tbuckley/cabot-search huggingface dataset:
Abstract 1990: Single cell co-expression profiles of immunotherapy targets in the tumor microenvironment of NSCLC samples
Authors: Jeffrey Kim, Nan Su, Xiao-Jun Ma, Emily Park
Journal: Cancer Research (2017)

Abstract Cancer immunotherapies have made great strides in recent years, yet identifying key molecules in the tumor microenvironment is necessary to develop improved approaches to achieve more durable responses in a greater number of patients. Obstacles such as adaptive resistance to individual checkpoint marker blockade, such as PD1 and CTLA4, have led researchers down the path of pursuing multiple immune targets that may be upregulated on the same lymphocyte as a consequence of mono-antibody therapies. While several clinical trials taking a combinatorial approach are currently in progress, including targeting multiple checkpoint markers, it is clear that these new strategies may rely on the pre-existing immune system, regardless of being treatment naïve or previously treated. The challenge now is to identify the relevant biomarkers and to stratify patients to provide the most appropriate treatment. As a proof of concept, here we evaluate single cell co-expression profiles of key therapeutic targets in archived tissues of non-small cell lung cancer (NSCLC) samples using the RNAscope® Duplex Assay, an advanced in situ hybridization platform that allows for the visualization of single cell gene expression of mRNA targets directly in tissue. In our investigation of 60 archived formalin-fixed paraffin embedded NSCLC tissues, co-expression profiles of PD1 or PD-L1 coupled with another therapeutic target (IDO1, LAG3, 4-1BB, GITR, and TIM3) were assessed, bringing to light substantial variations in the tumor microenvironment between tissue samples. These marked differences of co-expressed targets on tumor infiltrating lymphocytes were scrutinized through quantitative image analysis to further reveal both the diversity and degree of individuality between tissue samples. Quantitatively measuring the expression of multiple targets in single cells within intact tissues exposed the distinct milieu of targetable therapeutic molecules, leading to the potential identification of responsive tumors which could help guide in stratifying patients for different combinatorial approaches. Citation Format: Jeffrey Kim, Nan Su, Xiao-Jun Ma, Emily Park. Single cell co-expression profiles of immunotherapy targets in the tumor microenvironment of NSCLC samples [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 1990. doi:10.1158/1538-7445.AM2017-1990
Abstract 4090: Preclinical pharmacokinetics of CASC-578, a novel, selective, potent, and orally bioavailable small molecule checkpoint kinase 1 inhibitor
Authors: Dina Leviten, Teresa Sierra, Ashley Dozier, Richard Boyce, Bob Boyle, Scott Peterson, Alex C. Vo
Journal: Cancer Research (2017)

Abstract Introduction: Checkpoint kinase 1 (Chk1) is a serine/threonine protein kinase that regulates cell division in response to genotoxic stress by arresting cell cycle progression in the S &amp; G2 phases. Pharmacological inhibition of Chk1 is proposed to selectively uncouple the completion of DNA replication from G2/M phase transition in tumor cells that have impaired DNA damage response networks, resulting in mitotic catastrophe and cell death. CASC-578 is a novel small molecule inhibitor of Chk1 that is selective, highly potent and orally bioavailable in multiple preclinical species. Methods: The in vitro ADME properties of CASC-578 were evaluated, including in vitro intrinsic microsomal clearance, Caco2 permeability, plasma protein binding and stability, blood to plasma partitioning, cytochrome P450 inhibition and induction, and transporter inhibition. Pharmacokinetic studies of CASC-578 were conducted in mice, rats, and cynomolgus monkeys as either single dose (IV and/or PO) or repeat dose (PO only). Multiple oral dose pharmacokinetic studies were conducted in mice, rats and cynomolgus monkeys for 5-7 days. Results: CASC-578 is highly bound in plasma protein across all species. The apparent permeability is high in Caco2 bi-directional transport study and correlated well with a rapid absorption profile observed in vivo. CASC-578 is not a substrate of P-glycoporotein (efflux =1). There was no direct nor time dependent inhibition on human CYP450 enzymes, and only a slight induction of CYP3A4 was seen at 10 uM drug concentration in a transporter cell-based induction assay. In all animal species, CASC-578 exhibited species-dependent systemic clearance resulting from both phase I and phase II metabolism, and a moderate to high volume of distribution. The elimination kinetics appeared to be monophasic. Oral bioavailability was high in all species studied (&amp;gt;60% F). There was no significant difference in the pharmacokinetics of the drug between genders. Maximal plasma concentration and total drug exposure (AUC) appeared to be proportional from repeat dose studies. Overall, CASC-578 has very desirable drug-like properties and ideal pharmacokinetics for an oral once daily drug, and represents a suitable candidate for clinical development as a novel potential therapeutic approach for the treatment of solid and hematological malignancies Citation Format: Dina Leviten, Teresa Sierra, Ashley Dozier, Richard Boyce, Bob Boyle, Scott Peterson, Alex C. Vo. Preclinical pharmacokinetics of CASC-578, a novel, selective, potent, and orally bioavailable small molecule checkpoint kinase 1 inhibitor [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 4090. doi:10.1158/1538-7445.AM2017-4090
Abstract CT041: The clinical study on CD19-directed chimeric antigen receptor-modified T cells in patient with Richter Syndrome
Authors: Leiming Xia, Qian Chen, Qiao Li, Tan Li, Yi Wang, Yangyi Bao
Journal: Cancer Research (2017)

Abstract Richter syndrome (RS) indicates the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma (mostly DLBCL). RS is a rare complication with unfavorable clinical outcome. There is no effective treatment for it currently. As a new type of cell-based immune therapy, chimeric antigen receptor modified T (CAR-T) cell treatment is now widely used in treating hematological malignancies, especially in CD19+ B cell malignancy. Therefore, CD19-directed chimeric antigen receptor modified T cells (CART-19) treatment is worthwhile to be developed as a new method for Richter Syndrome’s patients. In this study, the patient with Richter Syndrome expressing high level of CD19 was enrolled in a clinical trial. The patient had received a series of standard treatments with no therapeutic effect before 4.55 x 108 autologous CART-19 cells were infused, of which approximately 50% were transduced with the CAR. After CART-19 infusion, the main side effects were repeated fever, pancytopenia and significant rises of serum cytokines, including IFN-γ, IL-6 and IL-10. However, before discharge, the level of cytokines reduced to normal level. In addition, we detected K+, Ca2+, creatinine and glutamic-pyruvic transaminase, and found all of these were normal, which suggested that there was no significant tumor necrosis after treatment. The treatment included two courses. During the first course, the patient was infused with 4 x 107 CART-19 cells twice, followed by 1 x 108 cells in the 3rd infusion and then 1x106 cells in the 4th infusion. After these infusions, the proportion of B cells in the patient’s peripheral blood decreased from 72% to 40%, accompanied by reduced size of cervical, mediastinal and axillary lymph nodes. Eighteen days later, the patient was infused in the second course with 3.7x107 CART-19 cells twice, followed by 1x108 cells twice. After the second course, the proportion of B cells maintained at approximate 85%, and the lymph nodes enlargement was observed as disease progression. Based on the recent therapeutic landscape for hematological malignancies including B cell lymphomas, CD19-CAR T cell therapy may offer a new therapeutic option for RS, which aims to reduce the patients’ tumor burden, prolong their survival time, and provide opportunities for combined therapy with chemotherapy and bone marrow transplantation. Note: This abstract was not presented at the meeting. Citation Format: Leiming Xia, Qian Chen, Qiao Li, Tan Li, Yi Wang, Yangyi Bao. The clinical study on CD19-directed chimeric antigen receptor-modified T cells in patient with Richter Syndrome [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 CT041. doi:10.1158/1538-7445.AM2017-CT041
Abstract 2272: A prospective study of urinary prostaglandin E2 metabolite, <i>Helicobacter pylori</i> antibodies, and gastric cancer risk
Authors: Tianyi Wang, Hui Cai, Wei Zheng, Angelika Michel, Michael Pawlita, Ginger Milne, Yong-Bing Xiang, Yu-Tang Gao, Hong-Lan Li, Nathaniel Rothman, Qing Lan, Xiao-Ou Shu, Meira Epplein
Journal: Cancer Research (2017)

Abstract Background. Previous studies suggest that a stable end-product of prostaglandin E2, the urinary metabolite PGE-M, is excreted in the urine and can be used as an index of systemic prostaglandin E2 (PGE2) production. In the present study we investigate the PGE-M, Helicobacter pylori (H. pylori), and gastric cancer association. Methods. The present analysis included 359 prospectively ascertained gastric cancer cases and 700 individually matched controls from two population-based prospective cohort studies, the Shanghai Women’s Health Study and Shanghai Men’s Health Study. Urinary PGE-M was measured by a liquid chromatography/tandem mass spectrometric method. Sero-positivity to 15 H. pylori recombinantly expressed fusion proteins was detected by H. pylori multiplex serology. Results. Adjusting for H. pylori, increasing PGE-M was associated with higher risk of gastric cancer (Quartile 4 vs. 1, OR=1.76, 95% CI: 1.17-2.66, Ptrend =0.004). This association remained after excluding those diagnosed within two years from sample collection (OR=1.73, 95% CI: 1.12-2.65, Ptrend =0.007). However it was no longer present among individuals with 10 or more years of follow-up (2-4.9 years, OR=3.15, 95% CI: 1.11-8.91; 5-9.9 years, OR=2.23, 95% CI: 1.22-4.06; ≥10 years, OR=0.73, 95% CI: 0.31-1.70). The association of PGE-M with gastric cancer risk was not modified by H. pylori status, but added predictive ability beyond H. pylori; compared to H. pylori-negative individuals with below-median PGE-M levels, H. pylori-positive individuals with above-median PGE-M levels had a 5-fold increase in the odds ratio of gastric cancer (OR=5.08, 95% CI: 2.47-10.43). Conclusion. In China, higher PGE-M levels may indicate an increased risk of gastric cancer independent of the risk conferred by H. pylori infection status, particularly for cancers diagnosed within 10 years of sample collection. Citation Format: Tianyi Wang, Hui Cai, Wei Zheng, Angelika Michel, Michael Pawlita, Ginger Milne, Yong-Bing Xiang, Yu-Tang Gao, Hong-Lan Li, Nathaniel Rothman, Qing Lan, Xiao-Ou Shu, Meira Epplein. A prospective study of urinary prostaglandin E2 metabolite, Helicobacter pylori antibodies, and gastric cancer risk [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 2272. doi:10.1158/1538-7445.AM2017-2272
Abstract 4539: Novel feature selection strategies for enhanced predictive modeling and deep learning in the biosciences
Authors: Pengwei Yang, Ryan Abo, Chang Liu, Zehua Chen, Haiguo Wu, Jike Cui, Chandri Yandava, Shannon T. Bailey, Curt Balch, Jeffery R. Gulcher, Thomas W. Chittenden
Journal: Cancer Research (2017)

Abstract Artificial Intelligence (AI) is the single most transformative technology in human history. Advancements in personalized medicine depend upon significantly furthering our current understanding of how genetic variation and somatic mutation regulate aberrant gene activity and subsequent disease biology, including the myriad of dysregulated molecular mechanisms of cancer. To this end, we have built a robust AI method to precisely assess pathogenicity for all genomic missense variants. Coupled with our advanced deepCODE feature selection strategy for constructing deep learning models, we can quantitatively integrate a priori pathway-based biological knowledge with multiple types of high-throughput omics data. This approach significantly improves performance of established classification methods via enhanced semantic interoperability for mapping between multiple biomedical ontologies and the subsequent identification of genes and molecular pathways more highly predictive of cancer type etiology. Specifically, our deepCODE AI methods greatly improve tumor subtype and drug-response classification accuracies by combining tumor DNA- and RNA-seq data. Our results indicate classification of human breast and lung cancer subtypes with 96% and greater than 99% accuracy, respectively. Our novel multinomial statistical-learning method, which was validated with 6 cancer type patient-derived tumor xenograft (PDTX) mouse models, achieved greater than 95% accuracy across 10,000 human tumors within the collection of 28 TCGA cancer types. Finally, our stepwise deepCODE drug target discovery approach systematically integrates our deep learning classification strategy with advanced Bayesian Network modeling to identify causative driver genes, representing probable novel drug targets. This stepwise machine learning approach also serves as a unique means to assess drug efficacy. Taken together, our advanced deepCODE AI tools greatly expand the means to fully understand the underlying molecular determinants of human cancer. We have developed user-friendly decision support and research tools for in-depth tumor analysis and large-scale case-control methods that afford investigators access to our deepCODE variant annotation algorithms. Citation Format: Pengwei Yang, Ryan Abo, Chang Liu, Zehua Chen, Haiguo Wu, Jike Cui, Chandri Yandava, Shannon T. Bailey, Curt Balch, Jeffery R. Gulcher, Thomas W. Chittenden. Novel feature selection strategies for enhanced predictive modeling and deep learning in the biosciences [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 4539. doi:10.1158/1538-7445.AM2017-4539
Abstract 4377: EBV associated gastric cancer in Korean
Authors: Woochan Lee
Journal: Cancer Research (2017)

Abstract Gastric cancer was the third leading cause of death worldwide and most prevalent malignant cancer in Korea, comprising 20.8% of all cancers. The Cancer Genome Atlas (TCGA) divided gastric cancer to four subgroups; EBV (Epstein-Barr Virus infected, 9%), MSI (Microsatellite instability, 22%), GS (Genomically stable, 20%), CIN (Chromosomal instability, 50%). We sequenced transcriptomes of 11 gastric cancers associated with EBV infection (EBVaGC) tissues, 11 gastric cancers not associated with EBV infection (EBVnGC) tissues and 22 matched normal gastric mucosa for find unique features of Korean EBVaGC. We compared RNA expression, EBV gene expression, germline mutations, and somatic mutation between EBVaGC and EBVnGC. We found IKBKE gene, which is taking an essential role in regulating antiviral signaling pathways, expressed higher on EBVaGC tumor than EBVnGC tumor (p-value=1.73 x 10-4). While most EBV genes appeared to be similar, BMRF1,2 genes made distinctive patterns compared to previous TCGA report in expression of EBV which integrated into human cells. The BMRF-2 gene is associated with cell-to-cell spread of EBV, which is major infection mechanism of EBV. We found novel germline mutations on PABPC3, PGA3, and C4A,B in almost every samples, which are candidate for Korean specific mutations. Citation Format: Woochan Lee. EBV associated gastric cancer in Korean [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 4377. doi:10.1158/1538-7445.AM2017-4377
Abstract SY29-01: Targeting DNA repair factor dysfunction in advanced prostate cancer
Authors: Karen E. Knudsen
Journal: Cancer Research (2017)

Abstract Prostatic adenocarcinoma (PCa) is the third leading cause of cancer death in U.S. men. Organ-confined PCa can be effectively managed, but there is no durable treatment for advanced disease. Advanced PCa is treated through androgen deprivation therapy, often coupled with direct androgen receptor (AR) antagonists, as PCa is exquisitely dependent on AR activity for cell survival and proliferation. Unfortunately, relapse is common; recurrent disease arises largely due to resurgent AR activity with 2-3 years, and there is no cure for this castration-resistant phase (castration-resistant PCa; CRPC). Thus, there is a significant need to develop new means for targeting recurrent AR activity or to develop adjuvant therapies in advanced PCa. Emerging data from our laboratory and others strongly support the concept that alterations in DNA damage repair (DDR) pathways are more common than previously thought in sporadic PCa, and that alterations in these pathways may afford new, more effective means of therapeutic intervention. New studies to be discussed will address underlying mechanisms of action with regard to the pathway and identify clinically actionable ramifications of DNA repair dysfunction. Major concepts to be considered include 1) new findings implicating differential functions of p53 somatic mutations on PCa behavior and response to therapeutic intervention and 2) differential roles of DNA-dependent protein kinase (DNAPK) in controlling PCa progression. Findings to be discussed strongly support a model wherein selected DDR pathways can be developed as therapeutic targets to tailor treatment for prostate cancer and improve outcome for advanced disease. Citation Format: Karen E. Knudsen. Targeting DNA repair factor dysfunction in advanced 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 SY29-01. doi:10.1158/1538-7445.AM2017-SY29-01
Abstract 877: Real-time imaging of adherent and non-adherent cell interactions: utility of an automated microfluidic trap platform to recapitulate <i>in vivo</i> cell culture microenvironment
Authors: Rekha Kannan, Victor Yeh, James Helton, Amedeo Cappione
Journal: Cancer Research (2017)

Abstract The study of dynamic cell processes and their interactions is of crucial importance to understand the complexities of tissue microenvironments. Simulation of in vivo cell culture microenvironments can greatly improve biologic relevance of cell-cell interaction studies, and so there is an ongoing demand for heuristic optimization of cell co-culture devices and protocols. One particularly challenging task is establishing real-time image analysis while co-culturing non-adherent cells in contact with adherent cell layers under precisely controlled environmental parameters. To address this challenge, we present a novel microfluidic approach to trap two different cell types in precise locations in order to image and study their interactions over time. The platform utilizes a well plate format that contains multiple microfluidic units. Each unit consists of a 3 mm x 3 mm x 40 µm (L x W x H) chamber for culture, and an array of microscopic trap areas tailored to the dimensions of the cells of interest, typically ~15 µm. The micro-scale geometries of the traps physically confine non-adherent cells, and co-cultures can be achieved by trapping the non-adherent cells over a monolayer of cells. The microfluidic plate is integrated with a system which enables perfusion-based nutrient supply along with gas and temperature control for long-term cell culture. Each chamber within the plate can be addressed by programmable and on-demand perturbation of up to 6 reagents, enabling uninterrupted real-time live cell imaging assays. We present here the use of this microfluidic platform to replicate tumor microenvironment by maintaining adjacent co-cultures of cancer and immune cells. We have successfully imaged and cultured monolayers of tumor cell lines for 7 days followed by subsequent loading and trapping of immune (non-adherent) cells. In conclusion, the microfluidic platform enables unique co-cultures with environmental control and real-time imaging to facilitate the investigation of cell-cell interactions in a wide range of applications such as drug response and screening in tumor microenvironments, invasion, evasion pathways and other mechanisms governing cell-cell interactions. Citation Format: Rekha Kannan, Victor Yeh, James Helton, Amedeo Cappione. Real-time imaging of adherent and non-adherent cell interactions: utility of an automated microfluidic trap platform to recapitulate in vivo cell culture microenvironment [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 877. doi:10.1158/1538-7445.AM2017-877
Abstract 2515: Understanding metabolic dysfunction in retinoblastoma development
Authors: Nilanjan Guha, Carolina Livi, Vishnu Suresh Babu, Lisa Winer, Deepak SA, Syed Lateef, Seetaraman Gundimeda, Arunkumar Padmanabhan, Brian Dranka, Arkasubhra Ghosh
Journal: Cancer Research (2017)

Abstract Metabolic dysfunction or reprogramming is the underlying cause of many diseases including cancer. In this study, we looked into the transcriptomic and metabolomic profile of retinoblastoma (Rb), a pediatric eye cancer, from tumor and normal tissue, aqueous humor, vitreous humor and tear. The samples were collected from enucleated eyes of 9 subjects and 2 deceased controls, whose cause of death is not due to any eye related disease. The study was corroborated with cell line models of retinoblastoma, used for metabolic phenotyping. Combined pathway analysis of transcriptomics data from subject tissue samples and retinoblastoma cell line WERI-Rb-1 revealed a significant overlap in the differentially regulated genes belonging to both glycolysis and OXPHOS pathways. The results were correlated with Rb1 overexpressed and its respective control also. To better understand the implications of these two major pathways in the progression of retinoblastoma, metabolic study using Seahorse analyzer enables measurement of extracellular flux (oxygen consumption rate and extracellular acidification rate) to provide insight into mitochondrial function and glycolytic activity. Using a pharmacological approach, the contribution of glucose, glutamine and fatty acid oxidation pathways can be assessed. Overall the study demonstrates the value of using a multi-omics approach with functional metabolic profiling to understand the extent of metabolic dysfunction in retinoblastoma and also to identify implications of various biological pathways in Rb. Citation Format: Nilanjan Guha, Carolina Livi, Vishnu Suresh Babu, Lisa Winer, Deepak SA, Syed Lateef, Seetaraman Gundimeda, Arunkumar Padmanabhan, Brian Dranka, Arkasubhra Ghosh. Understanding metabolic dysfunction in retinoblastoma development [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 2515. doi:10.1158/1538-7445.AM2017-2515