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Kai Zhao, Hon-Cheong So
The cost of new drug development has been increasing, and repurposing known medications for new indications serves as an important way to hasten drug discovery. One promising approach to drug repositioning is to take advantage of machine learning (ML) algorithms to learn patterns in biological data related to drugs and then link them up to the potential of treating specific diseases. Here we give an overview of the general principles and different types of ML algorithms, as well as common approaches to evaluating predictive performances, with reference to the application of ML algorithms to predict repurposing opportunities using drug expression data as features...
2019: Methods in Molecular Biology
Kaitlyn Gayvert, Olivier Elemento
Inhibition of oncogenes and reactivation of tumor suppressors are well-established goals in anticancer drug development. Unfortunately many oncogenes and tumor suppressors are not classically druggable, in that they lack a targetable enzymatic activity and associated binding pockets that small molecule drugs can be directed to. This is especially relevant for transcription factors, which have long been thought to be undruggable. To address this gap, we have developed and described CRAFTT, a broadly applicable computational drug-repositioning approach for targeting transcription factors...
2019: Methods in Molecular Biology
Alireza Fotuhi Siahpirani, Deborah Chasman, Sushmita Roy
Transcriptional regulatory networks specify the regulatory proteins of target genes that control the context-specific expression levels of genes. With our ability to profile the different types of molecular components of cells under different conditions, we are now uniquely positioned to infer regulatory networks in diverse biological contexts such as different cell types, tissues, and time points. In this chapter, we cover two main classes of computational methods to integrate different types of information to infer genome-scale transcriptional regulatory networks...
2019: Methods in Molecular Biology
Joanna Walkowska, Thomas Kallemose, Göran Jönsson, Mats Jönsson, Ove Andersen, Mads Hald Andersen, Inge Marie Svane, Anne Langkilde, Mef Nilbert, Christina Therkildsen
Colorectal cancers associated with Lynch syndrome are characterized by defective mismatch repair, microsatellite instability, high mutation rates, and a highly immunogenic environment. These features define a subset of cancer with a favorable prognosis and high likelihood to respond to treatment with anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) drugs. With the aim to define immune-evasive mechanisms and a potential impact hereof in colorectal cancers from Lynch syndrome versus hereditary cases with retained mismatch repair function, we immunohistochemically and transcriptionally profiled 270 tumors...
2019: Oncoimmunology
Frederick S Varn, Yue Wang, Chao Cheng
Immune checkpoint inhibitors have shown great potential in treating solid tumors, inducing durable remission and prolonged survival time in responders. Despite their promise, a large fraction of patients remains unresponsive to these treatments highlighting the need for biomarkers that can predict patient sensitivity. Pre-treatment gene expression profiles for patients receiving immune checkpoint inhibitors have recently become available, establishing a new medium by which to discover biomarkers that predict therapy response...
2019: Oncoimmunology
Dustin T Proctor, Zeel Patel, Sanju Lama, Lothar Resch, Guido van Marle, Garnette R Sutherland
Meningioma is the most common brain tumor in adults. Surgical resection remains the primary treatment. No chemotherapy exists. However, gene mutations now could explain ~ 80% of meningioma and targeted therapies based on these are being investigated. Furthermore, with the recent discovery of PD-L1 in malignant meningioma, clinical trials using immunotherapy have commenced. Here, we report for the first time the expression profiles of immune checkpoint proteins PD-L2, B7-H3 and CTLA-4 in meningioma and their association to common gene mutations...
2019: Oncoimmunology
Tiziana Triulzi, Luca Forte, Viola Regondi, Martina Di Modica, Cristina Ghirelli, Maria Luisa Carcangiu, Lucia Sfondrini, Andrea Balsari, Elda Tagliabue
Through whole-transcriptome profiling of HER2+ breast carcinomas (BCs), we previously showed that those sensitive to trastuzumab are addicted to this oncoprotein and are enriched in immune pathways, raising the hypothesis that HER2 itself regulates immune cell recruitment. In the present study we investigated the relationship between HER2 activity and the pro-trastuzumab tumor immune milieu. Gene expression profiling and immunohistochemistry analysis of 53 HER2+ BCs showed that trastuzumab-sensitive tumors expressed significantly higher levels of chemokines involved in immune cell recruitment, with higher infiltration of T cells and monocytes, and higher levels of PD-1 ligands than tumors that do not benefit from trastuzumab...
2019: Oncoimmunology
Katsunobu Hagihara, Stephen Chan, Li Zhang, David Y Oh, Xiao X Wei, Jeffry Simko, Lawrence Fong
Sipuleucel-T is the only FDA-approved immunotherapy for metastatic castration-resistant prostate cancer. The mechanism by which this treatment improves survival is not fully understood. We have previously shown that this treatment can induce the recruitment of CD4 and CD8 T cells to the tumor microenvironment. In this study, we examined the functional state of these T cells through gene expression profiling. We found that the magnitude of T cell signatures correlated with the frequency of T cells as measured by immunohistochemistry...
2019: Oncoimmunology
Fabien B Vincent, Emily Lin, Joanne Sahhar, Gene-Siew Ngian, Rangi Kandane-Rathnayake, Rachel Mende, Alberta Y Hoi, Eric F Morand, Tali Lang, James Harris
Objectives: Macrophage migration inhibitory factor (MIF) and D-dopachrome tautomerase (DDT), members of the same cytokine superfamily, are linked to the pathogenesis of a number of inflammatory diseases. The aim of this study was to investigate their clinical relevance in systemic sclerosis (SSc). Methods: Serum MIF and DDT were quantified in 105 SSc patients by ELISA and levels compared to healthy controls (HC) (47) and patients with systemic lupus erythematosus (SLE) (184)...
2018: Clinical & Translational Immunology
Naoya Himuro, Yumiko Niiya, Takao Minakata, Yutaka Oshima, Daisuke Kataoka, Shigeru Yamamoto, Takashi Suzuki, Mitsutaka Kadokura
The expression levels of thymidine phosphorylase ( TP ), dihydropyrimidine dehydrogenase ( DPD ), thymidylate synthase ( TS ) and orotate phosphoribosyltransferase ( OPRT ) may predict the clinical efficacy of 5-fluorouracil-based chemotherapy in patients with cancer. We herein investigated the differences in the mRNA levels of these enzymes in non-small-cell lung cancer (NSCLC) and evaluated their prognostic value for NSCLC treated by surgical resection. The intratumoral mRNA levels of TP, DPD, TS , and OPRT were quantified in 66 patients with pathological stage I and II NSCLC (adenocarcinoma or squamous cell carcinoma) following complete resection according to the Danenberg Tumor Profile method...
December 2018: Molecular and Clinical Oncology
Oliver D Mrowczynski, Achuthamangalam B Madhankumar, Jeffrey M Sundstrom, Yuanjun Zhao, Yuka Imamura Kawasawa, Becky Slagle-Webb, Christine Mau, Russell A Payne, Elias B Rizk, Brad E Zacharia, James R Connor
Radiation is utilized in the therapy of more than 50% of cancer patients. Unfortunately, many malignancies become resistant to radiation over time. We investigated the hypothesis that one method of a cancer cell's ability to survive radiation occurs through cellular communication via exosomes. Exosomes are cell-derived vesicles containing DNA, RNA, and protein. Three properties were analyzed: 1) exosome function, 2) exosome profile and 3) exosome uptake/blockade. To analyze exosome function, we show radiation-derived exosomes increased proliferation and enabled recipient cancer cells to survive radiation in vitro ...
November 16, 2018: Oncotarget
Wen-Jing Ding, Yi Yang, Zi-Xing Chen, Yuan-Yuan Wang, Wan-Li Dong, Jian-Nong Cen, Xiao-Fei Qi, Feng Jiang, Su-Ning Chen
Previous studies on the pathogenesis of myelodysplastic syndrome (MDS) have identified multiple associated gene mutations, including mutations of tetmethylcytosinedioxygenase 2, isocitrate dehydrogenase [NADP(+)] 1 cytosolic, isocitrate dehydrogenase [NADP(+)] 2 mitochondrial and additional sex combs like 1 transcriptional regulator, all of which may be considered epigenetic regulators. Furthermore, mutations of RAS type GTPase family genes have been identified in 10-15% patients with MDS. The authors' previous study on the gene expression profile of cluster of differentiation 34+ cells using microarray analysis identified elevated expression of RAP1GTPase activating protein 1 (Rap1GAP) in patients with MDS compared with that in non-malignant blood diseases (NM) control group...
December 2018: Oncology Letters
Ning Yu, Peng Zhang, Li Wang, Xinjia He, Shanshan Yang, Haijun Lu
Retinoblastoma-binding protein 7 (RBBP7) is an important component of several complexes that regulate chromatin metabolism. It is overexpressed in certain cancer types and serves conflicting roles in tumor progression. In the present study, the expression and roles of RBBP7 were explored in esophageal squamous cell carcinoma (ESCC). Immunohistochemical staining was used to detect RBBP7 expression in ESCC tissues. The mRNA sequencing profiles from the Cancer Genome Atlas and Genotype-Tissue Expression databases were mined to analyze the mRNA expression of RBBP7 in tissues...
December 2018: Oncology Letters
Feng Yuan, Wei Wang, Hongtao Cheng
Brain metastasis occurs in ~30% of patients with breast cancer, and patients with human epidermal growth factor receptor 2 (HER2)+ breast cancer have a particularly high frequency of brain metastasis. Weighted gene co-expression network analysis was conducted to identify the hub differentially expressed genes from patients with HER2+ breast cancer between brain metastases and primary tumors. The potential candidate genes were investigated in another set of patient samples to confirm their relevance. The results indicated that a number of pathways altered significantly when breast cancer metastasized to the brain...
December 2018: Oncology Letters
Dong-Yue Wen, Jia-Cheng Huang, Jie-Yu Wang, Wen-Ya Pan, Jiang-Hui Zeng, Yu-Yan Pang, Hong Yang
In order to determine the diagnostic efficacy of microRNA (miR)-122-5p and to identify the potential molecular signaling pathways underlying the function of miR-122-5p in hepatocellular carcinoma (HCC), the expression profiles of data collected from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and literature databases were analyzed, along with any associations between clinicopathological characteristics and the diagnostic value of miR-122-5p in HCC. The intersection of 12 online prediction databases and differentially expressed genes from TCGA and GEO were utilized in order to select the prospective target genes of miR-122-5p in HCC...
December 2018: Oncology Letters
Yaning Feng, Feihu Bai, Yanjie You, Fangyun Bai, Chuanxia Wu, Ruijuan Xin, Xue Li, Yongzhan Nie
Despite significant developments in its clinical treatment, the reported incidence and mortality of gastric cancer have exhibited marked increases. The molecular mechanisms of gastric cancer initiation and progression remain to be fully elucidated. The aim of the present study was to identify novel microRNAs (miRNAs/miRs) with a role in the peritoneal metastasis of gastric cancer by comparing the miRNA expression in the gastric cancer cell line GC9811 with that in its variant GC9811-P, a sub-cell line with a high potential for peritoneal metastasis...
December 2018: Experimental and Therapeutic Medicine
Jaana van Gastel, Jhana O Hendrickx, Hanne Leysen, Paula Santos-Otte, Louis M Luttrell, Bronwen Martin, Stuart Maudsley
G protein coupled receptors (GPCRs) were first characterized as signal transducers that elicit downstream effects through modulation of guanine (G) nucleotide-binding proteins. The pharmacotherapeutic exploitation of this signaling paradigm has created a drug-based field covering nearly 50% of the current pharmacopeia. Since the groundbreaking discoveries of the late 1990s to the present day, it is now clear however that GPCRs can also generate productive signaling cascades through the modulation of β-arrestin functionality...
2018: Frontiers in Pharmacology
Daniel Heudobler, Michael Rechenmacher, Florian Lüke, Martin Vogelhuber, Sebastian Klobuch, Simone Thomas, Tobias Pukrop, Christina Hackl, Wolfgang Herr, Lina Ghibelli, Christopher Gerner, Albrecht Reichle
Classic tumor therapy, consisting of cytotoxic agents and/or targeted therapy, has not overcome therapeutic limitations like poor risk genetic parameters, genetic heterogeneity at different metastatic sites or the problem of undruggable targets. Here we summarize data and trials principally following a completely different treatment concept tackling systems biologic processes: the principle of communicative reprogramming of tumor tissues, i.e., anakoinosis (ancient greek for communication) , aims at establishing novel communicative behavior of tumor tissue, the hosting organ and organism via re-modeling gene expression, thus recovering differentiation, and apoptosis competence leading to cancer control - in contrast to an immediate, "poisoning" with maximal tolerable doses of targeted or cytotoxic therapies...
2018: Frontiers in Pharmacology
James J Anderson
A model describes the relationship between mammal body mass and survivorship by combining replicative senescence theory postulating a cellular basis of aging, metabolic theory relating metabolism to body mass, and vitality theory relating survival to vitality loss and extrinsic mortality. In the combined framework, intrinsic mortality results from replicative senescence of the hematopoietic stem cells and extrinsic mortality results from environmental challenges. Because the model expresses the intrinsic and extrinsic rates with different powers of body mass, across the spectrum of mammals, survivorship changes from Type I to Type II curve shapes with decreasing body mass...
April 2018: Population Ecology
Bin Zhou, Rui Guo
The dysregulation of transcription factors has an important impact on the oncogenesis and tumor progression. Nonetheless, its functions in colorectal cancer metastasis are still unclear. In this study, four transcription factors (HNF4A, HSF1, MECP2 and RAD21) were demonstrated to be associated with the metastasis of colorectal cancer in both RNA and protein levels. To comprehensively explore the intrinsic mechanisms, we profiled the molecular landscape of these metastasis-related transcription factors from multiple perspectives...
December 13, 2018: Scientific Reports
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