tbuckley/cabot-search huggingface dataset:
Abstract 4563: Profiling the tumor immune microenvironment of adenocarcinoma and squamous cell NSCLC
Authors: Kayla Harmeyer, Jiehui Deng, Suhagi Shah, Ece Bagdatlioglu, Aarif Ahsan, Christopher Reid, Aatish Thennavan, Charles Perou, Kwok-Kin Wong, Harvey Pass
Journal: Cancer Research (2019)

Abstract The emergence of immune checkpoint inhibitors has changed the treatment paradigm for NSCLC. Recently, immunotherapy in combination with chemotherapy was shown to be a promising first-line treatment strategy for patients with squamous cell lung cancer, where targeted therapy has had little efficacy due to the pathological driver mutations for this disease being poorly understood. However, for both adenocarcinoma and squamous cell NSCLC, use of such immune checkpoint inhibitors has shown to improve the outcome for only a subset of patients with advanced or metastatic disease. Understanding the diversity in the tumor immune microenvironment will be critical to not only advance immune oncology research but to also determine potential clinical distinctions that dictate therapeutic response. Here, we take a multifaceted approach to compare the tumor immune microenvironments of over 50 patients diagnosed with either adenocarcinoma or squamous cell NSCLC. To this end, we performed a comprehensive multicolor flow cytometry analysis to compare tumor immune infiltrates and expression of suppressive markers to adjacent normal lung tissue as well as peripheral blood immune cells from the same patient. This analysis showed differences in the CD4+ and CD8+ T cell, CD19+ B cell, NK cell, and CD14+/CD16+ myeloid cell populations between the tumor and matched tissue and blood. These immune profiles were then compared between adenocarcinoma and squamous cell carcinoma subtypes as well as early versus late stage disease. We then integrated these findings with multiplexed immunofluorescence analysis on a panel of immune cell markers. Finally, 10x genomics single-cell RNA sequencing (scRNAseq) data were used to analyze single-cell transcriptomes from both adenocarcinoma and squamous cell lung tumors. Our result showed great heterogeneity of immune infiltrates across different patient samples, including different subtypes and different disease stages. This detailed comparative analysis will help us further understand the involvement of tumor infiltrating immune cells for different subtypes of lung cancer. Citation Format: Kayla Harmeyer, Jiehui Deng, Suhagi Shah, Ece Bagdatlioglu, Aarif Ahsan, Christopher Reid, Aatish Thennavan, Charles Perou, Kwok-Kin Wong, Harvey Pass. Profiling the tumor immune microenvironment of adenocarcinoma and squamous cell NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4563.
Abstract 15791: Myocardial Induction of Tissue Inhibitor of Matrix Metalloproteinase-4 Modifies Post Myocardial Infarction Left Ventricular Remodeling
Authors: Francis G Spinale, Juozas A Zavadzkas, Robert E Stroud, William T Rivers, Richard A McKinney, Eileen I Chang, Rebecca A Plyler, Shenikqua Bouges, Rupak Mukherjee
Journal: Circulation (2010)

Background: Alterations in the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) contribute to adverse LV remodeling following myocardial infarction (MI). In pa...
Risk of rash with nilotinib: A systematic review of the literature and meta-analysis.
Authors: Aaron Mark Drucker, Shenhong Wu, Ellin Berman, Mario E. Lacouture
Journal: Journal of Clinical Oncology (2012)

9088 Background: Nilotinib is indicated for the treatment of chronic myelogenous leukemia (CML). The reported incidence and risk of rash from this medication vary widely and have been inconsistently reported in published trials. Therefore we conducted a systematic review and meta-analysis of the literature to determine the incidence and risk of developing rash. Methods: Relevant studies were identified from the PubMed database (1998-2012), abstracts presented at ASCO and ASH Conferences (2004-2011) and Web of Science database (1998-2012). Eligible studies were limited to prospective Phase II-III clinical trials in which patients received nilotinib at doses of either 300 mg or 400 mg twice daily. Incidence, relative risk (RR), and 95% confidence intervals (CI) were calculated using random-effects or fixed-effects models based on heterogeneity of included studies. Results: Data from a total of 3,186 patients receiving nilotinib in 16 clinical trials were available for analysis. The overall incidence of all-grade and high-grade (grade ≥3) rash were 33.1% (95% CI: 27.7-39.1) and 2.6% (95% CI: 2.1-3.4), respectively. Incidence of all-grade rash for patients with CML, gastrointestinal stromal tumor (GIST) and systemic mastocytosis were 33.2% (95% CI: 27.2-39.9), 25.7% (95% CI: 14.0-42.5) and 25.0% (95% CI: 15.7-37.4), respectively. Nilotinib was associated with increased risk of all-grade rash (RR=2.891, 95% CI: 2.079-4.020; P&lt;0.001) when compared to patients treated with imatinib. Risk of high-grade rash was increased compared to imatinib (RR=1.823, 95% CI: 0.670-4.957), but this was not statistically significant (P=0.24). Conclusions: Patients with hematologic malignancies and GIST who are treated with nilotinib are at significant risk for developing a rash. Further studies for characterization, prevention and treatment of this untoward toxicity are needed in order to maintain patients’ quality of life and minimize the need for dose modification, which may impact clinical outcome.
Circulating tumor cell detection and microsatellite instability status in predicting outcomes of advanced CRC patients
Authors: I. Messaritakis, M. Sfakianaki, K. Vogiatzoglou, A. Koulouridi, O. Dimitriou, N. Gouvas, E. Athanasakis, I. Tsiaoussis, E. Xynos, D. Mavroudis, M. Tzardi, J. Souglakos
Journal: Annals of Oncology (2019)
Serum Wisteria floribunda agglutinin-positive human Mac-2 binding protein level predicts recurrence of hepatitis B virus-related hepatocellular carcinoma after curative resection
Authors: Hye Soo Kim, Seung Up Kim, Beom Kyung Kim, Jun Yong Park, Do Young Kim, Sang Hoon Ahn, Kwang-Hyub Han, Young Nyun Park, Dai Hoon Han, Kyung Sik Kim, Jin Sub Choi, Gi Hong Choi, Hyon-Suk Kim
Journal: Clinical and Molecular Hepatology (2019)

Background/Aims To investigate whether serum Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA+-M2BP) can predict the recurrence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative resection. Methods Patients with chronic hepatitis B (CHB) who underwent curative resection for HCC between 2004 and 2015 were eligible for the study. Recurrence was sub-classified as early (<2 years) or late (≥2 years). Results A total of 170 patients with CHB were selected. During the follow-up period (median, 22.6 months), 64 (37.6%) patients developed recurrence. In multivariate analyses, WFA+-M2BP level was an independent predictor of overall (hazard ratio [HR]=1.490), early (HR=1.667), and late recurrence (HR=1.416), together with male sex, des-gamma carboxyprothrombin level, maximal tumor size, portal vein invasion, and satellite nodules (all P<0.05). However, WFA+-M2BP level was not predictive of grade B-C posthepatectomy liver failure. The cutoff value that maximized the sum of sensitivity (30.2%) and specificity (90.6%) was 2.14 (area under receiver operating characteristic curve=0.632, P=0.010). Patients with a WFA+-M2BP level >2.14 experienced recurrence more frequently than those with a WFA+-M2BP level ≤2.14 (P=0.011 by log-rank test), and had poorer postoperative outcomes than those with a WFA+-M2BP level ≤2.14 in terms of overall recurrence (56.0 vs. 34.5%, P=0.047) and early recurrence (52.0 vs. 20.7%, P=0.001). Conclusions WFA+-M2BP level is an independent predictive factor of HBV-related HCC recurrence after curative resection. Further studies should investigate incorporation of WFA+-M2BP level into tailored postoperative surveillance strategies for patients with CHB. Keywords: Hepatitis B; Liver fibrosis; Biomarkers; Hepatocellular carcinoma; Prognosis
Abstract 1653: Application of high-density tiling CRISPR screen technology to identify chromatin remodeler complex targets for drug discovery
Authors: Luis Soares, Michael Bocker, Qianhe Zhou, Cigall Kadoch, Ho Man Chan
Journal: Cancer Research (2019)

Abstract The mammalian SWI/SNF (mSWI/SNF or BAF) complexes are widely mutated in different human pathologies, presenting new therapeutic opportunities in a range of genetically well-defined cancers, including lung, endometrial, malignant rhabdoid tumor, synovial sarcoma, and others. In each of these settings, disruption of different SWI/SNF subunits have been shown to contribute to the tumorigenic potential via distinct mechanisms. This observation suggests the potential for a range of therapeutic targeting strategies to effectively inhibit cancer cell proliferation. Using high-density tiling sgRNA CRISPR/Cas9 screens, we have developed large-scale efforts to systematically identify critical protein functional domains within chromatin remodeling complex components to inform drug discovery strategies across several different cancer indications. Using this approach, we have successfully identified and validated critical functional domains in mSWI/SNF complex components with promising drug target potential in indications such as BRG1-mutated non-small cell lung adenocarcinoma and synovial sarcoma. Citation Format: Luis Soares, Michael Bocker, Qianhe Zhou, Cigall Kadoch, Ho Man Chan. Application of high-density tiling CRISPR screen technology to identify chromatin remodeler complex targets for drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1653.
Abstract 12231: T-Type and N-Type Calcium Channel Blockers Attenuate Cardiac Sympathetic Nervous Activity More Effectively Compared With L-Type Calcium Channel Blocker in Patients with Hypertension
Authors: Chika Ogura, Shoichi Miyamoto, Akiko Ikai, Shiro Tanaka, Masatoshi Fujita
Journal: Circulation (2011)

Introduction: Sympathetic nervous activity is augmented with the calcium channel blocker (CCB) treatment as a result of decreased blood pressure despite the advent of long-acting CCBs. Dihydropyrid...
Abstract 2404: Mechanistic insight into anti-tumor activity of DKN-01, a therapeutic antibody with immune modulatory activity
Authors: Michael Haas, Heidi Heath, Franziska Schurpf-Huber, Yinyuan Wu, Xinjun Zhang, Xi He, Min Yang, Walter Newman, Michael Kagey
Journal: Cancer Research (2019)

Abstract Wnt signaling is a fundamental pathway that is dysregulated in oncology. The Wnt signaling modulator DKK1 is expressed in a variety of tumor types and elevated levels frequently correlate with poor survival. DKK1 promotes tumor growth by stimulating proliferation, metastasis, and angiogenesis, and has been implicated in contributing to an immune suppressive tumor microenvironment. DKN-01 is a humanized monoclonal therapeutic antibody that binds DKK1 with high affinity and selectivity. It is currently being evaluated clinically as a monotherapy and in combination with chemotherapies and other immunotherapies in a variety of solid tumors. Here we demonstrate that efficacy from a murine version of DKN-01 (mDKN-01) in a syngeneic tumor model requires NK cells. mDKN-01 also reduces lung metastasis, further supporting a model where DKK1 neutralization stimulates a NK mediated anti-cancer response. In addition, DKN-01 has efficacy in a human prostate xenograft model that expresses high levels of DKK1 and retains functioning NK cells. Taken together, these data support an innate immunotherapeutic mechanism of action of DKN-01 and suggest that tumor expression of DKK1 may predict response. As such, evaluation of peripheral blood and tumor biopsies from patients undergoing treatment with DKN-01 in combination with chemotherapy or other immunotherapies are underway to demonstrate innate immune mediated anti-tumor activity and validate DKK1 expression as a biomarker. Citation Format: Michael Haas, Heidi Heath, Franziska Schurpf-Huber, Yinyuan Wu, Xinjun Zhang, Xi He, Min Yang, Walter Newman, Michael Kagey. Mechanistic insight into anti-tumor activity of DKN-01, a therapeutic antibody with immune modulatory activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2404.
Abstract 2020: Adipocytes up-regulates CD36 expression, fatty acid uptake and oxidation enhancing breast cancer cell progression
Authors: Junjeong Choi, Jones Gyamfi
Journal: Cancer Research (2019)

Abstract The role of the tumor microenvironment in tumor progression has recently gained enormous attention, with studies reporting heterogeneous interactions between tumor cells and tumor stroma cells driving tumor progression. The breast cancer microenvironment is unique since the breast tissue within which the tumor originates comprises predominantly of adipocytes. This makes adipocytes a unique component in the breast cancer microenvironment. Adipocytes secrete various growth factors and cytokines that influence tumor progression by induction of epithelial-mesenchymal transition (EMT) which enhances cancer cell migration, invasion and metastasis. This study presents an alternative approach by which adipocytes may enhance cancer progression via the transfer of free-fatty acids from tumor-associated adipocytes to breast cancer cells. The uptake of free fatty acid subsequently serves as a secondary source of energy to drive breast cancer progression. The study aimed to provide an in-depth understanding of the molecular mechanism by which free fatty acid are imported and metabolized in cancer cells in an adipocyte-rich microenvironment. Human adipocytes were co-cultured with cancer cells and the fatty acid (FA) translocase (CD36) activity was inhibited by the chemical inhibitor sulfosuccinimidyl oleate (SSO). Silencing RNA and expression plasmids were used to evaluate CD36 activity in cancer cells. Expression levels of key genes and proteins involved in lipid transfer and metabolism were evaluated by qtPCR and western blot. Inhibition of CD36 reduces free fatty acid uptake and induces intracellular lipogenesis with upregulation of fatty acid synthase (FASN). Breast cancer cells co-cultured with human adipocytes express high levels of the CD36 facilitating free fatty acid uptake from adipocytes. Co-cultured cells had increased levels of fatty acid oxidation (FAO) and oxygen consumption, with increased migration and invasion characteristics. We also observed a significant increase in the expression of CPT1A required for mitochondrial fatty acid import and ATGL required for triglyceride metabolism. Our findings indicate an enhanced dependence on FAO in co-cultured cancer cell. Indicating a potential bioenergetic adaptation of breast cancer cells to the adipocyte-rich microenvironment. Inhibition of CD36 and CPT1 significantly decreased breast cancer cell migration and invasion. These results suggest that cancer-associated adipocytes induce free fatty acid uptake via upregulation of CD36 and reprogram breast cancer cell metabolism. Thus, targeting CD36 may have a potential targeted therapy. Citation Format: Junjeong Choi, Jones Gyamfi. Adipocytes up-regulates CD36 expression, fatty acid uptake and oxidation enhancing breast cancer cell progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2020.
Optimizing panel-based tumor mutational burden (TMB) measurement
Authors: J. Budczies, M. Allgäuer, K. Litchfield, E. Rempel, P. Christopoulos, D. Kazdal, V. Endris, M. Thomas, S. Fröhling, S. Peters, C. Swanton, P. Schirmacher, A. Stenzinger
Journal: Annals of Oncology (2019)
Abstract 1358: Tumor-derived extracellular vesicles as kidney cancer biomarkers
Authors: Richard C. Zieren, Liang Dong, Sarah R. Amend, Philip M. Pierorazio, Theo M. de Reijke, Kenneth J. Pienta
Journal: Cancer Research (2019)

Abstract Renal cell carcinoma (RCC) is a fairly common and lethal cancer. The wide variety of RCC histological subtypes constitutes a challenge in treatment decision-making. Exosomes are extracellular membrane vesicles that are produced by all cell types in physiological conditions. Extracellular vesicles (EVs) are now accepted as a mode of intercellular communication and transport proteins, RNAs, DNA, and lipids to surrounding and distant cells. The lipid bilayer membrane of the EVs helps to protect these cargos. EVs are involved in many pathological processes, such as cancer, and can be easily obtained through liquid biopsy. Currently, EVs are rarely considered as candidate biomarkers for kidney cancer. However, improvements in the characterization of tumor-derived EVs could lead to the implementation of blood- and urine-derived EVs as biomarkers in the management of oncologic patients. Since all organs, not just the tumor, contribute to EV population, the thoughtful discrimination of tumor-derived EVs remains an unmet need for the clinical application of this kind of liquid biopsy technology. To determine the contribution of the tumor to blood- and urine-derived EVs, we utilize a novel approach to isolate tissue-derived EVs in parallel with liquid biopsy-derived EVs. To our knowledge, only a handful of studies (only one in RCC) have studied EVs directly derived from tissue. We propose the use tissue-derived EVs to screen for candidate EV biomarkers in plasma and/or urine. We hypothesize that using tissue-derived EVs would increase the tumor specificity for the characterization of EVs as liquid biopsy biomarkers. We optimized a protocol in which we used tissue of RCC patients (normal kidney or tumor) to condition media and isolate tumor-derived EVs alone by ultracentrifugation. Additionally, we isolated plasma- and urine EVs by ultracentrifugation using standard protocols. Nanoparticle Tracking Analysis (NTA) showed normalized concentrations of &amp;gt;2 x 109 particles/mL with a size distribution in the small EV-range. Transmission Electron Microscopy (TEM) images showed typical exosome morphology, with the characteristic cup-shaped membrane vesicles. Western Blot (WB) confirmed the presence of exosome markers. We successfully isolated EVs from human RCC and healthy kidney tissue. We will proceed with screening the EV-samples for candidate miRNA-biomarkers by multiplexed gene expression analysis, followed by confirmation of the candidate markers by RT-qPCR. Citation Format: Richard C. Zieren, Liang Dong, Sarah R. Amend, Philip M. Pierorazio, Theo M. de Reijke, Kenneth J. Pienta. Tumor-derived extracellular vesicles as kidney cancer biomarkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1358.
Abstract 1583: Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development
Authors: Yafang Li, Xiangjun Xiao, Ivan Gorlov, Younghun Han, Rayjean Hung, Christopher Amos
Journal: Cancer Research (2019)

Abstract The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10-11 in overall lung cancer and OR=0.41, p value=9.71x10-11 in non-small cell lung cancer), SYNE1:RNF43(OR=0.73, p value=1.01x10-12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10-11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. We further explored the impact of identified genetic interactions on the expression of involved cancer-related genes using the lung eQTL dataset including a total of 409 subjects with both genotyping and gene expression data. In the study between TSPAN8 gene and rs1882898:rs1705235 SNP pair, we identified decreased gene expression in individuals with reduced lung cancer risk which supports the oncogene function of TSPAN8. In the gene expression analysis between SYNE1 and rs10515157:rs1554783 SNP pair, we also identified consistent evidence between gene expression and lung cancer risk. Finally, we conducted gene set enrichment analysis to reveal potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play important roles in lung tumorigenesis. Epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes. Citation Format: Yafang Li, Xiangjun Xiao, Ivan Gorlov, Younghun Han, Rayjean Hung, Christopher Amos. Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1583.