tbuckley/cabot-search huggingface dataset:
Abstract 3731: Deciphering the transcriptional role of estrogen receptor alpha in ovarian cancer
Authors: Irene Lee, Myles Brown
Journal: Cancer Research (2018)

Abstract Ovarian cancer is the leading cause of death among gynecologic malignancies. Despite years of research, the 5-year survival rate for ovarian cancer patients has remained poor and the standard of care is largely the same as it was decades ago. Epidemiological evidence and previous studies have suggested a role for steroid hormones in the pathogenesis of ovarian cancer, however, the role of steroid hormones in ovarian cancer remains understudied. We hypothesized that Estrogen Receptor α (ERα) is transcriptionally active and drives a transcriptional program that is sufficient to promote ovarian cancer cell proliferation and survival in a subset of ER+ ovarian cancers. Preliminary data generated in our laboratory has suggested that estradiol (E2) treatment increases cell proliferation in PEO1 cells, an ERα+ ovarian cancer cell line. This increase in cell proliferation can be inhibited by co-administration with the selective estrogen receptor modulator, Tamoxifen, and the selective estrogen receptor degrader, Fulvestrant. To further interrogate the mechanism of action of ERα in ovarian cancer, we performed RNA-seq on PEO1 cells treated with Vehicle, 10 nM E2, 100 nM Fulvestrant, and E2+Fulvestrant for 24 hours. We identified 659 significantly differentially expressed genes following E2 treatment. Fulvestrant inhibited the majority of E2-induced differentially expressed genes, confirming that these genes are dependent upon ERα. Gene Set Enrichment Analysis (GSEA) indicated that the Hallmark early and late estrogen responses are enriched in the E2 dataset, confirming that classical ER activity is intact in these cells. Furthermore, we identified G2/M checkpoint as positively enriched in our dataset, indicating that proliferation genes are upregulated by ERα in these cells. Additionally, we found that apoptosis was negatively enriched in our dataset, indicating that apoptosis pathway genes are suppressed by E2 treatment. Future investigation in this project will center on exploring the mechanisms of ERα transcriptional activity through examining the ERα-dependent cistrome, regulation of target genes, and its interactions with other cofactors. These data will give us insight into how ER is regulated and what pathways and processes ER is driving. Additionally, we will use CRISPR/Cas9 screening to uncover the key genes downstream of ER that are executing the estrogen-dependent effects on proliferation and survival. We believe that these studies will provide additional drug targets that may suggest a combinatorial therapeutic approach in conjunction with endocrine therapies for the treatment of ovarian cancer. Citation Format: Irene Lee, Myles Brown. Deciphering the transcriptional role of estrogen receptor alpha in ovarian 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 3731.
Abstract 17569: Transapical Aortic Valve Implantation With the 2nd Generation Self-Expandable Symetis Acurate TA™ TAVI System - First Clinical Experience and 1-Year Follow-up Results
Authors: SusannePasa, DanielWendt, PhilippKahlert, KarimEl-Chilali, FadiAl-Rashid, PolykarposPatsalis, MareikeEißmann, RaimundErbel, HeinzJakob, MatthiasThielmann
Journal: Circulation (2014)

Introduction: We report our first clinical experience and 1-year outcome of transapical transcatheter aortic valve implantation (TAVI) with the use of the 2nd generation self-expandable ACURATE TA™ device. Methods: The Symetis (Symetis S.A., Ecublens, Switzerland) ACURATE TA™ system is composed of a porcine bioprosthesis attached into a self-expandable nitinol stent. This 2nd generation system enables anatomical orientation and facilitates intuitive implantation providing tactile feedback. Between 08/2010 and 06/2014 a total of 85 high-risk patients with symptomatic aortic stenosis were enrolled. All patients gave written informed consent. Clinical and hemodynamic data were prospectively recorded. Hemodynamic performance was evaluated by transthoracic echocardiography including mean pressure gradients (MPG) at baseline, discharge, 30-days, 6 and 12 months after surgery. Results: Patients mean age was 79±7years (mean ±SD) and 55% were female. Logistic EuroSCORE was 32.6±10.7% and STS-score 6.8±3.0% on aver...
Abstract 340: Short Telomeres Induce Autophagy and Modulate Cardiac Progenitor Cell Fate
Authors: Nirmala Hariharan, Collin Matsumoto, Jacqueline Emathinger, Saba Daneshpooy, Minyoung Shin, Aimee B Levinson, Pearl Quijada, Nathalie Nguyen, Mark Sussman
Journal: Circulation Research (2017)

Aging severely limits myocardial regeneration. Delineating the impact of age-associated factors such as short telomeres is critical to enhance the regenerative potential of cardiac progenitor cells (CPCs). We hypothesize that short telomeres induce autophagy and elicit the age-associated change in cardiac progenitor cell fate. We compared mouse strains with different telomere lengths (TL) for phenotypic characteristics of aging and also isolated CPCs from them. Naturally occurring wild mouse strain Mus musculus castaneus (CAST) possessing short telomeres (TL:18Kb) exhibits early cardiac aging with diastolic dysfunction, hypertrophy, fibrosis and increase in senescence markers p53 and p16, as compared to common lab strains FVB (TL:75Kb) and C57 (TL:50Kb). CAST CPCs with short TLs have altered cell fate as characterized by slower proliferation (p&lt;0.01); increased senescence identified by beta-galactosidase activity (p&lt;0.05); increased basal commitment as determined by expression of lineage markers smooth muscle actin, Tie2, and sarcomeric actinin (16.6, 1.7 and 1.75, p&lt;0.05); as well as loss of quiescence marker expression. Consistent findings of altered cell fate are also evident in old CPCs isolated from aged mice with significantly shorter TLs. Cell fate changes occurring downstream from short TL are at least partially p53 dependent, as p53 inhibition rescues the irreversible cell cycle arrest observed in CAST CPCs. Mechanistically, short TLs induce autophagy, a catabolic protein degradation process. Autophagy flux is increased in CAST CPCs as evidenced by increased LC3 (p&lt;0.05), reduced p62 expression (-52%, p&lt;0.05) and increased accumulation of autophagic puncta. Pharmacological inhibition of autophagosome formation, but not autolysosome formation reverses the cell fate to a more youthful phenotype. Overall the data suggests that short TLs activate autophagy to accommodate cell fate changes that tip the equilibrium away from quiescence and proliferation into differentiation and senescence, leading to age-associated exhaustion of CPCs. The study provides the mechanistic basis underlying age-associated cell fate changes that will enable identification of molecular strategies to enhance the therapeutic effects of aged CPCs.
Abstract 747: A new class of DNA alkylating indolino-benzodiazepine agents (BIAs) linked with a DNA binding moiety for use with antibody-drug conjugates (ADCs)
Authors: Michael L. Miller, Emily E. Reid, Katie E. Archer, Manami Shizuka, Molly A. McShea, Erin K. Maloney, Olga Ab, Leanne Lanieri, Alan J. Wilhelm, Jose F. Ponte, Nicholas C. Yoder, Ravi V. Chari
Journal: Cancer Research (2018)

Abstract We have previously disclosed antibody-drug conjugates (ADCs) that incorporate our highly potent novel DNA alkylating indolino-benzodiazepine (termed IGN) pseudo dimer. ADCs of these DNA alkylating IGNs were found preclinically to demonstrate better tolerability and an improved overall therapeutic index (TI) compared with those of DNA crosslinking IGNs (Miller, et al., AACR 2017 #53). In our ongoing effort to further explore DNA alkylating effector molecules for ADCs, we disclose here a new class of IGNs (termed BIAs) in which one IGN monomer subunit is connected to a bis-aryl moiety with affinity for the DNA binding pocket. Our initial structure activity relationship (SAR) studies around a series of BIAs identified a set of scaffolds that met our requirement for high in vitro potency. These scaffolds were subsequently modified to incorporate functionalities that allow linkage to an antibody using various linker chemistries. These linkable BIAs displayed high in vitro potency across a panel of cell lines, indicating that the incorporation of a linker was not detrimental to their overall potency. Furthermore, we found that the potency of these linkable BIAs could be modulated by careful selection of substituents on the bis-aryl moiety providing enhanced binding affinity with DNA. Upon identification of lead BIA molecules, conjugates with a folate receptor-α (FRα)-binding antibody were prepared. These ADCs displayed potent, antigen-specific in vitro activity across a panel of FRα-expressing cell lines. In vivo, these ADCs demonstrated potent efficacy in xenograft models at doses well below the maximum tolerated dose. In light of these findings, BIA ADCs represent a promising new class of DNA alkylating effector molecules for use in the development of ADCs. Citation Format: Michael L. Miller, Emily E. Reid, Katie E. Archer, Manami Shizuka, Molly A. McShea, Erin K. Maloney, Olga Ab, Leanne Lanieri, Alan J. Wilhelm, Jose F. Ponte, Nicholas C. Yoder, Ravi V. Chari. A new class of DNA alkylating indolino-benzodiazepine agents (BIAs) linked with a DNA binding moiety for use with antibody-drug conjugates (ADCs) [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 747.
Abstract 48: Age-associated Imbalance of Vasorin/TGF-β1 Signaling in VSMC Facilitates Collagen Production
Authors: MingyiWang, GianfrancoPintus, RobertaGiordo, JingZhang, LiqunJiang, RobertMonticone, EdwardLakatta
Journal: Circulation Research (2014)

Collagen deposition, a hallmark of arterial aging that resembles post-injury arterial restenosis, is perpetrated by angiotensin II (Ang II) signaling in arterial wall. Collagen aggregation at sites of arterial injury is regulated by the coordinated signaling of pro-fibrotic TGF-β1 and anti-fibrotic vasorin within VSMCs. The Ang II/TGF-β1/vasorin signaling relationship within VSMCs with aging, however, remains unknown. In vivo studies in old vs. young FXBN rats show that aortic transcription and translation of vasorin markedly decrease with aging. In vitro studies in VSMCs isolated from old vs. young aortae. Ang II-associated reduction of vasorin protein abundance in young VSMCs and age-associated changes in vasorin protein levels are reversed by the AT1 antagonist, Losartan (Los) (Figure). Dual immunolabeling and co-immunoprecipitation demonstrate that the co-incidence and physical interaction of vasorin and TGF-β1 within VSMCs are significantly decreased with aging. Importantly, exposure of young VSMCs t...
Abstract 12291: Contribution of Rare Mutations in Mendelian Hypercholesterolemia Genes to Risk for Premature Coronary Artery Disease in the Population
Authors: Hong-Hee Won, Ron Do
Journal: Circulation (2014)

Introduction: Low-density lipoprotein cholesterol (LDL-C) is a causal risk factor for coronary artery disease (CAD). Rare mutations in at least 6 genes lead to Mendelian forms of high or reduced LDL-C; three ( APOB, LDLR, PCSK9 ) act in a dominant pattern whereas three ( ABCG5, ABCG8, LDLRAP1 ) in a recessive pattern. We address to what extent rare mutations in Mendelian LDL-C genes contribute to early CAD risk in the population. Methods: We sequenced the exons of the 6 genes in 9,329 early CAD cases (myocardial infarction, angiographic CAD, or coronary revascularization in men≤50 and women≤60) and 10,245 controls from 9 studies using targeted and whole exome next-generation sequencing. We tested 3 sets: ‘Null alleles’ (nonsense, splice-site, or frameshift); ‘Deleterious (7/7)’ (null and missense annotated as damaging by 7 algorithms); and ‘Deleterious (6/7)’ (null and missense annotated as damaging by at least 6 algorithms). Given the rarity of deleterious mutations, we aggregated these mutations in each gene and tested for an excess or deficit in cases vs . controls. Results: Counts of mutations are provided in Table. Null mutations in LDLR , carried by 1:500 participants, confered a 8-fold increase in CAD risk (P=8х10 -7 ) whereas heterozygosity for a null mutation in ABCG5 (1:650 frequency) was associated with a 3-fold increased risk (P=5х10 -3 ). ‘Deleterious (7/7)’ mutations in LDLR , carried by 1:100 participants, confered a 4-fold increased risk (P=8х10 -17 ) whereas heterozygosity for a ‘Deleterious (7/7)’ mutation in ABCG5 (1:250 frequency) was associated with a 2-fold increased risk (P=2х10 -3 ). Heterozygous null allele carriers at LDLR and ABCG5 had increased LDL-C (P&lt;0.001). Conclusions: Of early CAD cases, 2-3% carry a rare, deleterious mutation at LDLR or ABCG5 associated with increased risk. Although previously reported to cause recessive sitosterolemia, we find that heterozygosity for a null allele at ABCG5 is associated with markedly higher early CAD risk.
Abstract 3149: Collagen XIII induces β1-integrin activation and triple-negative breast cancer metastasis
Authors: Hui Zhang, Tricia Fredericks, Ren Xu
Journal: Cancer Research (2018)

Abstract Increased collagen expression and deposition is a risk factor for breast cancer development. Collagen XIII is a type II transmembrane protein within the collagen superfamily. Experiments in tissue culture and knockout mouse model show that collagen XIII is involved in cell adhesion and differentiation of certain cell types. However, function of collagen XIII in cancer development and progression largely remains to be determined. We found that collagen XIII expression is significantly induced during breast cancer development, especially in triple negative breast cancer. Increased collagen XIII mRNA level is associated with poor prognosis. Importantly, silencing collagen XIII expression in MDA MB 231 cells slow down xenograft growth and significantly reduced cancer metastasis in mice. Using gain- and loss-of function approaches, we showed that collagen XIII enhanced cell migration, invasion, and mammosphere/tumorsphere formation. We also found that collagen XIII induced integrin-β1 activation, and subsequently enhanced TGF-β signaling. Blocking integrin-β1 activation with AIIB2 antibody significantly reduced collagen XIII-induced cell migration and mammosphere formation. These findings demonstrate a novel function of collagen XIII in promoting cancer metastasis through enhancing β1 integrin-dependent cell migration and invasion Citation Format: Hui Zhang, Tricia Fredericks, Ren Xu. Collagen XIII induces β1-integrin activation and triple-negative breast cancer metastasis [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 3149.
Glycemic Control and Risk of Infections Among People With Type 1 or Type 2 Diabetes in a Large Primary Care Cohort Study
Authors: Julia A. Critchley, Iain M. Carey, Tess Harris, Stephen DeWilde, Fay J. Hosking, Derek G. Cook
Journal: Diabetes Care (2018)

Diabetes mellitus (DM) increases the risk of infections, but the effect of better control has not been thoroughly investigated.With the use of English primary care data, average glycated hemoglobin (HbA1c) during 2008-2009 was estimated for 85,312 patients with DM ages 40-89 years. Infection rates during 2010-2015 compiled from primary care, linked hospital, and mortality records were estimated across 18 infection categories and further summarized as any requiring a prescription or hospitalization or as cause of death. Poisson regression was used to estimate adjusted incidence rate ratios (IRRs) by HbA1c categories across all DM, and type 1 and type 2 DM separately. IRRs also were compared with 153,341 age-sex-practice-matched controls without DM. Attributable fractions (AF%) among patients with DM were estimated for an optimal control scenario (HbA1c 6-7% [42-53 mmol/mol]).Long-term infection risk rose with increasing HbA1c for most outcomes. Compared with patients without DM, those with DM and optimal control (HbA1c 6-7% [42-53 mmol/mol], IRR 1.41 [95% CI 1.36-1.47]) and poor control (≥11% [97 mmol/mol], 4.70 [4.24-5.21]) had elevated hospitalization risks for infection. In patients with type 1 DM and poor control, this risk was even greater (IRR 8.47 [5.86-12.24]). Comparisons within patients with DM confirmed the risk of hospitalization with poor control (2.70 [2.43-3.00]) after adjustment for duration and other confounders. AF% of poor control were high for serious infections, particularly bone and joint (46%), endocarditis (26%), tuberculosis (24%), sepsis (21%), infection-related hospitalization (17%), and mortality (16%).Poor glycemic control is powerfully associated with serious infections and should be a high priority.
Abstract 15896: Higher Baseline Body Mass Index Predicts Longitudinal Increase in C-Reactive Protein but not Vice Versa
Authors: Dhananjay Vaidya, Lisa R Yanek, Brian G Kral, Rasika A Mathias, Lewis C Becker, Diane M Becker
Journal: Circulation (2015)

Introduction: Basic research shows that adipose tissue is proinflammatory, and inflammation in turn may cause adipose tissue accumulation through insulin resistance. However, it is not well understood whether adiposity or inflammation, or equally both, are drivers of this vicious cycle. We examined this question through longitudinal structural equation modeling (SEM). Methods: We analyzed data from 869 GeneSTAR Study participants from 374 families who were free of clinical cardiovascular disease throughout the follow-up period, and had two study visits 2 to 8 years apart. Body Mass Index (BMI) was used as a measure of adiposity, and log transformed high sensitivity C-Reactive Protein (CRP) as a measure of inflammatory state. The crossed lag SEM for correlations is presented in the Figure, adjusting for demographic factors and smoking during the two visits. The predictive associations of follow-up BMI and CRP with baseline CRP and BMI, respectively, are adjusted for cross sectional correlations and longitudinal inertia of variables. We also estimated the beta coefficients of the crossed lag associations using generalized SEM, accounting for non-independence of families. Results: Baseline BMI was associated with follow-up CRP (3.6% increase/BMI unit, p&lt;0.001), but baseline CRP was not associated with follow-up BMI (p = 0.66). The crossed lag correlations were significantly different (p &lt; 0.001). Conclusions: Higher adiposity is the driver of its vicious cycle with inflammation. For future studies, we conjecture that weight control is likely to be more effective as compared to treatment of inflammation in improving the coupled metabolic and inflammatory profile over time.
Abstract 1482: SON represses RUNX1 expression and impairs megakaryocytic differentiation in Down syndrome acute megakaryoblastic leukemia (DS-AMKL)
Authors: Lana Vukadin, Eun young Park, Jung Hyun Kim, Erin Eun Young Ahn
Journal: Cancer Research (2018)

Abstract Individuals with Down syndrome (DS) are highly predisposed to develop hematopoietic malignancies, especially acute megakaryoblastic leukemia (DS-AMKL). Generally, genes located on chromosome 21 tend to be increased in Down syndrome patients, but how these individual genes contribute to development of DS-AMKL is still unclear. SON, a gene located on chromosome 21, is upregulated in Down syndrome patients, and it has been reported that DS-AMKL cells have higher level of SON expression. The SON protein functions as a splicing factor and a transcription regulator in leukemia but the role of SON upregulation in DS-AMKL pathogenesis is still not fully elucidated. In addition, runt-related transcription factor 1 (RUNX1) is also located on chromosome 21, but its expression level is downregulated in DS-AMKL patients despite the increased gene dosage. We show that SON represses RUNX1 expression and blocks terminal megakaryocytic differentiation in DS-AMKL. Knockdown of SON in DS-AMKL cell lines leads to morphologic changes and increased cell adhesion. Moreover, cell surface marker analyses demonstrate that the depletion of SON induces increased CD41+ CD61+ populations as well as polyploidy cells, indicating megakaryocytic differentiation. Consistent with these results, SON deletion causes upregulation of RUNX1, which is a critical factor in the megakaryocytic differentiation. Furthermore, our data show that knockdown of SON increases several megakaryocytic transcription factors and decreases erythropoietic transcription factors, facilitating terminal megakaryocytic differentiation of leukemic blasts. Mechanistically, SON binds to the proximal promoter region as well as two intronic enhancer regions upstream of the proximal promoter at the RUNX1 gene locus, and suppresses transcription of RUNX1 by lowering the level of H3K4me3. Taken together, we propose that the increased genomic dosage of SON in Down syndrome impairs terminal differentiation of megakaryo-erythroblasts into mature megakaryocytes through binding to the RUNX1 promoter/enhancer to repress its transcription, which contributes to the higher incidence of AMKL in Down syndrome patients. Our results reveal a novel connection of SON to DS-AMKL pathogenesis and provide clinical importance of SON upregulation in DS. These findings suggest that SON could be a promising therapeutic target for DS-AMKL patients. Citation Format: Lana Vukadin, Eun young Park, Jung Hyun Kim, Erin Eun Young Ahn. SON represses RUNX1 expression and impairs megakaryocytic differentiation in Down syndrome acute megakaryoblastic leukemia (DS-AMKL) [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 1482.
<i>KMT2C</i> Mutations in Diffuse-Type Gastric Adenocarcinoma Promote Epithelial-to-Mesenchymal Transition
Authors: Soo-Jeong Cho, Changhwan Yoon, Jun Ho Lee, Kevin K. Chang, Jian-xian Lin, Young-Ho Kim, Myeong-Cherl Kook, Bülent Arman Aksoy, Do Joong Park, Hassan Ashktorab, Duane T. Smoot, Nikolaus Schultz, Sam S. Yoon
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Lauren diffuse-type gastric adenocarcinomas (DGAs) are generally genomically stable. We identified lysine (K)-specific methyltransferase 2C (KMT2C) as a frequently mutated gene and examined its role in DGA progression. Experimental Design: We performed whole exome sequencing on tumor samples of 27 patients with DGA who underwent gastrectomy. Lysine (K)-specific methyltransferase 2C (KMT2C) was analyzed in DGA cell lines and in patient tumors. Results: KMT2C was the most frequently mutated gene (11 of 27 tumors [41%]). KMT2C expression by immunohistochemistry in tumors from 135 patients with DGA undergoing gastrectomy inversely correlated with more advanced tumor stage (P = 0.023) and worse overall survival (P = 0.017). KMT2C shRNA knockdown in non-transformed HFE-145 gastric epithelial cells promoted epithelial-to-mesenchymal transition (EMT) as demonstrated by increased expression of EMT-related proteins N-cadherin and Slug. Migration and invasion in gastric epithelial cells following KMT2C knockdown increased by 47- to 88-fold. In the DGA cell lines MKN-45 and SNU-668, which have lost KMT2C expression, KMT2C re-expression decreased expression of EMT-related proteins, reduced cell migration by 52% to 60%, and reduced cell invasion by 50% to 74%. Flank xenografts derived from KMT2C-expressing DGA organoids, compared with wild-type organoids, grew more slowly and lost their infiltrative leading edge. EMT can lead to the acquisition of cancer stem cell (CSC) phenotypes. KMT2C re-expression in DGA cell lines reduced spheroid formation by 77% to 78% and reversed CSC resistance to chemotherapy via promotion of DNA damage and apoptosis. Conclusions: KMT2C is frequently mutated in certain populations with DGA. KMT2C loss in DGA promotes EMT and is associated with worse overall survival.