tbuckley/cabot-search huggingface dataset:
Proteomic analysis of proteome and histone post-translational modifications in heat shock protein 90 inhibition-mediated bladder cancer therapeutics.
Authors: Qingdi Quentin Li, Thomas Sanford, Spencer Krane, Kai Hans Hammerich, Jane B Trepel, Len Neckers, Piyush K. Agarwal
Journal: Journal of Clinical Oncology (2017)

e16030 Background: Heat shock protein 90 (HSP90) is a chaperone for many proteins integral development of cancer, making inhibition of HSP90 an attractive strategy for cancer treatment. However, little is known about HSP90 inhibition-mediated bladder cancer therapy. Here, we present a quantitative proteomic study that evaluates alterations in protein expression and histone post-translational modifications (PTMs) in bladder cancer in response to HSP90 inhibition. Methods: We assessed the antitumor activity of five HSP90 inhibitors in 5637 bladder cancer cell line using MTS, cell viability, and caspase 3/7 assays. We then performed a proteomic analysis of cells before and after treatment with the HSP90 inhibitors and assessed for changes. Results: We show that the five HSP90 inhibitors (AUY922, ganetespib, SNX2112, AT13387, and CUDC305) potently inhibited the proliferation of bladder cancer 5637 cells. HSP90 inhibitors also had differential effects on cell survival between bladder cancer cells and uroepithelial cells. Our proteomic study quantified 518 twofold up-regulated and 811 twofold downregulated proteins common to both AUY922 and ganetespib treatment (P &lt; 0.05). The subsequent bioinformatic analysis revealed that those differentially expressed proteins were involved in chromatin modifications and cell death-associated pathways. Further, quantitative proteome studies identified 14 different types of PTMs with 93 marks on the core histones, including 34 novel histone marks of butyrylation, citrullination, 2-hydroxyisobutyrylation, propionylation, and succinylation in AUY922- and ganetespib-treated 5637 cells, suggesting that HSP90 inhibitors may exert multiple cytotoxic actions in bladder cancer cells by inhibiting HSP90 activity or altering the structure of chromatin. Conclusions: This study outlines the association between proteomic changes and histone PTMs in response to HSP90 inhibitor treatment in bladder cancer cells, and supports the notion that HSP90 inhibitors both as single agents and in combination might provide new therapeutic options for bladder cancer treatment and thus warrant further preclinical exploration.
Abstract 14521: Biochemical Risk Markers and 10-Year Incidence of ASCVD - Independent Predictors, Improvement in Pooled Cohort Equation, and Risk Reclassification
Authors: Emmanuel Akintoye, Alexandros Briasoulis, Luis Afonso
Journal: Circulation (2016)

Background: Given the notable drawbacks of the pooled cohort equation (PCE), the risk assessment working group (RAWG) of the ACC/AHA had specifically called for further research to identify novel risk markers that could improve the predictive ability of the PCE. We therefore explored the ability of biochemical risk markers in predicting 10-year risk of ASCVD as well as additional benefit of adding these markers to the PCE Methods: We explored this clinically important question using the prospectively collected database of the Multi-ethnic Study of Atherosclerosis (MESA) that include subjects free of ASCVD at baseline and followed for more than 10 years. Cox proportional hazard model was used to evaluate the association between each biomarker and incidence of ASCVD. Additional benefit of each biomarker was explored using C-statistic, net reclassification index and integrated discrimination index Results: Based on the principle used in the development of PCE, adults with age up to 79 years who had baseline ...
Prediction of post-operative residual disease in advanced-stage ovarian cancer (AOC) using whole transcriptome expression: An exploratory analysis of the AGO-OVAR 11 (ICON7) trial.
Authors: Florian Heitz, Stefan Kommoss, Boris J. N. Winterhoff, Constantin Aliferis, Alexander Burges, Chen Wang, Ulrich Canzler, Jinhua Wang, Antje Kristina Belau, Lars Christian Hanker, Sisi Ma, Felix Hilpert, Jalid Sehouli, Roshan Tourani, Rainer Kimmig, Christian Kurzeder, Barbara Schmalfeldt, Sean Christopher Dowdy, Andreas Du Bois, Jacobus Pfisterer
Journal: Journal of Clinical Oncology (2018)

5550 Background: Complete resection (CR) at primary debulking surgery is the single most important prognostic factor in AOC. It has been demonstrated, that suboptimal debulking (residual disease > 1cm) might be associated with TCGA molecular subtypes and de novo generated gene expression (GE) signatures. The aim of this study was to validate previous findings and to investigate the impact whole transcriptome GE analyses might have on postoperative residual tumor prediction in a phase III ovarian cancer frontline trial. Methods: Core biopsies from formalin fixed paraffin embedded tumor tissue of FIGO stage IIIC/IV AGO-OVAR 11/ICON7 pts were used to generate whole-genome DASL GE data. TCGA molecular subtype and two previously published GE debulking signatures (7 genes and 11 genes) were correlated with size of residual disease (CR vs. any residual disease). Logistic Regression (LR), support vector machine with polynomial kernel, and random forest were used as classifiers. We built models with all GE features as well as gene selected with HITON-PC, a method that select the markov blanket of the outcome. Results: 283 pts met inclusion criteria, of those 114 (40.3%) had complete resection. Previous reported debulking signatures using 7 and 11 genes respectively did not predict residual disease in this cohort. Best Area under the Curve (AUC) for 7 gene signature was generated using LR 0.50 ± 0.05, while 11 gene signature had an AUC of 0.53 ± 0.04. Similarly, TCGA molecular subtypes (AUC = 0.56 ± 0.04), an independent de novo developed signature (AUC = 0.51 ± 0.04) and the total gene expression data set using all 21,000 genes (AUC = 0.55 ± 0.03) were not able to predict residual disease status. Conclusions: In contrast to previous findings, we were not able to predict residual disease using GE in tumor samples from the AGO-OVAR11/ICON7 phase III trial. A standardized radical surgical approach resulting in a higher frequency of complete resection might allow detection of biologic factors responsible for sub-optimal debulking. The ongoing AGO-OVAR TRUST trial might be able to address this important clinical question.
Diverse model systems reveal common principles of meiosis
Authors: Weronika E. Borek, Adele L. Marston
Journal: Genome biology (2018)

A meeting report on the 14th Gordon Research Conference on Meiosis, held at Colby Sawyer College, New London, NH, USA, 9–15 June 2018, chaired by Monica Colaiacovo, Harvard Medical School.
Addition of a polygenic risk score, mammographic density, and endogenous hormones to existing breast cancer risk prediction models: A nested case–control study
Authors: Xuehong Zhang, Megan Rice, Shelley S. Tworoger, Bernard A. Rosner, A. Heather Eliassen, Rulla M. Tamimi, Amit D. Joshi, Sara Lindstrom, Jing Qian, Graham A. Colditz, Walter C. Willett, Peter Kraft, Susan E. Hankinson
Journal: PLoS Medicine (2018)

Background No prior study to our knowledge has examined the joint contribution of a polygenic risk score (PRS), mammographic density (MD), and postmenopausal endogenous hormone levels—all well-confirmed risk factors for invasive breast cancer—to existing breast cancer risk prediction models. Methods and findings We conducted a nested case–control study within the prospective Nurses' Health Study and Nurses' Health Study II including 4,006 cases and 7,874 controls ages 34–70 years up to 1 June 2010. We added a breast cancer PRS using 67 single nucleotide polymorphisms, MD, and circulating testosterone, estrone sulfate, and prolactin levels to existing risk models. We calculated area under the curve (AUC), controlling for age and stratified by menopausal status, for the 5-year absolute risk of invasive breast cancer. We estimated the population distribution of 5-year predicted risks for models with and without biomarkers. For the Gail model, the AUC improved (p-values < 0.001) from 55.9 to 64.1 (8.2 units) in premenopausal women (Gail + PRS + MD), from 55.5 to 66.0 (10.5 units) in postmenopausal women not using hormone therapy (HT) (Gail + PRS + MD + all hormones), and from 58.0 to 64.9 (6.9 units) in postmenopausal women using HT (Gail + PRS + MD + prolactin). For the Rosner–Colditz model, the corresponding AUCs improved (p-values < 0.001) by 5.7, 6.2, and 6.5 units. For estrogen-receptor-positive tumors, among postmenopausal women not using HT, the AUCs improved (p-values < 0.001) by 14.3 units for the Gail model and 7.3 units for the Rosner–Colditz model. Additionally, the percentage of 50-year-old women predicted to be at more than twice 5-year average risk (≥2.27%) was 0.2% for the Gail model alone and 6.6% for the Gail + PRS + MD + all hormones model. Limitations of our study included the limited racial/ethnic diversity of our cohort, and that general population exposure distributions were unavailable for some risk factors. Conclusions In this study, the addition of PRS, MD, and endogenous hormones substantially improved existing breast cancer risk prediction models. Further studies will be needed to confirm these findings and to determine whether improved risk prediction models have practical value in identifying women at higher risk who would most benefit from chemoprevention, screening, and other risk-reducing strategies.
Immune profiling in a randomized phase II trial of acalabrutinib and pembrolizumab (PA) versus pembrolizumab (P) for patients with metastatic urothelial cancer (mUC).
Authors: Tian Zhang, Janet S. Staats, Cliburn Chan, Michael Roger Harrison, Peter H. O'Donnell, Kristen A Batich, Tianling Chen, Cecile Krejsa, Raquel Izumi, Daniel J. George, Kent J. Weinhold
Journal: Journal of Clinical Oncology (2018)

4533 Background: Response rates for checkpoint inhibitors (CPIs) in cisplatin refractory mUC range from 15% to 21%. Thus, biomarkers are needed to predict for treatment responses. We conducted a Ph2 clinical trial in patients with mUC, randomized to P or PA (NCT02351739). From this trial, we performed the first correlation analysis of circulating immune cells with clinical outcomes in mUC patients receiving CPI therapy. Methods: 75 patients with cisplatin refractory mUC were treated with P or PA. Pre- and on-study flow cytometry was performed on peripheral blood mononuclear cells for these markers: CD3, CD4, CD8, PD-1, PD-L1, PD-L2, B7-H3, CTLA-4, ICOS, LAG3, TIM3, Ki-67, CD45RA, CCR7, CD38, CD14, HLA-DR, CD16/CD56, CD19/CD20, CD25, CD127, CD39, and CCR4. Single and selected double marker positivity was analyzed on CD4 and CD8 T-cells and monocytes (M). Mean (± SD) of relative cell subset frequency (RCSF) was calculated and associated with clinical responses (best radiographic response as defined per RECIST 1.1 criteria). Unadjusted p-values were derived from Kruskal-Wallis testing, with responses as outcomes and RCSF or delta RCSF as correlatives. Results: Clinical responses (PR+CR) did not differ between treatments (P = 25% vs. PA = 20%); therefore, pooled results from all treated patients were used for analysis. Baseline RCSF (n = 57) or changes in RCSF from baseline to week 4 (n = 51) were correlated with responses. Patients who had CR had lower expression of LAG3, PDL2, CTLA4 and B7H3 on M at baseline. Among T-cells, lower levels of CTLA4+, PD1+, and ICOS+ CD4 T-cells; and higher CD28-/TIM3- CD8 cells were also associated with CR. Changes from baseline to week 4 were observed for actively proliferating CD4 or CD8 T-cells, CD8 T-cells that co-express TIM3 with CD28 or PD-1, and for TIM3-expressing M subsets, suggesting that early increases in immune cell activation (Ki-67, CD28, PD-1) and interferon response (TIM3) are associated with clinical responses. Conclusions: Immune profiling in patients with mUC showed activation and interferon response markers on subsets of T-cells and monocytes that were associated with treatment responses to CPI therapy.
TCT-347 Culprit Lesion Types and Vascular Healing in Patients with ST-segment Elevation Myocardial Infarction after Primary Percutaneous Intervention
Authors: Kirstine Hansen, Lisbeth Antonsen, Akiko Maehara, Michael Maeng, Julia Ellert, Ole Ahlehoff, Karsten Veien, Troels Thim, Evald Christiansen, Lisette Okkels Jensen
Journal: Journal of the American College of Cardiology (2018)
Abstract 13135: Association of Three-Dimensional Tricuspid Valve Deformation With Functional Tricuspid Regurgitation
Authors: Keiko Ryo, Hidekazu Tanaka, Kumiko Dokuni, Yutaka Hatani, Hiroki Matsuzoe, Keiko Hatazawa, Hiroyuki Shimoura, Hiroyuki Sano, Takuma Sawa, Yasuhide Mochizuki, Yoshiki Motoji, Kazuhiro Tatsumi, Kensuke Matsumoto, Ken-ichi Hirata
Journal: Circulation (2015)

Introduction: Background: Functional tricuspid regurgitation (FTR) is widely recognized as being associated with poor outcomes in patients with various cardiac diseases, and the tricuspid valve (TV) deformation is an important mechanism of FTR. However, the precise assessment of TV deformation by means of two-dimensional echocardiography is limited. Purpose: The purpose of this study was thus to investigate the association of TV deformation with FTR by using three-dimensional transthoracic echocardiography (3D-TTE). Methods: We studied 65 patients with FTR. Their mean age was 60±16 years and 36 patients (55%) were female. FTR was quantified by the ratio of the jet area and corresponding RA area, and more than moderate FTR was defined as significant. 3D-TTE was performed to analyze the tricuspid deformation. Tricuspid tenting height and area were analyzed at the time of maximal systolic closure. TV area index, anterior-posterior (A-P) and septal-lateral (S-L) TV annular diameters were analyzed at end-diastole. Right ventricular longitudinal length, end-diastolic and end-systolic area index (EDAI, ESAI) and right atrial area index (RAA) were also obtained from 3D data set. Results: Twenty-one patients were classified as having significant FTR. Tenting height (6.5±3.1 vs. 4.0±1.8 mm, p&lt;0.001), tenting area (1.3±0.8 vs. 0.7±0.4 cm2, p=0.003), TV area (6.9±1.7 vs. 5.0±1.4 cm2/m2, p&lt;0.001) and S-L (35±4 vs. 28±6 mm, p&lt;0.001) in patients with FTR were significantly larger than those in patients with non-significant FTR, but A-L was not (38±6 vs. 36±7mm). After adjusting for age, ESAI, RAA and tenting height, a multivariate logistic regression analysis showed that TV area (odds ratio 3.1, p=0.04) was independently associated with significant FTR. Conclusions: TV-related parameters were associated with FTR, and TV area was the most important factor for FTR. Our findings by means of 3D-TTE may well have clinical implications for better management of patients with FTR.
Fertility issues among Mexican young breast cancer patients and impact of a dedicated program for preservation decisions.
Authors: Cynthia Mayte Villarreal-Garza, Alejandra Platas, Bertha Alejandra Martinez-Cannon, Arnoldo Gil-Moran, Andrea Castro-Sanchez, Pier Anyelo Ramos-Elias, Enrique Bargallo-Rocha, Servando Cardona-Huerta, Karina Tellez, Cristina N. Aguilar, Alejandro Mohar, Ann H. Partridge
Journal: Journal of Clinical Oncology (2016)

e21678 Background: In Latin America there are no previous studies addressing the attitudes of young women with breast cancer (YWBC) regarding infertility risk and associated factors. Also, it is unknown whether patients in the region receive information on the risks of fertility loss and if timely referrals to a fertility specialist occur. The aim of this study was to evaluate the attitudes of YWBC towards the risk of infertility due to systemic treatment in two referral centers in Mexico and to compare the influence of a systematic fertility needs assessment program on preservation decisions. Methods: Patients ≤ 40y at diagnosis that were under follow-up completed an adapted Fertility Issues Survey regarding fertility concerns at the time of diagnosis. Bivariate and multivariate modeling was used to identify predictors of fertility concern in the follow-up group. In a second cohort, all newly diagnosed YWBC were asked about their interest in future pregnancies, systematically informed about fertility preservation (FP) strategies and referred to the fertility specialists as needed.Results: Patients with no children had higher levels of fertility concerns compared with those who had children (88% vs. 11%, OR = 13.5, p < 0.001).Degree of fertility concern was also significantly related with having a partner, children desire and prior difficulty to achieve pregnancy in the bivariate analysis.Conclusions: The impact of a dedicated program for YWBC allows delivering standardized information and support to patients. Informing all patients about infertility risk and available options for FP are essential aspects in the supportive care of YWBC, including low-middle income settings. Since the coverage of FP procedures is currently not covered by our healthcare system and out-of-pocket payment is a limitation for underserved patients, actions should take place to guarantee FP for this vulnerable subgroup. Follow-up patients n = 57 Newly diagnosed patients n = 143 p value % with no prior pregnancies 28 23 0.470 % with fertility concerns 46 Not assessed % received information 32 100 < 0.001 # who pursued FP 0 9 (2 and 3 partial and total costs covered, respectively) 0.062
Effect of prophylactic fentanyl buccal tablet (FBT) on exertional dyspnea in patients with cancer: A pilot double-blind, placebo-controlled, randomized trial.
Authors: David Hui, Kelly L. Kilgore, Susan Frisbee-Hume, Minjeong Park, Diane D Liu, Eduardo Bruera
Journal: Journal of Clinical Oncology (2017)

10085 Background: Exertional dyspnea is one of the most common, debilitating and difficult-to-treat symptoms in cancer patients. Few clinical trials have been conducted. We tested the hypothesis that FBT, a rapid onset opioid, given prophylactically prior to exertion can improve exertional dyspnea. Methods: In this double-blind parallel (1:1) RCT, we asked cancer patients who were opioid-tolerant and had exertional dyspnea to complete a 6 minute walk test (6MWT) at baseline, and then randomly assigned them to either FBT proportional to 20-50% of daily dose or placebo 30 minutes before a second 6MWT. The primary outcome was a validated 11-point dyspnea NRS assessing dyspnea “now” (where 0 = none and 10 = worst possible) every minute during each 6MWT. Secondary outcomes included walk distance, vital signs and neurocognitive testing, adverse effects, and global impression. Ten evaluable patients in the FBT provided 80% power to detect an effect size as small as 1.0 using a two-sided paired t-test with a significance level of 5% to compare the change of dyspnea between the first and second walk tests. We compared the outcomes between the first and second 6MWTs using paired t-test. Results: Among 22 patients enrolled, 20 (91%) completed the study (9 FBT, 11 placebo). FBT was associated with a significant within-arm reduction in dyspnea NRS between 0 and 6 minutes (mean change -2.4, 95% confidence interval [CI] -3.5, -1.3) and respiratory rate (mean change -2.6, 95% CI -4.7, -0.4). Placebo was also associated with a non-statistically significant decrease in dyspnea (mean change -1.1). Between arm comparison of dyspnea scores in the second 6MWT favored FBT, albeit not statistically significant (estimate -0.25, P = 0.068). Global impression revealed more patients in the FBT group than placebo group reporting their dyspnea was at least “somewhat better” in the second 6MWT (4/9 vs. 0/11, P = 0.03). The other secondary outcomes did not differ significantly between arms. Conclusions: These data support our hypothesis that proportionally dosed FBT was associated with improvement in exertional dyspnea, and highlights the need for larger confirmatory trials. Clinical trial information: NCT01856114.
Abstract 19315: Geometry, Reintervention, and Growth Patterns in the Reconstructed Aortic Arch With Interdigitating Technique in Patients With Hypoplastic Left Heart Syndrome and Variants
Authors: Christoph Haller, Devin Chetan, Matthew Doyle, Arezou Saedi, Rachel Parker, Glen Van Arsdell, Osami Honjo
Journal: Circulation (2015)

Objectives: The interdigitating technique in aortic arch reconstruction in hypoplastic left heart syndrome and variants (HLHS) is very effective to minimize the recoarctation rate. Little is known on the aortic arch’s growth characteristics and the resulting clinical impact. Methods: 139 patients with HLHS underwent staged palliation between 2007 and 2014. 72 patients who underwent Norwood arch reconstruction with the interdigitating technique were included. Dimensions of the ascending aorta (AA), transverse arch (TA), isthmus (IA) and descending aorta (DA) in pre-stage II (P1, n=50) and pre-Fontan (P2, n=21) angiograms were measured and geometry and growth characteristics of the aortic arches were analyzed. Correlations between the aortic dimensions and clinical outcomes were assessed. Results: There were significant increases in diameters in all segments between P1 and P2 (p &lt; .0005). The z-scores in AA, TA and IA were unchanged between P1 and P2 (p = .931/.425/.121), but increased significantly in DA at P2 (p = .039). The percent increase in diameters were comparable among 4 segments (mean, 146% in IA, 144 in DA, p=.648). There were correlations in dimensions and z-scores between P1 and P2 in AA (p = .029/.013) and TA (p = .001/ &lt; .0005), but no correlations were found in IA (p = .140/.747) and DA (p = .075/.432). The most significant tapering in the arch dimension occurred between TA and IA in both time points (P1, 67.3% vs. P2, 61.1%, p=.303). The reverse coarctation index (TA/IA ratio) at P1 (r = .381, p = .042), but not coarctation index (CoAI, IA/DA ratio) at P1 (p = .774) had a significant correlation with post-stage II ventricular function. Balloon dilatation for recoarctation was needed in 2 (2.7%) patients prior to stage II palliation. CoAI at P1 was a predictor for ventricular dysfunction at latest follow-up (p=.017). Conclusions: Aortic arch growth after interdigitating reconstruction in HLHS is substantial and relatively constant. The isthmus growth is proportional to other segments. Overall reintervention rate for recoarctation is exceptionally low. CoAI prior to stage II palliation may be associated with long-term ventricular function.
TCT-691 National Trends of Percutaneous Coronary Intervention for the Elderly
Authors: Ayman Elbadawi, Islam Elgendy, Marwan Saad, Karim Mahmoud, Jyotirmayee Lenka, Odunayo Olorunfemi, Gbolahan Ogunbayo
Journal: Journal of the American College of Cardiology (2018)