tbuckley/cabot-search huggingface dataset:
Burst Emergence of Intracellular Ca2+ Waves Evokes Arrhythmogenic Oscillatory Depolarization via the Na+–Ca2+ Exchanger
Authors: KatsujiFujiwara, HideoTanaka, HirokiMani, TakuoNakagami, TetsuroTakamatsu
Journal: Circulation Research (2008)

Intracellular Ca2+ waves (CaWs) of cardiomyocytes are spontaneous events of Ca2+ release from the sarcoplasmic reticulum that are regarded as an important substrate for triggered arrhythmias and delayed afterdepolarizations. However, little is known regarding whether or how CaWs within the heart actually produce arrhythmogenic membrane oscillation because of the lack of data confirming direct correlation between CaWs and membrane potentials (Vm) in the heart. On the hypothesis that CaWs evoke arrhythmogenic oscillatory depolarization when they emerge synchronously and intensively in the heart, we conducted simultaneous fluorescence recording of intracellular Ca2+ ([Ca2+]i) dynamics and Vm of ventricular myocytes on subepicardial surfaces of Langendorff-perfused rat hearts using in situ dual-view, rapid-scanning confocal microscopy. In intact hearts loaded with fluo4/acetoxymethyl ester and RH237 under perfusion with cytochalasin D at room temperature, individual myocytes exhibited Ca2+ transients and acti...
Abstract 2282: VIP: A system biology platform for cell line centric integrative analysis of molecular and functional genomics data
Authors: Julio Fernandez, Ying Ding, Zhengyan Kan
Journal: Cancer Research (2018)

Abstract Cancer is a heterogeneous disease that is classified by its tissue of origin or molecular characteristics such as genetic alterations that drive tumorigenesis. Large-scale efforts using loss-of-function genetic screens to systematically identify genes essential for the proliferation and survival of cancer cells provide a powerful approach for studying cancer biology and discovering drug targets. However, cancer cell lines from different lineages or molecular background vary in their dependencies on specific genes or pathways. Functional ablation of a gene may be only lethal in one segment of cancer cell lines harboring certain molecular deficiencies or activation of a specific oncogenic signaling pathway, a phenomenon called synthetic lethality. A key challenge here would be to identify the true synthetic lethal interactions from a combinatorially large number of possible interactions between molecular aberrations and gene-level sensitivity to functional perturbation. With recent advances in large-scale studies such as CCLE and Achilles, genome-wide functional genomics screens using CRISPR-Cas9 or shRNA technologies as well as comprehensive molecular profiles have become available for a large number of cancer cell lines. Here we present the Variant Interpretation Portal (VIP), a system biology tool designed to enable integrative analysis of molecular and functional genomics data in cell lines for identifying synthetic lethal interactions. VIP consists of a command-line pipeline and a web-based user interface. The VIP pipeline rigorously filters out germline events and classifies genomic variants into multiple functional tiers. The VIP web portal provides users with a graphic interface to perform exploratory visual analyses of associations between two variables or multiple variables, where a variable could be a genetic alteration or a gene-level sensitivity profile. VIP also enables systematic search for significant association between one variable, such as the sensitivity profile, vs. a database of variables such as histology or molecular attributes. VIP is optimized to perform real-time analytics and enables the incorporation and analysis of user-provided data. The code can be accessed from https://github.com/juferban/vip. Citation Format: Julio Fernandez, Ying Ding, Zhengyan Kan. VIP: A system biology platform for cell line centric integrative analysis of molecular and functional genomics data [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 2282.
Abstract 13885: Excessive Daytime Sleepiness is Associated With Depression Scales but Not With Sleep Disordered Breathing in Patients Hospitalized With Cardiovascular Diseases
Authors: Mikiko Ohashi, Takashi Kohno, Rikako Noda, Risa Matsuda, Ryoma Fukuoka, Shun Kohsaka, Yuichiro Maekawa, Motoaki Sano, Seiji Takatsuki, Keiichi Fukuda
Journal: Circulation (2016)

Background: Excessive daytime sleepiness (EDS) is a significant public health problem, and one of its most common causes is sleep disordered breathing (SDB), which is known to be associated with the development of cardiovascular disease. However, the relationship between EDS and SDB in patients hospitalized with cardiovascular diseases is unknown. The aims of this study were to assess the prevalence of EDS in cardiovascular patients, and examine its related factors including SDB and mental status. Methods and Results: A total of 1783 patients (mean age, 65±15 years; 28.7% female) hospitalized for a spectrum of cardiovascular diseases in Keio University Hospital were enrolled (coronary artery disease n=564, arrhythmia n=658, heart failure n=137, valvular heart disease n=230, and other n=194). We assessed EDS using the Epworth sleepiness scale (ESS; mean 6.8±4.3), and EDS was defined as ESS&gt;10 (n=335[18.8%]). We screened SDB using nocturnal pulse oximetry, a non-invasive method for detecting nocturnal intermittent hypoxia. The prevalence of SDB (3% oxygenation desaturation index&gt;15/hour) did not differ between patients with EDS and those without (29% vs 29%, p=0.86). EDS was associated with younger age, alcohol use, higher eGFR, lower BNP level, and lower prevalence of hypertension, diabetics mellitus, and dyslipidemia (all p&lt;0.05). Sex, BMI, and the prevalence of heart failure, coronary artery disease, or arrhythmia did not differ between patients with EDS and those without. The patients with EDS had significantly higher depression scales (Patient Healthcare Questionnaire [PHQ-9]; 5.2±4.6 vs 3.4±3.5, p&lt;0.001, Hospital Anxiety and Depression Scale-Depression [HADS-D]; 5.5±4.0 vs 4.1±3.3 p&lt;0.001). Multiple regression analysis revealed that depressive scales by PHQ-9 (OR=1.14; p=0.002; 95% CI, 1.05-1.24) and HADS-D (OR=1.16; p&lt;0.001; 95% CI, 1.08-1.25) were independent determinants of EDS. Conclusions: EDS is associated with depression symptoms, but not with SDB in patients admitted with cardiovascular diseases. These findings suggest that cardiovascular patients with EDS should be thoroughly assessed for depression.
Abstract 5414: The correlation between the expression of microRNA hsa-miR-101 and the prognosis of the patient with hepatocellular carcinoma
Authors: Go Nakajima, Kazuhiko Hayashi
Journal: Cancer Research (2018)

Abstract Aim: MicroRNAs (miRNA) are small RNAs that regulate gene expression at the post-transcriptional level, and they play a various role in cancer cell such as proliferation, migration and metastasis. Our previous study identified forty-nine miRNAs that are differentially expressed by comparing 26 pair samples of hepatocellular carcinoma (HCC) tumor and adjacent liver tissue using next-generation sequencer system. One of them, hsa-miR-101 is chosen in this validation study. The hsa-miR-101 expression in HCC tumor samples and its adjacent liver tissues were measured by real-time PCR, and were examined the correlation between the miRNA expression and clinical data. Patients and Methods: Forty-three patients diagnosed as HCC had undergone surgical removal from 1991 to 1997 at the Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Japan. The formalin-fixed paraffin embedded samples were prepared using the standard protocol. The paraffin blocks were cut into 10 micrometer sections, and the tumor and its adjacent non-tumor liver tissue were collected using laser-captured microdissection and total RNA including miRNA fraction were isolated. After synthesized cDNA using miRNA specific primer, real-time PCR was performed using miRNA specific primer/probe. Results: The expression of hsa-miR-101 in tumor tissue was downregulated compared to adjacent liver tissue (P=0.003). No significant differences were obtained in survival time between higher or lower intratumoral expression level (P=0.8039). The patients were divided into two groups, higher/lower hsa-miR-101 expression in the tumor or in the adjacent liver tissue, the group of the higher expression in adjacent liver tissue and the lower in tumor was longer survival time compared to the other groups (P=0.0184). Conclusion: The hsa-miR-101 expression may be related to tumorigenesis, and both the expression in the tumor and in the adjacent liver tissue may be potential prognostic factor for HCC patients. Citation Format: Go Nakajima, Kazuhiko Hayashi. The correlation between the expression of microRNA hsa-miR-101 and the prognosis of the patient with 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 5414.
Effect of goshajinkigan on peripheral neuropathy in breast cancer patients treated with docetaxel.
Authors: Hajime Abe, Tsuyoshi Mori, Yuki Kawai, Hirotomi Cho, Yoshihiro Kubota, Tomoko Umeda, Eiji Mekata, Tohru Tani
Journal: Journal of Clinical Oncology (2012)

e11564 Background: Although taxanes have become a key chemotherapeutic drug in breast cancer treatment, one of the side effects is peripheral neuropathy. Goshajinkigan (GJG) is a traditional Japanese medicine that is used for the treatment of several neurological symptoms including pain and numbness. Recently, GJG has been reported to prevent anticancer drug-induced peripheral neuropathy in colorectal cancer in the gynecology field. We investigated the efficacy of GJG and mecobalamin (B12) on peripheral neurotoxicity associated with docetaxel (DOC) in breast cancer patients. Methods: Between 2007 and 2011, 60 breast cancer patients were treated with DOC. Thirty-three patients (GJG group) received oral administration of 7.5 g/day GJG every day during DOC therapy and 27 patients (B12 group) received oral administration of 1500 μg/day B12. Peripheral neuropathy was evaluated during every course according to DEB-NTC (Neurotoxicity Criteria of Debiopharm), Common Terminology Criteria for Adverse Events (CTCAE) ver. 3.0, and a visual analogue scale (VAS). Results: The median age of the GJG group was 58 years old (35 to 70 years old), the B12 group was 55 years old (33 to 69 years old), and they were all females. For the regimens, in the GJG group, TC (DOC and cyclophosphamide), DOC only, and XT (capecitabine and DOC) were administered in 19 cases, 13 cases and 1 case, respectively. In the B12 group, they were 15 cases, 11 cases and 12 cases, respectively. The cumulative dose of DOC was 338.5 mg/m 2 in the GJG group, and 340 mg/m 2 in the B12 group. The completion rate was 100% in both groups. The incidence of peripheral neuropathy was 39.3% in the GJG group, and 88.9% in the B12 group (p &lt; 0.01). In the GJG group, grade 1 DEB-NTC was observed in 2 cases, grade 2 in 5 cases and grade 3 in 5 cases. Grade 1 CTCAE was observed in 7 cases, grade 2 in 6 cases, and VAS was 2.7 ± 2.2. In the B12 group, grades 1, 2 and 3 DEB-NTC were observed in one case, 12 cases and 12 cases, respectively; and grades 1 and 2 CTCAE were observed in 12 cases each, and VAS was 4.9 ± 2.4. Peripheral neuropathy was significantly controlled in the GJG group. Conclusions: Concomitant administration of GJG is useful in preventing peripheral neuropathy in breast cancer patients treated with DOC regimen.
Abstract LB-274: Overcoming colorectal cancer resistance to death receptor agonists: Design and delivery of treatment combinations
Authors: Mandana T. Manzari, Xinghai Li, Grace Anderson, Kris Wood, Ashutosh Chilkoti
Journal: Cancer Research (2018)

Abstract Death Receptor 5 (DR5) is a key upregulated marker in colorectal cancer (CRC), overexpressed in over 90% of patients. There is a dire clinical need for drugs that can deliver targeted cell killing via this receptor. Over the past decade, various DR5 agonists have shown poor clinical efficacy, including both engineered antibodies and TRAIL, the natural ligand for this receptor. Comprehensive studies suggest that there are three major obstacles to success of these agents: 1) potency, 2) delivery, and 3) resistance. If these issues are addressed, DR5 will be an excellent therapeutic target for a variety of cancers, and provide a novel means for substantially advancing the clinical treatment of CRC. To improve delivery and overcome drug resistance, we have developed a platform that harnesses the power of genetic screening and protein engineering to design and deliver efficacious protein drug combinations. To pinpoint the genetic drivers of CRC resistance to a multivalent DR5 agonist (DRA), we used a CRISPR/Cas9 knockout screen. The screen identified genes that confer sensitivity to the DRA in resistant CRC cell lines. Over twenty small molecule drugs targeting pathways and proteins identified from the screens were then tested in combination with the DRA to identify highly synergistic combinations using cytotoxicity assays. Clonogenic, time-to-progression, and cell viability assays showed that pharmacological blockade of XIAP, Bcl-XL, and CDK4/6 strongly enhances antitumor activity of DRA in established human CRC cell lines and patient-derived CRC cells. To address the need for sustained delivery of therapeutic proteins, we developed injectable depots of anti-cancer proteins recombinantly fused to thermally responsive elastin-like polypeptide (ELP) biopolymers. The bioactive DRA-ELP fusions undergo temperature-driven phase transition upon subcutaneous injection in vivo, resulting in the formation of a gel-like depot suitable for sustained drug delivery. A single 30 mg/kg injection of the gel-like DRA-ELP depot induced significant tumor regression in Colo205 mouse xenografts. By addressing both delivery and resistance issues with our protein engineering and genomics platform, we have overcome key obstacles to clinical translation of a pro-apoptotic DRA. Citation Format: Mandana T. Manzari, Xinghai Li, Grace Anderson, Kris Wood, Ashutosh Chilkoti. Overcoming colorectal cancer resistance to death receptor agonists: Design and delivery of treatment combinations [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-274.
Abstract 3765: An anti-CD137 antibody can show greater efficacy in syngeneic mouse tumor models when combined with other immuno-oncology (IO) therapies
Authors: Matthew J. Robinson, Ines Osma-Garcia, Jane Coates-Ulrichisen, Amanda Watkins, Suzanne Mosely, Chrisopher Lloyd, Geoff Williams, Michelle Morrow, Simon Dovedi, Ronald Herbst, Robert Wilkinson
Journal: Cancer Research (2018)

Abstract CD137 is a costimulatory molecule associated with tumour infiltrating lymphocytes and cytotoxic T lymphocytes in particular. Murine anti-CD137 monoclonal antibodies (mAbs) have shown potent anti-tumour effects in syngeneic tumour models, which can be further enhanced by combination with checkpoint inhibitor (CPI) mAbs to PD-1, or CTLA-4 and OX40. Two anti-CD137 monoclonal antibodies (mAbs), Urelumab and Utomilumab, are in development for both haematological and solid cancers, and studies include combinations with other IO therapies such as anti-PD-1, anti-PD-L1 and anti-OX40 mabs. We studied the impact of combining anti-CD137 with CPIs anti-PD-L1, anti-CTLA4, and IO agonist GITRL fusion protein (GITRL-FP) and anti-OX40 on pharmacodynamic responses, tumour growth and survival in mouse syngeneic models. In a responsive model, CT26, combining anti-CD137 with anti-PD-L1 had a greater impact on tumour growth inhibition, which correlated with an enhanced proliferation of CD8 T cells, as determined Ki67 expression using flow cytometry. In MC-38, a model that is less sensitive to both monotherapies, the combination was synergistic and resulted in enhanced tumour growth inhibition. Next, we compared the anti-CTLA4, anti-OX40 and GITRL-FP as monotherapies and in combination with anti-CD137 in the CT26 model. As before, anti-CD137 alone induced CD8 T cell proliferation, whereas anti-OX40 and GITRL-FP stimulated expansion of CD8 and CD4 T cells. Interestingly, in all combinations anti-CD137 appeared to enhance both CD8 and CD4 T cell proliferation. Anti-CTLA4 and GITR-FP had a greater impact on tumour growth inhibition when combined with anti-CD137. In summary, in vivo models indicate that anti-CD137 mAbs are a promising therapy in cancer, but the most benefit may be obtained in combination with other IO therapies. Citation Format: Matthew J. Robinson, Ines Osma-Garcia, Jane Coates-Ulrichisen, Amanda Watkins, Suzanne Mosely, Chrisopher Lloyd, Geoff Williams, Michelle Morrow, Simon Dovedi, Ronald Herbst, Robert Wilkinson. An anti-CD137 antibody can show greater efficacy in syngeneic mouse tumor models when combined with other immuno-oncology (IO) therapies [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 3765.
Abstract 5694: Evaluation of the in vivo efficacy of immune-oncology drugs targeting stimulatory immune checkpoint molecules using humanized knock-in mice
Authors: Tongmei Xia, Chaoshe Guo, Yuelei Shen, Yanan Guo
Journal: Cancer Research (2018)

Abstract Cancer immunotherapy is one of the most promising research areas in the field of cancer therapy. Many pharmaceutical and biotech companies in the world are devoting great effort to develop cancer immunity-related treatment antibodies. However, along the IO drug development process, in vivo efficacy models have always been a rate-limiting step. In most cases, a human monoclonal antibody does not have mouse cross-reactivity. Mouse surrogate antibodies were often used in immune-competent syngeneic mouse models to evaluate in vivo efficacy of IO drugs. However, the efficacy of a surrogate antibody cannot fully represent the human drug in the clinical scenario. Therefore, we generated humanized knock-in mice to evaluate the in vivo efficacy of human IO antibodies. For example, human OX40 knock-in (B-hOX40) mice were generated with a chimeric OX40 receptor, which is recognizable by stimulatory human OX40 antibodies. Additionally, more knock-in mice targeting stimulatory immune checkpoint molecules were developed and validated, such as B-hCD137, B-hGITR, B-hCD27, B-hCD40, B-hCD28, B-hCD3 et al,. All these mouse models response well to the corresponding human IO antibodies, proving that they are powerful tools for in vivo efficacy evaluation of human stimulatory immune checkpoint antibodies. Citation Format: Tongmei Xia, Chaoshe Guo, Yuelei Shen, Yanan Guo. Evaluation of the in vivo efficacy of immune-oncology drugs targeting stimulatory immune checkpoint molecules using humanized knock-in mice [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 5694.
Abstract LB-362: A TGF-beta linked ECM-dysregulation programme in CAFs drives immune evasion and immunotherapy resistance
Authors: Ankur Ravinarayana Chakravarthy, Lubaba Khan, Nathan P. Bensler, Pinaki Bose, Daniel Diniz De Carvalho
Journal: Cancer Research (2018)

Abstract Background One of the key hallmarks of cancer is metastasis, which involves extensive extracellular matrix remodelling to permit extravasation from the primary tumour site before colonisation of distant sites. In this study, we defined the landscape of ECM-associated transcriptional dysregulation and performed in-silico associative analyses in terms of multiple -omics platforms, cellular composition and immunological parameters. Methods We defined the landscape of ECM gene dysregulation by integrating curated Gene Ontology ECM genes with genes differentially expressed between cancer and normal tissues from TCGA. ssGSEA scores for this set were then correlated with purity (ABSOLUTE), tested for stromal association using microdissected tumours and MethylCIBERSORT, and neoepitope counts derived using Topiary. Single-cell RNAseq data was used to validate CAF-origin. Linear models were used to identify transcriptomic, proteomic and genomic correlates, and finally, RNAseq data from three cohorts of PD1-blockade treated patients and 0.632 bootstrap evaluation of logistic regression or Random Forest models based on ECM genes, Cytolytic Activity, Mutational burden or their combinations was performed. Results A core set of 58 ECM genes is dysregulated and significantly enriched amongst genes differentially expressed between cancer and normal tissues pan-cancer. Those upregulated in cancers were found to be a negative prognostic factor pan-cancer and through integrative analysis of microdissected samples, deconvolution and single-cell RNAseq, were found to originate in Cancer Associated Fibroblasts. Transcriptome, proteome and genomics analyses implicated TGF-beta as a driver of this ECM-dysregulation signature and most notably, this programme was associated with heavily-mutated, neoantigen-high, CD8 high cancers, M1-macrophage-skewed tumours suggesting a role as a putative adaptation permitting immune evasion. Indeed, ECM dysregulation scores were significantly better predictors of response to PD1-blockade in pretreatment biopsies compared to cytolytic activity, an interferon gene signature, and mutational-burden, while TGF-beta expression alone was not, implicating a key role for CAF-specific ECM gene dysregulation in immune evasion. Conclusion A TGF-beta associated, CAF-derived signature of ECM-gene dysregulation broadly in operation across cancer types constitutes an immune evasion mechanism that indicates refractoriness to PD1-blockade. Citation Format: Ankur Ravinarayana Chakravarthy, Lubaba Khan, Nathan P. Bensler, Pinaki Bose, Daniel Diniz De Carvalho. A TGF-beta linked ECM-dysregulation programme in CAFs drives immune evasion and immunotherapy resistance [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-362.
Changes in Renal Function in Patients With Chronic HBV Infection Treated With Tenofovir Disoproxil Fumarate vs Entecavir
Authors: Sam Trinh, An K. Le, Ellen T. Chang, Joseph Hoang, Donghak Jeong, Mimi Chung, Mei-Hsuan Lee, Uerica Wang, Linda Henry, Ramsey Cheung, Mindie H. Nguyen
Journal: Clinical Gastroenterology and Hepatology (2018)