tbuckley/cabot-search huggingface dataset:
Abstract CT108: Tumor treating fields (TTFields) in combination with Lomustine (CCNU) in the EF-14 phase III clinical study: A safety analysis
Authors: Adrian Kinzel, Gitit Lavy-Shahaf, Eilon D Kirson
Journal: Cancer Research (2018)

Abstract Introduction: TTFields are low intensity (1-3V/cm), intermediate frequency (100-300 KHz) alternating electrical fields for the treatment of solid tumors. In the EF-14 phase 3 study, TTFields showed a significant overall and progression-free survival benefit for patients with newly diagnosed glioblastoma (GBM), in combination with Temozolomide (TMZ) (OS from randomization 20.9 vs. 16.0 months, p-value&amp;lt;0.001). The OS and PFS benefit of TTFields was seen in all patient subgroups, and was independent of MGMT promotor methylation-status, age, performance status and gender. TTFields were not associated with additional systemic toxicity. At recurrence, patients were allowed to continue TTFields with second line therapies. Here, we analyzed the safety data of TTFields + lomustine (CCNU) to evaluate the safety and feasibility of this combination. Methods: Patients in the EF-14 trial received TTFields until second progression, or for 24 months. Change in chemotherapy regimen was allowed in both groups after tumor progression. We compared the patients who received lomustine as second-line chemotherapy in combination with TTFields (n=134) to the patients who received lomustine as monotherapy after first progression (n=39). We compared baseline characteristics and the adverse event profile between the two groups. Results: Baseline characteristics were well balanced between both groups except for less female patients in the lomustine only group (7.7% vs. 22.4%). Median age in the TTFields/lomustine group was 55.5 years (29-83) compared to 50.0 years (19-71) for lomustine alone. The addition of TTFields to lomustine therapy was not associated with any significant increase in rates of systemic adverse events compared to lomustine therapy alone (number of patients with &amp;gt; 1 SAE 30 % vs. 31 %) and the distribution, severity and overall incidence of adverse events were not statistically different in patients in the two treatment groups. Discussion: The data show that the combination of TTFields and lomustine is a safe and feasible combination. This analysis emphasizes again the strong safety profile of TTFields and the high potential of combining TTFields with other therapy modalities. This data is especially important in light of the recently presented promising data from a small randomized trial that tested the combination of lomustine + TMZ in newly diagnosed (MGMT promotor-methylated only) GBM patients. Citation Format: Adrian Kinzel, Gitit Lavy-Shahaf, Eilon D Kirson. Tumor treating fields (TTFields) in combination with Lomustine (CCNU) in the EF-14 phase III clinical study: A safety analysis [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 CT108.
Abstract CT084: HEPANOVA: A phase II trial of tumor treating fields concomitant with sorafenib for advanced hepatocellular carcinoma
Authors: Anca-Ligia Grosu, Josif Strouthos, Thomas Brunner, Uri Weinberg
Journal: Cancer Research (2018)

Abstract Tumor Treating Fields (TTFields) are a non-invasive, regional antimitotic treatment modality, which has been approved for the treatment of glioblastoma by the FDA. TTFields predominantly act by disrupting the formation of the mitotic spindle during metaphase. TTFields were effective in multiple preclinical models of hepatocellular carcinoma (HCC), leading to a significant increase in cell death. The Phase 2 HEPANOVA study is the first trial testing TTFields in HCC patients, and is designed to test the safety and efficacy of adding TTFields to sorafenib in advanced HCC. Trial Design: Patients (N=25) with unresectable HCC who are not amenable to any local treatment will be enrolled in this prospective, single-arm study. The study enrolls patients with ECOG score of 0-2 and Barcelona clinic liver cancer (BCLC) stage 0-C. Patients must have a measurable disease per RECIST Criteria. Having implanted electronic devices in the torso is exclusionary. Sorafenib will be administered at standard dose (400 mg daily). TTFields (150kHz) will be deilvered for 18 hours/day until local disease progression per RECIST Criteria. Clinical follow up will be performed q4w, and a CT/MRI scan q12w. Following disease progression in the liver, patients will discontinue TTFields and be followed monthly for survival. Overall response rate will be the primary endpoint and in-field control rate, progression-free survival rate at 12 month (PFS12), OS rate at 1 year and toxicity will all be secondary endpoints. Sample size was calculated using an Exact test for proportions considering the weighted average of ORR of patients who had either complete or partial response per RECIST criteria in historical studies with sorafenib is 4.5%. A sample size of 25 patients was required to achieve a power of approximately 80% at a one-sided alpha level of 0.05 using a single sample Exact test for proportions. Citation Format: Anca-Ligia Grosu, Josif Strouthos, Thomas Brunner, Uri Weinberg. HEPANOVA: A phase II trial of tumor treating fields concomitant with sorafenib for advanced hepatocellular carcinoma [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 CT084.
Effects of Rapid Atrial Pacing on the Arrhythmogenic Activity of Single Cardiomyocytes From Pulmonary Veins
Authors: Yi-JenChen, Shih-AnnChen, Yao-ChangChen, Hung-IYeh, PaulChan, Mau-SongChang, Cheng-ILin
Journal: Circulation (2001)

Background Pulmonary veins (PVs) are important sources of paroxysmal atrial fibrillation. Long-term rapid atrial pacing (RAP) changes atrial electrophysiology and facilitates the maintenance of atrial fibrillation. It is not clear whether RAP alters the arrhythmogenic activity of PVs. The purpose of this study was to isolate single PV cardiomyocytes from control and RAP dogs and evaluate their electrophysiological characteristics. Methods and Results The action potential and ionic currents were investigated in PV cardiomyocytes from control and long-term (6 to 8 weeks) RAP (780 bpm) dogs by use of the whole-cell clamp technique. Dissociation of PVs yielded rod-shaped single cardiomyocytes without (n=91, 60%) or with (n=60, 40%) pacemaker activity. Compared with the control group, the RAP dog PV cardiomyocytes had faster beating rates (0.86±0.28 versus 0.45±0.07 Hz, P<0.05) and shorter action potential duration. The RAP dog PV cardiomyocytes with pacemaker activity have a higher incidence of delayed (59% v...
胸水における可溶性メソテリン関連ペプチド(SMRP)は悪性胸膜中皮腫の早期診断のための実用的なバイオマーカーとなり得るか
Authors: Nakano T, Kuribayashi K, Yamada S, Fukuoka K
Journal: Journal of Thoracic Oncology (2009)
Predicting Sudden Death in the Population
Authors: XavierJouven, MichelDesnos, ClaudeGuerot, PierreDucimetière
Journal: Circulation (1999)

Background—Sudden death was found to share the same set of usual risk factors as coronary events and therefore could not be specifically predicted in the population. It appears, however, that parental history of sudden death has not been investigated yet as a risk factor for sudden death. Therefore, we assessed risk factors, including parental sudden death, associated with the occurrence of sudden death in a long-term cohort study. Methods and Results—We included 7746 men employed by the city of Paris who were 43 to 52 years of age in 1967 to 1972 in the Paris Prospective Study I. Each subject underwent a physical examination and an ECG, provided blood for laboratory tests, and answered questionnaires administered by trained interviewers who paid particular attention to family medical history. Men with known ischemic cardiac disease were further excluded from analysis. For 95.5% of the men, vital status was obtained from specific inquiries until retirement, then by death certificates. Resting heart rate, ...
Contribution of α-Adrenergic and β-Adrenergic Stimulation to Ischemia-Induced Glucose Transporter (GLUT) 4 and GLUT1 Translocation in the Isolated Perfused Rat Heart
Authors: SilviaEgert, NgocNguyen, MarkusSchwaiger
Journal: Circulation Research (1999)

Abstract—The intracellular signaling mechanism of the ischemia-stimulated glucose transporter (GLUT) translocation in the heart is not yet characterized. It has been suggested that catecholamines released during ischemia may be involved in this pathway. The purpose of this study was to evaluate the contribution of α-adrenoceptors and β-adrenoceptors to ischemia-mediated GLUT4 and GLUT1 translocation in the isolated, Langendorff-perfused rat heart. Additionally, GLUT translocation was studied in response to catecholamine stimulation with phenylephrine (Phy) and isoproterenol (Iso). The results were compared with myocardial uptake of glucose analogue [18F]fluorodeoxyglucose (FDG). Subcellular analysis of GLUT4 and GLUT1 protein on plasma membrane vesicles (PM) and intracellular membrane vesicles (IM) using membrane preparation and immunoblotting revealed that α- and β-receptor agonists stimulated GLUT4 translocation from IM to PM (2.5-fold for Phy and 2.1-fold for Iso, P<0.05 versus control), which was comp...
Abstract LB-168: Inhibitory activities of Sesamum indicum L. leaf extract against the growth, invasion, migration, and adhesion of human colon cancer cells
Authors: Seoyun Kim, Jihyeung Ju
Journal: Cancer Research (2018)

Abstract Colorectal cancer is one of the most common cancers in both incidence and mortality among men and women worldwide. Sesame (Sesamum indicum L.) leaves (SL) are used as vegetables and traditional medicines in Asian and African countries. In the current study, we aimed to investigate the effects of ethanol extract of sesame leaves (SLE) against key characteristics of cancer cells, including unrestricted growth, resisted apoptosis, and activated metastasis, and to evaluate whether thermal treatment of SL alter the inhibitory effects. Two human colon cancer cell lines were used in this study, HT29 colon adenocarcinoma cells and HCT116 colorectal carcinoma cells. In 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, treatment with SLE at the concentrations of 50-500 µg/mL for 24-72h resulted in dose-dependent and time-dependent growth inhibition in HT29 and HCT116 cells. In cell cycle analyses, SLE caused significantly increased cell population at sub-G1 (in HT29 and HCT116) and G2/M (in HCT116) phases, suggesting that the observed growth inhibition is associated with induction of apoptosis and cell cycle arrest. SLE at non-cytotoxic concentrations was effective in inhibiting critical events during metastasis in HT29 and HCT116, such as invasion (determined by matrigel-coated transwell assay), migration (determined by wound-healing assay), and adhesion (determined using fibronectin-coated plates). Thermal treatment of SL (at 150°C for 15 min) resulted in significantly enhanced inhibitory activities of SLE against the invasion, migration and adhesion in HCT116 cells, but did not change the growth-inhibitory and apoptosis-inducing activities. These results suggest that SLE possesses in vitro anti-cancer activities against colon cancers and that thermal treatment of SL enhances the anti-metastatic activities of SLE. Further studies are needed to verify whether similar effects are reproduced in vivo and to identify active ingredients of SLE responsible for the inhibitory activities. Citation Format: Seoyun Kim, Jihyeung Ju. Inhibitory activities of Sesamum indicum L. leaf extract against the growth, invasion, migration, and adhesion of human colon cancer cells [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 LB-168.
Abstract 2923: BET inhibitors synergize with HDAC inhibitors and downregulate expression of interferon response genes in glioblastoma
Authors: Olga Gusyatiner, Minh Diêu Thanh Pham, Yvonne Lei, Jungyeon Park, Pierre Bady, Mauro Delorenzi, Monika Hegi
Journal: Cancer Research (2018)

Abstract Glioblastoma (GBM) is the most aggressive brain tumor in adults with a median overall survival of only 15 months. Despite multiple attempts, single agent therapies have failed in clinical trials and new strategies for combination treatments are urgently needed. Here, our aim was to predict rational combination therapies with BET inhibitors (BETi) that target bromodomain and extra-terminal tail (BET) proteins and are currently evaluated as anti-cancer drugs. In order to identify BETi-induced vulnerabilities in cancer relevant pathways that may be targeted with a second drug, we obtained differential expression profiles of glioma sphere lines (GS-lines) treated with the BETi JQ1. Gene set enrichment analysis revealed several significantly disturbed pathways that included IFN-alpha response genes and signatures of response to histone deacetylase inhibitors (HDACi). In order to validate the observed down regulation of the interferon response gene signature, we primed the GS-lines with IFN-alpha and confirmed that interferon-stimulated genes (ISGs), such as MX1, OAS1, and CD274 are down regulated after a 4-hour exposure to JQ1. Importantly, the levels of pSTAT1 in the nucleus remained unchanged upon JQ1 treatment, suggesting that JQ1 was acting directly on the transcriptional level of ISGs and not on the canonical JAK-STAT pathway. Similar results were obtained in adherent GBM cell lines that constitutively express ISGs. Moreover, in U87MG orthotropic xenografts in mice, a single i.p. injection of JQ1 downregulated OAS1 and CD274 expression. Currently we are studying the mechanism of how BETi represses transcription of ISGs by chromatin immuno-precipitation. Finally, we show that HDACi and JQ1 synergize to reduce cell viability of GS-lines in vitro. Further experiments will test HDACi and BETi drug combinations in mouse orthotopic xenografts of GS-lines. Citation Format: Olga Gusyatiner, Minh Diêu Thanh Pham, Yvonne Lei, Jungyeon Park, Pierre Bady, Mauro Delorenzi, Monika Hegi. BET inhibitors synergize with HDAC inhibitors and downregulate expression of interferon response genes in glioblastoma [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 2923.
Abstract 1383: A CRISPR-Cas9 tiling screen to identify functional domains within DNMT1 and/or DNMT3B that can be targeted for therapeutic intervention in AML
Authors: Balpreet Bhogal, Barbara Weir, Ramona Crescenzo, Min Chul Kwon, Ulrike Philippar, Ricardo Attar, Glenn Cowley, David Pocalyko
Journal: Cancer Research (2018)

Abstract DNA methylation is an epigenetic mechanism that regulates gene expression during many stages of development, including genomic imprinting, stem cell regulation, and X-chromosome inactivation. Moreover, aberrant DNA methylation patterns, characterized by genome-wide hypomethylation and promoter-specific hypermethylation, are a prominent feature of cancer. Methylation of DNA at the 5-position of cytosines is mediated by the DNA methyltransferase (DNMT) protein family, which regulates both maintenance methylation (DNMT1) and de novo methylation (DNMT3A and DNMT3B). Loss-of-function mutations of DNMT3A have been identified in hematological malignancies including acute myeloid leukemia (AML), where DNMT3A is mutated in approximately 25% of known cases. Published reports suggest the existence of a synthetic lethal interaction between DNMT3A and DNMT1/3B. To further study this potential genetic interaction, we are performing a CRISPR-Cas9 tiling screen to identify functional domains within DNMT1 and/or DNMT3B that are synthetic lethal with DNMT3A. We generated a lentiviral library containing 777 and 421 single guide RNAs (sgRNAs) that tile the coding region of DNMT1 and DNMT3B, respectively and performed viability screens in AML cell lines that are either wild-type or mutant for DNMT3A. This screen was designed to identify in-frame alterations within functional domains that lead to effects on cell viability. Next generation sequencing of sgRNAs identified three functional domains of DNMT1 which, when mutated, leads to decreases in cell viability. Current efforts are focused on verifying the essentiality of these functional domains using CRISPR-Cas9-based approaches as well as mutagenesis by integrated tiles (MITE)-seq analyses. Citation Format: Balpreet Bhogal, Barbara Weir, Ramona Crescenzo, Min Chul Kwon, Ulrike Philippar, Ricardo Attar, Glenn Cowley, David Pocalyko. A CRISPR-Cas9 tiling screen to identify functional domains within DNMT1 and/or DNMT3B that can be targeted for therapeutic intervention in AML [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 1383.
Abstract 1118: DOT1L epigenetically regulates cancer stem cell properties and tumor progression in glioblastoma brain tumor stem cells
Authors: Danielle Bozek, Xiaoguang Hao, H. Artee Luchman, Samuel Weiss
Journal: Cancer Research (2018)

Abstract The median survival for patients diagnosed with Glioblastoma (GBM) is only 14 months, due to recurrence, despite current treatment options of surgery, radio- and chemo-therapies. Brain tumor stem cells (BTSCs) are thought to underlie disease recurrence and lethality as they exhibit self-renewal, multipotency and tumorigenesis. The epigenetic regulation of BTSCs are relatively un-characterized and unlike genomic mutations are potentially reversible. Disrupter of telomeric silencing-1-like (DOT1L) is the only known histone methyltransferase responsible for histone-3-lysine-79 methylation (H3K79me), an epigenetic mark associated with active gene transcription. Previous studies investigating the therapeutic implications of targeting DOT1L in cancer have shown that its inhibition in leukemia results in cancer cell death and, in solid cancers, decreases metastasis. We investigated the role of DOT1L in GBM BTSCs. We find that short-term DOT1L inhibition in BTSCs in vitro has limited effects on viability but alters growth morphology, as neurospheres become flattened and adherent. Furthermore, inhibition decreases BTSC invasion and promotes differentiation. Long-term inhibition of DOT1L had a more pronounced effect on sphere morphology and decreased BTSC proliferation and survival. Pre-treatment with the DOT1L inhibitor EPZ-5676 followed by orthotopic xenografts of BTSCs led to slowed tumor growth and improved overall survival. Initial H3K79me2 ChIP-sequencing and RNA-sequencing results show that H3K79me2 levels and gene expression are decreased for stem and progenitor cell markers SOX2 and OLIG2 respectively, in BTSCs treated with EPZ-5676. These results suggest that DOT1L may be an important regulator of GBM cancer stem cell properties and tumor progression. Current studies aim to further investigate how DOT1L regulates BTSCs by overlaying H3K79me2 ChIP-sequencing, RNA-sequencing and ATAC-sequencing in a panel of BTSCs following DOT1L inhibition and overexpression. These findings highlight the potential clinical implications of epigenetic targeted therapies for GBM. Citation Format: Danielle Bozek, Xiaoguang Hao, H. Artee Luchman, Samuel Weiss. DOT1L epigenetically regulates cancer stem cell properties and tumor progression in glioblastoma brain tumor stem cells [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 1118.
Abstract 4664: Enzymatically-responsive tumor-targeted mesoporous silica nanoparticle for identification of pancreatic cancer
Authors: Kylie Nairon, Abhilash Samykutty, Molly W. McNally, Girish Mishra, William E. Grizzle, Lacey R. McNally
Journal: Cancer Research (2018)

Abstract Purpose: Pancreatic cancer remains an unsolved health issue, with its rapid progression and resistance to modern therapy leading to poor prognoses for most patients. The prevalence of metastasis in pancreatic cancer makes complete tumor location and removal rare, and those who do have resectable disease have only a 20% 5-year survival rate. In recent years, nanoparticles have been explored as targeted delivery agents for chemotherapeutic drugs and imaging dyes, however few have achieved clinical success due to overestimation of biological phenomena and reliance on passive targeting systems. In this work, an enzyme-responsive nanoparticle has been developed for increased active pancreatic tumor targeting and specific release at biologically-significant enzyme concentrations. Methods: Mesoporous silica nanoparticles were formed using a scaffold of hexadecyltrimethylammonium bromide (CTAB) at 80°C. The scaffold was removed to form wormhole-like pores using a series of dialysis procedures. Transmission electron microscopy (TEM) confirmed the 35 nm diameter and porous structure of the particles. The particles were then loaded with IR780 dye, and surfaces were functionalized with (3-aminopropyl) triethoxysilane (APTES). The loaded particles were then encapsulated with a combination of Type A and Type B gelatin, followed by a stabilizing polyvinylpyrrolidone (PVP) layer. Dynamic light scattering (DLS) and zeta potential were used to confirm coating. Coated particle samples were exposed to collagenase type IV (MMP-9) enzyme to test encapsulation efficiency and enzyme sensitivity. Enzyme-treated and intact samples were transferred to tissue phantoms, and Multispectral optoacoustic tomography (MSOT) was used for comparative analysis. Results: TEM confirmed the formation of stable 35 nm silica nanoparticles with a wormhole-like pore structure. Zeta potential decrease from 55 mV to 5 mV and DLS particle diameter increase from 35 nm to 334.5 nm indicated binding of gelatin and PVP to particle surfaces. MSOT imaging showed 10 X increased signals from untreated nanoparticles as compared to enzyme-treated nanoparticles, indicating that dye molecules remained inside the pores of coated particles and were released when exposed to MMP-9. Conclusion: Gelatin/PVP-coated mesoporous silica nanoparticles encapsulated dye and demonstrated MMP-9 activated dye release at biologically-relevant enzyme concentrations. Citation Format: Kylie Nairon, Abhilash Samykutty, Molly W. McNally, Girish Mishra, William E. Grizzle, Lacey R. McNally. Enzymatically-responsive tumor-targeted mesoporous silica nanoparticle for identification of pancreatic 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 4664.
Abstract 14794: A Slow-Release Synthetic Prostacyclin Agonist “YS1402” Combined With Pedicle Omental Flap Reduces Microvascular Resistance and Increases Myocardial Blood Flow, Associated With Functional Recovery, in a Porcine Chronic Myocardial Infarction Model
Authors: Shin Yajima, Shigeru Miyagawa, Satsuki Fukushima, Yoshiki Sakai, Akima Harada, Hiroko Iseoka, Motoko Shiozaki, Tadashi Watabe, Kayako Isohashi, Hayato Ikeda, Genki Horitsugi, Jun Hatazawa, Yoshiki Sawa
Journal: Circulation (2016)

Introduction: YS1402 is a slow-release synthetic prostacyclin agonist, being developed as multi-proangiogenic cytokines inducer. In addition, the pedicle omental flap covering over the left ventric...
Infographic. Cardiorespiratory fitness and health
Authors: Bruno Paula Caraça Smirmaul, Ross Arena
Journal: British Journal of Sports Medicine (2018)

![Figure][1]</img> 1. 1. 2. Ross R , 3. Blair SN , 4. Arena R , et al . Importance of assessing cardiorespiratory fitness in clinical practice: a case for fitness as a clinical vital sign: a scientific statement from the American Heart Association. Circulation 2016