shed new light on the regulatory mechanisms that could modulate the formation of clusters of circulating tumor cells. References: Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, Yu M, Pely A, Engstrom A, Zhu H et al: Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 2014, 158(5):1110-1122. Saias L, Gomes A, Cazales M, Ducommun B, Lobjois V: Cell-Cell adhesion and cytoskeleton tension are key but opposing regulators of tumor cell aggregation. Cancer Research 2015, 75(12):1-8. Gava, F., Rigal, L ., Mondesert, O., Pesce, E., Ducommun, B. and Lobjois, V. Gap junctions contribute to anchorage-independent clustering of breast cancer cells (Submitted). Citation Format: Fabien Gava, Lise Rigal, Odile Mondesert, Elise Pesce, Bernard Ducommun, Valérie Lobjois. Gap junctions contribute to anchorage-independent clustering of breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4023.