tbuckley/cabot-search huggingface dataset:
Therapeutic modulation of RNA-binding protein Rbm38 facilitates re-endothelialization after arterial injury
Authors: Kristina Sonnenschein, Jan Fiedler, Angelika Pfanne, Annette Just, Saskia Mitzka, Robert Geffers, Andreas Pich, Johann Bauersachs, Thomas Thum
Journal: Cardiovascular Research (2019)

Delayed re-endothelialization after balloon angioplasty in patients with coronary or peripheral artery disease impairs vascular healing and leads to neointimal proliferation. In the present study, we examined the effect of RNA-binding motif protein 38 (Rbm38) during re-endothelialization in a murine model of experimental vascular injury.Left common carotid arteries of C57BL/6 mice were electrically denudated and endothelial regeneration was evaluated. Profiling of RNA-binding proteins revealed dysregulated expression of Rbm38 in the denudated and regenerated areas. We next tested the importance of Rbm38 in human umbilical vein endothelial cells (HUVECS) and analysed its effects on cellular proliferation, migration and apoptosis. Rbm38 silencing in vitro demonstrated important beneficial functional effects on migratory capacity and proliferation of endothelial cells. In vivo, local silencing of Rbm38 also improved re-endothelialization of denuded carotid arteries. Luciferase reporter assay identified miR-98 and let-7f to regulate Rbm38 and the positive proliferative properties of Rbm38 silencing in vitro and in vivo were mimicked by therapeutic overexpression of these miRNAs.The present data identified Rbm38 as an important factor of the regulation of various endothelial cell functions. Local inhibition of Rbm38 as well as overexpression of the upstream regulators miR-98 and let-7f improved endothelial regeneration in vivo and thus may be a novel therapeutic entry point to avoid endothelial damage after balloon angioplasty.
EV-301: Phase III study to evaluate enfortumab vedotin (EV) versus chemotherapy in patients with previously treated locally advanced or metastatic urothelial cancer (la/mUC).
Authors: Daniel Peter Petrylak, Jonathan E. Rosenberg, Ignacio Duran, Yohann Loriot, Guru Sonpavde, Chunzhang Wu, Elaina M Gartner, Amal Melhem-Bertrandt, Thomas Powles
Journal: Journal of Clinical Oncology (2019)

TPS497 Background: Standard first-line treatment for patients (pts) with la/mUC is cisplatin-based chemotherapy or carboplatin-based chemotherapy for pts unfit for cisplatin. Immune checkpoint inhibitors (CPIs) are standard treatment options for pts who progressed during or after platinum-based chemotherapy. While some pts with la/mUC achieve durable responses with CPIs, less than 25% of pts respond. Following failure of a CPI, no therapies are approved. Enfortumab vedotin is a fully humanized monoclonal antibody that delivers the microtubule-disrupting agent monomethyl auristatin E to tumors expressing Nectin-4, which is expressed in 97% of mUC pt samples (Petrylak et al. ASCO, 2017). In a phase 1 study (EV-101; NCT02091999), single-agent EV 1.25 mg/kg was generally well tolerated and demonstrated a confirmed objective response rate (ORR) of 42% across the overall population of pts with mUC; in pts with prior CPI therapy or liver metastasis at baseline confirmed ORRs of 42% and 36% were observed. A pivotal phase 2 study of EV in la/mUC pts with prior CPI treatment (EV-201; NCT03219333) is ongoing. Methods: EV-301 is a global, multicenter, open-label phase 3 trial (NCT03474107) enrolling adult pts with la/mUC and an ECOG performance status score ≤1, who have received a prior platinum-containing chemotherapy, and have experienced disease progression during or following treatment with a CPI. Approximately 550 pts will be randomized (1:1) to receive EV (1.25 mg/kg) administered by IV infusion over approximately 30 minutes on Days 1, 8, and 15 of each 28-day cycle ( Arm A), or investigator choice of IV docetaxel, paclitaxel, or vinflunine (EU only) on Day 1 of each 21-day cycle ( Arm B). Treatment with the study drug will continue until radiological disease progression, intolerance, or other discontinuation criterion is met. Radiological assessments of tumor response status will be performed at baseline and every 8 weeks. The primary endpoint is overall survival; secondary endpoints include progression-free survival, duration of response, and overall response rate, as well as assessment of safety/tolerability, and quality-of-life parameters. Clinical trial information: NCT02091999.
Serlopitant reduced pruritus in patients with prurigo nodularis in a phase 2, randomized, placebo-controlled trial
Authors: Sonja Ständer, Paul Kwon, Joe Hirman, Andrew J. Perlman, Elke Weisshaar, Martin Metz, Thomas A. Luger
Journal: Journal of the American Academy of Dermatology (2019)

BackgroundAnecdotal evidence suggests that neurokinin 1 receptor antagonism reduces pruritus intensity in chronic pruritic conditions such as prurigo nodularis (PN).ObjectiveThis study assessed safety and efficacy of the neurokinin 1 receptor antagonist serlopitant for treatment of pruritus in PN.MethodsIn this randomized, double-blind, placebo-controlled study, 128 patients with chronic, treatment-refractory PN for more than 6 weeks received serlopitant, 5 mg, or placebo orally once daily for 8 weeks. The primary end point was change in average itch visual analog scale score at weeks 4 and 8.ResultsAverage itch visual analog scale scores significantly improved with serlopitant versus with placebo at weeks 4 and 8: the least squares mean difference (serlopitant minus placebo) was −1.0 at week 4 (P = .02) and −1.7 at week 8 (P < .001). The least squares mean difference between serlopitant and placebo reached statistical significance at week 2 (−0.9 [P = .011]). The most frequently reported treatment-emergent adverse events in the serlopitant group were nasopharyngitis, diarrhea, and fatigue.LimitationsThe 8-week duration may be insufficient to assess clinically relevant resolution of PN lesions.ConclusionsSerlopitant reduced pruritus in patients with treatment-refractory PN and was well tolerated. Anecdotal evidence suggests that neurokinin 1 receptor antagonism reduces pruritus intensity in chronic pruritic conditions such as prurigo nodularis (PN). This study assessed safety and efficacy of the neurokinin 1 receptor antagonist serlopitant for treatment of pruritus in PN. In this randomized, double-blind, placebo-controlled study, 128 patients with chronic, treatment-refractory PN for more than 6 weeks received serlopitant, 5 mg, or placebo orally once daily for 8 weeks. The primary end point was change in average itch visual analog scale score at weeks 4 and 8. Average itch visual analog scale scores significantly improved with serlopitant versus with placebo at weeks 4 and 8: the least squares mean difference (serlopitant minus placebo) was −1.0 at week 4 (P = .02) and −1.7 at week 8 (P < .001). The least squares mean difference between serlopitant and placebo reached statistical significance at week 2 (−0.9 [P = .011]). The most frequently reported treatment-emergent adverse events in the serlopitant group were nasopharyngitis, diarrhea, and fatigue. The 8-week duration may be insufficient to assess clinically relevant resolution of PN lesions. Serlopitant reduced pruritus in patients with treatment-refractory PN and was well tolerated.
Frequency of <i>BRCA1/2</i> and <i>PTEN</i> Alterations Identified by Clinical Next Generation Sequencing.
Authors: Naomi Yoo, Jonathan Heusel, Andrew J Bredemeyer, Chad Storer, Catherine E Cottrell
Journal: Journal of Clinical Oncology (2015)

e12550 Background: Germline alterations in BRCA1/2 result in deficiency of the homologous recombination repair pathway, which confers susceptibility to specific therapies including inhibitors of poly ADP ribose polymerase (PARPi). Somatic molecular defects in genes associated with DNA repair, including BRCA1/2 and PTEN, may identify a larger proportion of sporadic cancers susceptible to similar treatments and with a similar phenotype designated “BRCAness.” Notably, some evidence shows concomitant loss of PTEN and BRCA1 may reduce sensitivity to PARPi; therefore determination of mutation status across multiple genes is of interest. We evaluated the prevalence of BRCA1/2 and PTEN mutations in all tumors submitted for clinical next generation sequencing (NGS) over 29 months. Methods: DNA was extracted from tumor-involved tissue. Target enrichment was performed using in-solution cRNA capture for coding gene regions. Paired-end sequencing was performed with on-target depth of ~1000x. Sequence variants were called using GATK v1.2. Assay specificity and sensitivity to detect single nucleotide variants (SNV) in coding regions were 99.6% and ~100.0%. BRCA1/2 and PTEN SNV and indels were filtered for non-synonymous variants not commonly observed as germline SNPs. Variants were categorized by a 5-tier system using publically available and proprietary databases. Results: After filtering, analysis revealed 199 variants within 866 clinical cases, of which 154 were non-recurrent in the dataset. The highest prevalence of non-recurrent variants was identified in skin, endocrine, and gynecologic tumors. Sixty-five pathogenic (P) or likely pathogenic (LP) variants were identified in 61 cases, and were most frequently identified in lung (12), gynecologic (11) and GI-luminal (10) samples. Three cases had a P/LP or variant of uncertain significance in both BRCA1 and PTEN. Truncating mutations were more frequent in PTEN vs BRCA1/2. Conclusions: BRCA1/2 and PTEN variants were common across many tumor types, including P/LP variants in approximately 7% of cases and may be targeted for PARPi. Only 3 cases (0.3%) had potentially significant variants in both PTEN and BRCA1.
Effect of Neprilysin Inhibition on Various Natriuretic Peptide Assays
Authors: Nasrien E. Ibrahim, Cian P. McCarthy, Shreya Shrestha, Hanna K. Gaggin, Renata Mukai, Jackie Szymonifka, Fred S. Apple, John C. Burnett, Seethalakshmi Iyer, James L. Januzzi
Journal: Journal of the American College of Cardiology (2019)
Phase I/II study of tecemotide cancer immunotherapy for Japanese patients with unresectable stage III non-small cell lung cancer (NSCLC).
Authors: Hiroshi Nokihara, Nobuyuki Katakami, Toyoaki Hida, Fumio Imamura, Hiroshi Sakai, Shinji Atagi, Makoto Nishio, Christoph Helwig, Hiroyuki Achiwa, Tomohide Tamura
Journal: Journal of Clinical Oncology (2015)

3036 Background: Tecemotide is a MUC1 antigen-specific cancer immunotherapy. We report results from a phase I/II study of tecemotide in Japanese patients (pts) with no disease progression (PD) after primary chemoradiotherapy (CRT) for stage III NSCLC. Methods: The phase II part of the study evaluated efficacy using the treatment schedule and dose confirmed in the phase I part. Eligible pts had unresectable stage III NSCLC with no PD after CRT (platinum-based chemotherapy and ≥ 50 Gy radiotherapy). In the phase II part, pts were randomized (2:1, double-blind) to tecemotide (930ug lipopeptide) or placebo (PBO) via subcutaneous administration weekly x8 then q6 weeks until PD or withdrawal. Cyclophosphamide 300–600mg/m2 x1 or saline was given 3 days before first tecemotide or PBO dose, respectively. The primary endpoint was overall survival (OS). Results: A total of 172 pts were enrolled in the phase II part from Feb 2010 to Feb 2012, with 114 randomized to tecemotide and 58 to PBO. In the ITT population, baseline characteristics were well balanced between both arms. The majority (94%) of pts received concurrent CRT. Median OS was 32.4 vs 32.2 months with tecemotide vs PBO (HR 0.95, 95% CI 0.61–1.48, p = 0.828). Secondary endpoints were progression-free survival: 11.6 vs 8.0 months (HR 0.95, 95% CI 0.66–1.37, p = 0.773); time to progression: 11.3 vs 7.0 months (HR 0.94, 95% CI 0.65–1.35, p = 0.723); time to treatment failure: 8.0 vs 6.2 months (HR 1.07, 95% CI 0.75–1.54; p = 0.700). A predefined subgroup analysis showed no OS improvement with tecemotide vs PBO in the subgroups examined. Tecemotide was associated with a higher incidence of grade 3/4 adverse events vs PBO, but no new safety concerns were identified. No treatment-related grade 3/4 injection site reactions were detected. Conclusions: In this study, the design of which was comparable to the global phase III START trial, tecemotide maintenance therapy did not improve OS compared with PBO in Japanese patients with stage III NSCLC; in addition, no improvement in secondary endpoints was observed. Tecemotide was well tolerated, with no clinically relevant increase in adverse events. Clinical trial information: NCT00960115.
Abstract P039: Change in Blood Pressure and Glucose Are Major Determinants of Increasing Carotid IMT in Young Adults
Authors: Zhiqian Gao, Lawrance Dolan, Thomas Kimball, Elaine Urbina
Journal: Circulation (2019)

Increased carotid intima-media thickness (cIMT) is associated with CV events in adults and thicker cIMT is found in youth with CV risk factors including obesity. Which risk factors have the most direct effect upon cIMT in youth and whether obesity has direct or indirect effects is not known. We used structural equation modeling to elucidate direct and indirect pathways through which obesity and other risk factors were associated with increase in cIMT. Demographics, anthropometrics, laboratory and carotid ultrasound data were collected on 426 participants aged 17.5 at baseline (32% type 2 diabetes) and after 5 years of follow-up. Latent change score variables were defined by baseline and follow-up measurements. Latent baseline and follow-up cIMT, glucose variables were defined for each cIMT segmemt (common, bulb and internal), HbA1c, and fasting glucose. SAS 9.4 CALIS procedure was used for analyses with maximal likelihood estimation. Comparative fit index (CFI &gt;0.9) and root mean squared error of approximation (RMSEA &lt;0.1) were considered good model fit. At follow up, there were increases in BMI, MAP, LDL, TG, HDL, CRP and fasting glucose, decrease in fasting insulin and HbA1c (all p≤0.05). There was no increase in common, but significant increase in bulb (0.031 mm) and internal (0.027 mm) cIMT (all p ≤0.001). Significant direct effects on changes of cIMT were baseline MAP (β 0.23) and BMI z-score (β 0.16) plus change in glucose (β 0.37) and age (β 0.37; all p≤0.05). Change in MAP showed a trend in the model (β 0.14, p=0.10). BMI also had significant indirect effect (b 0.17) while non-HDL demonstrated no significant effect. We conclude that baseline adiposity drives increasing BP and glucose in high risk youth leading to accelerated accumulation of carotid atherosclerosis. Prevention of acquisition of obesity is critical in slowing development of CV disease. NIH R01 HL105591 (Urbina) and UL1 TR001425.
Characterizing delays in tumor biomarker testing.
Authors: Mihailo Veljovic, Gillian Gresham, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2015)

e17698 Background: Biomarkers are integral to the delivery of personalized cancer care, but the costs and complexities associated with an increasing number of different tests can pose logistical challenges. We aimed to characterize the timeliness of biomarker testing in a population-based cohort as well as determine the potential causes of delays. Methods: We reviewed patients (pts) diagnosed with metastatic colorectal cancer (MCRC) from 2009 to 2013 in British Columbia and who received biomarker-guided therapy. In the MCRC setting, EGFR inhibitors are approved and funded for pts with KRAS wild type tumors after progression on 2 prior lines of therapy. Dates along the biomarker testing trajectory were collected and intervals between key time points were analyzed. Multivariate logistic regression models that adjusted for confounders were constructed to examine for predictors of testing and treatment delays. Results: We identified 268 pts among whom 257 (96%) achieved a successful biomarker test result: median age 60.5 years, 63% men, and 84% ECOG 0-1. In this cohort, 47 (17%) pts underwent testing before progressing on 2 lines of therapy. The median time intervals between test ordered by a physician and receipt of tumor specimen at a test center and between test center and availability of biomarker results were 11.5 (IQR 8-18.5) and 14 (IQR 10-17) days, respectively. From this time point, there was a significant lapse of 83 (IQR 29-147) days prior to pts actually initiating treatment with an EGFR inhibitor. There was no difference in timeliness based on type of agent administered (mean 15 and 20 days for cetuximab and panitumumab, respectively, p = 0.36). In multivariate analyses, testing performed at a non-local or non-cancer center affiliated laboratory was associated with greater likelihood of testing delays of > 2 weeks (p < 0.001) and > 4 weeks (p = 0.012) Conclusions: In this population-based cohort of MCRC pts, the wait for biomarker test results was reasonable although there was wide variation among pts. To minimize impact on management, clinicians appear to request testing significantly earlier than required for treatment decision making. Centralization of all testing can streamline the process and allow physicians to test for biomarkers only when clinically warranted.
Impact of increased visceral fat on colon adenocarcinoma stage.
Authors: Ahmad Mahamid, Itamar Ashkenazi, Abdel-Rauf Zeina, Oded Olsha, Ricardo Alfici
Journal: Journal of Clinical Oncology (2015)

e14510 Background: Both retrospective and prospective studies suggest an association between obesity and the risk of developing colon cancer. Some of these studies also show worse long-term outcome for obese patients. The aim of this study was to examine whether obesity is associated with advanced T and N stage on presentation. Methods: This is a retrospective analysis of patients who underwent surgery for adenocarcinoma of the colon, between 2007 and 2010 in a single medical center. Patients were included if both pathology report and preoperative abdominal CT were available for evaluation. T and N stage retrieved from the pathology report were compared to visceral adipose tissue (VAT) thickness measured by CT. The number of patients in each T and N stage was compared between quartiles of VAT thickness using Fisher exact probability test and chi-square. Results: 104 patients were included in this study. There were 46 males and 58 females. Median age was 71y' (range 38-90y'). The table presents the number of patients in each T and N stage according to quartile. Patients with thicker VAT presented with lower T stage and N stage (TInSitu-2 vs. T3-4, p=0.02; N0 vs. N1-2, p=0.04). Conclusions: The relation between VAT and colon cancer T and N stage in this study does not demonstrate a worse stage at presentation for patients with increased VAT. The detrimental effect of obesity on prognosis does not appear to be related to T and N stage at presentation and other factors should be evaluated. Number of patients 1st Quartile 2nd Quartile 3rd Quartile 4th Quartile TInSitu 1 1 0 1 T1 0 1 2 1 T2 0 2 7 4 T3 22 19 17 18 T4 3 3 0 2 N0 9 15 19 12 N1 9 7 1 10 N2 8 4 6 4 N(neg) 9 15 19 12 N(pos) 17 11 7 14
Abstract MP63: How Much Does Exclusive Breastfeeding to the Recommended Six Months Increase Maternal Postpartum Weight Loss in Healthy Women?
Authors: Muna J Tahir, Jacob L Haapala, Kara M Whitaker, Laurie P Foster, Katy M Duncan, April M Teague, Elyse O Kharbanda, Patricia M McGovern, Tonya C Schoenfuss, Lisa Harnack, David A Fields, David R Jacobs, Ellen W Demerath
Journal: Circulation (2019)

Objective: Postpartum weight retention increases the risk of future obesity and cardiovascular disease. Although exclusive breastfeeding (EBF) has been promoted as an effective means to lose gestational weight gain, previous studies report mixed findings for the relationship between duration of EBF and maternal postpartum weight loss (PPWL). This study evaluates whether meeting the recommended 6-months of EBF is associated with greater PPWL by 6-months than a shorter duration of EBF. Methods: The Mothers and Infants LinKed for Health (MILK) study is an ongoing prospective cohort of non-diabetic, non-smoking mother-infant dyads, all of whom were exclusively breastfeeding at 1-month postpartum. Breastfeeding exclusivity was subsequently self-reported by mothers at 3 and 6-months postpartum. Maternal pre-pregnancy weight and weight at delivery were abstracted from medical records. PPWL was calculated as maternal weight measured at 1, 3 and 6-months minus maternal weight at delivery. Mixed effects linear regression models were used to test the association of duration of EBF with repeated measures of PPWL after adjustment for covariates including maternal pre-pregnancy weight, gestational weight gain, parity, physical activity and infant sex. Results: Among 315 mothers who were exclusively breastfeeding at 1-month, 93% and 75% continued EBF to 3 and 6-months, respectively. By 6-months postpartum, weight loss (least square means ± standard error) was -8.55 ± 1.31 kg among EBF to 1-month, -10.60 ± 0.82 kg among EBF to 3-months and -11.73 ± 0.37 kg among EBF to 6-months (Figure). EBF to 6-months was associated with greater PPWL by 6-months postpartum than EBF to 1 or 3-months (p&lt;0.05) after covariate adjustment. Conclusion: EBF to 6-months postpartum was associated with greater maternal PPWL than shorter EBF durations. Interventions may promote prolonged EBF as a means of increasing maternal weight loss by 6-months postpartum, but additional research is needed to explore whether these differences persist after weaning.
Abstract P277: Short Sleep Duration is Associated With Greater Arterial Stiffness Independent of Sleep Quality
Authors: Christopher E Kline, Christy Taylor, Andrea M Kriska, Emma Barinas-Mitchell
Journal: Circulation (2019)

Introduction: Sleep duration is commonly associated with cardiovascular disease risk. Surprisingly, though, relatively few studies have examined the association between sleep duration and arterial stiffness, an early marker of cardiovascular risk. The available evidence remains equivocal, and few studies have examined whether sleep quality confounds the association between sleep duration and arterial stiffness. Purpose: The purpose of these analyses was to examine the association between sleep duration, sleep quality, and arterial stiffness in a sample of young- and middle-aged adults. Methods: The present analyses utilized baseline data from a sample of adults enrolled in a lifestyle intervention (N=324; 37.8±6.2 y, body mass index [BMI]: 32.8±3.9 kg/m 2 , resting systolic blood pressure [SBP]: 113.5±10.4 mmHg, 77.2% female, 80.6% white). Sleep was assessed with the Pittsburgh Sleep Quality Index (PSQI); sleep duration and sleep quality were each assessed with single PSQI items; duration was classified into three categories (&lt; 6 h, ≥ 6 to &lt; 7 h, ≥ 7 h) and quality was dichotomized into good (very good/fairly good) and poor (very bad/fairly bad). Risk for sleep apnea was assessed with the Berlin Questionnaire. Arterial stiffness was assessed with carotid-femoral pulse wave velocity; values were log-transformed prior to analysis. Analysis of covariance models were used to examine the associations between sleep duration and quality with arterial stiffness. All models adjusted for age, sex, race, BMI, SBP, and sleep apnea risk. Results: Approximately 13%, 34%, and 53% of participants reported &lt; 6 h, ≥ 6 but &lt; 7 h, or ≥ 7 h sleep duration, respectively; 18% of participants reported poor sleep quality. Arterial stiffness significantly differed across categories of sleep duration (η p 2 =.02; P=.03); adults reporting &lt; 6 h sleep duration had significantly greater arterial stiffness than adults reporting either ≥ 6 but &lt; 7 h (P=.02) or ≥ 7 h (P=.01). In contrast, arterial stiffness did not differ according to sleep quality (η p 2 =.00; P=.75). When included in the same model, sleep duration remained a significant predictor of arterial stiffness (η p 2 =.02; P=.03), while sleep quality remained nonsignificant (η p 2 =.00; P=.66). Conclusion: In a sample of young- to middle-aged adults with overweight or obesity, short sleep duration was associated with greater arterial stiffness independently of sleep quality. Whether increasing sleep duration can improve arterial stiffness deserves further exploration.