tbuckley/cabot-search huggingface dataset:
Abstract 4452: Study of the mechanisms of emetine dihydrochloride on inhibiting NSCLC tumor progression and attenuating EGFR signaling pathway
Authors: Yi-Hua Lai, Wan-Ting Huang, Sheng-Yi Lin, Yao-Ting Huang, Yuh-Ling Chen, Hsuan-Yu Chen, Huei-Wen Chen, Jeremy J.W. Chen
Journal: Cancer Research (2017)

Abstract Epidermal growth factor receptor (EGFR) is a transmembrane receptor protein and can mediate the cellular biological responses including regulation of cellular proliferation, differentiation, migration and survival. More than 60 % of non-small cell Lung cancers (NSCLCs) express relatively high level of EGFR. Therefore, EGFR has become an important therapeutic target for the treatment of NSCLC. However, almost all NSCLC patients ultimately develop drug resistance to targeted therapy agents. The most common secondary mutation is found to harbor EGFR mutation in T790M, which is acquired resistance to EGFR TKIs. In order to overcome the resistance of T790M mutation in lung cancer, we used EGFR pY1068 ELISA as drug-screening platform to screen the candidate compounds with the capacity to suppress EGFR activity from the compound library of more than 300 plant active ingredients. Among the compounds identified, the emetine could most significantly restrain EGFR pY1068 activity and reduce cancer cell viability. Moreover, the Western blotting results showed that emetine treatment can repress EGFR phosphorylation and expression in a dose-dependent manner as well as inhibit its downstream substrates including PI3K, STAT3 and Src in three different Iressa-resistant cell lines. In addition, emetine also could inhibit cell proliferation, migration, invasion, and clonogenicity in vitro and xenograft tumor growth in vivo. Taken together, our data suggest that emetine might be a novel inhibitory modulator of EGFR activity and might be through suppressing the phosphorylation and expression of PI3K, STAT3, and Src to inhibit lung cancer progression. These findings will help us to develop the anti-cancer drugs for lung cancer in the future. Citation Format: Yi-Hua Lai, Wan-Ting Huang, Sheng-Yi Lin, Yao-Ting Huang, Yuh-Ling Chen, Hsuan-Yu Chen, Huei-Wen Chen, Jeremy J.W. Chen. Study of the mechanisms of emetine dihydrochloride on inhibiting NSCLC tumor progression and attenuating EGFR signaling pathway [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 4452. doi:10.1158/1538-7445.AM2017-4452
Abstract 1438: The dynamics of genetic aberrations in Crohn's disease associated colorectal carcinogenesis
Authors: Daniela D. Hirsch, Darawalee Wangsa, Yue Hu, Jack Zhu, David Petersen, Daniel C. Edelman, Paul S. Meltzer, Bao Tran, Kerstin Heselmeyer-Haddad, Thomas Ried, Timo Gaiser
Journal: Cancer Research (2017)

Abstract Crohn’s disease, a condition of chronic inflammation of the intestine, significantly increases the risk for the development of colorectal cancer (CRC). Sporadic CRCs are characterized by a specific pattern of genomic imbalances and a landscape of acquired gene mutations. In this study we aimed to compare CRCs that arise as a consequence of chronic inflammation in Crohn’s disease with sporadic CRCs. We analyzed 26 Crohn’s disease associated CRCs, four matched dysplastic lesions, six matched inflamed mucosa samples, and two matched lymph node metastases using array comparative genomic hybridization, targeted sequencing (564 cancer related genes) and gene expression profiling. As a control, we used normal intestinal mucosa from the resection margin of these CRCs and 24 sporadic CRCs. In general, CRCs that developed in patients with Crohn’s disease had a similar distribution of genomic imbalances compared to sporadic CRC. However, we identified distinct mutation signatures: in the Crohn's disease associated CRCs the most frequently mutated gene was TP53, which occurred in 65% of the samples. The second, third and fourth most frequently mutated genes were KRAS (27%), APC (23%) and PIK3CA (19%). In the control group of sporadically arising CRCs, the most commonly mutated gene was APC (75%), followed by KRAS (54%), TP53 (33%), SMAD3 (29%) and SMAD2 (25%). The genetic analyses of multiple lesions from individual patients revealed a high degree of intertumoral heterogeneity with diverse patterns of gene mutations and allowed the reconstruction of the sequence of genetic events during Crohn’s disease associated tumorigenesis. In contrast to sporadic colorectal carcinogenesis, TP53 mutations were observed as early and common events while APC mutations occurred rather late and were infrequent. Our comprehensive molecular profiling of Crohn’s disease associated CRCs suggests that the genetic landscape of CRC is influenced by the activation of inflammation related pathways. Furthermore, our findings offer potential for establishing an early detection marker for dysplasia in patients with Crohn’s disease. Citation Format: Daniela D. Hirsch, Darawalee Wangsa, Yue Hu, Jack Zhu, David Petersen, Daniel C. Edelman, Paul S. Meltzer, Bao Tran, Kerstin Heselmeyer-Haddad, Thomas Ried, Timo Gaiser. The dynamics of genetic aberrations in Crohn's disease associated colorectal carcinogenesis [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 1438. doi:10.1158/1538-7445.AM2017-1438
THU0513 Neonatal manifestations of immune-mediated rheumatic diseases: a retrospective longitudinal study in a tertiary hospital
Authors: J Bernardo, I Brito, H Guimarães, M Guimarães, R Fonseca
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Autoimmune rheumatic diseases such as systemic lupus erythematosus (SLE), antiphospholipid antibody syndrome (APS) and Sjögren9s syndrome (SS) are part of a clinical spectrum eligible to affect women in child-bearing ages, affecting neonatal outcomes. Cardiac, cutaneous, haematological, hepatic complications and, more rarely, pulmonary complications have been described. <h3>Objectives</h3> This project aims to describe the occurrence of neonatal lupus manifestations and possible associated clinical factors among women with immune-mediated rheumatic diseases. <h3>Methods</h3> A retrospective longitudinal study was performed including pregnant women with immune-mediated rheumatic diseases seen in a multidisciplinary group for autoimmune diseases during pregnancy between January 2010 and December 2015. Clinical and demographic data as well as and pregnancy outcomes and neonatal manifestations were collected through consultation of clinical files. Patients with and without neonatal lupus were compared using Mann-Whitney, qui-square and fisher tests (SPSS 24.0). Significance level was set as &lt;0.05. <h3>Results</h3> We included 151 gestations from a total of 140 women with a mean age of 32,5±4,4 years; 4 gestations were twin pregnancies. Within these 151 gestations, 54 (35,8%) women had SLE, 17 (11,3%) had Sjögren9s syndrome, 17 (11,3%) had rheumatoid arthritis, 41 had APS (27,2%), 11 (7,3%) had Behçet9s disease, 4 (2,6%) had systemic sclerosis, 8 (5,3%) had mixed connective tissue disease and 16 (10,6%) had other immune-mediated diseases. 35 (23,2%) had anti-SSA/La antibodies, 18 (11,9%) had anti-SSB antibodies, 6 (4,0%) had anti-URNP antibodies and 43 (28,5%) had anti-nuclear antibodies. During follow-up, 142 (94,0%) babies were born and 7 (4,6%) abortions and 2 (1,3%) foetal losses occurred. 6 (4,2%) neonates were born with neonatal lupus and 1 (0,7%) died <i>in uterus</i> with a complete heart block. Out of the 6 babies with manifestations, 4 (66,7%) were cardiac, 2 (33,3%) were cutaneous, 1 (16,7%) was hepatic, 2 (33,3%) were haematological and 1 (16,7%) was pulmonary. Neonatal lupus manifestations occurred more frequently in mothers with SS (23.5% vs 2.2%; p=0.003), anti-SSa/Ro (20% vs 0%; p&lt;0.001), and anti-SSb/La (27.7% vs 1.5%; p&lt;0.001). <h3>Conclusions</h3> Our study proved a link between immune-mediated rheumatic diseases and specific neonatal outcomes. <h3>Disclosure of Interest</h3> None declared
Abstract 2972: SPINK1, a soluble factor released by the therapy-damaged tumor microenvironment, promotes prostate cancer resistance
Authors: Fei Chen, Da Fu, Eric Lam, Yu Sun
Journal: Cancer Research (2017)

Abstract Cancer evolution is driven by not only the genetic and/or epigenetic alterations of cancer cells, but also diverse factors that are derived from the surrounding tumor microenvironment (TME). Upon chemotherapy or radiation, stromal cells in the TME become senescent and develop a senescence-associated secretory phenotype (SASP) that is characterized by secretion of a large number of cytokines, chemokines, growth factors, and proteases. In most cases, the SASP is functionally regulated by the DNA damage secretory program (DDSP) and pathophysiologically responsible in vivo for disease exacerbation. We recently disclosed significant upregulation of the serine protease inhibitor Kazal type I (SPINK1) in primary normal human prostate fibroblasts after exposure to DNA damaging agents. SPINK1 plays critical roles in cancer cell proliferation, survival and motility in multiple human malignancies, but its influence as a soluble TME-associated factor on cancer progression remains unknown. In this study, we performed a series of molecular and cellular studies to define the biological roles of SPINK1 in an activated TME. Promoter analysis indicated that SPINK1 expression in the fibroblasts is regulated by multiple transcriptional factors including the NF-κB complex in response to genotoxic stress. Fibroblast-derived SPINK1 can significantly enhance the aggressiveness of prostate cancer cells including accelerated proliferation, increased migration, elevated invasion and more importantly, enhanced chemoresistance. SPINK1 triggers a typical epithelial-mesenchymal transition (EMT) in cancer cells, a process mediated by EGFR/PI3K/Akt and MAPK/Erk signaling pathways. Consistent with the in vitro data, our in vivo studies suggested that SPINK1 expression in the prostate TME substantially promoted cancer survival and disease progression. Clinical investigation revealed increased expression of SPINK1 in the stroma of multiple organ types including the prostate, lung and breast of cancer patients after chemotherapy, implying the systemic induction of SPINK1 by anticancer agents. Overall, our study demonstrates that SPINK1 is a soluble biomarker of therapeutically damaged TME and represents a potentially exploitable molecular target in human prostate cancer clinics. Note: This abstract was not presented at the meeting. Citation Format: Fei Chen, Da Fu, Eric Lam, Yu Sun. SPINK1, a soluble factor released by the therapy-damaged tumor microenvironment, promotes prostate cancer resistance [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 2972. doi:10.1158/1538-7445.AM2017-2972
The importance of immunization in cancer prevention, treatment, and survivorship
Authors: Elizabeth M. Ward, Christopher R. Flowers, Ted Gansler, Saad B. Omer, Robert A. Bednarczyk
Journal: CA A Cancer Journal for Clinicians (2017)

Abstract Answer questions and earn CME/CNE A measles outbreak originating in California during 2014 and 2015 called attention to the potential for infectious disease outbreaks related to underimmunized populations in the United States and the potential risk to pediatric patients with cancer attending school when such outbreaks occur. Compliance with vaccine recommendations is important for the prevention of hepatitis B‐related and human papillomavirus‐related cancers and for protecting immunocompromised patients with cancer, and these points are often overlooked, resulting in the continued occurrence of vaccine‐preventable neoplastic and infectious diseases and complications. This article provides an overview of the importance of vaccines in the context of cancer and encourages clinician, health system, and public policy efforts to promote adherence to immunization recommendations in the United States. CA Cancer J Clin 2017;67:398–410. © 2017 American Cancer Society.
Abstract 4605: Efficient targeting of BCMA-positive multiple myeloma cells by antibody-coupled T-cell receptor (ACTR) engineered autologous T cells in combination with an anti-BCMA antibody
Authors: Tooba Cheema, Taylor Hickman, Katie O'Callaghan, Lori Westendorf, Luke Manlove, Shyra Gardai, Allison Nelson, Ryan Boomer, Kathleen McGinness, Birgit Schultes, Seth Ettenberg, Django Sussman, Heather Huet
Journal: Cancer Research (2017)

Abstract B cell maturation antigen (BCMA) has recently emerged as an attractive therapeutic target in multiple myeloma. BCMA has restricted expression on plasma cells with little to no expression on other normal tissues, but is upregulated on the surface of multiple myeloma cells. BCMA can regulate proliferation and survival of myeloma cells via binding to its ligands APRIL and BAFF and induce downstream signaling pathways. Thus, several approaches to target BCMA are currently under clinical investigation, including chimeric antigen receptor (CAR) T cell therapies, bispecific antibodies and antibody drug conjugates. The Antibody-Coupled T cell Receptor (ACTR) technology is a universal, engineered T cell therapy consisting of the extracellular domain of human CD16 and the intracellular T cell co-stimulatory and signaling domains. ACTR is designed to engage the Fc domain of therapeutic antibodies opsonized to target cells to mediate anti-tumor activity. Previous work has demonstrated ACTR T cell activity in combination with rituximab, trastuzumab, and hu14.18 K322A against CD20, Her2, and GD2 expressing cell lines, respectively (Kudo et al. Cancer Res 2014; 74:93-103). Currently ACTR is being evaluated in Phase I clinical trials with rituximab to treat relapsed refractory B cell lymphoma. Here we demonstrate a humanized afucosylated anti-BCMA antibody, SEA-BCMA, binds to ACTR expressing T cells with high affinity and mediates T cell activation, potent cytotoxicity, cytokine release and proliferation across a wide range of BCMA expressing myeloma cells. ACTR activity was specific to SEA-BCMA - opsonized target cells, dose dependent and had no activity on BCMA negative tumor lines. Furthermore, the SEA-BCMA antibody has additional properties that might contribute to a therapeutic effect, including blocking the binding of ligands to BCMA and driving natural killer cell mediated ADCC effects. These preclinical studies demonstrate a promising multi-faceted activity of ACTR T cells in combination with the anti-BCMA antibody, SEA-BCMA, for clinical consideration in multiple myeloma patients. Citation Format: Tooba Cheema, Taylor Hickman, Katie O'Callaghan, Lori Westendorf, Luke Manlove, Shyra Gardai, Allison Nelson, Ryan Boomer, Kathleen McGinness, Birgit Schultes, Seth Ettenberg, Django Sussman, Heather Huet. Efficient targeting of BCMA-positive multiple myeloma cells by antibody-coupled T-cell receptor (ACTR) engineered autologous T cells in combination with an anti-BCMA antibody [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 4605. doi:10.1158/1538-7445.AM2017-4605
Abstract 1567: Oncogenesis may result from multiple different combinations of a small number of tumorigenic mutations
Authors: Ramu Anandakrishnan, Robin Varghese, Nick Kinney, Harold R. Garner
Journal: Cancer Research (2017)

Abstract Cancer is known to result from genetic mutations, both inherited and somatic. Yet, decades of investigation and the availability of extensive genomic data, have failed to reveal the specific mutations that directly result in tumorigenesis for most cancers. One possible reason is that tumorigenesis may result from one or more of multiple different combinations of mutations, while investigators generally search for a single set of mutations. A mathematical model of the probability of “hitting” one of many possible combinations of a small number of mutations was compared to the actual distribution of accumulated mutations at diagnosis as reported on the cancer genome atlas (TCGA). This “multi-combination multi-hit” model reproduces the distribution of accumulated mutations from the TCGA database with surprising accuracy (RMSD = 1.5%) for a model where one or more of 100 different possible combinations of three mutations result in tumorigenesis. We speculate that each of the three mutations affects one of the several genes in three distinct cell proliferation control pathways, such as senescence, apoptosis, autophagy and necrosis, and different combinations of mutations affecting three of these pathways may result in tumorigenesis. We have identified several such combinations for further investigation. Citation Format: Ramu Anandakrishnan, Robin Varghese, Nick Kinney, Harold R. Garner. Oncogenesis may result from multiple different combinations of a small number of tumorigenic mutations [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 1567. doi:10.1158/1538-7445.AM2017-1567
Abstract 1293: ABO blood type and cancer risk: preliminary findings from a phenome analysis
Authors: Alicia Beeghly-Fadiel, Ayush Giri, Lisa Bastarache, Jill Pulley, Jeremy Warner, Josh Denny
Journal: Cancer Research (2017)

Abstract Introduction: ABO blood type has long been implicated in disease susceptibility, including cancer. However, evidence for associations with many malignancies is mixed. We applied a novel phenome approach to test to cancer codes from electronic medical records (EMR) in relation to ABO blood type in a large predominantly Caucasian study population. Approach: Among adults aged 18-100, cancer case and control status were assigned using 58 general neoplasm related phenome codes to de-identified EMR at the Vanderbilt University Medical Center. Blood type from serologic assays was ascertained from EMR-linked laboratory reports. Associations between blood type and cancer phenomes were quantified with Odds Ratios (OR) and corresponding 95% Confidence Intervals (CI) from logistic regression in models adjusted for sex and stratified by race/ethnicity. Only analyses with at least 100 cases per strata were conducted. Results: Among 221,015 Non-Hispanic Caucasians, 37,841 Blacks, 7,714 Hispanic Caucasians, and 3,616 Asian subjects with ABO blood type available in linked EMR, we evaluated 56, 37, 4, and 3 general cancer phenome codes, respectively. After employing Bonferroni corrections, ABO blood type was significantly associated with cancers of the pancreas, ovary, cervix, skin, and hematopoietic system. Caucasians with blood type O were less likely to have ovarian cancer (OR: 0.82, 95% CI 0.73-0.91) and pancreatic cancer (OR: 0.83, 95% CI: 0.74-0.92), and more likely to have squamous cell or other skin cancer (OR: 1.08, 95% CI: 1.04-1.13) and myeloid leukemia (OR: 1.15, 95% CI: 1.06-1.25) than those with other blood types (A, B, or AB). Hispanic Caucasians with blood type O were less likely to have cervical cancer (OR: 0.56, 95% CI: 0.38-0.82) than those with other blood types. No associations surpassed correction for multiple comparisons among Blacks or Asians. Conclusions: Our phenome approach confirmed known associations between blood type and risk of pancreatic and ovarian cancer, and adds to accumulating evidence supporting associations with skin cancer and leukemia. Our novel cervical cancer association among Hispanic Caucasians and other nominally significant findings, especially in understudied non-Caucasians, should be further evaluated in large and diverse populations. In addition, research to determine how ABO blood type may influence cancer development and progression, and if such associations can be exploited for risk prediction or cancer prevention is warranted. Citation Format: Alicia Beeghly-Fadiel, Ayush Giri, Lisa Bastarache, Jill Pulley, Jeremy Warner, Josh Denny. ABO blood type and cancer risk: preliminary findings from a phenome analysis [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 1293. doi:10.1158/1538-7445.AM2017-1293
Abstract 3503: Transcriptome analysis reveals differentially expressed lncRNAs between oral squamous cell carcinoma and healthy oral mucosa
Authors: Lu Feng, John R. Houck, Pawadee Lohavanichbutr, Chu Chen
Journal: Cancer Research (2017)

Abstract Objective: Oral cavity and oropharyngeal squamous cell carcinoma (OSCC) is a major cancer type in the head and neck region. To better understand the roles long non-coding RNA (lncRNA) play in OSCC carcinogenesis, we compared the genome-wide gene expressions of lncRNA in OSCC and in the oral mucosa from healthy individuals. Materials and methods: We compared the expression levels of 3,054 probe sets for lncRNAs between 167 OSCCs and 45 healthy controls using an Affymetrix HG U133 plus 2.0 array dataset. We validated the top differentially expressed lncRNAs in three independent datasets in the Gene Expression Omnibus (GEO) repository: GSE42743, GSE9844, and GSE6791. We further tested the differential expression of the three lncRNAs showing the highest fold change by quantitative RT-PCR in a subset of 20 OSCCs and 10 control samples. Results: We found 658 lncRNA transcripts (790 probe sets) to be significantly differentially expressed between OSCC and healthy oral mucosa using a criteria of FDR&amp;lt;0.01, with 36 of them (39 probe sets) showing more than a 2-fold change. Among the 36, 14 (15 probe sets) lncRNAs were validated in all three independent datasets using the criteria FDR&amp;lt;0.01: LOC441178, C5orf66-AS1, HCG22, FLG-AS1, CCL14/CCL15-CCL14, LOC100506990, TRIP10, PCBP1-AS1, LINC01315, LINC00478, COX10-AS1/LOC100506974, MLLT4-AS1, MIR31HG, and DUXAP10/LINC01296. The differential expressions of LOC441178, HCG22 and C5orf66-AS1 were verified by qRT-PCR. Conclusion: We identified a number of differentially expressed lncRNAs using transcriptomic data between OSCCs and healthy oral mucosa. Further investigations into their potential role in OSCC carcinogenesis or to serve as OSCC biomarkers and/or therapeutic targets are warranted. Citation Format: Lu Feng, John R. Houck, Pawadee Lohavanichbutr, Chu Chen. Transcriptome analysis reveals differentially expressed lncRNAs between oral squamous cell carcinoma and healthy oral mucosa [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 3503. doi:10.1158/1538-7445.AM2017-3503