tbuckley/cabot-search huggingface dataset:
Abstract 1489: Differential gene expression profiles between normal cervical tissue and high-grade squamous intraepithelial lesion expressing p16 and high-risk HPV E6/E7 mRNA
Authors: Ines Benedetti, Lia Barrios, Niradiz Reyes
Journal: Cancer Research (2018)

Abstract Background: HPV is necessary but not sufficient for development of uterine cervix carcinoma. There are genetic factors that influence the progression of premalignant lesions. Gene expression profile differences between healthy and premalignant lesion could contribute to identify potential biomarkers for each step of cervical tumor progression. Design: A female patient with an initial diagnosis of low grade squamous intraepithelial lesion (SIL) was invited to participate in the study. During follow-up a high grade SIL was observed by colposcopy, and two samples were obtained from the lesion: one sample was processed for histopathologic diagnosis, and additionally stained by IHC with p16 antibody; the other sample, along with a matched sample of healthy tissue taken distantly from the lesion were stored in a nucleic acids preservation reagent for subsequent analysis of gene expression. Differences in gene expression between healthy tissue and high grade SIL tissue were assessed in triplicate using the cDNA gene expression Illumina microarray Human-HT-12-V4. A statistical p value was computed comparing expression levels from the tissue lesion and healthy tissue. Genes with a fold-change ≥ 2 and a p value &amp;lt;0.05 were regarded as differentially expressed. Additionally, two cervix swabs were obtained for detection of HPV DNA by PCR, and for assessment of high risk HPV E6/E7 mRNA expression by RT-PCR. Results: Histopathological evaluation of the lesion confirmed a high grade squamous intraepithelial lesion, with positive p16 staining. HPV-18 DNA was detected and E6/E7 HPV 18 mRNA expression was confirmed. Gene expression analysis detected 33 overexpressed genes, including TMEM45A, SPRR2B, KRT16 and RBP1, and 30 underexpressed genes, including SPARCL1, GCNT3, TMPRSS11b and ESR1, in high grade SIL compared to healthy uterine cervical tissue. Overexpressed genes belonged to important cellular pathways, such as queratinization, defensins, cytoskeletal signaling, cellular adhesion and extracellular matrix remodeling. Underexpressed genes belonged to metabolic pathways, cell trafficking, and chemokine signaling, among others. Conclusions: Microarray analysis identified differential expression between healthy cervical tissue and high grade SIL with confirmed HPV-18 transforming infection. Differentially expressed genes belonged to important cellular pathways. Further studies are required to evaluate the usefulness of these genes as risk markers for progression. Citation Format: Ines Benedetti, Lia Barrios, Niradiz Reyes. Differential gene expression profiles between normal cervical tissue and high-grade squamous intraepithelial lesion expressing p16 and high-risk HPV E6/E7 mRNA [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 1489.
Abstract 17101: Low-intensity Anticoagulant Treatment in Chinese Patients with Mechanical Heart Valve Prostheses: Early Outcomes of a Prospective, Multicenter Registry in China
Authors: Jiahu, Bofu, Jian-pingXu, Ying-kangShi, LiDong
Journal: Circulation (2014)

Background: Current guidelines recommend vitamin K antagonist treatment with relatively higher international normalized ratio (INR) targets for patients with mechanical heart valve prostheses. However, there is lack of data from large clinical trials about the outcomes of low-intensity anticoagulant treatment in Chinese patients with mechanical heart valves. Methods: The Low-intensity Anticoagulation Therapy after Heart Valve Replacement is an ongoing multicenter, prospective, observational cohort study (ChiCTR-OCH-10001185). Between January 2011 and August 2013, qualified patients from 34 cardiac centers in China mainland were recruited in the Anticoagulation Therapy Database of Chinese Patients after Heart Valve Replacement. Baseline characteristics were collected and patients were followed up for anticoagulant treatment, INRs and adverse events till March 2014. Results: The database recruited 11,769 patients, and 11,040 patients (93.8%) undergoing mechanical heart valve replacement were analyzed in thi...
Abstract 734: Thienoindoles: New highly promising agents for antibody-drug conjugates generation
Authors: Michele Caruso, Fabio Gasparri, Barbara Valsasina, Clara Albanese, Italo Beria, Ilaria Candiani, Marina Ciomei, Nicoletta Colombo, Sabrina Cribioli, Ulisse Cucchi, Eduard Felder, Ivan Fraietta, Arturo Galvani, Antonella Isacchi, Aurelio Marsiglio, Paolo Orsini, Rita Perego, Simona Rizzi, Attilio Tomasi, Sonia Troiani, Carlo Visco, Daniele Donati
Journal: Cancer Research (2018)

Abstract Thienoindoles are a new proprietary class of highly potent DNA minor groove alkylating agents. This class is characterized by a fused thiophene ring whose intrinsic electron-withdrawing character provides a nearly optimal increase in stability and potency of alkylating subunits. Furthermore, the presence of a solubilizing moiety on the minor groove portion provides compounds with physicochemical properties highly compatible with deployment as antibody payloads. Extensive optimization of this class has led to the identification of the highly potent toxin NMS-P528 with sub-nanomolar IC50 in proliferation assay across a large panel of tumor cell lines. NMS-P945, a drug-linker generated from NMS-P528, is highly suited for conjugation with targeted antibodies, consistently yielding ADCs with favorable drug-antibody ratios in the absence of significant antibody aggregation and with full maintenance of antigen binding capability. Proof of concept efficacy and mechanism of action studies were performed using NMS-P945 conjugated with trastuzumab, observing for the resulting conjugate excellent in vitro target-directed cytotoxicity in HER2-positive vs. negative cancer cell lines. In animal efficacy studies against HER2-positive human breast cancer tumors, trastuzumab-NMS-P945 ADC administration yielded complete tumor regression with no effects on body weight gain, while unarmed trastuzumab and armed control antibody showed little and no effect, respectively. PK data indicated long plasma half-life of our novel ADCs in the monkey. Promising results were also obtained with a range of different antibody/antigen systems, e.g. with an antibody directed to the ALK receptor tyrosine kinase. Extensive process research has been completed for the production of NMS-P528 and NMS-P945, resulting in an efficient stereoselective method for the preparation of GMP materials on the 100g scale and both products are proposed as a licensing opportunity for conjugation with tumor-targeting antibodies. Citation Format: Michele Caruso, Fabio Gasparri, Barbara Valsasina, Clara Albanese, Italo Beria, Ilaria Candiani, Marina Ciomei, Nicoletta Colombo, Sabrina Cribioli, Ulisse Cucchi, Eduard Felder, Ivan Fraietta, Arturo Galvani, Antonella Isacchi, Aurelio Marsiglio, Paolo Orsini, Rita Perego, Simona Rizzi, Attilio Tomasi, Sonia Troiani, Carlo Visco, Daniele Donati. Thienoindoles: New highly promising agents for antibody-drug conjugates generation [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 734.
Abstract 16862: Transfer of Exosome-Enclosed MicroRNAs From Host Myocardial Cells to Transplanted Cardiac Stem Cells Facilitates Improved Survival in the Ischemic Myocardium
Authors: Sang-Ging Ong, Mei Huang, Won Hee Lee, Devaveena Dey, Joseph Wu
Journal: Circulation (2013)

Background: Despite the promises held by cardiac stem cells (CSCs) for restoration of cardiac function following MI, the poor survival of CSCs have been a major issue. Hypoxia-inducible factor 1-al...
Colorectal tumor patterns among adolescents, emerging adults, and young adults.
Authors: Andreana Natalie Holowatyj, Mark Andrew Lewis, Stephanie Schmit, Anne C. Kirchhoff, Jane Figueiredo, Cornelia M Ulrich
Journal: Journal of Clinical Oncology (2018)

567 Background: Despite overall reductions in colorectal cancer (CRC) incidence, this trend has shifted among young individuals. Incidence rates continue to rise in this population, yet causes remain unknown. We examined CRC tumor patterns within the adolescent, emerging adult, and young adult (AYA) population in the United States. Methods: Using Surveillance, Epidemiology, and End Results program data, we identified individuals aged 15 to 39 years diagnosed with CRC from 2010-2014. Unadjusted and adjusted multinomial logistic regression models were used to quantify the associations between age of onset [adolescents (15-18 years), emerging adults (19-25 years) and young adults (26-29, 30-34, 35-39 years)] and CRC tumor site and sidedness. Results: We identified 4,417 AYA patients (33 adolescents; 298 emerging adults; 4,086 young adults) with CRC over the 5-year study period. The percentage of cases diagnosed with colon cancer decreased across all AYA groups compared to rectal cancer cases ( P-trend=0.03). Age group was associated with sidedness ( P-trend=0.01). Individuals aged 26 to 29 years remained more likely to be diagnosed with right-sided (Odds ratio, OR=1.35, 95% CI 1.08-1.69, P=0.009) and high-grade (OR=1.29, 95% CI 1.02-1.64, P=0.03) colorectal tumors compared to counterparts aged 35 to 39 years, after adjusting for sex, race/ethnicity, stage, grade, and county-level poverty. Conclusions: CRC site and sidedness were associated with age at diagnosis within the AYA population. These data are the first to define clinical patterns of CRC among AYAs. Elucidating etiologies underlying these patterns in young-onset CRCs are needed for tailoring CRC screening/surveillance and treatment.
Abstract 4908: Exemestane worsens everolimus-associated stomatitis in cancer patients
Authors: Vladmir C. de Lima, Matheus H. de Lima, Fabio A. Alves, Gláucia N. Hajj
Journal: Cancer Research (2018)

Abstract Everolimus is an antitumor drug usually indicated for the treatment of breast, kidney and neuroendocrine malignancies that inhibits the activation of the mammalian Target of Rapamycin (mTOR). Despite the efficacy and success of the treatment, side effects are not uncommon, and stomatitis is quite prevalent. mTOR inhibitor associated stomatitis (mIAS) is described as ulcerated aphthous-like lesions associated with mTOR inhibitors use. mIAS may cause severe pain, leading to nutritional deficiency and general health decline, besides drug dose reduction or suspension. Clinical observation suggested mIAS to be more common among breast cancer patients. Thus, we hypothesized that exemestane could contribute to increase everolimus toxicity in the oral mucosa. We prospectivelly collected clinical data from patients who used everolimus, associated or not with exemestane, from March 2016 to September 2017, and correlated them with information regarding mIAS (date of onset, number of lesions in the oral cavity, grading). We also performed in vitro experiments with Dysplastic Oral Keratinocytes (DOK). Cells were treated with vehicle, everolimus, exemestane or the combination of everolimus and exemestane. Drug induced citotoxicity was evaluated by MTT assay and migration inhibition by scratch wound healing assay. All assays were done in triplicate. Frequencies were compared by Fisher's exact or McNemar test. Log-rank and Wilcoxon tests were employed to compare time to mIAS development. Multivariate ANOVA was used to compare results from in vitro experiments. SPSS and Image J were used to make all statistical analysis. One hundred and thirty patients were evaluated. Mostly were females, with mean age of 60 years, and had previously treated advanced stage (IV) breast cancer. 30.3% developed mIAS. Breast cancer patients (treated with exemestane plus everolimus) had 2.29 higher chance to develop mIAS when compared to neuroendocrine tumos patients (treated with everolimus alone). In vitro experiments showed that the association of everolimus and exemestane increased cell death and migration (wound healing) inhibition of DOK in comparison with cells treated with everolimus or exemestane alone. The clinical data suggests that exemestane increases the risk of developing mIAS, and the in vitro experiments reinforces the idea that exemestane may enhance oral mucosa toxicity mediated by everolimus. Citation Format: Vladmir C. de Lima, Matheus H. de Lima, Fabio A. Alves, Gláucia N. Hajj. Exemestane worsens everolimus-associated stomatitis in cancer patients [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 4908.
Abstract 5703: Immunoscore as prognostic biomarkers in patients with epithelial ovarian cancer
Authors: Shin-Wha Lee, Min-Je Kim, Ju-hyun Kim, Young-Jae Lee, Yong-Man Kim, Yong-Man Kim
Journal: Cancer Research (2018)

Abstract Background: The analysis of single parameters alone may not provide sufficient insights about complex immune system-tumor interactions. This study is to validate the immune contexture as prognostic biomarkers in high-grade serous ovarian cancer (HGS-OC) and to find new era of immunoscore in HGS-OC. Methods: We collected FFPE samples from 187 patients with HSOC and produced TMA samples. We accomplished the OPAL multiplex IHC assay for the quantitative analysis of immune markers, including CD4, CD8, CD20, FoxP3, PD-L1, and CK. Multiplex Biomarker Imaging and inForm® Image Analysis Software was used. Results: FIGO stage III and IV patients were 84.5% (158/187). The optimal debulking surgery was done in 66.8% (125/187). The 3-year disease-free survival and 5-year overall survival were 35.1% and 50.0%, respectively. Any single marker was not related to the survival, including CD8, FoxP3, and PD-L1. However, high CD8:FoxP3 and CD8:PD-L1 ratios were correlated with good survival. In Cox regression model, the risk factors for HGS-OC survival were FIGO stage (HR 1.784, 95% CI: 1.295-2.457, p&amp;lt;0.001) and platinum resistance (HR 4.257, 95% CI: 2.753-6.582, p&amp;lt;0.001). Additionally, CD8:PD-L1 ratio was a favorable prognostic factor (HR 0.621, 95% CI: 0.042-0.917, p=0.017). Conclusion: These findings indicate that although any single immune marker is not related to the survival, CD8:FoxP3 and CD8:PD-L1 ratios provide the positive correlation with the prognosis in HGS-OC; especially, CD8:PD-L1 ratio is prognostic biomarker that is comparable to clinical biomarkers. The next study for immunoscore is necessary to define immunoscore in ovarian cancer. Citation Format: Shin-Wha Lee, Min-Je Kim, Ju-hyun Kim, Young-Jae Lee, Yong-Man Kim, Yong-Man Kim. Immunoscore as prognostic biomarkers in patients with epithelial 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 5703.
Abstract 4671: Rapid, no-wash measurement of immune checkpoint molecules expression induced by interaction with peripheral blood mononuclear cells in breast and cervical cancer cell models
Authors: Jeanine M. Hinterneder, Jen Carlstrom, Adam Carlson, Dawn Nida
Journal: Cancer Research (2018)

Abstract The purpose of this study was to examine the pathways involved in the induction of immune checkpoint molecules in basal breast and cervical cancer cell lines by measuring classical biomarker expression using AlphaLISA no-wash homogeneous assays. Programmed cell death-ligand 1 (PD-L1) expression increases with tumor severity in basal-like breast cancer and is enhanced in intraepithelial neoplasia and cervical cancers. Basal-breast tumors can adapt to lymphocytic infiltration by responding to heightened concentrations of interferon gamma (IFN-y) secreted by Type 1 helper T cells with upregulation of PD-L1 protein allowing the tumors to evade immune targeting and reduce the immune response. We show here that human peripheral blood mononuclear cells (PBMCs) secrete IFN-y and other cytokines in response to stimulation with CD3/CD38 Dynabeads. We then examined modulation in expression of immune checkpoint molecules (PD-L1 and others) in HCC38 (basal breast cancer-derived) and HeLa (cervical cancer) cells in response to co-culturing with activated PBMCs, treatment with conditioned media collected from activated PBMCs, and direct treatment with recombinant IFN-y. As expected, IFN-y treatment induced dose-dependent upregulation of PD-L1 protein expression in both HCC38 and HeLa cell lines, whereas the effects of conditioned media and direct co-culturing with PBMCs resulted in more complex effects which are discussed. To determine if tumor cytoarchitecture influences responsiveness to the PBMCs, biomarker expression was measured from cultures grown in both traditional adherent monolayers and in 3D spheroid cultures using Ultra-Low Attachment (ULA) microplates. Cellular health and proliferation was assessed by measuring ATP concentration with ATPlite luminescence assays and cellular imaging with viability dyes. The upregulation of PD-L1 expression was observed to be largely independent of cellular proliferation and is further shown to be dependent on signaling through the JAK/STAT pathway by probing with AlphaLISA SureFire phosphorylation assays. These data illustrate and address some of the challenges in developing a biologically relevant culture system for examining the complex mechanisms involved in tumor evasion of the innate immune response. Citation Format: Jeanine M. Hinterneder, Jen Carlstrom, Adam Carlson, Dawn Nida. Rapid, no-wash measurement of immune checkpoint molecules expression induced by interaction with peripheral blood mononuclear cells in breast and cervical cancer cell 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 4671.
Abstract 20890: Ddah1 Protects From Angiotensin II-Induced Development of Hypertension and Vascular Remodeling
Authors: Irakli Kopaliani, Natalia Jarzebska, Silke Brilloff, Anne Kolouschek, Jens Martens-Lobenhoffer, Stefan R Bornstein, Stefanie M Bode-Böger, Norbert Weiss, Andreas Deussen, Roman N Rodionov
Journal: Circulation (2017)

Angiotensin II-dependent development of hypertension and vascular remodeling are mediated via endothelial dysfunction. The latter is mediated via ANGII-induced threonine (Thr) phosphorylation of the protein kinase AKT. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is a cytoplasmic protein, which has been shown to prevent Thr phosphorylation of AKT. We tested the hypothesis that DDAH1 prevents ANGII-dependent development of hypertension and vascular remodeling. DDAH1 transgenic (TG) and wild type (WT) littermate mice were infused with moderate (0.75 mg/kg/day) and high (1.5 mg/kg/day) doses of ANGII for 4 weeks using osmotic minipumps. Systolic blood pressure (SBP) was measured using the tail cuff method. Endothelial function was assessed in isolated aortic rings. Structural changes in aortic wall were assessed by histological analysis. SBP was not different between TG and WT mice before ANGII infusion and at the 1 st  week of infusion, however, TG mice had significantly lower ( P  P  P  P  + , CD3 + , CD8 +  and CD4 +  T-cells was significantly lower ( P
Rho Kinases in Cardiovascular Physiology and Pathophysiology
Authors: GervaiseLoirand, PatriceGuérin, PierrePacaud
Journal: Circulation Research (2006)

Rho kinases (ROCKs) are the first and the best-characterized effectors of the small G-protein RhoA. In addition to their effect on actin organization, or through this effect, ROCKs have been found to regulate a wide range of fundamental cell functions such as contraction, motility, proliferation, and apoptosis. Abnormal activation of the RhoA/ROCK pathway has been observed in major cardiovascular disorders such as atherosclerosis, restenosis, hypertension, pulmonary hypertension, and cardiac hypertrophy. This review, based on recent molecular, cellular, and animal studies, focuses on the current understanding of ROCK signaling and its roles in cardiovascular physiology and pathophysiology.
Abstract 11387: Examining Mortality Based on Changes in Peak Oxygen Consumption After Cardiac Rehabilitation
Authors: Sergey Kachur, Alban De Schutter, Carl Lavie, Eiman Jahangir, Homeyar Dinshaw, Richard Milani
Journal: Circulation (2016)

Introduction: Cardiac rehabilitation (CR) in stable coronary heart disease (CHD) has been shown to improve mortality commensurate with levels of improvement in cardiorespiratory fitness (CRF). We examine here if relative improvement is as important as absolute improvement on mortality. Hypothesis: We assessed the hypothesis that effects of absolute and relative changes in fitness, on mortality in a cardiac rehab population are different. Methods: 890 subjects with stable CHD referred for CR were stratified according to baseline peak oxygen consumption (VO2) and post-CR improvement in VO2 (absolute group divided at 2.5 cc/kg/min, relative group divided at 20%) as measured during maximal cardiopulmonary exercise testing. Results: After adjusting for age, gender, left ventricular ejection fraction, baseline VO2, and body mass index, participants with higher absolute improvement had a twofold lower mortality (HR 0.56, p&lt;0.001), whereas high relative improvement had no significant mortality effect. When post-rehab VO2 was used as a covariate, VO2 improvement was no longer associated with changes in mortality (HR 0.82, p = 0.37). High relative improvement without high absolute improvement was independently associated with increased mortality (HR 2.63, p&lt;0.001, Figure 1) and lower baseline fitness (p &lt; 0.001) than groups with high absolute improvement. Conclusions: In patients with CHD, absolute fitness after CR is the primary modulator of mortality, high absolute changes appear to be related to mortality benefits within the scope of increasing post-CR absolute CRF. This explains why high relative changes without associated absolute improvement reflects an especially low baseline CRF and high associated mortality. These results indicate that setting absolute targets for exercise capacity during CR can improve outcomes.
1α,25-Dihydroxyvitamin D3 and Its Potent Synthetic Analogs Downregulate Tissue Factor and Upregulate Thrombomodulin Expression in Monocytic Cells, Counteracting the Effects of Tumor Necrosis Factor and Oxidized LDL
Authors: MaiOhsawa, TakatoshiKoyama, KeikoYamamoto, ShinsakuHirosawa, SachikoKamei, RyuichiKamiyama
Journal: Circulation (2000)

Background—We have recently found that a hormonally active form of vitamin D, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], exerts anticoagulant effects by upregulating the expression of an anticoagulant glycoprotein, thrombomodulin (TM), and downregulating the expression of a critical coagulation factor, tissue factor (TF), in monocytic cells including human peripheral monocytes. In this study, we investigated the counteracting effects of 1,25(OH)2D3 and its potent analogs on TF induction and TM downregulation by tumor necrosis factor and oxidized LDL in monocytic cells and the modulatory effects of potent analogs on TF and TM expression. Methods and Results—Effects of 1,25(OH)2D3 and its potent synthetic analogs (22R)-22-methyl-20-epi-1,25(OH)2D3 (KY3) and 22-oxacalcitriol on TF and TM antigen levels, cell surface activities, and mRNA levels in monocytic cells were examined. 1,25(OH)2D3 and its potent analogs showed anticoagulant effects in monocytic cells by downregulating TF and upregulating TM expression,...