tbuckley/cabot-search huggingface dataset:
Abstract 4743: Identification of metastasis-associated biomarker PLEC1 by iTRAQ-based proteomic approach and prognostic role of PLEC1 in patients with hepatocellular carcinoma
Authors: Lin-lan Song, Yu Chen, Di Mu, Xiao-Yan Jiang, Yu-Nong Li, Ling-Yu Jiang, Zhen-Fang Zhang, Liang Yan, Min Yang, Yi-xuan Yang, Hong Ren, Yong Liao
Journal: Cancer Research (2017)

Abstract Purpose: Hepatocellular Carcinoma(HCC)is the fifth most prevalent cancer and the second most frequent cause of cancer-related death in men worldwide because of high incidence of recurrence and widespread metastasis. However, to date, there have been no direct metastesis-associated biomarker which is critical for the effective treatment of patients with HCC, we thus aimed to identify novel HCC metastasis-associated biomarkers with prognostic significance.E xperimental Design: Two human HCC cell lines, MHCC97-L and MHCC97-H with similar genetic background and stepwise increasing metastatic potentials, were used to explore potential metastasis-associated biomarkers for HCC by isobaric tag for relative and absolute quantitation (iTRAQ) combination with 2D-LC-MS/MS. Ninety-five HCC cancerous and paracancerous tissues were further analyzed by immunohistochemistry to validate the correlations between the expression levels of PLEC1 with various clinicopathologic factors and patient survival. Results: Using iTRAQ combination with 2D-LC-MS/MS, a total of 47 differentially expressed proteins were found in MHCC97-L and MHCC97-H cells, of which 26 proteins were up regulated and 21 proteins were down regulated. Plectin-1 (PLEC1) was identified and re-confirmed as a potential biomarker for HCC that was highly up-regulated in tumor tissues, in comparison with that of para-cancerous tissues. Over-expression of PLEC1 was also strongly correlated with tumor size (P &amp;lt; 0.05) and TMN stages (P &amp;lt; 0.05). In addition, both univariate and multivariate analyses demonstrate that PLEC1 expression is an independent prognostic factor for patients with HCC(p&amp;lt;0.05). Conclusions: In this study, iTRAQ-based proteomic technology was explored to uncover novel metastasis-associated biomarkers in HCC. We identified and validated metastasis-associated protein PLEC1 as a potential prognostic marker in patients with HCC. Note: This abstract was not presented at the meeting. Citation Format: Lin-lan Song, Yu Chen, Di Mu, Xiao-Yan Jiang, Yu-Nong Li, Ling-Yu Jiang, Zhen-Fang Zhang, Liang Yan, Min Yang, Yi-xuan Yang, Hong Ren, Yong Liao. Identification of metastasis-associated biomarker PLEC1 by iTRAQ-based proteomic approach and prognostic role of PLEC1 in patients with hepatocellular carcinoma [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 4743. doi:10.1158/1538-7445.AM2017-4743
Abstract 560: A pan-inflammatory and precancerous disease analysis reveals key biological characteristics in chronic inflammatory diseases with high oncogenic risk
Authors: Chi Zhang, Fang Yao, Sha Cao, Tao Sheng, Sen Liang, Wei Du, Ying Xu
Journal: Cancer Research (2017)

Abstract It has long been observed that cancer development tends to be associated with chronic inflammation. Recent epidemiology studies have suggested chronic inflammation may be causally linked to a larger number of sporadic cancers. In this work, we have conducted a Pan-inflammatory and precancerous diseases analysis by comparing the 173 transcriptomics data sets consisting 4073 disease and 2669 normal human tissue samples of 10 cancer prone and 8 cancer independent inflammatory diseases, 11 precancerous diseases or benign tumors and 20 cancer types, aiming to identify fundamental differences between cancer-prone chronic inflammations and cancer-independent chronic inflammations and what biological characteristics cause cancer initiation or increased oncogenic risk. By applying differential gene expression, co-expression network, our in-house immune cell deconvolution and machine learning based hypoxia/oxidative stress prediction methods on the collected data, we have discovered the cancer prone chronic inflammatory diseases consistently have: (1) elevated relative proportion of CD4+ T, Macrophage, and Neutrophil cells, (2) decreased CD8 + T, adipocyte, monocyte and B cells, (3) highly disorder tissue repair phase I - IV related pathways, (4) increased oxidative stress level associated with Macrophage and Neutrophil proportions, (5) elevated iron ion metabolism, (6) over expressed extracellular glycosaminoglycan metabolism and (6) suppressed mitochondrial activity. These analyses results strongly suggest that there is a necessary pathway for the majority or all chronic inflammatory diseases to become cancerous, namely consecutively dysregulated tissue repair process, increased reactive oxygen species producing immune cells, damage of extracellular matrix, Fenton reaction and production of hydroxyl radical and dysregulated mitochondrial activity. We believe these new insights could provide highly useful information in guiding future studies of inflammation associated cancers. Citation Format: Chi Zhang, Fang Yao, Sha Cao, Tao Sheng, Sen Liang, Wei Du, Ying Xu. A pan-inflammatory and precancerous disease analysis reveals key biological characteristics in chronic inflammatory diseases with high oncogenic 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 560. doi:10.1158/1538-7445.AM2017-560
Abstract 5895: Targeting RhoA-regulated gene transcription in drug-resistant melanoma
Authors: Sean A. Misek, Kathleen A. Gallo, Richard R. Neubig
Journal: Cancer Research (2018)

Abstract Much of the recent focus of melanoma targeted therapy has been on the ERK pathway, which is aberrantly activated in approximately 90% of melanoma tumors. Over half of these express BRAFV600E. Current targeted therapies such as Vemurafenib (BRAFV600E inhibitor), or a combination therapy of BRAF + MEK inhibitors show profound initial effects in a majority of BRAFV600E expressing tumors. However, these responses are often short-lived and resistance typically develops within months. The goal of this work is to identify pharmacologically targetable resistance mechanisms so that effective combination therapies can be developed. Preliminary bioinformatics analysis suggests that the RhoA subfamily of Rho GTPases is activated in BRAFi-resistant cancer cell lines and BRAFi/MEKi-resistant human melanoma tumors. Thus, we hypothesize that RhoA promotes BRAFi resistance, so simultaneously targeting RhoA and BRAF may reverse drug resistance. Using cell line models of acquired BRAFi-resistance we demonstrated that the RhoA pathway is activated in a subset of resistant cell lines. The cell lines with increased RhoA activation have increased sensitivity to multiple ROCK inhibitors. In addition to regulating the cytoskeleton, RhoA can also regulate gene transcription through activation of multiple transcriptional co-activators, including MRTF and YAP. MRTF and YAP regulated gene transcription through their role as transcriptional co-activators and their interaction with chromatin remodeling complexes. MRTF and YAP are both activated in BRAFi-resistant cell lines. Indirectly targeting MRTF with CCG-222740 or YAP with the YES1 inhibitor Dasatinib effectively kills BRAFi-resistant melanoma cells. Sox10 was previously identified as a gene which promotes BRAFi resistance. Expression of Sox10 is downregulated, and Sox9 is upregulated, 100-1000-fold exclusively in the resistant cell lines which have RhoA activation. Further, a Sox10 gene signature is inversely correlated with a RhoA/C signature in the TCGA dataset and melanoma scRNA-seq data. Sox10 loss is a major drug resistance melanoma in melanoma. These data suggest that targeting RhoA-regulated gene transcription may be an effective mechanism to target Sox9High/Sox10Low cells, and ultimately prevent or reverse drug resistance. Taken together these data suggest that MRTF and YAP promote Vemurafenib resistance in Sox9High/Sox10Low melanoma cells. Citation Format: Sean A. Misek, Kathleen A. Gallo, Richard R. Neubig. Targeting RhoA-regulated gene transcription in drug-resistant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5895.
Pertussis surveillance and control: exploring variations and delays in testing, laboratory diagnostics and public health service notifications, the Netherlands, 2010 to 2013
Authors: Jeanne Heil, Henriëtte L G ter Waarbeek, Christian J P A Hoebe, Peter H A Jacobs, Dirk W van Dam, Thera A M Trienekens, Jochen W L Cals, Inge H M van Loo, Nicole H T M Dukers-Muijrers
Journal: Eurosurveillance (2017)

Pertussis is most severe among unvaccinated infants (&lt; 1 year of age), and still leads to several reported deaths in the Netherlands every year. In order to avoid pertussis-related infant morbidity and mortality, pertussis surveillance data are used to guide pertussis control measures. However, more insight into the accuracy of pertussis surveillance and control, and into the range of healthcare and public health-related factors that impede this are needed. We analysed a unique combination of data sources from one Dutch region of 1.1 million residents, including data from laboratory databases and local public health notifications between 2010 and 2013. This large study (n = 12,090 pertussis tests) reveals possible misdiagnoses, substantial under-notification (18%, 412/2,301 laboratory positive episodes) and a delay between patient symptoms and notification to the local public health services (median 34 days, interquartile range (IQR): 27–54). It is likely that the misdiagnoses, under-notification and overall delay in surveillance data are not unique to this area of the Netherlands, and are generalisable to other countries in Europe. In addition to preventive measures such as maternal immunisation, based on current findings, we further recommend greater adherence to testing guidelines, standardisation of test interpretation guidelines, use of automatic notification systems and earlier preventive measures.
Abstract 2343: The novel potential of palbociclib (CDK4/6 inhibitor) in the treatment of triple-negative breast cancer
Authors: Shinichiro Kashiwagi, Yuka Asano, Wataru Goto, Koji Takada, Tsutomu Takashima, Tamami Morisaki, Satoru Noda, Naoyoshi Onoda, Kosei Hirakawa, Masaichi Ohira
Journal: Cancer Research (2017)

Abstract Background: The effectiveness of palbociclib (CDK4/6 inhibitor) for estrogen receptor positive breast cancer has been demonstrated by large-scale clinical studies, with the drug garnering attention as a key drug for breast cancer subtypes with endocrine sensitivity in the future. According to PALOMA-3 trial, palbociclib has been demonstrated to contribute to the extension of progression-free survival in patients with advanced hormone receptor-positive and HER2-negative metastatic breast cancer after endocrine therapy. On the other hand, in the case of triple-negative breast cancer (TNBC), luminal AR (LAR) related to androgen signaling is believed to have endocrine activity. Previous clinical data revealed that palbociclib shows high sensitivity in luminal breast cancer cell lines with endocrine activity, with effectiveness also expected in LAR. In this study, we created TNBC cell lines that forcibly express AR and examined the effectiveness of palbociclib for TNBC. Materials and Methods: MCF-7 and T-47D were used as luminal breast cancer cell lines, while MDA-MB-231 and BT-549 were used as TNBC cell lines. In addition, we created TNBC cell lines that forcibly express AR, called AR-MDA-MB-231, by the transfection of pEGFP-C1-AR Plasmid Vector using Lipofectamine® 3000 Reagent. We confirmed the expression of AR by qRT-PCR as well as Western blotting and examined the impact of palbociclib on proliferation as well as apoptosis of breast cancer cell lines. Results: AR was found to have been expressed only in luminal breast cancer cell lines but not TNBC cell lines. It was confirmed that AR was expressed in AR-MDA-MB-231 which are stable cell lines with the properties of LAR. In a CCK assay, palbociclib showed high sensitivity in AR-MDA-MB-231 as in luminal breast cancer cell lines. Furthermore, in an apoptosis assay using FACS and cell cycle assay, apoptosis was induced in AR-MDA-MB-231 and cell cycle arrest at the G1S check point was confirmed. Conclusion: palbociclib (CDK4/6 inhibitor) showed effectiveness for TNBC cell lines that compulsively express AR, suggesting it may be one treatment option for TNBC in the future. Citation Format: Shinichiro Kashiwagi, Yuka Asano, Wataru Goto, Koji Takada, Tsutomu Takashima, Tamami Morisaki, Satoru Noda, Naoyoshi Onoda, Kosei Hirakawa, Masaichi Ohira. The novel potential of palbociclib (CDK4/6 inhibitor) in the treatment of triple-negative breast 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 2343. doi:10.1158/1538-7445.AM2017-2343
DARC extracellular domain remodeling in maturating reticulocytes explains Plasmodium vivax tropism
Authors: Elina Ovchynnikova, Francesca Aglialoro, Arthur E. H. Bentlage, Gestur Vidarsson, Nichole D. Salinas, Marieke von Lindern, Niraj H. Tolia, Emile van den Akker
Journal: Blood (2017)
Abstract 5587: Novel monoclonal antibodies block N-glycosylation Sites of the MUC16 ectodomain in ovarian carcinoma
Authors: Dharmarao Thapi, Alberto Fernandez-Tejada, Abraham J. Axelrod, Nestor Rosales, Xiujun Yan, Marina Stasenko, Sahityasri Thapi, Amy Wang, Samuel J. Danishefsky, David R. Spriggs
Journal: Cancer Research (2017)

Abstract The MUC16 gene encodes the CA125 antigen that imparts a negative survival impact on patients with high-grade serous ovarian cancer. Short elements from the C-terminal region of MUC16 transform 3T3 cells. Introduction of the 114 amino acid C-terminal portion of MUC16 promotes invasive growth in xenograft models. This effect is dependent on N-glycosylation sites of MUC16 and interactions present on the cell surface. Mechanisms by which the ectodomain promotes MUC16 oncogenic behaviors, the function of N-glycosylation and the implicated cell surface receptors are not fully delineated. To unravel the complex MUC16 cancer biology, in this study we investigated the glycosylation-based mechanisms and potential partners involved in MUC16 oncogenic effects, and show that site-specific glycosylation of MUC16 plays a key role in mucin-related transformation by mediating complex cell surface interactions. These effects are mediated through MGAT5-dependent N-glycosylation of two proximal N- glycosylation sites within the 58 amino acid retained MUC16 ectodomain acting in combination with Galectin-3 and growth factor receptors. Neither N- nor O-glycosylation sites in the more distally located MUC16 regions can functionally substitute for those two sites. The tumor-enhancing properties of MUC16 depend on co-localization of MUC16, Galectin-3, and growth factors receptors on lipid rafts. Loss of either Galectin-3 expression or the glycosylation enzyme MGAT5 completely abrogates MUC16 tumor promotion. Using synthetic glycopeptides, we have developed novel monoclonal antibodies (mAbs) directed at the crucial ectodomain N-glycosylation sites to inhibit the glycosylation- dependent effects of MUC16 on metastasis and invasion. These novel antibodies were characterized in vitro and in vivo studies using various ovarian cancer cell lines. All of the antibodies against the N- glycosylation sites closest to the cell membrane of MUC16 block Galectin-3-mediated polymerization to cell surface signaling molecules and inhibit the tumor-promoting effects of MUC16. The implications are broad: both for the biological understanding of cancer mucin biology and for potential therapeutic strategies. Citation Format: Dharmarao Thapi, Alberto Fernandez-Tejada, Abraham J. Axelrod, Nestor Rosales, Xiujun Yan, Marina Stasenko, Sahityasri Thapi, Amy Wang, Samuel J. Danishefsky, David R. Spriggs. Novel monoclonal antibodies block N-glycosylation Sites of the MUC16 ectodomain in ovarian carcinoma [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 5587. doi:10.1158/1538-7445.AM2017-5587
Abstract 340: SRMS regulates normal and oncogenic KIT signaling
Authors: Sachin Raj M Nagaraj, Julhash U. Kazi, Lars Rönnstrand
Journal: Cancer Research (2017)

Abstract SRMS (Src-related tyrosine kinase lacking C-terminal regulatory tyrosine and N-terminal myristoylation sites) belongs to a family of non-receptor tyrosine kinases, which harbours a Src homology 3 and a Src homology 2, as well as a protein kinase domain. SRMS was first identified in a screen for the genes that regulate the growth and differentiation of neuroepithelial cells. SRMS, however, is an understudied member of this family. The present study was undertaken in order to explore the role of SRMS in signaling downstream of KIT. The receptor tyrosine kinase KIT, also known as the stem cell factor receptor, plays a key role in several developmental processes and have been implicated in many human cancers such as gastrointestinal stromal tumors, acute myeloid leukemia and testicular carcinoma. To understand the role of SRMS in KIT signaling, we generated Ba/F3 cell lines overexpressing KIT and SRMS. We observed that SRMS regulates normal and oncogenic KIT signaling differentially with respect to cell proliferation and apoptosis. SRMS association triggers KIT ubiquitination which in turn downregulates the receptor. Further, expression of SRMS downregulates wild-type KIT-mediated phosphorylation of AKT, ERK1/2, p38. Taken together the data demonstrates that SRMS regulates both normal KIT and an oncogenic mutant of KIT, and have differential impact on receptor downstream signaling. Citation Format: Sachin Raj M Nagaraj, Julhash U. Kazi, Lars Rönnstrand. SRMS regulates normal and oncogenic KIT signaling [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 340. doi:10.1158/1538-7445.AM2017-340
Search for tumor suppressor genes on chromosome 18 in pancreatic cancer
Authors: Masaharu Ishida, Makoto Sunamura, Shinichi Egawa, Toru Furukawa, Akira Horii, Michiaki Unno
Journal: Cancer Research (2006)

835  Pancreatic cancer has a well-known reputation as one of the leading causes of cancer deaths worldwide. Thus, acquisition of efficient approaches and markers for accurate detection at earlier stages of the disease should be prioritized. We have been focusing on tumor suppressor genes activity in pancreatic cancer to find effective method for its genetic diagnosis and treatment. We previously identified that loss of heterozygosity (LOH) of the long arm of chromosome 18 at the SMAD4 locus, along with LOHs on 17p and 12q, positively associated with poor prognoses of pancreatic cancer patients. However, restoration of the SMAD4 gene did not suppress in vitro proliferation of pancreatic cancer cells that harbored homozygous deletion of this gene. Intraductal papillary-mucinous neoplasm (IPMN) is thought to be one of the premalignant lesions of the pancreas that progresses to carcinoma. Although the frequent LOH was found at the SMAD4 locus in IPMN samples, SMAD4 protein was observed immunohistochemically in tumor cells, and no mutations of the SMAD4 gene were observed. It suggested the existence of a tumor suppressor gene(s) in 18q, other than SMAD4 that suppresses cell growth. To functionally assess the activity of chromosome 18 in pancreatic cancer, we utilized the technique of micro-cell-mediated chromosome transfer to introduce a normal copy of human chromosome 18 into a pancreatic cancer cell. Subsequently, the tumorigenic ability of the resulting hybrids was assessed. The in vitro growth of the hybrid cells was significantly suppressed, compared with the parental cells, regardless of the initial SMAD4 status. To identify and characterize the genes that are involved in the progression of pancreatic cancer, we used micro-array expression analysis on these cells, employing a 20k oligo-array system. Fourteen genes on chromosome 18 were increased in the hybrid cells compared with the parental cells. For example, PMAIP1, that is induced by p53 or HIF1alpha to promotes apoptosis, and colon cancer-associated protein MIC1, were included in this group of 14 gene. But the well known tumor suppressor genes, such as SMAD4, DCC, and MASPIN were not involved in the group, and did not show any difference between the hybrid cells and the parental cells in the light of the expression. An additional set of 40 genes on whole genome showed higher expression levels, and another set of 40 genes was identified to be down-regulated in the hybrid clone, which showed slow growth. In summary, this study provides the functional evidence of the existence of an additional tumor suppressor gene(s) on chromosome 18, whose absence is responsible for the pathogenesis in pancreatic ductal carcinogenesis. And we are now analyzing the function of the genes, extracted by micro-array expression analysis, that are the candidate of the tumor suppressor genes.
Abstract 1753: Refining breast cancer characterization through single-cell analysis ofex vivoreprogrammed tumor and adjacent normal cells
Authors: Harikrishna Nakshatri, Manjushree Anjanappa, Angelo Cardoso, Lijun Cheng, Safa Mohamad, Andrea Gunawan, Susan Rice, Yan Dong, Lang Li, Edward Srour
Journal: Cancer Research (2017)

Abstract Discovery of inter-individual functional variations in gene regulatory elements and the observation that tumor and normal tissues of the same organ are in different differentiation states necessitate rethinking of gene expression based subclassification/characterization of tumors. To address this issue, we performed single cell genomics of breast tumors and adjacent-normal cells propagated using epithelial reprogramming growth conditions for a short duration. Epithelial cells analyzed were either unselected for specific subpopulation or phenotypically defined undifferentiated ALDH+/CD49f+/EpCAM+ luminal progenitors present in the normal breast, which express both basal and luminal-enriched genes. Expression of 93 genes that included PAM50 intrinsic subtype classifier and stemness-related genes was analyzed in 420 tumor and 284 adjacent-normal cells. ALDH+/CD49f+/EpCAM+ tumor and normal cells clustered differently compared to unselected tumor and normal cells. PAM50 genes-set analyses of ALDH+/CD49f+/EpCAM+ populations efficiently identified major and minor clones of tumor cells with the major clone resembling clinical parameters of the tumor. Similarly, stemness-associated gene set identified clones with divergent stemness pathway activation within the same patient sample. This refined technique distinguished genes truly deregulated in cancer from genes that identify cellular precursors of tumors. Collectively, assays presented here may enable precise identification of genes deregulated in cancer, early identification of therapeutically-targetable minor population of tumor cells, and eventually to refinement of precision therapeutics. Citation Format: Harikrishna Nakshatri, Manjushree Anjanappa, Angelo Cardoso, Lijun Cheng, Safa Mohamad, Andrea Gunawan, Susan Rice, Yan Dong, Lang Li, Edward Srour. Refining breast cancer characterization through single-cell analysis of ex vivo reprogrammed tumor and adjacent normal cells [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 1753. doi:10.1158/1538-7445.AM2017-1753