tbuckley/cabot-search huggingface dataset:
Back to the future: forget ultrasound and focus on clinical assessment in rheumatoid arthritis management
Authors: Roberto Caporali, Josef S Smolen
Journal: Annals of the Rheumatic Diseases (2017)

Ultrasound (US) unquestionably improves many aspects of rheumatoid arthritis (RA) diagnosis and management, but no consensus has been reached regarding the optimal US methodology that should be used, and high levels of standardisation have not yet been attained. Current evidence from two randomised controlled trials does not support the US in directing treatment decisions. A return to the endorsement of clinical assessment and the adoption of T2T strategies aiming at ACR/EULAR remission still represent the standard of care for RA and should be pursued through appropriate educational programmes. Thus, for now, the major application of sonography in arthritis should have a focus on diagnostic and especially differential diagnostic aspects.
Abstract 2840: Integrative approach to biomarker discovery by performing comparative analysis of two cancers, hepatocellular carcinoma and endometrioid endometrial carcinoma, using genetics and transcriptomics from RNA sequencing data
Authors: Jean-Noel Billaud, Stuart Tugendreich, Debra Toburen
Journal: Cancer Research (2017)

Abstract Hepatocellular Carcinoma (HCC) and Endometrioid Endometrial Carcinoma (EEC) are two lethal diseases of public health importance worldwide. Using QIAGEN’s RNA sequencing solution, we were able to highlight key molecular and biological processes that indicate similarities in the tumor progression toward metastasis between one EEC patient and the three HCC patients. We have identified ITGB1-001 isoform as a potential common biomarker between these two complex cancers. We have also shown these two cancers share activated pathways such as actin cytoskeleton signaling, and RAF1 as an upstream regulator indicating similar transcriptional program between these patients. Furthermore, we have identified as a potential therapeutic target the master regulator CTGF that connects a network of 286 downstream targets to invasion of tumor cells. We have filtered a set of unique variants in the EEC patient that affect a network of upstream regulators common with HCC. This approach may be useful in the context of precision or personalized medicine. Examining the gene expression in tumors from groups of patients with each disease revealed that at a molecular level, early stages of EEC resemble established HBV-positive, HCV-negative, liver cirrhosis positive HCC. Citation Format: Jean-Noel Billaud, Stuart Tugendreich, Debra Toburen. Integrative approach to biomarker discovery by performing comparative analysis of two cancers, hepatocellular carcinoma and endometrioid endometrial carcinoma, using genetics and transcriptomics from RNA sequencing data [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 2840. doi:10.1158/1538-7445.AM2017-2840
Abstract LB-006: Oncology model fidelity scores
Authors: Debajyoti Datta, Theodore Goldstein, Zhiping Gu, Atul Butte
Journal: Cancer Research (2017)

Abstract Animal models remain a cornerstone of research efforts in Oncology to model the complexity of cancer progression and to discover new therapeutic approaches to disease management. With the advent of new genomic manipulation techniques such as CRISPR, and advances in mouse modeling with genetically engineered mice (GEM) and patient-derived xenografts (PDX), we can expect the development of novel and powerful animal models in the near future. These techniques are expanding our capability for pre-clinical testing of novel therapeutic agents or for n-of-1 patient-specific disease modeling. However, the reliability of animal models to faithfully recapitulate human disease, especially cancer, remains controversial, as evidenced by numerous therapeutic agents that show promise in animal models but fail in clinical trials. We propose a new scoring system called the Oncology Model Fidelity Scores, which allow researchers and clinicians to compare animal models and select those most suited for the question at hand, whether in basic science, for translational research, or within clinical applications. The formalism and tools we are developing for the analysis of mouse models and other model organisms are based on the Hallmarks of Cancer and therapeutic pathways as well as The Cancer Genome Atlas (TCGA) and other comprehensive systems. The scoring system begins with RNASEQ expression data and DNA variation analysis, and is designed for use in mapping animal models both to individual patients and to a TCGA cohort. We are applying this scoring system to mouse models available through NCI’s Oncology Model Forum and we are analyzing how these animal models compare to human cancers based on TCGA data. Ultimately, the development of an Oncology Model Fidelity Score will help to advance patient care through efficient identification and validation of animal models for a variety of applications, from pre-clinical testing of novel therapeutics to the use of patient-specific animal models. Citation Format: Debajyoti Datta, Theodore Goldstein, Zhiping Gu, Atul Butte. Oncology model fidelity scores [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-006. doi:10.1158/1538-7445.AM2017-LB-006
GATA4 loss of function in liver cancer impedes precursor to hepatocyte transition
Authors: Francis O. Enane, Wai Ho Shuen, Xiaorong Gu, Ebrahem Quteba, Bartlomiej Przychodzen, Hideki Makishima, Juraj Bodo, Joanna Ng, Chit Lai Chee, Rebecca Ba, Lip Seng Koh, Janice Lim, Rachael Cheong, Marissa Teo, Zhenbo Hu, Kwok Peng Ng, Jaroslaw Maciejewski, Tomas Radivoyevitch, Alexander Chung, London Lucien Ooi, Yu Meng Tan, Peng-Chung Cheow, Pierce Chow, Chung Yip Chan, Kiat Hon Lim, Lisa Yerian, Eric Hsi, Han Chong Toh, Yogen Saunthararajah
Journal: Journal of Clinical Investigation (2017)

The most frequent chromosomal structural loss in hepatocellular carcinoma (HCC) is of the short arm of chromosome 8 (8p). Genes on the remaining homologous chromosome, however, are not recurrently mutated, and the identity of key 8p tumor-suppressor genes (TSG) is unknown. In this work, analysis of minimal commonly deleted 8p segments to identify candidate TSG implicated GATA4, a master transcription factor driver of hepatocyte epithelial lineage fate. In a murine model, liver-conditional deletion of 1 Gata4 allele to model the haploinsufficiency seen in HCC produced enlarged livers with a gene expression profile of persistent precursor proliferation and failed hepatocyte epithelial differentiation. HCC mimicked this gene expression profile, even in cases that were morphologically classified as well differentiated. HCC with intact chromosome 8p also featured GATA4 loss of function via GATA4 germline mutations that abrogated GATA4 interactions with a coactivator, MED12, or by inactivating mutations directly in GATA4 coactivators, including ARID1A. GATA4 reintroduction into GATA4-haploinsufficient HCC cells or ARID1A reintroduction into ARID1A-mutant/GATA4-intact HCC cells activated hundreds of hepatocyte genes and quenched the proliferative precursor program. Thus, disruption of GATA4-mediated transactivation in HCC suppresses hepatocyte epithelial differentiation to sustain replicative precursor phenotype.
Abstract 2513: Multi-omics-based approach to colorectal cancer metabolism
Authors: Kiyotoshi Satoh, Tomoyoshi Soga
Journal: Cancer Research (2017)

Abstract Cancer cells exhibit many metabolic alterations to acquire energy and cellular components required for their proliferation and thus, cancer specific metabolic pathways are attractive targets for cancer therapy. However, the regulation mechanisms underlying metabolic reprogramming are poorly understood. Here, we performed multi-omics-based analyses of paired normal and tumor tissues from patients with colorectal cancer (CRC) to understand the regulation mechanisms of metabolism in colorectal cancer. First, we carried out capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS)-based metabolome profiling of tumor and normal tissue obtained from 275 patients with CRC. S-adenosylmethionine (SAM), a principal methyl group donor produced by one-carbon metabolism, was the most increased metabolite in tumor tissue. Glucose was the second most decreased metabolite in tumor tissue, whereas lactate was accumulated, indicating activation of glycolysis, commonly known as the Warburg effect. Every amino acid except glutamine, the starting metabolite in glutaminolysis, was significantly accumulated in tumor tissue. Interestingly, most of the changes in metabolite levels were occurred in the adenoma stage. In addition, next-generation and Sanger sequencing analyses of genomic DNA obtained from tumor tissue revealed that metabolic alterations occurred independently of mutations in oncogenes and tumor suppressor genes, such as KRAS, APC, and TP53. Furthermore, DNA microarray analysis of paired normal and tumor tissues from CRC patients demonstrated that expression profiles of many metabolic genes were also altered at the adenoma stage. Most of genes regulating purine/pyrimidine synthesis, one-carbon metabolism and fatty acid synthesis were highly expressed, whereas those in fatty acid oxidation were down-regulated in tumor tissue. We will discuss the raised questions, which molecules contribute to the regulation of metabolic reprogramming of colorectal cancer metabolism. Citation Format: Kiyotoshi Satoh, Tomoyoshi Soga. Multi-omics-based approach to colorectal cancer metabolism [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 2513. doi:10.1158/1538-7445.AM2017-2513
Abstract 711: Mechanistic implications of COL1A1 as a prostate cancer biomarker
Authors: Andrej Jedinak, Camille Vuichoud, Andrew El-Hayek, Katherine Kaplan, Jason Savage, Sarah Prophet, Adam S. Feldman, Kevin A. Camphausen, Kevin R. Loughlin, Marsha A. Moses
Journal: Cancer Research (2017)

Abstract Prostate cancer (PCa) is the second most frequently diagnosed form of male cancer and shares similar symptoms with BPH (Benign Prostate Hyperplasia), a disease characterized by prostate enlargement. Elevated levels of prostate-specific antigen (PSA) can be observed with either benign or malignant growth of the prostate and therefore cannot effectively discriminate between these two prostate diseases. Currently, a test that sensitively and accurately distinguishes between BPH and localized prostate cancer does not exist creating an urgent need for novel biomarkers that can successfully distinguish between these two prostate diseases. The goal of this study was to identify and validate non-invasive urinary biomarkers that distinguish between BPH and PCa. Our previous proteomic study identified elevated levels of several proteins, including EGF (epidermal growth factor), HE-4 (human epididymis protein 4), COL1A1 (collagen, type I, alpha 1) and other proteins in the urine of PCa patients compared to urine samples from patients with BPH. In this current study we have analyzed and validated the presence of EGF, HE-4 and COL1A1 by enzyme-linked immunosorbent assay (ELISA). Our ELISA experiments revealed that COL1A1 was significantly (P &amp;lt; 0.002) elevated in the urine of patients diagnosed with early or localized PCa vs. BPH. In vitro experiments performed on seven different prostate cell lines identified cells from the tumor microenvironment that secrete the highest levels of COL1A1. Expression of COL1A1 by these cells was confirmed by immunohistochemistry (IHC) using prostate tissue microarrays (TMA). In addition, protein array experiments identified elevated levels of several proteases in the urine of PCa patients, including MMP-9, uPA, ADAM-TS1 and several cathepsins. Substrate gel electrophoresis (zymography) revealed elevated activity of both MMP-9 and MMP-2 in urine from PCa patients. These data suggest that MMP-9 and MMP-2 may participate in the cleavage of collagen type 1, resulting in elevated levels of COL1A1 in urine of PCa patients. We are currently testing this hypothesis. In summary, COL1A1 may represent a novel non-invasive urinary biomarker that can effectively discriminate between BPH vs. localized PCa. (Supported by The Ellison Foundation) Citation Format: Andrej Jedinak, Camille Vuichoud, Andrew El-Hayek, Katherine Kaplan, Jason Savage, Sarah Prophet, Adam S. Feldman, Kevin A. Camphausen, Kevin R. Loughlin, Marsha A. Moses. Mechanistic implications of COL1A1 as a prostate cancer biomarker [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 711. doi:10.1158/1538-7445.AM2017-711
Abstract 2477: Genomic instability in BRCA1-deficient cells is a result of the anti-recombinogenic activity of BLM helicase
Authors: Dharm S. Patel, Sarah M. Misenko, Samuel F. Bunting
Journal: Cancer Research (2017)

Abstract Mutations in BRCA1 are responsible for approximately 5% of cases of breast cancer, and there are few treatment options that substantially alter the probability of disease onset in individuals with BRCA1 mutations. BRCA1-deficient cells exhibit increased genomic instability following DNA damaging treatments due to a defect in the homologous recombination (HR) DNA repair pathway. Presently, Olaparib, a PARP inhibitor, is approved as a targeted monotherapy for germline BRCA1 mutated advanced ovarian cancers. As use of this treatment has expanded, data suggests that patients exhibit a further relapse and resistance to PARP inhibitors via mechanisms that include the development of secondary BRCA1 reversion mutations, enhanced drug efflux relating to P-glycoprotein, and mutations in other DNA repair proteins that restore HR. Here, we show that the RECQ helicase, BLM, mediates the genomic instability observed in BRCA1-deficient cells by a mechanism that depends in part on its anti-recombinogenic activity. We have generated conditional knockout mice with single and combined deficiencies in BRCA1, BLM, and 53BP1 in the B lymphocyte cell population. Ablation of BLM in BRCA1-deficient cells allows the HR repair pathway to be restored, leading to a partial rescue of the genomic instability that is present in BRCA1-deficient cells. The stable accumulation of RAD51, a marker for HR, at DNA double-strand break sites is inhibited by BLM in BRCA1-deficient B cells. However, DNA end resection is not impacted by single or co-deletion of BRCA1 and BLM. Furthermore, cells co-deficient in BRCA1 and BLM display limited sensitivity to PARP inhibition. The rescue in HR and PARPi sensitivity phenotypes following deletion of BLM is only present in hypomorphic BRCA1Δ11/Δ11 cells and not the RING domain deficient BRCA1Δ2/Δ2. These results demonstrate that the anti-recombinogenic activity of BLM is of potentially great significance for regulating the balance of HR versus other error-prone repair pathways. Mutation of BLM in BRCA1-deficient tumors is therefore a potential pathway leading to resistance to PARPi and other DNA damaging agents. Citation Format: Dharm S. Patel, Sarah M. Misenko, Samuel F. Bunting. Genomic instability in BRCA1-deficient cells is a result of the anti-recombinogenic activity of BLM helicase [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 2477. doi:10.1158/1538-7445.AM2017-2477
Abstract 1134: Tissue transglutaminase is a new therapeutic target to overcome steroid resistance in T cell acute lymphoblastic leukemia
Authors: Hyun Joo Jung
Journal: Cancer Research (2017)

Abstract Background: The treatment response to steroid is the most important predictive factor for treatment outcome of T-cell acute lymphoblastic leukemia (T-ALL). To improve survival for steroid-resistant T-ALL patients, it is necessary to develop innovative therapeutic strategies to overcome steroid resistance. This study attempts to determine new therapeutic strategies to overcome steroid resistance for patients with T-ALL. Tissue transglutaminase (TG2) is a intracellular calcium-dependent protein cross-linking enzyme reported to be highly expressed in various metastatic or drug-resistant cancer cells, and chronic expression of TG2 constitutively activates nuclear factor kappa B (NF-kappaB). Methods: We used biochemical and molecular methodologies to demonstrate that TG2 modulation leaded to overcome the steroid resistance in T-ALL. Results: We generated the steroid-adapted subclones of T-ALL cell lines that were extremely less sensitive to steroid than their parent T-ALL cells. We found that steroid-resistant subclones of T-ALL cells expressed much higher levels of TG2 than their parent cells and the modulation of TG2 activities altered NF-kappaB expression in this steroid-resistant cells. Inhibition of TG2 suppressed steroid resistance and improved the cytotoxicity of leukemia cells in steroid-adapted subclones of T-ALL. Conclusion: This study shows that TG2 expression is elevated with steroid resistance in T-ALL and the modulation of TG2 induces the cytotoxicity of steroid-adapted T-ALL. TG2 could be a new therapeutic target to overcome steroid resistance in T-ALL. Furthermore, change of TG2 expression could serve as markers of induced steroid resistance in T-ALL. Citation Format: Hyun Joo Jung. Tissue transglutaminase is a new therapeutic target to overcome steroid resistance in T cell acute lymphoblastic leukemia [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 1134. doi:10.1158/1538-7445.AM2017-1134
Abstract 5453: Dysregulation of miRNAs in esophageal cancer: function and clinical implication
Authors: Rinu Sharma
Journal: Cancer Research (2017)

Abstract Background: Growing evidence suggests importance of aberrant microRNA (miRNA) expression in development and progression of cancer. Recent studies have demonstrated the potential of miRNA panels as promising diagnostic, prognostic and predictive biomarkers. Objective: The purpose of the present study was to evaluate the clinical and functional significance of miRNAs in esophageal cancer (EC). Methods: Herein, we evaluated the diagnostic potential of a five miRNA panel (consisting of miR-21, miR-144, miR-107, miR-93 and miR-342) in EC detection using quantitative real time PCR (qRTPCR). To evaluate the discriminatory power of miRNA panel, receiver operating characteristic curve (ROC) curves were generated for each of the miRNAs followed by risk score analysis. Briefly, linear regression models were fitted using the cancer status and each of the risk score as input. ROC curves were then used to evaluate the diagnostic potential of the panel and to find out the appropriate cut-off point. Sensitivity and specificity of the panel were then determined. Further, pathway enrichment analysis was carried out to find the most significant pathways targeted by these miRNAs. Next, we elucidated the role of miR-144, by silencing it in KYSE-410 cells followed by MTT assay, cell cycle analysis, colony formation assay and scratch assay. Potential targets of miR-144 were predicted by in silico approach followed by in vitro validation by luciferase reporter assay. Results: The ROC curve analysis indicated that the panel of five miRNAs (AUC=0.851, p&amp;lt;0.001) constitutes a more sensitive and specific diagnostic marker as compared to any of the single miRNAs. Most importantly, panel of circulating miRNAs showed enhanced sensitivity (87.5%) and specificity (90.4%) with an AUC of 0.96 (p&amp;lt;0.001) in discriminating EC patients from normal subjects. Inhibition of miR-144 significantly suppressed the proliferation of ESCC cells by 42.085±1.73% at 72 h post transfection. Moreover, knockdown of miR-144 decreased (p=0.046) the migration potential of KYSE-410 cells as compared to the cells treated with negative control. In silico analysis and further validation by dual-luciferase reporter assay revealed PURA to be a direct downstream target of miR-144. Conclusion: Herein, we have demonstrated the potential diagnostic implication of five miRNA panel. Further, we have shown that mir-144 acts as an oncogenic miRNA by targeting PURA and promotes EC cell proliferation. Citation Format: Rinu Sharma. Dysregulation of miRNAs in esophageal cancer: function and clinical implication [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 5453. doi:10.1158/1538-7445.AM2017-5453
Abstract 2462: Whole-exome sequencing reveals genetic variants in ERC1 and KCNG4 in complete hydatidiform moles from Chinese Han women
Authors: Yan Yu, Bingjian Lu, Weiguo Lu, Xinyu Wang, Pengyuan Liu, Yan Lu, Xiaodong Cheng, Xing Xie
Journal: Cancer Research (2017)

Abstract Complete hydatidiform mole (CHM) is an uncommon pregnancy-related disease with an invasive potential. The genetic background of the sporadic CHM has not been addressed previously despite the possible mechanisms of maternal genetic variants to the development of this disease with biparental origin. We performed the whole-exome sequencing analysis on 51 CHM patients and 47 normal healthy women, then the second screening of the probable mutations by mass spectrometry in 199 CHM patients and 400 normal healthy women. Finally the candidate genetic polymorphisms were validated by direct Sanger sequencing in 247 cases and 599 controls with another 205 new controls. We eventually found that two SNPs c.G48C(p.Q16H) in ERC1 and c.G1114A(p.G372S) in KCNG4, were associated with an increased risk for CHM (p&amp;lt;0.05). These genetic variants will facilitate our understanding on the pathogenesis of CHM and related tumors as well as the oogenesis and embryonic implantation. They will provide beneficial information for the pregnant women both in physiology and psychology. Further multiple-disciplinary collaborations should be encouraged to clarify the accurate pathogenesis of CHM. Citation Format: Yan Yu, Bingjian Lu, Weiguo Lu, Xinyu Wang, Pengyuan Liu, Yan Lu, Xiaodong Cheng, Xing Xie. Whole-exome sequencing reveals genetic variants in ERC1 and KCNG4 in complete hydatidiform moles from Chinese Han women [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 2462. doi:10.1158/1538-7445.AM2017-2462