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Cancer regulatory

Hui Feng, Yalei Wang, Jiaojiao Su, Hongwei Liang, Chen-Yu Zhang, Xi Chen, Weiyan Yao
OBJECTIVES: ErbB3 (HER3) has been associated with pancreatic cancer progression, but little is known about its regulatory mechanisms. We investigated whether microRNAs (miRNAs) regulate levels of ErbB3 in pancreatic cancer cells. METHODS: We used bioinformatic analyses to search for miRNAs that can potentially target ERBB3. Furthermore, the biological consequences of the targeting of ERBB3 by miR-148a were examined by cell proliferation and migration assays in vitro...
October 2016: Pancreas
Peter M Fischer
Kinase inhibitor research is a comparatively recent branch of medicinal chemistry and pharmacology and the first small-molecule kinase inhibitor, imatinib, was approved for clinical use only 15 years ago. Since then, 33 more kinase inhibitor drugs have received regulatory approval for the treatment of a variety of cancers and the volume of reports on the discovery and development of kinase inhibitors has increased to an extent where it is now difficult-even for those working in the field-easily to keep an overview of the compounds that are being developed, as currently there are 231 such compounds, targeting 38 different protein and lipid kinases (not counting isoforms), in clinical use or under clinical investigation...
October 24, 2016: Medicinal Research Reviews
Wentian Guo, Yuan Ji, Daniel V T Catenacci
In precision medicine, a patient is treated with targeted therapies that are predicted to be effective based on the patient's baseline characteristics such as biomarker profiles. Oftentimes, patient subgroups are unknown and must be learned through inference using observed data. We present SCUBA, a Subgroup ClUster-based Bayesian Adaptive design aiming to fulfill two simultaneous goals in a clinical trial, 1) to treatments enrich the allocation of each subgroup of patients to their precision and desirable treatments and 2) to report multiple subgroup-treatment pairs (STPs)...
October 24, 2016: Biometrics
Magdalena Paolino, Josef M Penninger
The TAM receptor protein tyrosine kinases-Tyro3, Axl, and Mer-are essential regulators of immune homeostasis. Guided by their cognate ligands Growth arrest-specific gene 6 (Gas6) and Protein S (Pros1), these receptors ensure the resolution of inflammation by dampening the activation of innate cells as well as by restoring tissue function through promotion of tissue repair and clearance of apoptotic cells. Their central role as negative immune regulators is highlighted by the fact that deregulation of TAM signaling has been linked to the pathogenesis of autoimmune, inflammatory, and infectious diseases...
October 21, 2016: Cancers
Kyle J Seamon, Namandje N Bumpus, James T Stivers
Sterile Alpha Motif and HD Domain Protein 1 (SAMHD1) is a unique enzyme that has important roles in nucleic acid metabolism, viral restriction, and the pathogenesis of autoimmune diseases and cancer. Although much attention has been focused on its dNTP triphosphohydrolase activity in viral restriction and disease, SAMHD1 also binds to single-stranded RNA and DNA. Here we utilize a UV crosslinking method using 5-bromodeoxyuridine-substituted oligonucleotides coupled with high-resolution mass spectrometry (HRMS) to identify the binding site for single-stranded nucleic acids (ssNA) on SAMHD1...
October 24, 2016: Biochemistry
Steffen Grampp, James L Platt, Victoria Lauer, Rafik Salama, Franziska Kranz, Viviana K Neumann, Sven Wach, Christine Stöhr, Arndt Hartmann, Kai-Uwe Eckardt, Peter J Ratcliffe, David R Mole, Johannes Schödel
Clear cell renal cell carcinoma (ccRCC) is characterized by loss of function of the von Hippel-Lindau tumour suppressor (VHL) and unrestrained activation of hypoxia-inducible transcription factors (HIFs). Genetic and epigenetic determinants have an impact on HIF pathways. A recent genome-wide association study on renal cancer susceptibility identified single-nucleotide polymorphisms (SNPs) in an intergenic region located between the oncogenes MYC and PVT1. Here using assays of chromatin conformation, allele-specific chromatin immunoprecipitation and genome editing, we show that HIF binding to this regulatory element is necessary to trans-activate MYC and PVT1 expression specifically in cells of renal tubular origins...
October 24, 2016: Nature Communications
Hongli Hu, Wenwei Zhu, Jun Qin, Min Chen, Liyan Gong, Long Li, Xiangyuan Liu, Yongzhen Tao, Huiyong Yin, Hu Zhou, Lisha Zhou, Dan Ye, Qinghai Ye, Daming Gao
: Phosphoglycerate kinase 1(PGK1) is an important enzyme in metabolic glycolysis pathway. In this study, we observed a significant over-expression of PGK1 in liver cancer tissues and a negative correlation between PGK1 expression and liver cancer patients survival. Furthermore, depletion of PGK1 dramatically reduced cancer cell proliferation and tumorigenesis, indicating an oncogenic role of PGK1 in liver cancer progression. Moreover, we identified the acetylation at K323 site of PGK1 as an important regulatory mechanism for promoting its enzymatic activity and cancer cell metabolism...
October 24, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Veronica Vella, Roberta Malaguarnera, Rosamaria Lappano, Marcello Maggiolini, Antonino Belfiore
Prostate cancer is the most common cancer in men in many industrialized countries. A role for androgens in prostate tumor progression is well recognized, while estrogens may cooperate with androgens in prostate carcinogenesis. The incidence of prostate cancer is highly variable in the different countries, suggesting an important role of environmental factors. Heavy metals are common environmental contaminants and some of them are confirmed or suspected human carcinogens. Some metals are endowed with estrogenic and/or androgenic activities and may play a role as cancer risk factors through this mechanism...
October 20, 2016: Molecular and Cellular Endocrinology
Vidya Narayanaswami, Linda P Dwoskin
Obesity is a global epidemic that contributes to a number of health complications including cardiovascular disease, type 2 diabetes, cancer and neuropsychiatric disorders. Pharmacotherapeutic strategies to treat obesity are urgently needed. Research over the past two decades has increased substantially our knowledge of central and peripheral mechanisms underlying homeostatic energy balance. Homeostatic mechanisms involve multiple components including neuronal circuits, some originating in hypothalamus and brain stem, as well as peripherally-derived satiety, hunger and adiposity signals that modulate neural activity and regulate eating behavior...
October 20, 2016: Pharmacology & Therapeutics
Daibiao Xiao, Ming Yue, Hexiu Su, Ping Ren, Jue Jiang, Feng Li, Yufeng Hu, Haining Du, Hudan Liu, Guoliang Qing
MYCN amplification in human cancers predicts poor prognosis and resistance to therapy. However, pharmacological strategies that directly target N-Myc, the protein encoded by MYCN, remain elusive. Here, we identify a molecular mechanism responsible for reciprocal activation between Polo-like kinase-1 (PLK1) and N-Myc. PLK1 specifically binds to the SCF(Fbw7) ubiquitin ligase, phosphorylates it, and promotes its autopolyubiquitination and proteasomal degradation, counteracting Fbw7-mediated degradation of N-Myc and additional substrates, including cyclin E and Mcl1...
October 4, 2016: Molecular Cell
J Budna, Ł Spychalski, M Kaczmarek, M Frydrychowicz, J Goździk-Spychalska, H Batura-Gabryel, J Sikora
Tumors exert suppressive effects on the host immune system and tumor progression can be linked to functional impairments of immune cells. Regulatory T cells (Treg) are a subpopulation of T lymphocytes and play a key role in suppressing immune responses against autoimmune diseases and cancer. The aim of the study was to investigate the prevalence of Treg in malignant and benign pleural effusions and to evaluate the relationship between Treg frequency and disease advance. Pleural effusions from 76 patients were subjected to a routine laboratory diagnosis and analyzed by conventional cytology...
October 18, 2016: Immunobiology
C Genova, A Alama, S Coco, E Rijavec, M G Dal Bello, I Vanni, F Biello, G Barletta, G Rossi, F Grossi
Vinflunine belongs to the class of vinca alkaloids and acts by disrupting the microtubule dynamics during cell cycle; this agent is currently available for previously treated advanced transitional cell carcinoma in Europe. The aim of this invited review is to evaluate the potential role of vinflunine for the treatment of non-small cell lung cancer (NSCLC). Areas covered: The potential role of vinflunine in NSCLC is discussed on the basis of the available data, including full papers and meeting abstracts. Relevant preclinical studies describing the pharmacological properties of vinflunine are also included...
October 22, 2016: Expert Opinion on Investigational Drugs
Sophie Plumejeaud, Amelia Paula Reis, Virginie Tassistro, Carla Patinha, Yves Noack, Thierry Orsière
Due to their behavioral characteristics, young children are vulnerable to the ingestion of indoor dust, often contaminated with chemicals that are potentially harmful. Exposure to potentially harmful elements (PHEs) is currently exacerbated by their widespread use in several industrial, agricultural, domestic and technological applications. PHEs cause adverse health effects on immune and nervous systems and can lead to cancer development via genotoxic mechanisms. The present study is an integrated approach that aims at assessing the genotoxicity of bioaccessible PHEs following ingestion of contaminated house dust...
October 22, 2016: Environmental Geochemistry and Health
Aaron Wilson, Vasily A Yakovlev
Cancer development and progression have been linked to oxidative stress, a condition characterized by unbalanced increase in ROS and RNS production. The main endogenous initiators of the redox imbalance in cancer cells are defective mitochondria, elevated NOX activity, and uncoupled NOS3. Traditionally, most attention has been paid to direct oxidative damage to DNA by certain ROS. However, increase in oxidative DNA lesions does not always lead to malignancy. Hence, additional ROS-dependent, pro-carcinogenic mechanisms must be important...
October 19, 2016: Free Radical Biology & Medicine
Manjit Kaur, Raj K S Badhan
Clinical translation of BCRP inhibitors have failed due to neurotoxicity and novel approaches are required to identify suitable modulators of BCRP to enhance CNS drug delivery. In this study we examine 18 compounds, primarily phytochemicals, as potential novel modulators of AhR-mediated regulation of BCRP expression and function in immortalised and primary porcine brain microvascular endothelial cells as a mechanism to enhance CNS drug delivery. The majority of modulators possessed a cellular viability IC50 > 100µM in both cell systems...
October 19, 2016: Brain Research
Megumi Funakoshi-Tago, Kentaro Ohsawa, Toshiyuki Ishikawa, Fumika Nakamura, Fumihito Ueda, Yuji Narukawa, Fumiyuki Kiuchi, Hiroomi Tamura, Kenji Tago, Tadashi Kasahara
Flavonoids, particularly those derived from plants, harbor biological effects such as anti-inflammation and the inhibition of cancer progression. In the present study, we investigated the effects of 10 kinds of flavonoids isolated from Nepalese propolis on the LPS signaling pathway in order to clarify their anti-inflammatory activities. Five types of flavonoids: isoliquiritigenin, chrysin, 3',4'-dihydroxy-4-methoxydalbergione, 4-methoxydalbergion, and cearoin, markedly inhibited inflammatory responses including LPS-induced NO production by suppressing the expression of iNOS mRNA and LPS-induced mRNA expression of TNFα and CCL2...
October 19, 2016: International Immunopharmacology
Junsik Park, Minsuk Kwon, Eui-Cheol Shin
During immune responses antigen-specific T cells are regulated by several mechanisms, including through inhibitory receptors and regulatory T cells, to avoid excessive or persistent immune responses. These regulatory mechanisms, which are called 'immune checkpoints', suppress T cell responses, particularly in patients with chronic viral infections and cancer where viral antigens or tumor antigens persist for a long time and contribute to T cell exhaustion. Among these regulatory mechanisms, cytotoxic T lymphocyte associated protein-4 (CTLA-4) and programmed cell death 1 (PD-1) are the most well-known receptors and both have been targeted for drug development...
October 21, 2016: Archives of Pharmacal Research
Miriam Krischke, Georg Hempel, Swantje Völler, Nicolas André, Maurizio D'Incalci, Gianni Bisogno, Wolfgang Köpcke, Matthias Borowski, Ralf Herold, Alan V Boddy, Joachim Boos
PURPOSE: Doxorubicin is a key component in many pediatric oncology treatment regimens; still pharmacology data on which current dosing regimens are based are very limited. METHODS: We conducted a multinational pharmacokinetic study investigating age dependency of doxorubicin metabolism and elimination in children with cancer. One hundred and one patients treated with doxorubicin according to a cancer-specific national or European therapeutic trial were recruited...
October 21, 2016: Cancer Chemotherapy and Pharmacology
Haniyeh Eyvani, Farima Moghaddaskho, Majid Kabuli, Ali Zekri, Majid Momeny, Javad Tavakkoly-Bazzaz, Kamran Alimoghaddam, Ardeshir Ghavamzadeh, Seyed H Ghaffari
AIMS: Cell cycle dysregulation is important in tumorigenesis. Transcriptional silencing of cell cycle regulatory genes, due to DNA methylation, is a common epigenetic event in malignancies. As2O3 has been shown to induce cell cycle arrest and also to be a potential hypomethylating agent. Our study aimed to investigate DNA methylation patterns of cell cycle regulatory genes promoters, the effects of Arsenic trioxide (As2O3) on the methylated genes and cell cycle distribution in colorectal cancer (CRC) cell lines...
October 18, 2016: Life Sciences
Liqing Wang, Suresh Kumar, Satinder Dahiya, Feng Wang, Jian Wu, Kheng Newick, Rongxiang Han, Arabinda Samanta, Ulf H Beier, Tatiana Akimova, Tricia R Bhatti, Benjamin Nicholson, Mathew P Kodrasov, Saket Agarwal, David E Sterner, Wei Gu, Joseph Weinstock, Tauseef R Butt, Steven M Albelda, Wayne W Hancock
Foxp3+ T-regulatory (Treg) cells are known to suppress protective host immune responses to a wide variety of solid tumors, but their therapeutic targeting is largely restricted to their transient depletion or "secondary" modulation, e.g. using anti-CTLA-4 monoclonal antibody. Our ongoing studies of the post-translational modifications that regulate Foxp3 demonstrated that the histone/protein acetyltransferase, Tip60, plays a dominant role in promoting acetylation, dimerization and function in Treg cells. We now show that the ubiquitin-specific protease, Usp7, controls Treg function largely by stabilizing the expression and promoting the multimerization of Tip60 and Foxp3...
October 15, 2016: EBioMedicine
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