tbuckley/cabot-search huggingface dataset:
Abstract 9: Suppression of the invasion and growth of human head and neck squamous cell carcinomas via regulating STAT3 signaling and miR-21/β-catenin axis with HJC0152
Authors: Yu Wang, Sinan Wang, Yansheng Wu, Jia Zhou, Qiang Shen, Xuan Zhou
Journal: Cancer Research (2017)

Abstract Signal transducer and activator of transcription 3 (STAT3) is involved in the tumor growth and metastasis of human head and neck squamous cell carcinoma (HNSCC) and is therefore a target with therapeutic potential. In this study, we show that HJC0152, a recently developed anticancer agent and a STAT3 signaling inhibitor, exhibits promising antitumor effects against HNSCC both in vitro and in vivo via inactivating STAT3 and downstream microRNA-21/β-catenin axis. HJC0152 treatment efficiently suppressed HNSCC cell proliferation, arrested the cell cycle at the G0/G1 phase, induced apoptosis, and reduced cell invasion in both SCC25 and CAL27 cell lines. Moreover, HJC0152 inhibited nuclear translocation of phosphorylated STAT3 at Tyr705 and decreased VHL/β-catenin signaling activity via regulation of microRNA-21. Loss-of-function of VHL remarkably compromised the antitumor effect of HJC0152 in both cell lines. In our SCC25-derived orthotopic mouse models, HJC0152 treatment significantly abrogated STAT3/β-catenin expression in vivo, which leading to a global decrease of tumor growth and invasion. With its favorable aqueous solubility and oral bioavailability, HJC0152 holds the potential to be translated into the clinic as a promising therapeutic strategy for patients with HNSCC. Citation Format: Yu Wang, Sinan Wang, Yansheng Wu, Jia Zhou, Qiang Shen, Xuan Zhou. Suppression of the invasion and growth of human head and neck squamous cell carcinomas via regulating STAT3 signaling and miR-21/β-catenin axis with HJC0152 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 9. doi:10.1158/1538-7445.AM2017-9
Abstract LB-113: Immune-mediated anti-tumor activity with a clinical stage BET bromodomain inhibitor ODM-207 in pre-clinical models
Authors: Pratima Deshpande, Ravi Krishna Babu, Prashant Yallappa Vadnal, Mahaboobi Jaleel, Murali Ramachandra, Chandrasekhar Abbineni, Susanta Samajdar, Anu-Maarit Moilanen, Pekka Kallio
Journal: Cancer Research (2017)

Abstract Background: ODM-207 is a potent and selective BET inhibitor that is structurally unrelated to the benzodiazepine-based inhibitors including JQ1, I-BET762, and OTX015. Phase I clinical trials have now been initiated with this agent based on its potent anti-tumor activity in various in vitro and in vivo models of hematologic malignancies and solid tumors. In view of the recent publications implicating a role for BET protein BRD4 in the suppression of PD-L1 expression, an immune checkpoint ligand for PD-1, we sought to evaluate ODM-207 for its effect on immune-mediated anti-tumor efficacy in pre-clinical models. Methods and Results: Mouse splenocytes were stimulated with anti-CD3 and anti-CD28 in the presence or absence of ODM-207 for four days and changes in immune cell population were analyzed by FACS. Results revealed an increase in the level of activated cytotoxic CD8+ T cells as indicated by increased intracellular IFNγ and granzyme B with ODM-207 treatment. After confirming the lack of direct anti-proliferative activity on the mouse colon carcinoma cell line CT26, in vivo evaluation of ODM-207 was carried out in the syngeneic CT26 subcutaneous tumor model established in BALB/c mice. Daily oral administration of ODM-207 at 30 mg/kg was well tolerated in this model and resulted in a statistically significant inhibition of tumor growth. Interestingly, the tumor growth inhibition observed with ODM-207 was comparable to that with a commercially available anti-mouse PD1 antibody. Studies to characterize the immune changes in the tumor and anti-tumor activity of ODM-207 in combination with an anti-mouse PD1 antibody are currently underway and the results will be presented. Conclusions: In summary, these studies demonstrate the anti-tumor activity of BET inhibitor in a syngeneic model of colon carcinoma in the absence of a direct anti-proliferative activity on tumor cells. Observed tumor growth inhibition correlated with the in vitro activation of cytotoxic CD8+ T cells supporting the immune-mediated effect leading to tumor growth inhibition. In view of the remarkable success with the immune-based therapeutic approaches, these findings are relevant in devising appropriate strategies for the continued clinical development of ODM-207. Citation Format: Pratima Deshpande, Ravi Krishna Babu, Prashant Yallappa Vadnal, Mahaboobi Jaleel, Murali Ramachandra, Chandrasekhar Abbineni, Susanta Samajdar, Anu-Maarit Moilanen, Pekka Kallio. Immune-mediated anti-tumor activity with a clinical stage BET bromodomain inhibitor ODM-207 in pre-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-113. doi:10.1158/1538-7445.AM2017-LB-113
A comprehensive strength testing protocol offers no clinical value in predicting risk of hamstring injury: a prospective cohort study of 413 professional football players
Authors: Nicol van Dyk, Roald Bahr, Angus F Burnett, Rod Whiteley, Arnhild Bakken, Andrea Mosler, Abdulaziz Farooq, Erik Witvrouw
Journal: British Journal of Sports Medicine (2017)

Hamstring injuries remain prevalent across a number of professional sports. In football, the incidence has even increased by 4% per year at the Champions League level over the last decade. The role of muscle strength or strength ratios and their association with risk of hamstring injury remain restricted by small sample sizes and inconclusive results.The purpose of this study is to identify risk factors for hamstring injury in professional football players in an adequately powered, prospective cohort study. Using both established (isokinetic) and novel (eccentric hamstring test device) measures of muscle strength, we aimed to investigate the relationship between these strength characteristics over the entire range of motion with risk of hamstring injury.All teams (n=18) eligible to compete in the premier football league in Qatar underwent a comprehensive strength assessment during their annual periodic health evaluation at Aspetar Orthopaedic and Sports Medicine Hospital in Doha, Qatar. Variables included isokinetic strength, Nordic hamstring exercise strength and dynamic hamstring: quadriceps ratios.Of the 413 players included (68.2% of all league players), 66 suffered a hamstring injury over the two seasons. Only isokinetic quadriceps concentric at 300°/s (adjusted for bodyweight) was associated with risk of hamstring injury when considered categorically. Age, body mass and playing position were also associated with risk of hamstring injury. None of the other 23 strength variables examined were found to be associated with hamstring injury.The clinical value of isolated strength testing is limited, and its use in musculoskeletal screening to predict future hamstring injury is unfounded.
Abstract 3770: CAR-T cell harboring a camelid single domain antibody as a targeting agent to kill tumors expressing VEGFR2
Authors: Heman Chao, Baomin Tian, Marni Uger, Wah Wong
Journal: Cancer Research (2017)

Abstract Modulation of the immune system is showing tremendous promise in the treatment of malignancies. In addition to checkpoint inhibitors that re-activate T cells present in the tumor microenvironment, exogenously transduced chimeric antigen receptor (CAR) T cells are providing excellent responses in clinical trials for the treatment of leukemias. In this study, we describe CAR-T cells that target VEGFR2-expressing tumors. Angiogenesis is the process of new blood vessel formation and is essential for a tumor to grow beyond a certain size. Tumors secrete the pro-angiogenic factor vascular endothelial growth factor (VEGF), which acts upon local endothelial cells by binding to vascular endothelial growth factor receptors (VEGFR). As VEGFR2 is also expressed by a variety of tumors, we investigated the utility of anti-VEGFR2 CAR-T cells as a method to treat VEGFR2-expressing tumors. Camelid antibodies are small (14 kD) single chain antibodies. To generate a camelid antibody targeting the extracellular domain of VEGFR2, a llama was immunized with recombinant VEGFR2/Fc. A phage display library was generated and screened to identify an antibody with high binding affinity to VEGFR2. The selected antibody was expressed in the E. coli. BL21 (DE3) pT7 system. The purified antibody was characterized by SEC, LC-MS peptide mapping and ELISA. CAR-T cells were engineered to express the camelid anti-VEGFR2 antibody in combination with the CD28 and 4-1BB costimulatory molecules and the CD3 zeta chain. Tumor cells were screened for expression of VEGFR2, and the HL-60 acute promyelocytic leukemia, ZR-75-30 breast ductal carcinoma and NCI-H23 non-small cell lung adenocarcinoma were identified. Co-incubation of anti-VEGFR2 CAR-T cells with the VEGFR-2-expressing cell lines resulted in dose-dependent target cell toxicity as measured by LDH release. In addition, T cell activity was confirmed, as high levels of IL-2 and IFN-γ were detected in the cell culture media. These results suggest that anti-VEGFR2 CAR-T may be useful in directly targeting VEGFR2-expressing tumors. We previously showed the utility of camelid antibodies in CAR-T constructs as anti-CEACAM6 CAR-T cells show both in vitro and in vitro efficacy against the pancreatic tumor Bx-PC3. The use of the a camelid V21 antibody to target VEGFR2-expressing tumors provides hope that camelid single domain antibodies can be developed for CAR-T therapies. Citation Format: Heman Chao, Baomin Tian, Marni Uger, Wah Wong. CAR-T cell harboring a camelid single domain antibody as a targeting agent to kill tumors expressing VEGFR2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3770. doi:10.1158/1538-7445.AM2017-3770
Abstract 4339: Single cell RNA sequencing dissects cellular growth factor dependencies and oncogenic driver effects in an organoid model of gastric cancer
Authors: Jiamin Chen, Noemi Andor, Susan M. Grimes, Billy Lau, Hanlee P. Ji
Journal: Cancer Research (2017)

Abstract Gastric cancer is a lethal malignancy with few therapeutic options. Gastric tumors rely on complex intercellular signaling “crosstalk” that enables tumor development, metastasis, and therapeutic resistance. To recapitulate the intercellular communications among various cell populations that exist in vivo, we are using a three-dimensional culture system to grow and manipulate mouse gastric tissue in vitro, otherwise referred to as organoids. Importantly, this organoid model contains epithelium with its endogenous mesenchymal niche and does not require exogenous Wnt stimulation. To systematically analyze the distinct cellular lineages and their interactions, we applied a massively-scaled single cell RNA-Seq platform to sequence thousands of individual cells from organoid cultures. With PCA and t-SNE analysis of the high-dimensional data generated from single cell RNA-seq, we characterized two major cell types, i.e. epithelial and mesenchymal cells. Leverage the information from single cell transcriptome profiles, we identified specific niche factors of the Wnt signaling pathways that are activated in different stomach cell lineages. These results suggest that the mesenchymal cell populations provide a potential source of the R-spondin, a Wnt agonist, that sustains the growth of epithelium. Furthermore, we compared cell populations from Cdh1-/-/Trp53-/- and Trp53-/-organoids, and characterized changes on the transcriptome profiles due to the loss of Cdh1, an early oncogenic event in diffuse gastric cancer development. Overall, using organoid model and high-throughput single cell RNA-Seq provides a novel approach to study early tumor transformation and critical cancer-stroma interactions. Citation Format: Jiamin Chen, Noemi Andor, Susan M. Grimes, Billy Lau, Hanlee P. Ji. Single cell RNA sequencing dissects cellular growth factor dependencies and oncogenic driver effects in an organoid model of gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4339. doi:10.1158/1538-7445.AM2017-4339
Abstract 100: Pancreatic cancer cells rely on the NADPH producing enzyme, IDH1, for adaptive survival against acute metabolic stress
Authors: Ali Vaziri-Gohar, Mahsa Zarei, Jonathan R. Brody, Jordan M. Winter
Journal: Cancer Research (2017)

Abstract We recently demonstrated that pancreatic cancer cells adapt to low nutrient conditions and chemotherapeutic stress through an adaptive response where HuR (ELAVL1) protects cells from oxidative damage induced by metabolic stress. RNA sequencing data and a series of protein-RNA interaction assays proved that HuR stabilizes transcript levels of the NADPH producing enzyme, isocitrate dehydrogenase 1 (IDH1). HuR-knockout cells had near-complete loss of IDH1 expression (manuscript under review). In light of the fact that IDH1-null mice are particularly sensitive to oxidative damage, we hypothesize that this enzyme plays a critical role in PDA survival of acute stress. We examined the expression levels of all eight well-characterized NADPH-generating enzymes in pancreatic cancer cells in vitro, and demonstrate that only IDH1 and phosphogluconate dehydrogenase (PGD) are upregulated by &amp;gt;2-fold after incubation in low glucose (5 mM) for 48 hours. IDH1-knockout MiaPaCa2 cells were generated through CRISPR gene editing, such that mRNA expression was detected at &amp;lt;5% of control levels. ROS levels detected by DCFDA measurements were increased by 55% in IDH1-knockout cells compared to isogenic controls under normal culture conditions, with even higher levels under low glucose and chemotherapy stress for 48 hours. Additionally, IDH1-knockout cells were more sensitive to chemotherapy under both high and low glucose conditions, compared to IDH1-proficient control cells. Taken together these results suggest that IDH1 expression is important for acute antioxidant defense in pancreatic cancer cells in the face of metabolic stress, and represents a potential therapeutic target. Citation Format: Ali Vaziri-Gohar, Mahsa Zarei, Jonathan R. Brody, Jordan M. Winter. Pancreatic cancer cells rely on the NADPH producing enzyme, IDH1, for adaptive survival against acute metabolic stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 100. doi:10.1158/1538-7445.AM2017-100
Abstract 1564: A computational framework for removing mouse contamination in tumors sequenced from patient-derived xenografts
Authors: Ali Amin-Mansour, Judit Jané-Valbuena, Xinmeng Jasmine Mu, Levi Garraway
Journal: Cancer Research (2017)

Abstract Introduction: Using patient derived xenograft (PDX) models has become an effective way for investigating response to standard or new therapeutics in cancer. Human cancer cells injected in mice are allowed to establish tumors and subjected to desired treatments. The PDX tumors are later harvested and characterized, often by massive parallel sequencing. However, a major challenge with analyzing these data is the presence of stromal mouse genomic material, frequently resulting in artifacts in downstream variant detection. We present a computational method to eliminate mouse contamination in PDX. Method: We used the Burrows-Wheeler Aligner to map reads obtained from sequencing the PDX samples to a combined human and mouse reference genome . We remove reads that are mapped to the mouse reference. The remaining reads are then processed through standard mutation calling pipelines for somatic mutation detection. To test the efficacy of our method, we created in silico mixtures of human and mouse whole-exome sequencing reads from a melanoma patient’s tumor and an immortalized mouse cell line captured with human exome baits. We then carried out a sensitivity analysis to examine how changing the mean target coverage of sequencing, or mouse contamination levels affects our results. For each of the computational experiments, we evaluated somatic mutations detected from the synthetic samples in comparison to the original human sample. Results: We calculated the sensitivity and specificity of detecting somatic mutations to determine our algorithm’s performance. In all instances, we found greater than 99% for both sensitivity and specificity. Conclusions: Our results demonstrate that our method works accurately towards removing mouse reads in PDX samples. This task could also be applied to separating sequence reads from other species. Citation Format: Ali Amin-Mansour, Judit Jané-Valbuena, Xinmeng Jasmine Mu, Levi Garraway. A computational framework for removing mouse contamination in tumors sequenced from patient-derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1564. doi:10.1158/1538-7445.AM2017-1564
Abstract 224: Critical variables for automated protein immunodetection using western blot
Authors: Alexander Margulis, David P. Chimento, Russ Yukhananov
Journal: Cancer Research (2017)

Abstract Reliable immunodetection of proteins is a critical step in the discovery of novel biomarkers. It is often performed manually. The immunodetection protocol consists of multiple steps including blocking of nonspecific binding sites, incubation using primary and secondary antibodies and extensive washing between steps that easily introduce bias and errors. The quality of results depends on multiple subjective and objective factors such as the qualification and technical skills of the personnel performing the assay and the accuracy of temporal and temperature control, especially during the immunodetection step. BlotCycler™, automated western blot processor, use fluidic control system that allows to eliminate the variability associated with immunodetection and to achieve higher sensitivity by optimized washing procedure. We used BlotCycler to analyze critical variables for immunodetection including temperature, incubation time and reagent mixing. Relatively small changes in duration and temperature of incubation significantly affect not only the intensity of signal but also the specificity of antibody interaction with antigen. Automated immunodetection at 4ºC significantly improve the specificity of detection and sensitivity that allows reproducible detection of low expressing proteins. Automated processing using BlotCycler allows optimization and control of critical variables leading to improved reproducibility and specificity of immunodetection and should be routinely used for biomarker candidate discovery and confirmation, reliable protein quantification, primary antibody specificity testing, and optimization of primary and secondary antibodies concentrations. Citation Format: Alexander Margulis, David P. Chimento, Russ Yukhananov. Critical variables for automated protein immunodetection using western blot [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 224. doi:10.1158/1538-7445.AM2017-224
Abstract 4917: Therapeutic inhibition of Notch1 in metastatic prostate cancer
Authors: Meghan A. Rice, En-Chi Hsu, Tanya Stoyanova
Journal: Cancer Research (2017)

Abstract Metastatic castration-resistant prostate cancer (CRPC) is the primary cause of prostate cancer specific mortality, and is currently incurable. Defining new mechanisms that can predict progression and drive lethal CRPC is critical. Notch1 receptor, a cell surface-signaling molecule dysregulated in many cancers, is highly expressed in CRPC. Chronic activation of Notch1 synergizes with multiple oncogenic pathways altered in early disease to promote the development of poorly differentiated prostate carcinoma. Consistent with its activation in clinical CRPC, tumors driven by NICD1 in combination with alternative pathways altered in prostate cancer are metastatic and resistant to androgen deprivation. Genetic and pharmacological inhibition of Notch1 activity decreases cell proliferation and colony formation of 22RV1 prostate cancer cells in vitro. 22RV1 subcutaneous xenograft growth was significantly impaired by treatment with pharmacological inhibitors of Notch1 activation over the course of 20-day treatment. Further, Notch1 inhibition in combination with other standard prostate cancer treatments compounded efficacy of individual treatments to attenuate colony formation potential of prostate cancer cells in vitro. The Notch1 signaling axis, confirmed to synergize with multiple pathways to promote metastatic CRPC already provides a novel pathway for diagnostic stratification of prostate cancer patients. Our studies additionally implicate Notch1 as a therapeutically relevant target for aggressive prostate cancer. Citation Format: Meghan A. Rice, En-Chi Hsu, Tanya Stoyanova. Therapeutic inhibition of Notch1 in metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4917. doi:10.1158/1538-7445.AM2017-4917