tbuckley/cabot-search huggingface dataset:
Abstract 5434: Screen for immune-related transcriptional targets of the Hippo pathway in human breast cancer cells
Authors: Helena J. Janse van Rensburg, Taha Azad, Min Ling, Yawei Hao, Lori M. Minassian, Brooke Snetsinger, Prem Khanal, Michael J. Rauh, Charles H. Graham, Xiaolong Yang
Journal: Cancer Research (2018)

Abstract The Hippo signaling pathway has recently emerged as a cellular network that is dysregulated in cancer. In breast cancer cells, aberrant activation of the Hippo transducers (and transcriptional co-activators) TAZ and YAP leads to altered expression of their downstream gene targets and endows cells with multiple “hallmarks of cancer”. While several transcriptional targets of TAZ and YAP underlying their pro-tumorigenic activity have been described (e.g. CTGF, CYR61), gene targets of TAZ and YAP that modulate immune cell behavior in the tumor microenvironment are poorly understood. We have performed a comprehensive screen for immune-related transcriptional targets of TAZ and YAP in human breast cells. We have identified many candidate genes that are potentially regulated by TAZ and YAP including the immune checkpoint molecules PD-L1 and PD-L2, the lymphocyte regulator S1PR1 and the inflammasome component NLRP3. We have further validated PD-L1 as a bona fide transcriptional target of TAZ and YAP. These findings reveal new functions for the Hippo pathway in modifying immune responses and implicate TAZ and YAP in cancer immune evasion. Citation Format: Helena J. Janse van Rensburg, Taha Azad, Min Ling, Yawei Hao, Lori M. Minassian, Brooke Snetsinger, Prem Khanal, Michael J. Rauh, Charles H. Graham, Xiaolong Yang. Screen for immune-related transcriptional targets of the Hippo pathway in human 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 5434.
Abstract 1538: Analysis of the paired TCRα- and β-V(D)J full-length chains of single-cell sequence from human naïve and antigen-experienced T cells
Authors: Fei Wang, Qing Zhou, Cheng-chi Chao
Journal: Cancer Research (2018)

Abstract The unbiased and paired characterization of T-cell receptor (TCR) alpha and beta chains is critical to understand the TCR repertoire and adaptive immunity. However, the direct cloning of the single human full-length TCRα- and TCRβ-chains has very few reports. We present a new methodology enabling capture of natively paired, full-length rearranged T-cell receptor (TCR) sequences at single-cell level of human T cells. More than 50% paired TCRα- and β- chains were captured in 100 single naïve human CD8+ T cells using 5'SMART and 3' TCRαβ constant region nested gene-specific primers (GSP). Furthermore, we sequenced the TCR of the specific T cells that were stimulated by representative tumor-associated antigens (TAA), virus-related antigens (VRA) and neoantigens. The highest proportion of TCR subtypes were extracted in the TCR abundance ranking by IMGT blast. Finally, we obtained the paired, full-length V(D)J TCR from melanoma antigen Melan A epitope 27-35 that was TRAV(12-2)J(47), TRBV(7-6)J(2-1), and the TCR from antigen EBV LMP2-FLY that was TRAV(26-1)J(7), TRBV(27)J(2-1). These results suggest that the method provides accurate identification of the paired, V(D)J rearrangements for each individual human naïve and antigen-experienced T cells. The information could be used in the construction of an engineered T-cell receptor for cancer immunotherapy and infectious diseases. Citation Format: Fei Wang, Qing Zhou, Cheng-chi Chao. Analysis of the paired TCRα- and β-V(D)J full-length chains of single-cell sequence from human naïve and antigen-experienced T 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 1538.
ErbB3 Targeting Enhances the Effects of MEK Inhibitor in Wild-Type BRAF/NRAS Melanoma
Authors: Claudia Capparelli, Timothy J. Purwin, Shea A. Heilman, Inna Chervoneva, Peter A. McCue, Adam C. Berger, Michael A. Davies, Jeffrey E. Gershenwald, Clemens Krepler, Andrew E. Aplin
Journal: Cancer Research (2018)

Abstract MEK–ERK1/2 signaling is elevated in melanomas that are wild-type for both BRAF and NRAS (WT/WT), but patients are insensitive to MEK inhibitors. Stromal-derived growth factors may mediate resistance to targeted inhibitors, and optimizing the use of targeted inhibitors for patients with WT/WT melanoma is a clinical unmet need. Here, we studied adaptive responses to MEK inhibition in WT/WT cutaneous melanoma. The Cancer Genome Atlas data set and tumor microarray studies of WT/WT melanomas showed that high levels of neuregulin-1 (NRG1) were associated with stromal content and ErbB3 signaling. Of growth factors implicated in resistance to targeted inhibitors, NRG1 was effective at mediating resistance to MEK inhibitors in patient-derived WT/WT melanoma cells. Furthermore, ErbB3/ErbB2 signaling was adaptively upregulated following MEK inhibition. Patient-derived cancer-associated fibroblast studies demonstrated that stromal-derived NRG1 activated ErbB3/ErbB2 signaling and enhanced resistance to a MEK inhibitor. ErbB3- and ErbB2-neutralizing antibodies blocked the protective effects of NRG1 in vitro and cooperated with the MEK inhibitor to delay tumor growth in both cell line and patient-derived xenograft models. These results highlight tumor microenvironment regulation of targeted inhibitor resistance in WT/WT melanoma and provide a rationale for combining MEK inhibitors with anti-ErbB3/ErbB2 antibodies in patients with WT/WT cutaneous melanoma, for whom there are no effective targeted therapy options. Significance: This work suggests a mechanism by which NRG1 regulates the sensitivity of WT NRAS/BRAF melanomas to MEK inhibitors and provides a rationale for combining MEK inhibitors with anti-ErbB2/ErbB3 antibodies in these tumors. Cancer Res; 78(19); 5680–93. ©2018 AACR.
The Association of leptin with severity of non-alcoholic fatty liver disease: A population-based study
Authors: Laura Rotundo, Alana Persaud, Mirela Feurdean, Sushil Ahlawat, Hyun-seok Kim
Journal: Clinical and Molecular Hepatology (2018)

Leptin is associated with metabolic disorders, which predispose one to non-alcoholic fatty liver disease (NAFLD). The role of leptin in NAFLD pathogenesis is not fully understood. We aim to investigate the association between serum leptin level and severity of NAFLD using U.S. nationally representative data.Data were obtained from the United States Third National Health and Nutrition Examination Survey. NAFLD was defined by ultrasound detection and severity of hepatic steatosis in the absence of other liver diseases. The severity of hepatic fibrosis was determined by NAFLD fibrosis score (NFS). We used multivariate survey-weighted generalized logistic regression to evaluate the association between leptin level and the degree of NAFLD. We also performed subgroup analyses by body mass index (lean vs. classic NAFLD).Among 4,571 people, 1,610 (35%) had NAFLD. By ultrasound findings, there were 621 people with mild, 664 with moderate, and 325 with severe steatosis. There were 885 people with low NFS (<-1.455, no significant fibrosis), 596 with intermediate NFS, and 129 with high NFS (>0.676, advanced fibrosis). Leptin levels for normal, mild, moderate and severe steatosis were 10.7±0.3 ng/mL, 12.1±0.7 ng/mL, 15.6±0.8 ng/mL, 16±1.0 ng/mL, respectively (trend P-value<0.001). Leptin levels for low, intermediate, and high NFS were 11.8±0.5 ng/mL, 15.6±0.8 ng/mL, 28.5±3.5ng/mL, respectively (trend P-value<0.001). This association remained significant even after adjusting for known demographic and metabolic risk factors. In the subgroup analysis, this association was only prominent in classic NAFLD, but not in lean NAFLD.Serum leptin level is associated with the severity of NAFLD, especially in classic NAFLD patients.
Abstract P204: Depressive Symptomatology, Anti-depressant Use and Hypertension in Young Adulthood
Authors: Shakira F Suglia, Danielle M Crookes, Katherine M Keyes, Karestan C Koenen
Journal: Circulation (2016)

Objective: While depression symptoms have been associated with cardiovascular disease in adulthood, little is known of the effects of adolescent-onset depression and hypertension in young adulthood. Furthermore, few studies have examined whether use of anti-depressants is associated with hypertension among young adults. Research Design and Methods: We examined the relation between depression symptoms and hypertension in young adulthood in the National Longitudinal Study of Adolescent Health (N=13,722). Adolescents completed the Center for Epidemiologic Studies Depression (CESD)-20 during wave 1 (1994-1995, mean age 16) and the CESD-10 during follow-up wave 4 (2007-2008, mean age 29). Depression symptoms were characterized as a score of 16 or above for the CESD-20 and 11 or above for CESD-10. During follow-up participants were asked to provide to the interviewer all medications they were currently taking or had taken in the previous six months. Antidepressant and antihypertensive medications were identified from all medications provided. Blood pressure was measured during an in-home visit. Hypertension was defined as measured SBP of at least 140mmHg or DBP of at least 90mmHG measured in adulthood, or use of antihypertensive medications. Results: The prevalence of hypertension was 20%. In models adjusting for sociodemographic factors, high depression symptoms in either adolescence or young adulthood were not significantly associated with hypertension in young adulthood. Use of anti-depressants in young adulthood was associated with hypertension (OR 2.89, 95%CI 1.82, 4.56) this association remained even after adjusting for obesity. No interactions by gender were noted. Conclusions: In this nationally representative sample, antidepressant use was associated hypertension in young adulthood. In accordance with a recent AHA Scientific Statement, our findings suggest that young adults with depression should be monitored closely to prevent the development of risk factors, such as hypertension, which may accelerate the development of cardiovascular disease.
Vitamin C Improves Endothelial Dysfunction of Epicardial Coronary Arteries in Hypertensive Patients
Authors: UlrichSolzbach, BurkhardHornig, MichaelJeserich, HanjörgJust
Journal: Circulation (1997)

Background There is evidence for increased formation of free radicals in patients with hypertension, raising the possibility that NO is inactivated by free radicals, which impairs coronary endothelial function. Therefore, we tested the hypothesis that the antioxidant vitamin C could improve abnormal endothelial function of coronary arteries in patients with hypertension. Methods and Results In 22 hypertensive patients without relevant coronary artery stenoses, endothelium-dependent vascular responses of the left anterior descending coronary artery (LAD) to acetylcholine (0.01, 0.1, and 1.0 μmol/L) were determined before and immediately after intravenous infusion of 3 g vitamin C (17 patients) or placebo (5 patients). In a subgroup of 10 patients, papaverine-induced flow-dependent vasodilation (FDD) was measured before and after vitamin C (5 patients) or placebo (5 patients) infusion. Segmental responses of the coronary artery luminal area were analyzed with quantitative coronary angiography. Before vitami...
Abstract 5364: Somatic mutations in African American and non-Hispanic White young-onset colorectal cancers
Authors: Laura S. Rozek, Tingting Qin, Erika Koeppe, Peter Ulintz, Joel K. Greenson, Michele L. Cote, Elean M. Stoffel
Journal: Cancer Research (2018)

Abstract The proportion of colorectal cancers (CRCs) diagnosed at age &amp;lt;50 years is two-fold higher among African-Americans (AAs) compared to non-Hispanic Whites (NHW). Additionally, despite the rising incidence of young-onset CRC, little is known about the molecular characteristics of these as only 23 young-onset tumors were profiled in the TCGA cohort. Studies of CRC diagnosed in older individuals (age &amp;gt;50) demonstrate that CRC tumors in AAs are more often right-sided and MMR proficient, with higher prevalence of KRAS mutations. Risk of death from CRC among AAs with MMR proficient tumors is 73% higher than for NHW, after adjusting for treatment and known prognostic factors. We analyzed archival FFPE CRC tumors diagnosed in individuals age &amp;lt;50 (NHW enrolled in the UM Cancer Genetics Registry N=38 and African American subjects ascertained through the Wayne State University EpiCore N=13) for somatic mutations. Mutation profiling of tumor DNA from 51 CRCs diagnosed age &amp;lt;50 was performed using NGS sequencing with multigene panels in 2 sets (Qiagen GeneRead Cancer panel of 124 genes [N=36 tumors], Qiagen Qiaseq Comprehensive Cancer Panel of 275 genes [15 tumors]). We observed differences in CRC somatic mutations by race and by age. There was marked heterogeneity among tumors with regard to numbers of somatic mutations, with an average of 659 (range 39-10,267) variants detected per tumor, with 19/51 (37%) tumors classified as hypermutated. Among the most frequently mutated genes in young CRC tumors were APC (98% of tumors), PIK3CA (92% of tumors), NOTCH2 (86% of tumors), PTCH1 (82%), BRCA2 (67%), BRCA1 (84%), HNF1A (100%), RAD50 (29%), POLE (27%), MSH6 (39%), and FGFR3 (39%). These mutation profiles differ markedly from those of TCGA older-onset, nonhypermutated tumors. We identified differences in somatic mutations by race, including mutations in PTEN (NHW: 21% vs. AA: 8%), TGFBR2 (NHW: 32% vs. AA: 15%), FBXW7 (NHW: 47% vs. AA: 8%), and KRAS (NHW: 45% vs. AA: 31%). The relatively high prevalence of hypermutated tumors in this racially diverse cohort highlights the critical gaps in knowledge about pathways involved in pathogenesis of young-onset CRCs and how genomic information could guide precision therapies. Citation Format: Laura S. Rozek, Tingting Qin, Erika Koeppe, Peter Ulintz, Joel K. Greenson, Michele L. Cote, Elean M. Stoffel. Somatic mutations in African American and non-Hispanic White young-onset colorectal cancers [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 5364.
Abstract 5758: Generation and characterization of novel monoclonal antibodies against overexpressed CD109 on pancreatic cancer cells for use in diagnosis and therapy
Authors: Gustavo A. Arias-Pinilla, Angus Dalgleish, Satvinder Mudan, Izhar Bagwan, Tony Walker, Helmout Modjtahedi
Journal: Cancer Research (2018)

Abstract Pancreatic cancer is one of the most aggressive and lethal types of cancer, and more effective therapeutic agents are urgently needed. Overexpressed cell surface antigens are ideal targets for therapy with monoclonal antibody (mAb)-based drugs, and several have been approved for the treatment of human cancers; however, none have approval for pancreatic cancer. Our aim was to discover novel overexpressed cell surface antigens in human pancreatic cancer cells using mAb technology. We have generated two novel mouse mAbs, KU42.33C and KU43.13A, against the human pancreatic cancer cell line BxPC-3. Using ELISA, flow cytometry, competitive assay and mass spectrometry, we discover that these two mAbs target two distinct epitopes on the external domain of CD109 that are overexpressed by varying amounts in human pancreatic cancer cell lines. Treatment with these two naked antibodies alone did not affect tumor cell growth in vitro or cell migration. Of the two mAbs, only KU42.33C was useful in determining the expression of CD109 in tumor cells by Western blot and immunohistochemistry. Immunohistochemistry of human pancreatic carcinoma arrays with mAb KU42.33C showed that 94% of the 65 human pancreatic adenocarcinoma cases were CD109 positive, with no expression in normal pancreatic tissues. Our results suggest that these two novel mAbs are excellent tools for determining the expression level of CD109 in the tumor specimens and sera of patients with a wide range of cancers, in particular pancreatic cancer, and for investigating its diagnostic, prognostic and predictive value. Further research should unravel the therapeutic potential of the humanized forms or the conjugated versions of such antibodies in patients whose tumors overexpress CD109 antigen. Citation Format: Gustavo A. Arias-Pinilla, Angus Dalgleish, Satvinder Mudan, Izhar Bagwan, Tony Walker, Helmout Modjtahedi. Generation and characterization of novel monoclonal antibodies against overexpressed CD109 on pancreatic cancer cells for use in diagnosis and therapy [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 5758.
Small-Molecule Inhibitors of the Wnt Pathway Potently Promote Cardiomyocytes From Human Embryonic Stem Cell–Derived Mesoderm
Authors: ErikWillems, SeanSpiering, HermanDavidovics, MarionLanier, ZebinXia, MarciaDawson, JohnCashman, MarkMercola
Journal: Circulation Research (2011)

Rationale:Human embryonic stem cells can form cardiomyocytes when cultured under differentiation conditions. Although the initiating step of mesoderm formation is well characterized, the subsequent steps that promote for cardiac lineages are poorly understood and limit the yield of cardiomyocytes. Objective:Our aim was to develop a human embryonic stem cell–based high-content screening assay to discover small molecules that drive cardiogenic differentiation after mesoderm is established to improve our understanding of the biology involved. Screening of libraries of small-molecule pathway modulators was predicted to provide insight into the cellular proteins and signaling pathways that control stem cell cardiogenesis. Methods and Results:Approximately 550 known pathway modulators were screened in a high-content screening assay, with hits being called out by the appearance of a red fluorescent protein driven by the promoter of the cardiac-specific MYH6 gene. One potent small molecule was identified that inh...
Involvement of Tissue Factor Pathway Inhibitor in the Coronary Circulation of Patients With Acute Coronary Syndromes
Authors: PaoloGolino, AmeliaRavera, MassimoRagni, PlinioCirillo, OrlandoPiro, MassimoChiariello
Journal: Circulation (2003)

Background— Tissue factor pathway inhibitor (TFPI) is the endogenous inhibitor of the extrinsic coagulation pathway; however, its involvement during thrombus formation in patients with acute coronary syndromes (ACS) is still unknown. Methods and Results— Transcardiac (aorta/coronary sinus) free and total TFPI (free + lipoprotein-bound form) levels, as well as TFPI/factor Xa (FXa) complex levels, were measured in plasma samples obtained from patients with acute myocardial infarction undergoing primary PTCA and patients with unstable angina undergoing urgent PTCA. Patients with stable angina undergoing elective PTCA served as controls. In addition, prothrombin fragment 1+2 and fibrinopeptide A plasma levels were measured. Samples were collected at baseline, after PTCA, and after stent deployment. In patients with ACS, both total and free TFPI plasma levels in the coronary sinus were significantly lower than the corresponding levels measured in the aorta at any time point of the study; conversely, a signific...
Abstract 5861: RX-3117 promotes epigenetic effects in cancer cells through enhanced degradation of DNMT1
Authors: Dzjemma Sarkisjan, Ferry Pronk, Rosan Kuin, Btissame el Hassouni, Young B. Lee, Deog J. Kim, Marc Dijk, Daan P. Geerke, G. J. Peters
Journal: Cancer Research (2018)

Abstract RX-3117 is a novel, investigational, oral, small molecule nucleoside compound that shows promising antitumor activity in xenografts including patient-derived xenografts resistant to gemcitabine. RX-3117 is currently being evaluated in a Phase IIa multi-center, open-label clinical study in patients with relapsed or refractory pancreatic cancer and advanced bladder cancer. RX-3117 can downregulate DNMT1 and activate genes controlled by methylation, such as E-cadherin and p16. We aimed to elucidate the mechanism of RX-3117 mediated downregulation of DNMT1. Expression of DNMT1 was evaluated by western blotting. Binding of DNMT1 to DNA was measured after DNA isolation, DNAse treatment and gel electrophoresis. DNMT1 trapping in the nucleus was also studied with ImageStream FACS analysis. DNMT1 ubiquitination was measured by immunoprecipitation and quantification of the ubiquitin tag K48. Translocation of DNMT1 was studied by confocal microscopy. Modeling studies were performed with Quantum Mechanics (QM) and Molecular Dynamics (MD). DNMT1 acts on the DNA during the so-called base flipping necessary for methyl transfer. To determine whether RX-3117 treatment would lead to trapping of DNMT1, NSCLC A549 and PDAC SUIT-028 cells were treated for 24 hr with 1 µM RX-3117. Immunostaining of DNMT1-DNA and ImageStream FACS analysis demonstrated binding of DNMT1 to DNA. Treatment with RX-3117 also resulted in DNMT1 ubiquitination, as shown by an increase in the ubiquitin tag K48, reaching the highest level after 48 hr. Incubation of A549 and SUIT-028 cells with 80 nM of the specific proteasome inhibitor bortezomib prevented RX-3117 mediated degradation of DNMT1 (at 24 and 24 hr exposure to 1 µM RX-3117). This underlines the role of the proteasome in DNMT1 degradation. With confocal microscopy it was demonstrated that DNMT1 and the proteasome co-localized and translocated to the cytosol of A549 and SUIT-028 cells treated for 48 hours with 1 µM RX-3117. With molecular modelling using QM and MD, changes in nucleophilicity of C4-C5 double bound were observed indicating that DNMT1 would initiate methyl transfer but cannot proceed. In summary we conclude that RX-3117 induces epigenetic changes in cancer cells by trapping DNMT1 in the nucleus followed by translocation of the protein to the proteasome for degradation. Citation Format: Dzjemma Sarkisjan, Ferry Pronk, Rosan Kuin, Btissame el Hassouni, Young B. Lee, Deog J. Kim, Marc Dijk, Daan P. Geerke, G. J. Peters. RX-3117 promotes epigenetic effects in cancer cells through enhanced degradation of DNMT1 [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 5861.
Collagen-Targeting Vascular Endothelial Growth Factor Improves Cardiac Performance After Myocardial Infarction
Authors: JingZhang, LiangDing, YannanZhao, WenjieSun, BingChen, HangLin, XiaWang, LujieZhang, BiaoXu, JianwuDai
Journal: Circulation (2009)

Background— Vascular endothelial growth factor (VEGF) is an important active protein for the induction of angiogenesis and improvement in cardiac function after myocardial ischemia; however, the lack of a delivery system targeted to the injured myocardium reduces the local therapeutic efficacy of VEGF and increases its possible adverse effects. Methods and Results— We produced a fusion protein (CBD-VEGF) consisting of VEGF and a collagen-binding domain (CBD). The fusion protein specifically bound to type I collagen in vitro. In addition, CBD-VEGF promoted human umbilical vein endothelial cell proliferation after binding to collagen, which indicates that it retained both growth factor activity and collagen-binding ability. When implanted subcutaneously in rats, collagen membranes loaded with CBD-VEGF were significantly vascularized. After it was injected into rats with acute myocardial infarction, CBD-VEGF was largely retained in the cardiac extracellular matrix, in which collagen I was rich. Four weeks af...