tbuckley/cabot-search huggingface dataset:
Abstract 2269: Transcription factor relationships associated with androgen-deprivation therapy response and metastatic progression in prostate cancer
Authors: Nitya V. Sharma, Kathryn L. Pellegrini, Veronique Ouellet, Felipe O. Giuste, Selvi Ramalingam, Kenneth Watanabe, Eloise Adam-Granger, Lucresse Fossouo, Sungyong You, Michael R. Freeman, Paula Vertino, Karen Conneely, Adeboye O. Osunkoya, Dominique Trudel, Anne-Marie Mes-Masson, John A. Petros, Fred Saad, Carlos S. Moreno
Journal: Cancer Research (2018)

Abstract Patients with recurrent, aggressive prostate cancer typically undergo androgen-deprivation therapy (ADT), but the benefits are often short-lived, and responses are variable. Failure to respond to ADT invariably leads to metastatic disease, and ultimately death. To investigate differential responses to ADT, we performed whole-transcriptome analysis of 20 patient-matched pre-ADT biopsies and post-ADT prostatectomy specimens, and observed that all patients lost transcriptional signatures indicative of the androgen receptor (AR)-dependent subtype, after treatment. We also identified two subgroups of patients with either a strong or weak transcriptional response to ADT. The strong responders maintained the more aggressive subtype signal, while the weak responders lost expression of these genes and more resembled an AR-suppressed, basal subtype. We generated a strong responder transcriptional network using the PANDA program and integrated expression data from our cohort, protein-protein interaction, and DNA binding motif data. We also leveraged the expression data from a large public dataset of over 800 metastatic and primary samples to construct a metastatic lesion transcriptional network. We identified 20 common transcription factor coordinated groups (TFCGs) associated with both the strong responders and metastatic lesions, including GLI3/GLI2, SOX4/FOXA2/GATA4, ERF/ETV5/ETV3/ELF4, and a TFCG containing JUN, JUNB, JUND, FOS, FOSB, and FOSL1. Many TFCGs in the metastatic network were subsets of larger groups in the strong responders network, implicating these transcription factor associations as potentially critical for both the differential ADT response and metastatic disease progression. Citation Format: Nitya V. Sharma, Kathryn L. Pellegrini, Veronique Ouellet, Felipe O. Giuste, Selvi Ramalingam, Kenneth Watanabe, Eloise Adam-Granger, Lucresse Fossouo, Sungyong You, Michael R. Freeman, Paula Vertino, Karen Conneely, Adeboye O. Osunkoya, Dominique Trudel, Anne-Marie Mes-Masson, John A. Petros, Fred Saad, Carlos S. Moreno. Transcription factor relationships associated with androgen-deprivation therapy response and metastatic progression in prostate 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 2269.
Angiotensin II Receptor Antagonist TCV-116 Reduces Graft Coronary Artery Disease and Preserves Graft Status in a Murine Model
Authors: YutakaFurukawa, AkiraMatsumori, ToshiroHirozane, ShigetakeSasayama
Journal: Circulation (1996)

Background Despite the current progress in immunosuppressive regimens, the incidence of graft coronary artery disease (CAD) after cardiac transplantation has not decreased. Recent study has revealed that angiotensin-converting enzyme (ACE) inhibition decreases CAD in rats; however, it is not clear whether this beneficial effect of ACE inhibition is due to a decrease in production of angiotensin II (Ang II) or inhibition of bradykinin degradation. To determine whether Ang II type 1 receptor (AT1-R) blockade has an inhibitory effect on CAD, we evaluated the effects of TCV-116, an AT1-R antagonist, in a murine model of cardiac transplantation. Methods and Results Hearts of DBA/2 mice (H-2d) were transplanted heterotopically to B10.D2 mice (H-2d). Recipients were treated orally with TCV-116 (10 mg/kg per day), captopril (100 mg/kg per day), or vehicle only. Graft status, as assessed by palpation and inspection at laparotomy 70 days after transplantation, was preserved better in the TCV-116–treated group (P<.0...
Abstract 17713: A Three year Retrospective Analysis of Adverse Cardiac Outcomes in Heart Failure Patients Using Cocaine on Beta-blockers
Authors: BimajeAkpa, VictorNwazue, VarijaBhoggireddy, HenryOkafor
Journal: Circulation (2014)

Background: It is an established fact that beta-blockers (BB) improve survival in patients with HFrEF. However cocaine abusers with HFrEF are currently excluded from this life-saving treatment due to concerns with a theoretical risk of unopposed alpha adrenergic receptor-mediated coronary vasospasms and possible myocardial infarctions (MI). Our study seeks to compare heart failure (HF) outcomes in patients on beta blockers with surreptitious cocaine abuse to those not receiving beta blockers. Methods: From our HF registry, we retrospectively identified 132 patients admitted to the hospital for CHF with related complaints like chest pain or shortness of breath between 2006 and 2008 and cocaine positive drug test. We reviewed the concomitant use of BB in relation to the primary composite end points: MI, total ER visits, HF related admissions 2006-2008, ejection fraction (EF), mean BNP and all- cause mortality. Characteristics of patients with and without BB use were compared using chi-square for categorical...
Abstract 3776: Generation and formatting of an Affimer® biotherapeutic for the inhibition of the PD-L1/PD-1 pathway: Proof of concept in mouse
Authors: Amrik Basran, Emma Stanley
Journal: Cancer Research (2018)

Abstract We have generated a range of potent Affimer antagonists to both human and mouse programmed death-ligand 1 (PD-L1) and have demonstrated that when formatted, possess the necessary affinity, pharmacokinetics (PK) and tissue penetration to modulate the immune system and demonstrate efficacy in mouse models. Affimer biotherapeutics are a new protein scaffold with great potential for the generation of biotherapeutics. Based on the human protease inhibitor Stefin A, the scaffold is small (12kDa), lacks any post translational modifications such as disulphide bonds and glycosylation. Large diverse phage display libraries have been created by engineering in two 9 amino acid peptide loops into the scaffold backbone. Using phage display, we have identified competitive binders to both mouse and human PD-L1 which are low single digit nM in affinity as determined by Biacore. By ELISA we have shown that the Affimer molecules identified compete against PD-1 and CD80 for the binding site on PD-L1 and bind to the target on a range of human cancer cell lines (e.g. lung adenocarcinoma cells), as demonstrated by FACs. Following formatting of the lead Affimer protein to the N-terminal Fc region of an IgG, we showed that we could further improve the affinity to give a KD of &amp;lt;40 pM as determined by Biacore. The PK properties of the Affimer-Fc fusion were determined in mouse dosed at 10 mg/kg and shown to have a terminal half-life of over 100 hours. When dosed in a tumor mouse model the Affimer-Fc fusion protein showed a statistically significant reduction in tumor volume when compared to a control antibody. We have demonstrated that the Affimer scaffold has all the necessary attributes to be developed as a therapeutic platform. The Affimer scaffold was well tolerated in vivo, demonstrated a potency and PK profile that ensured sufficient exposure in the animal to modulate the immune system to slow tumor progression in a relevant mouse model. Citation Format: Amrik Basran, Emma Stanley. Generation and formatting of an Affimer® biotherapeutic for the inhibition of the PD-L1/PD-1 pathway: Proof of concept in mouse [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 3776.
Myocardial Fibrosis in Patients With Primary Mitral Regurgitation With and Without Prolapse
Authors: Danai Kitkungvan, Faisal Nabi, Raymond J. Kim, Robert O. Bonow, Mohammad A. Khan, Jiaqiong Xu, Stephen H. Little, Miguel A. Quinones, Gerald M. Lawrie, William A. Zoghbi, Dipan J. Shah
Journal: Journal of the American College of Cardiology (2018)

Recent studies reported left ventricular (LV) fibrosis in patients with primary mitral regurgitation (MR) thought to be principally due to mitral valve prolapse (MVP).This study sought to evaluate the prevalence, characteristics, and prognostic implications of LV fibrosis in a large cohort of primary MR patients with and without MVP using cardiovascular magnetic resonance (CMR).Patients referred for contrast CMR assessment of chronic primary MR were enrolled and underwent comprehensive assessment of cardiac remodeling, severity of MR, and LV replacement fibrosis. Primary MR patients were stratified into: an MVP group if there was >2 mm mitral leaflet displacement on cine-CMR, or a non-MVP group. Patients were followed for arrhythmic events (sudden cardiac death, aborted sudden cardiac arrest, and sustained or inducible ventricular arrhythmia).A total of 356 primary MR patients (177 MVP and 179 non-MVP) were enrolled. LV fibrosis was more prevalent in the MVP group than the non-MVP group (36.7% vs. 6.7%; p < 0.001). The presence of MVP had the strongest association (odds ratio: 6.82; p < 0.001) with LV fibrosis even after adjustment for clinical variables, measures of cardiac remodeling, and MR severity. During follow-up (median 1,354 days), MVP patients with LV fibrosis had the highest event rate for arrhythmic events.In primary MR patients, LV fibrosis is more prevalent in MVP than non-MVP, suggesting a unique pathophysiology beyond volume overload in MVP. LV fibrosis in primary MR may represent a risk marker of arrhythmic events.
Abstract CT049: Long term outcome of EBV-associated lymphoma patients treated with post-remission therapy using EBV LMP1 and LMP2a specific CTLs
Authors: Nayoun Kim, Hyun-Jung Sohn, Keon-Il Im, Young-Woo Jeon, Young-Sun Nam, Yunejin Song, Jun Seok Lee, Tai Gyu Kim, Seok-Goo Cho
Journal: Cancer Research (2018)

Abstract Background: Conventional therapeutic approaches, such as chemotherapy and radiotherapy, have been limited in successfully achieving durable response in Epstein Barr virus (EBV)-associated malignancies causing frequent relapse, low overall survival rate and poor prognosis. EBV-specific cytotoxic T lymphocytes (EBV-CTLs) have emerged as an alternative therapeutic approach to treat EBV associated lymphoma by enhancing EBV-specific immunity. Methods: To evaluate the efficacy and safety of EBV latent membrane protein (LMP)-1 and LMP-2a specific CTLs (LMP1/2a CTLs) stimulated with LMP1/2a RNA-transferred dendritic cells, we treated ten EBV+ ENKTCL patients and two EBV+ PTLD patients who showed complete response to induction therapy. Patients who completed and responded to chemotherapy, radiotherapy, and/or high-dose therapy followed by stem cell transplantation were eligible to receive eight doses of 2 x107 LMP1/2a CTLs/m2. Results: Following infusion, there were no immediate or delayed toxicities. The seven-year overall survival (OS) and progression-free survival (PFS) were 100%, and 90% (95% CI: 71·4% to 100%) for ENKTCL patients respectively with a median follow-up of 94 months. Similarly, PTLD patients showed long-term remission with a follow-up of up to 70 months. Overall, circulating IFN-γ secreting LMP1 and LMP2a-specific T cells within the peripheral blood corresponded with decline in plasma EBV DNA levels in patients. Conclusion: Adoptive transfer of LMP1/2a CTLs in patients is a safe and effective post-remission therapeutic approach. Further randomized studies will be needed to define the role of EBV-CTLs in preventing relapse of EBV-associated lymphoma. Citation Format: Nayoun Kim, Hyun-Jung Sohn, Keon-Il Im, Young-Woo Jeon, Young-Sun Nam, Yunejin Song, Jun Seok Lee, Tai Gyu Kim, Seok-Goo Cho. Long term outcome of EBV-associated lymphoma patients treated with post-remission therapy using EBV LMP1 and LMP2a specific CTLs [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 CT049.
Abstract 2366: The tyrosine phosphatase, SHP-2, participates in regulating PD-L1 expression in non-small cell lung cancer
Authors: Keller Toral, Brent Harris, Jarrod Creameans, Penni Black
Journal: Cancer Research (2018)

Abstract Immune checkpoint inhibitors, specifically those which target T cell surface receptor Programmed Cell Death-1 (PD-1) and its ligand, Programmed cell death ligand-1 (PD-L1), have demonstrated clinical benefit in patients with non-small cell lung cancer (NSCLC). Currently, tumor expression of PD-L1 serves as the FDA-approved companion diagnostic for response to anti-PD-1/PD-L1 therapy. However, a fraction of patients who express PD-L1 exhibit a response to treatment, and in some cases, patient tumors that do not express PD-L1 demonstrate response to therapy, making this a poor predictive biomarker. Further, the mechanism by which PD-L1 expression is controlled remains under-studied. In this study, we seek to determine the impact of the protein tyrosine phosphatase, SHP-2, on PD-L1 expression through Jak/STAT- mediated signaling in NSCLC cell lines. SHP-2 can harbor activating mutations which prevent auto-inhibition of the catalytic phosphatase domain, and that may be pro-tumorigenic in some tumors. To understand the impact of SHP-2 activity on PD-L1 expression, we first assessed activation of STAT3 in NSCLC tumor cells after treatment with IFNγ and other mitogens. We then transfected NSCLC cells with wildtype and hyperactive SHP-2 mutants or ablated SHP-2 with siRNA specific for SHP-2 and measured both STAT3 and PD-L1 expression. Cell lines A549 and H661 exhibit low endogenous expression of both SHP-2 and PD-L1, and thus were chosen for transfection with hyperactive SHP-2 mutants (E76K and G503V), which also altered PD-L1 expression by western blot analysis. Quantitative real-time PCR (qPCR) and western blot analysis revealed that siRNA ablation of SHP-2 led to increased PD-L1 expression in the H460 cell line. Cells transfected with the SHP-2 activating mutants will also be assessed alteration of cell proliferation. Finally, using data obtained from The Cancer Genome Atlas project, STAT3 and PD-L1 expression levels are being evaluated in NSCLC tumor samples in which SHP-2 is mutated (E76K or G503V). With these data, we expect to gain a more complete understanding of the role of SHP-2 within the tumor microenvironment and the extent to which it controls PD-L1 expression, leading to new drug targets or combinations of drugs and better predictive biomarkers of response to PD-1 and PD-L1 inhibitors. Citation Format: Keller Toral, Brent Harris, Jarrod Creameans, Penni Black. The tyrosine phosphatase, SHP-2, participates in regulating PD-L1 expression in non-small cell lung 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 2366.
Abstract 1682: Combined treatment of aldose reductase inhibitor, fidarestat, and anti-PD1 antibodies synergistically prevents T cell- and NK cell-mediated colon cancer growth in murine models
Authors: Ashish Saxena, Himangshu Sonowal, Satish K. Srivastava, Kota V. Ramana
Journal: Cancer Research (2018)

Abstract Immune checkpoint inhibitors such as anti-programmed death 1 (PD1) and anti-PD-L1 monoclonal antibodies though have great potential for cancer immunotherapy, the acquired drug resistance and unwanted immune side effects limit their use. However, the combination therapy using conventional drugs and immune checkpoint inhibitors not only synergistically increase anti-tumor responses but it also reduces immune-associated adverse events. In our earlier studies, we have shown that inhibition of polyol pathway enzyme, aldose reductase (AR) prevents colon cancer growth and metastasis in culture as well as in mouse models. In this study, we investigated whether fidarestat, a potent AR inhibitor that has already gone through Phase-III clinical trial for diabetic neuropathy and found to safe for human use, can synergize with anti PD-1 to increase antitumor activity and decrease immune-associated adverse effects. Mice bearing syngeneic CT26 colon carcinoma tumors were treated with anti PD-1 alone or in combination with fidarestat, and the tumor growth was monitored. Our results indicate that fidarestat in combination with anti-PD1 synergistically increases tumor regression within 28 days of treatment. Further, a combination of fidarestat and anti-PD1 significantly increased the CD8+ T cells and natural killer (NK) cells and decreased the Myeloid-derived suppressor cells (MDSCs) at tumor milieu. Fidarestat plus anti-PD1 also increased CD8+ T cell and NK cell effector functions as determined by IFNg and granzyme B. Systemically, combination therapy also increased the number of CD8+ T cells and NK cells and decreased MDSCs in the mouse spleens. Further, the effector functions of CD8+ T cells and NK cells were increased with the combination treatment in mice spleens. Moreover, the levels of various inflammatory cytokines and chemokines in the serum and liver were significantly less in fidarestat plus anti-PD1 -treated mice as compared to anti-PD1 alone -treated mice indicating that fidarestat rescues immune-mediated adverse events in various organs. Thus, our results suggest that by regulating the number as well as effector function of CD8+ T cells, NK cells and MDSCs, AR inhibitor in combination with anti-PD1 would not only regress the tumor growth but would also provide a long-lasting specific immunity against colon cancer, which would decrease the chances of tumor recurrence. Citation Format: Ashish Saxena, Himangshu Sonowal, Satish K. Srivastava, Kota V. Ramana. Combined treatment of aldose reductase inhibitor, fidarestat, and anti-PD1 antibodies synergistically prevents T cell- and NK cell-mediated colon cancer growth in murine models [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 1682.
Abstract 5745: Effect of activator of G-protein signaling 3 (AGS3) on prostate tumorigenesis
Authors: Timothy O. Adekoya, Nikia Smith, Tonelia Mowatt, Temilade Aladeniyi, Ricardo M. Richardson
Journal: Cancer Research (2018)

Abstract Prostate cancer (PCa) is a leading cause of cancer death among men, with greater prevalence of the disease among the African American population in the US. Activator of G-protein Signaling 3 (AGS3/GPSM1), a receptor-independent activator of G-protein signaling has been shown to affect different cellular processes and cell cycle activity as well as tumor growth and development. AGS3 contains seven tetratricopeptide (TPR) repeats in its N-terminal half and four G-protein regulatory (GPR) motifs in its C-terminal half. The aim of this study is to assess the role of AGS3 in prostate cancer development and metastasis as well as to understand the molecular dynamics involved. To that end, the metastatic PCa cell lines LNCaP, PC3, MDA PCa 2b and DU-145 were analysed for AGS3 expression relative to RWPE-1, a non-metastatic Pca cell line. Quantitative RT-PCR and western blot analysis have shown that AGS3 expression varies in the PCa cell lines relative to control RWPE-1. Overexpression of AGS3 in PC3 and LNCaP cells significantly enhanced tumor progression in nude mice xenografts. Interestingly, expression of the TPR, not the GPR, repeats in LNCaP promoted tumor growth as well as the full length AGS3. Preliminary studies with a Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice deficient in AGS3 expression (TRAMP+/AGS3-/-) displayed decrease prostate tumorigenesis. Taken together, these results indicate that AGS3 expression promotes prostate tumor growth. The data also suggest that the effect of AGS3 in prostate tumorigenesis is mediated via its TPR, not GPR motif. Citation Format: Timothy O. Adekoya, Nikia Smith, Tonelia Mowatt, Temilade Aladeniyi, Ricardo M. Richardson. Effect of activator of G-protein signaling 3 (AGS3) on prostate tumorigenesis [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 5745.
Variation in Deaths From Intentional Injury and Substance Use
Authors: Ian R. H. Rockett, Hilary S. Connery
Journal: JAMA (2018)

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