tbuckley/cabot-search huggingface dataset:
Abstract 17080: The Anesthetized Rat Model of Exercise Faithfully Simulates Respiratory Abnormalities in Chronic Heart Failure
Authors: Akiko Nishizaki, Keita Saku, Tadayoshi Miyamoto, Takuya Kishi, Kenji Sunagawa
Journal: Circulation (2015)

Background: Abnormal respiration during exercise is one of the major manifestations and a powerful predictor of survival in chronic heart failure (CHF). There have not been proposed the appropriate animal model to investigate the mechanism of respiratory abnormalities in CHF during exercise. In this study, we developed an experimental model using anesthetized CHF rats to evaluate exercise-induced abnormal respiration and central chemoreflex control function during exercise in CHF. Methods: We used anesthetized 16 weeks old rats with/without myocardial infarction induced CHF. To mimic exercise, we induced muscle contraction by stimulating bilateral distal sciatic nerves. We recorded the respiratory change in response to sciatic nerve stimulation (SNS) with ramp (5 Hz, 0.01 Volts/sec) and step (5 Hz, 0.5 Volts) protocols. We also evaluated the change of the central chemosensitivity (ventilatory response to partial pressure of carbon dioxide in arterial blood; PaCO2) by CO2 gas inhalation (0, 3 and 5%) during exercise in normal and CHF. Results: In ramp protocol, SNS significantly increased minute ventilation (VE) in CHF to a greater extent than in that of normal (normal 155.2±27.9, CHF 211.2±48.6 mL/min, p&lt;0.01). CHF markedly steepened the VE-carbon dioxide production relationship (VE/VCO2 slope) (normal 26.8±12.7, CHF 38.5±5.9, p&lt;0.05) (Fig. 1). CHF shifted the relationship of tidal volume (TV) to respiratory rate (RR) rightward reflecting the rapid and shallow breathing during exercise (Fig. 2). The SNS-induced upward shift of the VE-PaCO2 line observed in CHF indicated that exercise-related respiratory abnormalities arise from pathophysiological change in the central chemoreflex control (Fig. 3). Conclusion: Anesthetized rat exercise model simulated respiratory abnormalities in CHF reasonably well. It will provide us an opportunity to clarify the physiological mechanisms of exercise-induced abnormal respiration in CHF.
Abstract 17103: SIRT1 in the Cardiomyocyte Counteracts Doxorubicin Cardiotoxicity in vivo
Authors: Miki Tsukamoto, Atsushi Kuno, Ryusuke Hosoda, Rio Sebori, Yoshiyuki Horio
Journal: Circulation (2015)

Background: Cardiotoxicity of doxorubicin (DOX) is mediated through mitochondrial perturbations. SIRT1, an NAD + -dependent deacetylase, has been reported to promote cellular adaptation to metabolic imbalances in part via mitochondrial biogenesis. Hypothesis: SIRT1 in the cardiomyocyte counteracts DOX cardiotoxicity in vivo. Methods: Tamoxifen (Tam)-inducible cardiomyocyte-specific SIRT1 knockout mice (SIRT1 cKO) were used. At 2 months of age, mice received Tam to induce knockout, and mice without Cre recombinase served as wild type (WT). Both groups of mice were treated with DOX (4 IP injections of 5 mg/kg/week) starting at 3 months of age. Echocardiography was performed before and after DOX treatment. Cardiac tissues were sampled after the final DOX injection. H9c2 cardiomyocytes were used for in vitro analysis. Results: At baseline, there were no differences in left ventricular (LV) dimension, thickness, fractional shortening (FS), and ejection fraction (EF) between the groups. DOX significantly reduced FS, EF, and LV thickness in both groups of mice. However, FS and EF after DOX injections were lower in SIRT1 cKO than in WT (FS, 26% vs. 30%; EF, 59% vs. 65%, P&lt;0.05). ANP and BNP mRNA levels were also higher in SIRT1 cKO (2.4-fold and 2.4-fold, respectively, P&lt;0.05), confirming worsening of cardiac function. Compared with WT, SIRT1 cKO showed reduced cardiac mitochondrial content determined by qPCR analysis of mitochondrial DNA level (-16%, P&lt;0.05). Unexpectedly, mRNA levels of nuclear-encoded mitochondria genes (Cox5b, Atp5a1, and citrate synthase) were not altered in the SIRT1 cKO heart, indicating preserved mitochondrial biogenesis in cKO. Instead, mRNA levels of parkin (+43% P&lt;0.05), PINK1 (+18%), and Bnip3 (+40%) were higher in SIRT1 cKO than in WT, suggesting enhanced mitochondrial degradation via mitophagy. Finally, SIRT1 knockdown in H9c2 cells enhanced DOX (10 μM, 24 h)-induced cell death examined by LDH release compared with control cells (13.2±1.4% vs. 8.6±0.7%, P&lt;0.05). Conclusions: The results suggested that SIRT1 in the cardiomyocyte counteracts DOX cardiotoxicity by preserving mitochondrial content in vivo. Enhanced degradation, but not impaired biogenesis, may be involved in mitochondrial depletion in SIRT1 cKO.
A phase II evaluation of nivolumab, a fully human antibody against PD-1, in the treatment of persistent or recurrent cervical cancer.
Authors: Alessandro Santin, Wei Deng, Michael M. Frumovitz, Warner King Huh, Samir Khleif, Heather A. Lankes, Elena Ratner, Roisin O'Cearbhaill, Amir A. Jazaeri, Michael Birrer
Journal: Journal of Clinical Oncology (2018)

5536 Background: Despite current treatments patients with persistent/recurrent cervical cancer (CC) after platinum-based chemotherapy have limited therapeutic options with a median survival limited to only ~7 months. Most of CC are infected with high-risk Human Papillomavirus (HPV) making these tumors potentially highly immunogenic. However, upregulation of the PD-1/PD-L1 pathway on CC or infiltrating immune cells may negatively regulate immunity and contribute to CC progression. We present the results of NRG-GY002, a 2-stage, phase II study with Nivolumab, an anti–PD-1 antibody, in patient with persistent or recurrent CC. Methods: Key eligibility criteria included persistent/recurrent CC, failure of prior systemic therapy and ECOG PS 0-1. Nivolumab 3 mg/kg was given every 2 wk for up to 46 doses over 92 wk or until disease progression, intolerable toxicity, death, or withdrawal of consent. Response was assessed every 8 wk for the first 6 mo and every 12 wk thereafter. The primary end point was objective tumor response by RECIST v1.1. Results: 26 pts with persistent/recurrent CC were enrolled (25 eligible and evaluable for response and toxicity); median age was 45 years old, 36.0% had an ECOG PS of 1, and 100% had received one prior systemic chemotherapy regimen for metastatic disease. As of February 5, 2018, all patients have been off study treatment; median follow-up for vital status was 18.7 months (range, 2 – 28.1). 21 (84%) pts experienced a treatment-related adverse event (TRAE), most of which were grade 1 and 2. Six (24 %) pts had grade 3 TRAEs, 1 of whom discontinued nivolumab (type I diabetes). No grade 5 TRAEs occurred, and grade 4 TRAEs occurred in 2 pts. There was 1 confirmed PR (4%; 90% CI, 0.4%-22.9%), duration of response 3.8 months. The proportion of patients with stable disease (SD) was 36% (9/25; 90% CI, 20.2%-54.4%); the median duration of SD was 5.7 months (range, 3.5-12.7). The estimated PFS and OS at 6 months was 16% and 78.4%, respectively. Conclusions: Single agent nivolumab exhibited low antitumor activity and an acceptable safety profile in pts with persistent or recurrent CC previously treated with platinum-based chemotherapy. (ClinicalTrials.gov NCT #02257528) Clinical trial information: NCT02257528.
Inhibition of Notch1 induces population and suppressive activity of regulatory T cell in inflammatory arthritis
Authors: Bo Youn Choi, Yuri Choi, Jong-Sung Park, Li-Jung Kang, Seung Hyun Baek, Jin Su Park, Gahee Bahn, Yoonsuk Cho, Hark Kyun Kim, Jihoon Han, Jae Hoon Sul, Sang-Ha Baik, Dong Hoon Hyun, Thiruma V Arumugam, Siyoung Yang, Jeung-Whan Han, Young Mo Kang, Yong-Woo Cho, Jae Hyung Park, Dong-Gyu Jo
Journal: Theranostics (2018)

Inhibition of Notch signalling has shown anti-inflammatory properties in vivo and in vitro models of rheumatoid arthritis (RA). The objective of this study was to determine whether Notch1 might play a role in regulating T-regulatory cells (Tregs) in animal models of RA. Methods: Collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) were induced in C57BL/6, Notch1 antisense transgenic (NAS) or DBA1/J mice. We examined whether pharmacological inhibitors of γ-secretase (an enzyme required for Notch1 activation) and antisense-mediated knockdown of Notch1 could attenuate the severity of inflammatory arthritis in CIA and CAIA mice. Proportions of CD4+CD25+Foxp3+ Treg cells were measured by flow cytometry. To assess the suppressive capacity of Treg toward responder cells, CFSE-based suppression assay of Treg was performed. Results: γ-secretase inhibitors and antisense-mediated knockdown of Notch1 reduced the severity of inflammatory arthritis in both CIA and CAIA mice. Pharmacological and genetic inhibition of Notch1 signalling induced significant elevation of Treg cell population in CIA and CAIA mice. We also demonstrated that inhibition of Notch signalling suppressed the progression of inflammatory arthritis through modulating the expansion and suppressive function of regulatory T (Treg) cells. Conclusion: Pharmacological and genetic inhibition of Notch1 signalling suppresses the progression of inflammatory arthritis through modulating the population and suppressive function of Treg cells in animal models of RA.
A randomized, open-label, phase II study of azacitidine (AZA) in combination with durvalumab in patients (pts) with previously untreated higher-risk myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) ineligible for hematopoietic stem cell transplantation (HSCT).
Authors: Lewis R. Silverman, Hartmut Dohner, Herve Dombret, Ghulam J. Mufti, Richard M. Stone, Shelonitda Rose, Torsten Gerike, Frederic Camus, Pierre Fenaux
Journal: Journal of Clinical Oncology (2017)

TPS7074 Background: Hypomethylating agents (HMAs) induce hematologic response in ~ 50% of higher-risk MDS pts; however, there are few treatment options for nonresponding pts at increased risk of AML progression and death. While older AML pts ineligible for HSCT have similar overall survival (OS) with AZA and chemotherapy (13.3 vs 12.2 months) (Döhner et al. Haematologica 2015;100:P566), there is an opportunity to further improve responses and OS in these pts. Blockade of the programmed cell death-1 (PD-1)/PD-ligand 1 (PD-L1) pathway with immune checkpoint inhibitors is an emerging paradigm in anticancer therapy. PD-L1 is expressed on cells from AML and MDS pts; expression is upregulated on myeloblasts following HMA therapy (Yang et al. Leukemia 2014;28:1280) and during MDS transformation to AML (Ogata et al. Leuk Res 2012;36:1229). Durvalumab (MEDI-4736), a human anti-PD-L1 monoclonal antibody, is well tolerated and induces durable responses in pts with solid tumors (Lutzky et al. JCO 2014;32:3001). This randomized, open-label, phase 2 study evaluates efficacy and safety of subcutaneous (SC) AZA ± durvalumab in pts with higher-risk MDS and older pts with AML. Methods: Eligible MDS pts ( &lt; 20% blasts) aged ≥ 18 years, with IPSS intermediate- or high-risk MDS, and AML pts (≥ 20% blasts) aged ≥ 65 years, are randomized 1:1 to receive either AZA 75 mg/m 2 SC for 7/28 days or AZA 75 mg/m 2 SC for 7/28 days plus durvalumab 1500 mg IV on day 1 of 28-day cycles. Pts are stratified by cytogenetic risk: intermediate- vs poor-risk AML, and intermediate- vs poor-/very-poor-risk MDS. Primary endpoint is overall response rate per IWG 2006 criteria in MDS pts, and proportion of pts achieving complete response (CR) or CR with incomplete blood count recovery (CRi) per modified IWG 2003 criteria in AML pts. Other endpoints include safety, time to response, overall survival and PD-1/PD-L1 activity. Pts will be followed every 3 months until discontinuation. Target enrollment is 182 pts: 72 MDS pts and 110 AML pts. Enrollment began in June 2016 (ClinicalTrials.gov NCT02775903).
Socioeconomic disparities in inflammatory response on cancer mortality using national health and nutrition examination survey.
Authors: Daniel Stuart Kapp, Joshua Chan, Amandeep Mann
Journal: Journal of Clinical Oncology (2018)

e13574 Background: The role of inflammation in cancer mortality has received considerable attention. Studies have also shown an association socioeconomic inequality and inflammatory response. We propose to determine the role association of socioeconomic status and inflammatory response in cancer patients. Methods: Data were extracted from the US National Health and Nutrition Examination Survey on all cancer patients from 1999-2002. Chi-squared, Multivariable Cox regression, and Kaplan-Meier estimates were employed for statistical analyses. Results: Of 432 patients (median age: 69 years), 88% were white and the remainder black. Low, middle, and upper socioeconomic status (SES) were represented in 33%, 41%, and 26%, respectively. The most common cancers were skin (20%), prostate (18%), and breast (13%). Lower SES patients were older (45.2% vs 42.8% vs 12.0%; p < 0.001), more likely to be black (41.2% vs. 43.7% vs. 15.0%; p < 0.001) and have a higher BMI (37.8% vs 28.6% vs 32.3%, p < 0.001) compared to middle and upper SES. Using C-reactive protein (CRP) (median:0.27 mg/dL) and fibrinogen (median: 374 mg/dL) as inflammatory biomarkers, those at lower SES had higher CRP and fibrinogen levels compare to middle and upper SES(CRP: 59.5% vs 52.4% vs 42.1%, p < 0.001; fibrinogen: 54.2% vs 51.7% vs 44.6%, p < 0.001). Additionally, high CRP level and fibrinogen was associated with older age, whites, females, and overweight and obese patients. On a multivariate analysis, high CRP (HR = 1.11, 95%CI:1.03-1.04; p < 0.001) and high fibrinogen (HR = 1.73, 95%CI:1.72-1.74, p < 0.001) were independent predictors for poorer survival. In addition, older age (HR = 1.03, 95%CI:2.62-2.67; p < 0.001), blacks (HR = 1.86, 95%CI: 1.98-2.01; p < 0.001), lower SES patients (HR: 3.27, 95%CI: 3.24-3.29, p < 0.001), and overweight (HR: 1.04, 95%CI: 1.02-1.05, p < 0.001) had a poorer survival. Conclusions: Our data suggest that the inflammatory biomarkers, C-reactive protein and fibrinogen, are associated with older age, black race, lower SES, and overweight and obese patients. Furthermore, high C-reactive protein and fibrinogen are an independent predictor for poorer cancer survival.
Circulating tumor DNA clone analysis to predict disease progression/indicates trastuzumab-resistant mechanism in advanced gastric cancer.
Authors: Yan Wang, Lianpeng Chang, Yu-Bo Jiang, Ru Jia, Rongrong Chen, Jin Li, Xuefeng Xia, Yan-Fang Guan, Rongrui Liu, Chuanhua Zhao, Yun Zhang, Xin Yi, Jian-Ming Xu
Journal: Journal of Clinical Oncology (2018)

e24030 Background: Circulating tumor DNA (ctDNA) detection could improve the accuracy of imaging methods for evaluating therapy efficacy in advanced gastric cancer (AGC). However, the feasibility of ctDNA analysis based on single genes or a few mutation positions is challenging in heterogeneous tumors. In addition, the trastuzumab resistance mechanism of AGC is incompletely understood. Methods: This prospective study enrolled 49 AGC patients (pts), including 21 pts receiving chemotherapy plus trastuzumab and 18 pts receiving chemotherapy alone. Serial peripheral blood samples (10 mL) were collected from each patient at baseline and every 2–4 treatment cycles. Fourteen matched formalin-fixed, paraffin-embedded tumor tissues were obtained. Pan-cancer panel sequencing was used to analyze somatic mutations. PyClone was employed to analyze the clonal structure. Molecular tumor burden index (mTBI) were calculated with clonal mutations. Results: A total of 121 and 146 functional mutations were identified in 14 paired tumor tissue and pretreatment plasma samples, respectively. Clonal mutations in plasma samples were derived from the matched tumor, with a median predicted cancer cell fraction of 89%. Compared with single gene analysis (TP53, patient coverage = 71%), mTBI based pan-cancer panel sequencing improved patient coverage to 100%. Serial mTBI analysis identified progressive disease (PD) 3–48 weeks (mean = 18 weeks) before imaging results. In validation cohort of 16 pts, mTBI increased to exceed the cutoff before or at clinical PD, demonstrating 94% sensitivity. We identified 32 expanding mutations potentially related to trastuzumab resistance by clonal structure analysis of ctDNA during anti-HER2 treatment. Multiple pathways activating in the same patients revealed the heterogeneity of the trastuzumab resistance mechanism. In addition, a higher mTBI in pretreatment ctDNA was also shown to be a risk factor for progression-free survival (HR, 13.75; 95% CI, 2.69–70.24; P= 0.002). Conclusions: Analysis of ctDNA clones based on pan-cancer panel sequencing is a promising approach to enhance the clinical management and improve therapeutic strategy for AGC patients.
TCT-430 In vitro and preclinical evaluation of a thin-strut bioresorbable scaffold: results from bench testing and acute phase study in a non-atherosclerotic porcine model.
Authors: Yuki Katagiri, Rasha Al-Lamee, Erhan Tenekecioglu, Norihiro Kogame, Taku Asano, Ply Chichareon, Rodrigo Modolo, Chun Chin Chang, Nial Bullett, Naveed Ahmed, Kadem Al-Lamee, Patrick Serruys, Yoshinobu Onuma
Journal: Journal of the American College of Cardiology (2018)
P01.048 A novel transducer array layout for delivering Tumor Treating Fields to the infratentorial brain at therapeutic levels
Authors: Z Bomzon, A Naveh, S Levy, E Kirson, U Weinberg
Journal: Neuro-Oncology (2018)

Tumor Treating Fields (TTFields) is an antimitotic cancer treatment that utilizes low intensity (1–3 V/cm) alternating electric fields in the intermediate frequency (100–300 kHz), approvedfor the treatment of Glioblastoma Multiforme (GBM) located in the supratentorial regions of the brain. A clinical trial testing the efficacy of TTFields for treating brain metastases is currently underway (METIS, NCT02831959). TTFields are delivered via two pairs of transducer arrays placed on the patient’s skin in proximity to the tumor. The standard array layouts used to deliver TTFields involve placement of the arrays on the supratentorial regions of the head. Using these layouts, therapeutic field intensities above 1 V/cm are achieved within the surpatentorial brain. However, field intensities in the infratenorium fall to sub-therapeutic levels. . Brain metastases commonly occur in the infratentorium. In addition, infratentorial tumors are common in the pediatric population. Hence, there is a need to for array layouts that can be used to deliver TTFields effectively to the infratentorial brain. Here we present a new array layout designed to deliver high field intensities to the infratentorial brain. To simulate delivery of TTFields to the brain, realistic computerized head models of an adult human female and an adult human male were used. Virtual transducer arrays were placed on the models, and boundary conditions were set to simulate delivery of TTFields at 200 kHz. Various array layouts were tested, and field distributions resulting from the layouts were evaluated. In both models, TTfields was delivered to the infratentorium most effectively with a layout, in which each array of one pair was laterally placed superficially to the lower region of the occipital lobe, and the two arrays of the second pair were placed on the calvarium and the superior aspect of the neck. In both models, the pair of arrays in which one array was placed on the calvarium and one array on the superior aspect of the neck delivered field intensities above 1.1 V/cm to over 95% of the volume of the infratentorial brain, and the pair of arrays placed on the lateral aspects of the occipital lobe delivered field intensities above 1 V/cm to over 95% of the infratentorial brain. Both pairs of arrays delivered field intensities above 1 V/cm to significant portions of the supratentorial brain. This work suggests a practical approach for delivering TTFields to the cerebellum, brain-stem and surrounding regions which are located inferior to the tentorium.
Effects of mindfulness meditation on quality of life in adults with advanced cancer and family caregivers: A randomized pilot.
Authors: Shelley A. Johns, Kathleen A. Beck-Coon, Linda F. Brown, Patrick V. Stutz, Joanne K. Daggy, Qing Tang, Jacob A. Pell, Erin V. Newton, Paul R. Helft
Journal: Journal of Clinical Oncology (2018)

10096 Background: Patients with advanced cancer often avoid emotionally sensitive discussions with family caregivers (FCGs) about their end-of-life (EOL) treatment preferences. Avoidance of these advance care planning (ACP) discussions inhibits EOL preparations and may reduce quality of life (QoL) for both patients and FCGs. Most ACP interventions fail to address emotional barriers that hinder timely ACP. Mindfulness training facilitates emotional regulation and adaptive coping, and was tested in this randomized pilot. Methods: Eligible patients had a: (1) locally-advanced solid malignancy; (2) life expectancy < 12 months as rated by their oncologist; (3) score of ≥ 7 on cancer-related cognitive avoidance (Mini-MAC); and (4) FCG willing to enroll. Patient-FCG dyads (n = 55) were randomly assigned to a 6-session mindfulness meditation class with communication training or usual care. Primary endpoints were feasibility, retention, QoL, and ACP confidence (patients only). Outcomes were assessed at baseline and 6- and 10-weeks using intent-to-treat analysis. Results: Of 133 patients who screened eligible, 41% enrolled. Dyadic retention was 84% through 10 weeks. Most patients (85%) had stage IV cancer, with breast (29%) and GI (27%) cancers being most prevalent. The majority of patients and FCGs were female (60-62%), white (94-95%), and college educated (63-64%). Mindfulness patients reported a large and significant improvement in existential QoL (d = 0.82, p = 0.009) at 6 weeks compared to controls; however, the magnitude of improvement was not sustained at 10 weeks (d = 0.24, p = 0.43). Mindfulness FCGs reported a significant within-group improvement in QoL at 10 weeks (d = 0.45, p = 0.03); however, between-group comparisons were not significant at any time point. A non-significant improvement in ACP confidence favoring mindfulness patients over controls at 6 weeks became significant at 10 weeks (d = 0.67, p = 0.03). Conclusions: Within limits of a small pilot, results suggest that mindfulness training is feasible and potentially beneficial for improving QoL and ACP confidence in dyads coping with advanced cancer. A full-scale efficacy trial with a more diverse sample is planned. Clinical trial information: NCT03257007.