tbuckley/cabot-search huggingface dataset:
Abstract 3694: Measuring oncogene signaling with transferrin-based PET: From bench to bedside
Authors: Michael J. Evans, Charles Truillet, Davide Ruggero, Jason S. Lewis, Rahul Aggarwal, Spencer C. Behr
Journal: Cancer Research (2018)

Abstract Background: Non-invasive tools that measure the activity of central oncogenes could be broadly useful for cancer detection and management. We have shown that radiolabeled transferrin molecules can be used to measure mTORC1 and MYC signaling in prostate cancer models, because the transferrin receptor is a MYC target gene. The purpose of this study was to complete the preclinical assessment of 89Zr-transferrin, as well as demonstrate that clinical disease harbors avidity for transferrin using 68Ga-citrate. Methods: Human prostate cancer cell lines have been manipulated pharmacologically and genetically to alter mTORC1 and/or MYC signaling, and radiolabeled transferrin has been used to study the impact of aberrant oncogene signaling on transferrin biology. A first in man study with 68Ga-transferrin PET was also performed at UCSF using a GE SIGNA PET/MR. A dose escalation study was performed in eight patients with castration resistant prostate cancer to identify the optimal signal to noise ratio. Results: Activation of mTORC1 or MYC resulted in higher transferrin receptor expression and higher transferrin uptake into cells, as expected. Pharmacological inhibition of either oncogene suppressed transferrin uptake in vitro and in vivo. 68Ga-transferrin PET/MR resolved ~75% of lesions that were detectable by CT or bone scan. Approximately 4 mCi and &amp;gt;3.5 hours post injection was required to visualize tumor lesions. Conclusions: These experiments establish that like MYC, mTOR activity can be quantified in prostate cancer models with 89Zr-transferrin. Moreover, our first in human study with 68Ga-transferrin shows that human disease is generally avid for the radiotracer, but the uptake is variable among lesions, consistent with a molecularly diverse disease. Citation Format: Michael J. Evans, Charles Truillet, Davide Ruggero, Jason S. Lewis, Rahul Aggarwal, Spencer C. Behr. Measuring oncogene signaling with transferrin-based PET: From bench to bedside [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 3694.
Abstract LB-036: Targeting the WNT-pathway in 3D-cultures of pancreatic cancer biopsies
Authors: Bram Herpers, Sander Basten, Kuan Yan, Thomas Dijkmans, Julia Schueler, Torsten Giesemann, Leo S. Price
Journal: Cancer Research (2018)

Abstract Creating patient-derived xenograft (PDX) models from human cancers allows bio-banking, propagation, characterization and drug testing on a large panel of tumor variants. We developed 3D in vitro culture methods for PDX model-derived cell isolates. Each individual model was subjected to a wide panel of culture medium formulations, amongst which some media contain WNT-pathway stimulating components. We identified an absolute dependency of a pancreatic in vitro PDX tumor to the WNT-signaling potentiating factor R-Spondin, while other pancreas tumors showed little or no dependency. To further study the dependency of pancreatic PDX tumors on the functionality and signaling of the WNT-pathway, we exposed in vitro PDX cultures to increasing doses of anti-FZD7, anti-FZD8 and to the Porcupine inhibitor LGK974, which blocks WNT palmitoylation and therefore secretion. We also applied the same approach to establish cultures from patient-derived pancreatic cancer biopsies. Our findings are that the WNT-pathway is functional and contributing to pancreas cancer outgrowth and morphological differentiation to different extents in different patient-models. Our in vitro culture system in combination with 3D phenotypic analysis allows in-detail study of the WNT-pathway, as well as by supplementation or omission of secreted factors, addition of small molecule inhibitors and by exposure to antibodies. These in vitro models can be used to test novel compounds and antibodies targeting the WNT pathway and underscore the WNT pathway as a potential target in pancreatic cancer. Citation Format: Bram Herpers, Sander Basten, Kuan Yan, Thomas Dijkmans, Julia Schueler, Torsten Giesemann, Leo S. Price. Targeting the WNT-pathway in 3D-cultures of pancreatic cancer biopsies [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 LB-036.
Abstract 20112: Lateral Tunnel and Extra-Cardiac Fontan Operations Have Equivalent Early and Late Outcomes in the Modern Era
Authors: Simone Bartelse, S. L Roche, William G Williams, Candice Silversides, Rachel Wald, Erwin Oechslin, Jack Colman, Michael Gritti, Eric Pham-Hung, Glen S Van Arsdell, Christopher A Caldarone, John Coles, Osami Honjo, Edward J Hickey
Journal: Circulation (2016)

Introduction:  Controversy continues regarding lateral tunnel (LT) versus extra-cardiac (EC) Fontan’s. Although we currently perform EC, there was a broad transition period. We aimed to compare long-term outcomes after LT or EC.   Methods   A. Total surgical experience: Of 906 Fontan operations (1976-2014), 223 were LT (1987-2005) and 412 EC (1995-2014) (median f/u 8.3 years; range 0-29). Survival and re-operations (including revisions, transplants and pacemakers) were compared.  B. Adults: Our ACHD program follows 102 LT and 78 EC (median 23 years post-Fontan; range 18-40). All were reviewed and risk-adjusted comparisons were made. Additional comparisons used propensity-matched pairs near-identical by diagnosis, morphology, age and era (LT=36, EC=36, parametric greedy matching, c-statistic .885).  Risk-adjustment was via parametric multivariable models and competing risks techniques, with bootstrapping.   Results   A. Early peri-operative mortality after Fontan was strongly era-dependent ( P  P   B. Adults with LT and EC exhibit comparable risk-adjusted late outcomes (table, figure) by i) unadjusted comparisons, ii) risk-adjusted comparisons and iii) propensity-matched comparisons.   Conclusions:  LT and EC in the modern era have equivalent early and late outcomes to 30 years including survival, re-operation, cardiopulmonary function, arrhythmia and Fontan failure.
Abstract 5786: Grabbing GRB2: The use of liposome-incorporated Grb2 antisense oligonucleotides as a novel therapy in gynecologic malignancies
Authors: Olivia D. Lara, Cristian Rodriquez-Aguayo, Emine Bayrakter, Paola Amero, Selanere Mangala, Chris LaFargue, Ana Tari-Ashizawa, Gabriel Lopez-Berestein, Anil Sood
Journal: Cancer Research (2018)

Abstract Prexigebersen (liposome-incorporated nuclease resistant antisense oligonucleotides specific for GRB2, L-GRB2) has proven highly effective in the treatment of leukemia, however its application in solid malignancies including gynecologic cancer has yet to be investigated. Given the biological significance of GRB2, we aim to assess the effect of prexigebersen in pre-clinical models. We tested the clinical significance of GRB2 using publicly available high-throughput data. We investigated the expression of GRB2 in a series of in vitro (Western Blotting) experiments in high-grade serous (HGSC) and uterine (UC) carcinoma models. We also tested in vivo (orthotopic mouse model) the biological effects of prexigebersen in HGSC models (OVCAR 5), first in a dose-defining experiment then in combination with standard dose paclitaxel. We first examined GRB2 using TCGA and GISTIC data and found alterations (amplifications, deletions and mutations) in 6% (33 of 594) of HGSC cases and 5% (25 of 547) of UC cases. Amplifications of GRB2 are associated with a decreased patient survival (p&amp;lt;0.01) in UC, suggesting it to be an attractive therapeutic target. GRB2 was expressed in most ovarian (HEYA8, OVCAR5, SKOV3, and OVCAR3) and uterine (MFE 319, Ishikawa and Hec1a) cancer cell lines tested. We performed a dose-defining in vivo experiment on an orthotopic mouse model of ovarian cancer (OVCAR 5). We found a maximum decrease in GRB2 expression at a dose of 15 mg/kg prexigebersen and a dose dependent decrease in tumor burden (p&amp;lt;0.05). We then performed an additional in vivo model in which prexigebersen was combined with standard dose paclitaxel. There was an eighty-six percent decrease in tumor burden (p&amp;lt;0.05), and multinodular burden (p&amp;lt;0.01) in the combination prexigebersen/paclitaxel group compared to control. Prexigebersen shows promising preclinical efficacy and may be a novel therapeutic strategy in gynecologic malignancies. Citation Format: Olivia D. Lara, Cristian Rodriquez-Aguayo, Emine Bayrakter, Paola Amero, Selanere Mangala, Chris LaFargue, Ana Tari-Ashizawa, Gabriel Lopez-Berestein, Anil Sood. Grabbing GRB2: The use of liposome-incorporated Grb2 antisense oligonucleotides as a novel therapy in gynecologic malignancies [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 5786.
Abstract 19445: Gender-Related Differences in Long-Term Outcomes of Hospital Survivors With Acute Type B Aortic Dissection
Authors: Eduardo Bossone, Sherene Shalhub, Hans-Henning Eckstein, Elizabeth A Jackson, Marc P Bonaca, Marek P Ehrlich, Linda A Pape, Toru Suzuki, G C Hughes, Anil Bhan, Lori D Conklin, Daniel G Montgomery, Alan C Braverman, Eric M Isselbacher, Kim A Eagle, Christoph A Nienaber
Journal: Circulation (2016)

Introduction:  While previous research has demonstrated that men and women differ in presentation and management of Type B aortic dissection (TBAD) in the acute phase, there is little data evaluating whether these differences persist post-discharge.   Methods:  TBAD patients (N=2222) enrolled in The International Registry of Acute Aortic Dissection between January 1996 and February 2016 were stratified by male (N=1456, 65.5%) and female (N=766, 34.5%) gender. Of the patients that survived to discharge (N=2012 overall; 1318 (90.5%) men vs. 694 (90.6%) women, p=0.914), 724 men (54.9%) and 360 women (51.9%) had follow-up data available. Mean follow-up length was 2.8 years for men and 2.7 years for women (p=0.193).   Results:  At the time of acute dissection, women were older (66.0±15.2 vs. 62.0±13.8, p   Conclusion:  Men were more likely to have aortic growth and surgical or endovascular intervention at 5 years post-discharge, indicating that a gender-based approach to follow-up may be useful. Kaplan-Meier analysis of 5-year morality was similar between men and women.
Abstract 11507: Subtotal Nephrectomy Accelerates Pathological Cardiac Remodelling Post Myocardial Infarction: Recapitulating the Phenotype of Cardiorenal Syndrome?
Authors: Shan Liu, Andrew R Kompa, Darren Kelly, Henry Krum, Bing H Wang
Journal: Circulation (2011)

Introduction:  A close relationship exists between chronic kidney disease and chronic heart failure, with failure of one organ having detrimental effects on the other (cardiorenal syndrome, CRS). The aim of this study was to investigate the pathophysiological changes that occur when a kidney insult (induced by 5/6 nephrectomy - STNx) follows that of myocardial infarction (MI) on heart and kidney structure and function.   Study design:  Male Sprague Dawley rats (n=24) were randomized into four groups: Sham-operated MI + Sham-operated STNx (Sham+Sham), MI + Sham-operated STNx (MI+Sham), Sham-operated MI + STNx (Sham+STNx) and MI+STNx. MI/Sham surgery was performed initially; STNx/Sham surgery was performed 4 weeks post-MI, and animals were followed for a further 10 weeks post-STNx.   Results:  Heart weight/body weight and lung weight/body weight ratios were significantly greater in MI+STNx vs MI+Sham animals at week 14 (P   Conclusions:  Subtotal nephrectomy accelerates pathophysiological cardiac changes whilst MI causes more severe renal fibrosis in the present study, supporting bi-directional interactions in cardiorenal syndrome. This pre-clinical model furthers our understanding of underlying pathophysiology of this condition.
A new editor of the JCI
Authors: Rexford S. Ahima
Journal: Journal of Clinical Investigation (2018)

This issue of the Journal of Clinical Investigation marks the transition of the position of editor from Gordon Tomaselli to me. It is with great humility that I begin my tenure as the editor of the flagship journal of the American Society for Clinical Investigation (ASCI). On behalf of the JCI editorial board and editorial staff, I wish Gordon Tomaselli all the best in his new position as the dean of the Albert Einstein College of Medicine.
Abstract 4193: Biochanin A in pancreatic cancer
Authors: Vilas Desai, Satya Murthy Tadinada, James C K Lai, Alok Bhushan
Journal: Cancer Research (2018)

Abstract Pancreatic cancer, with its dismally low survival rate (&amp;lt;5%), is one of the most aggressive forms of cancer and is the fourth leading cause of cancer-related deaths in the U.S. Gemcitabine, the first-line drug approved by the FDA, has been marginally effective as it improves survival by only six months. Epidemiologic studies have implicated a role for dietary isoflavones in lowering the incidence of different cancers in the Asian population. Isoflavones such as genistein, biochanin A and daidzein have been tested for their anticancer potential in different cancers; however, the clastogenic effect associated with genistein limits its therapeutic potential. Primarily used in management of hyperlipidemia and cardiovascular diseases, statins have been documented to exert antiproliferative effects. We hypothesized that a combination treatment of biochanin A and atorvastatin exerts enhanced anticancer effects on pancreatic cancer cells viz. AsPC1, PANC-1 and MIAPaCa-2. Our studies showed a decrease in cell viability on combination drug treatment with differential effects on mitogenic and cell signaling pathways in the cell lines investigated. In PANC-1 cells, biochanin A and atorvastatin combination treatment decreased invasiveness, dampened the expression of activated STAT3, and critical mediators of cell cycle progression. We also observed the involvement of enhanced proapoptotic effect of the combination treatment in AsPC-1 cell line and potential cell cycle arrest phenomenon in PANC-1 cells. Cell metabolism studies using seahorse XFp analyzer showed an increase in mitochondrial respiration and a decrease in glycolytic activity on combination treatment. Further, the XF-Plasma Membrane Permeabilizer (XF-PMP) assay used to evaluate the mitochondrial ETC complex activity showed a complete impairment of complex I and II (prominently), with MIAPaCa-2 being more susceptible to the combination treatment than AsPC1 and PANC-1. Together, the combination treatment-induced effects on pancreatic cancer cell lines may have potential implications in developing novel and improved therapies for the treatment of pancreatic cancer. Citation Format: Vilas Desai, Satya Murthy Tadinada, James C K Lai, Alok Bhushan. Biochanin A in pancreatic cancer [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 4193.
Cystathionine γ Lyase Sulfhydrates the RNA Binding Protein Human Antigen R to Preserve Endothelial Cell Function and Delay Atherogenesis
Authors: Sofia-Iris Bibli, Jiong Hu, Fragiska Sigala, Ilka Wittig, Juliana Heidler, Sven Zukunft, Diamantis I. Tsilimigras, Voahanginirina Randriamboavonjy, Janina Wittig, Baktybek Kojonazarov, Christoph Schürmann, Mauro Siragusa, Daniel Siuda, Bert Luck, Randa Abdel Malik, Konstantinos A. Filis, George Zografos, Chen Chen, Dao Wen Wang, Josef Pfeilschifter, Ralf P. Brandes, Csaba Szabo, Andreas Papapetropoulos, Ingrid Fleming
Journal: Circulation (2018)

Hydrogen sulfide (H2S), generated by cystathionine γ lyase (CSE), is an important endogenous regulator of vascular function. The aim of the present study was to investigate the control and consequences of CSE activity in endothelial cells under physiological and proatherogenic conditions.Endothelial cell CSE knockout mice were generated, and lung endothelial cells were studied in vitro (gene expression, protein sulfhydration, and monocyte adhesion). Mice were crossed onto the apolipoprotein E-deficient background, and atherogenesis (partial carotid artery ligation) was monitored over 21 days. CSE expression, H2S bioavailability, and amino acid profiling were also performed with human material.The endothelial cell-specific deletion of CSE selectively increased the expression of CD62E and elevated monocyte adherence in the absence of an inflammatory stimulus. Mechanistically, CD62E mRNA was more stable in endothelial cells from CSE-deficient mice, an effect attributed to the attenuated sulfhydration and dimerization of the RNA-binding protein human antigen R. CSE expression was upregulated in mice after partial carotid artery ligation and in atheromas from human subjects. Despite the increase in CSE protein, circulating and intraplaque H2S levels were reduced, a phenomenon that could be attributed to the serine phosphorylation (on Ser377) and inhibition of the enzyme, most likely resulting from increased interleukin-1β. Consistent with the loss of H2S, human antigen R sulfhydration was attenuated in atherosclerosis and resulted in the stabilization of human antigen R-target mRNAs, for example, CD62E and cathepsin S, both of which are linked to endothelial cell activation and atherosclerosis. The deletion of CSE from endothelial cells was associated with the accelerated development of endothelial dysfunction and atherosclerosis, effects that were reversed on treatment with a polysulfide donor. Finally, in mice and humans, plasma levels of the CSE substrate l-cystathionine negatively correlated with vascular reactivity and H2S levels, indicating its potential use as a biomarker for vascular disease.The constitutive S-sulfhydration of human antigen R (on Cys13) by CSE-derived H2S prevents its homodimerization and activity, which attenuates the expression of target proteins such as CD62E and cathepsin S. However, as a consequence of vascular inflammation, the beneficial actions of CSE-derived H2S are lost owing to the phosphorylation and inhibition of the enzyme.
The Cognitive Reserve Should Be Controlled When Using Neuroimaging to Assess Relapse in Major Depressive Disorder
Authors: Thibault Deschamps
Journal: JAMA Psychiatry (2018)

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Annual Risk of Major Bleeding Among Persons Without Cardiovascular Disease Not Receiving Antiplatelet Therapy
Authors: Vanessa Selak, Andrew Kerr, Katrina Poppe, Billy Wu, Matire Harwood, Corina Grey, Rod Jackson, Sue Wells
Journal: JAMA (2018)

<h3>Importance</h3> A decision to initiate aspirin therapy for primary prevention of cardiovascular disease (CVD) requires consideration of both treatment benefits and harms. The most significant harm associated with aspirin is major bleeding, yet there is a paucity of data on bleeding risk in suitable community populations. <h3>Objective</h3> To determine the risk of major bleeding among people without CVD who are not receiving antiplatelet therapy. <h3>Design, Setting, and Participants</h3> Prospective cohort study of 359 166 individuals aged 30 to 79 years receiving primary care in New Zealand who had CVD risk assessment between 2002 and 2015. Participants were censored at the earliest date on which they had a first major bleeding event, died, or met any baseline cohort exclusion criteria or the study end date of December 31, 2015. Analyses were repeated after excluding people with medical conditions associated with increased bleeding risk (non–high-risk cohort; n=305 057) and after further excluding people receiving other medications associated with increased bleeding risk (nonmedication cohort; n=240 254). <h3>Exposures</h3> Sex and age group in 10-year bands from 30 to 79 years. <h3>Main Outcomes and Measures</h3> Risk of a major bleeding event (hospitalization or death associated with bleeding); nonfatal gastrointestinal tract bleeding; and gastrointestinal tract bleeding–related case fatality. <h3>Results</h3> Mean participant age was 54 years (SD, 10 years), 44% were women, and 57% were European. Among the 359 166 individuals in the baseline cohort, 3976 had a major bleeding event during 1 281 896 person-years of follow-up. Most had gastrointestinal (GI) bleeding (n=2910 [73%]). There were 274 fatal bleeding events (7%), of which 153 were intracerebral. The risk of a nonfatal GI bleeding event per 1000 person-years was 2.19 (95% CI, 2.11-2.27), 1.77 (95% CI, 1.69-1.85) and 1.61 (95% CI, 1.52-1.69), in the baseline, non–high-risk, and nonmedication cohorts, respectively. Case fatality associated with GI bleeding was 3.4% (95% CI, 2.2%-4.1%), 4.0% (95% CI, 3.2%-5.1%), and 4.6% (95% CI, 3.6%-6.0%) in the baseline, non–high-risk, and nonmedication cohorts, respectively. <h3>Conclusions and Relevance</h3> In a population not receiving antiplatelet therapy, the annual risk of major bleeding events and nonfatal major bleeding was estimated. These findings could inform population-level guidelines for primary prevention of CVD.