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Molecular therapy

Zachary J Reitman, Frank Winkler, Andrew E H Elia
Glioblastoma (GBM) is the most common primary malignant tumor of the central nervous system. The current standard of care for GBM is maximal resection followed by postoperative radiation with concomitant and adjuvant temozolomide. Despite this multimodality treatment, the median survival for GBM remains marginally better than 1 year. In the past decade, genome-wide analyses have uncovered new molecular features of GBM that have refined its classification and provided new insights into the molecular basis for GBM pathogenesis...
February 2018: Seminars in Neurology
Julie J Miller, Wolfgang Wick
The majority of World Health Organization grade II and grade III gliomas harbor heterozygous mutations in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1), and tumors with an IDH wild-type status show molecular features of a glioblastoma and simply may constitute a separate disease entity. This discovery has led to a profound shift in the way that gliomas are classified and, consequently, how treatment decisions are made. We will review the current understanding of IDH- mutant gliomagenesis and the preclinical models being used to investigate the underlying biology of these tumors and to explore new therapeutic options for these patients...
February 2018: Seminars in Neurology
Silvia Salerno, Aída Nelly García-Argáez, Elisabetta Barresi, Sabrina Taliani, Francesca Simorini, Concettina La Motta, Giorgio Amendola, Stefano Tomassi, Sandro Cosconati, Ettore Novellino, Federico Da Settimo, Anna Maria Marini, Lisa Dalla Via
Inhibition of angiogenesis via blocking vascular endothelial growth factor receptor (VEGFR) signaling pathway emerged as an established approach in anticancer therapy. So far, many monoclonal antibodies and ATP-competitive small molecule inhibitors have been clinically validated and approved. In this study, structure-activity relationships (SAR) within the 2-phenylamino-substituted benzothiopyrano[4,3-d]pyrimidine class of kinase inhibitors were further refined by the synthesis and biological evaluation of new compounds 1-21 featuring different substitution patterns on the pendant phenyl moiety, combined with H, OCH3 , or Cl at 8-position...
March 7, 2018: European Journal of Medicinal Chemistry
Elodie Alessandri-Gradt, Fabienne De Oliveira, Marie Leoz, Véronique Lemee, David L Robertson, Felix Feyertag, Paul-Alain Ngoupo, Philippe Mauclere, François Simon, Jean-Christophe Plantier
OBJECTIVES: HIV/1 group P (HIV-1/P) is the last HIV/1 group discovered and to date, comprises only two strains. To obtain new insights into this divergent group, we screened for new infections by developing specific tools, and analysed phenotypic and genotypic properties of the prototypic strain RBF168. In addition, the follow-up of the unique patient monitored so far, has raised the knowledge of the natural history of this infection and its therapeutic management. DESIGN/METHODS: We developed an HIV-1/P specific sero-molecular strategy and screened over 29,498 specimen samples...
March 15, 2018: AIDS
Guido Kobbe, Thomas Schroeder, Rainer Haas, Ulrich Germing
Allogeneic blood stem cell transplantation (aBSCT) still is the only curative therapy for patients with myelodysplastic syndromes. While it carries the hope for cure for some patients, it may result in severe toxicity and death from complications or recurrent disease in others. Recent developments have improved patient and donor selection as well as technical aspects of the transplant procedure and post-transplant care, including early detection and treatment of relapse. Areas covered: This review will discuss current stratification tools to identify suitable patients, donors and transplant techniques...
March 16, 2018: Expert Review of Hematology
Stephan Bartels, Akinyele Adisa, Timothy Aladelusi, Juliana Lemound, Angelika Stucki-Koch, Sami Hussein, Hans Kreipe, Christian Hartmann, Ulrich Lehmann, Kais Hussein
The aim of this study was to evaluate the mutation profile of BRAF wild-type craniopharyngiomas and ameloblastomas. Pre-screening by immunohistochemistry and pyrosequencing for identifying BRAF wild-type tumors was performed on archived specimens of ameloblastic tumors (n = 20) and craniopharyngiomas (n = 62). Subsequently, 19 BRAF wild-type tumors (nine ameloblastic tumors and ten craniopharyngiomas) were analyzed further using next-generation sequencing (NGS) targeting hot spot mutations of 22 cancer-related genes...
March 15, 2018: Virchows Archiv: An International Journal of Pathology
Rishibha Sachdev, Karin Kappes-Horn, Lydia Paulsen, Yvonne Duernberger, Catharina Pleschka, Philip Denner, Bishwajit Kundu, Jens Reimann, Ina Vorberg
Sporadic inclusion body myositis (sIBM) is the most prevalent acquired muscle disorder in the elderly with no defined etiology or effective therapy. Endoplasmic reticulum stress and deposition of myostatin, a secreted negative regulator of muscle growth, have been implicated in disease pathology. The myostatin signaling pathway has emerged as a major target for symptomatic treatment of muscle atrophy. Here, we systematically analyzed the maturation and secretion of myostatin precursor MstnPP and its metabolites in a human muscle cell line...
March 15, 2018: Molecular Neurobiology
Lei Liu, Masashi Fujimoto, Fumi Nakano, Hirofumi Nishikawa, Takeshi Okada, Fumihiro Kawakita, Kyoko Imanaka-Yoshida, Toshimichi Yoshida, Hidenori Suzuki
Tenascin-C (TNC), a matricellular protein, is upregulated in brain parenchyma after experimental subarachnoid hemorrhage (SAH). Recent studies emphasize that early brain injury (EBI) should be overcome to improve post-SAH outcomes. The aim of this study was to investigate effects of TNC knockout (TNKO) on neuronal apoptosis and neuroinflammation, both of which are important constituents of EBI after SAH. C57BL/6 wild-type (WT) mice or TNKO mice underwent sham or filament perforation SAH modeling. Twenty-five WT mice and 25 TNKO mice were randomly divided into sham+WT (n = 10), sham+TNKO (n = 8), SAH+WT (n = 15), and SAH+TNKO (n = 17) groups...
March 15, 2018: Molecular Neurobiology
Sarva Mangala Praveena, Seoh Wei Teh, Ranjith Kumar Rajendran, Narayanan Kannan, Chu-Ching Lin, Rozaini Abdullah, Suresh Kumar
Phthalates have been blended in various compositions as plasticizers worldwide for a variety of purposes. Consequently, humans are exposed to a wide spectrum of phthalates that needs to be researched and understood correctly. The goal of this review is to focus on phthalate's internal exposure pathways and possible role of human digestion on liver toxicity. In addition, special focus was made on stem cell therapy in reverting liver toxicity. The known entry of higher molecular weight phthalates is through ingestion while inhalation and dermal pathways are for lower molecular weight phthalates...
March 15, 2018: Environmental Science and Pollution Research International
Ari Rosenberg, Mark Agulnik
Epithelioid hemangioendothelioma (EHE) is an extremely rare sarcoma, as such it can pose a clinical dilemma based solely on its rarity. Also, the spectrum of disease varies greatly between an indolent disease and aggressive disease with widespread metastases. In our clinical practice, the primary focus has been to get a handle on the aggressive nature of the disease, which will then dictate how urgently one needs to treat the patient. Pathological review with immunohistochemistry and molecular characterization is paramount...
March 15, 2018: Current Treatment Options in Oncology
Kaimin Lu, Xin Wang, Yuyu Chen, Danfeng Liang, Hao Luo, Li Long, Zongyue Hu, Jinku Bao
Osteosarcoma is the most common primary malignant bone tumor among adolescents worldwide with high mortality rate. Glycogen synthase kinase 3β (GSK3β) is a serine/threonine kinase and is considered as a validated target in osteosarcoma therapy. Therefore, the study of GSK3β inhibitors is one of the most popular fields in anti-osteosarcoma drug development. Here, the tools of bioinformatics were used to screen novel effective inhibitors of GSK3β from ZINC Drug Database. The molecular docking, molecular dynamic simulations, MM/GBSA, and energy decomposition analysis were performed to identify the inhibitors...
March 13, 2018: Acta Biochimica et Biophysica Sinica
Hannah Maier, Saskia Helm, Sermin Toto, Nicole Moschny, Wolfgang Sperling, Thomas Hillemacher, Kai G Kahl, Ewgeni Jakubovski, Stefan Bleich, Helge Frieling, Alexandra Neyazi
Background: Electroconvulsive therapy (ECT) is one of the most effective treatment options for refractory depressed patients. To date, there are only a few predictors of response. Aim: The aim was to identify predictive biomarkers of remission to ECT on a molecular level. Methods: 11 patients suffering from a major depressive episode-according to the Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-underwent 10 ECT sessions...
2018: Disease Markers
Long Chen, Yifeng Jiang, Zhen Du
Although previous studies have demonstrated that dental pulp stem cells (DPSCs) from mature and immature teeth exhibit potential for multi-directional differentiation, the molecular and biological difference between the DPSCs from mature and immature permanent teeth has not been fully investigated. In the present study, 500 differentially expressed genes from dental pulp cells (DPCs) in mature and immature permanent teeth were obtained from the Gene Expression Omnibus online database. Based on bioinformatics analysis using the Database for Annotation, Visualization and Integrated Discovery, these genes were divided into a number of subgroups associated with immunity, inflammation and cell signaling...
April 2018: Experimental and Therapeutic Medicine
Tianzhou Zha, Haorong Wu
This study investigated the expression of adenosine monophosphate deaminase 1 (AMPD1) in serum of patients with papillary thyroid carcinoma (PTC) and its clinical significance. The expression levels of AMPD1 mRNA in serum of 157 patients with PTC and 100 normal controls were detected by real-time fluorescent quantitative polymerase chain reaction (PCR), and the relationships between expression level of AMPD1 in serum of PTC patients and clinicopathological factors as well as prognosis were analyzed. The results of real-time fluorescent quantitative PCR showed that the expression of AMPD1 mRNA in serum of PTC patients was lower than that in normal human serum (P<0...
April 2018: Experimental and Therapeutic Medicine
Zhong Ni, Xiting Wang, Tianchen Zhang, Linlin Li, Jianxue Li
Small cell lung cancer (SCLC) is the subtype of lung cancer with the highest degree of malignancy and the lowest degree of differentiation. The purpose of this study was to investigate the molecular mechanisms of SCLC using bioinformatics analysis, and to provide new ideas for the early diagnosis and targeted therapy of SCLC. Microarray data were downloaded from Gene Expression Omnibus. Differentially expressed genes (DEGs) in SCLC were compared with the normal lung samples and identified. Gene Ontology (GO) function and pathway analysis of DEGs was performed through the DAVID database...
April 2018: Experimental and Therapeutic Medicine
Sandrine Loubière, Alexandre Drezet, Michèle Beau-Faller, Denis Moro-Sibilot, Sylvie Friard, Marie Wislez, Hélène Blons, Catherine Daniel, Virginie Westeel, Anne Madroszyk, Hervé Léna, Patrick Merle, Julien Mazières, Gérard Zalcman, Roger Lacave, Martine Antoine, Franck Morin, Pascale Missy, Fabrice Barlesi, Pascal Auquier, Jacques Cadranel
ALK rearrangement and EGFR / KRAS mutations constitute the primary biomarkers tested to provide targeted or nontargeted therapies in advanced nonsmall cell lung cancer (NSCLC) patients. Our objective was to assess the cost-effectiveness of biomarker testing for NSCLC.Between 2013 and 2014, 843 treatment-naive patients were prospectively recruited at 19 French hospitals into a longitudinal observational cohort study. Two testing strategies were compared, i.e. with "at least one biomarker status known" and "at least KRAS status known", in addition to "no biomarker testing" as the reference strategy...
March 2018: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
Tiziana Lazzarotto, Angela Chiereghin, Antonio Piralla, Giulia Piccirilli, Alessia Girello, Giulia Campanini, Liliana Gabrielli, Cristina Costa, Arcangelo Prete, Francesca Bonifazi, Alessandro Busca, Roberto Cairoli, Anna Amelia Colombo, Marco Zecca, Francesca Sidoti, Gabriele Bianco, Pierpaolo Paba, Carlo Federico Perno, Rossana Cavallo, Fausto Baldanti
Currently, no consensus has been reached on the optimal blood compartment to be used for surveillance of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) DNAemia. Although several comparative studies have been performed correlating CMV and EBV DNA loads in whole blood (WB) vs plasma, to our knowledge, no studies have ever analyzed the kinetics of both viruses in the two blood compartments. In this retrospective non-interventional multicenter cohort study the kinetics of CMV and EBV DNA in 121 hematopoietic stem cell transplant recipients (HSCTR) have been investigated by analyzing in parallel 569 and 351 paired samples from 80 and 58 sequential episodes of CMV and EBV DNAemia, respectively...
March 12, 2018: Biology of Blood and Marrow Transplantation
Jun Hao, Xinpei Ci, Hui Xue, Rebecca Wu, Xin Dong, Stephen Yiu Chuen Choi, Haiqing He, Yu Wang, Fang Zhang, Sifeng Qu, Fan Zhang, Anne M Haegert, Peter W Gout, Amina Zoubeidi, Colin Collins, Martin E Gleave, Dong Lin, Yuzhuo Wang
BACKGROUND: Although androgen deprivation therapy is initially effective in controlling growth of hormone-naive prostate cancers (HNPCs) in patients, currently incurable castration-resistant prostate cancer (CRPC) inevitably develops. OBJECTIVE: To identify CRPC driver genes that may provide new targets to enhance CRPC therapy. DESIGN, SETTING, AND PARTICIPANTS: Patient-derived xenografts (PDXs) of HNPCs that develop CRPC following host castration were examined for changes in expression of genes at various time points after castration using transcriptome profiling analysis; particular attention was given to pre-CRPC changes in expression indicative of genes acting as potential CRPC drivers...
March 12, 2018: European Urology
Jose J G Marin, Oscar Briz, Elisa Herraez, Elisa Lozano, Maitane Asensio, Silvia Di Giacomo, Marta R Romero, Luis M Osorio-Padilla, Ana I Santos-Llamas, Maria A Serrano, Carolina Armengol, Thomas Efferth, Rocio I R Macias
A characteristic shared by most frequent types of primary liver cancer, i.e., hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) in adults, and in a lesser extent hepatoblastoma (HB) mainly in children, is their high refractoriness to chemotherapy. This is the result of synergic interactions among complex and diverse mechanisms of chemoresistance (MOC) in which more than 100 genes are involved. Pharmacological treatment, although it can be initially effective, frequently stimulates the expression of MOC genes, which results in the relapse of the tumor, usually with a more aggressive and less chemosensitive phenotype...
March 12, 2018: Clinics and Research in Hepatology and Gastroenterology
Stefania Ferrari, Leda Severi, Cecilia Pozzi, Antonio Quotadamo, Glauco Ponterini, Lorena Losi, Gaetano Marverti, Maria Paola Costi
Human thymidylate synthase (hTS) has an important role in DNA biosynthesis, thus it is essential for cell survival. TS is involved in the folate pathways, specifically in the de novo pyrimidine biosynthesis. Structure and functions are intimately correlated, account for cellular activity and, in a broader view, with in vivo mechanisms. hTS is a target for anticancer agents, some of which are clinical drugs. The understanding of the detailed mechanism of TS inhibition by currently used drugs and of the interaction with the mechanism of action of other anticancer agents can suggest new perspective of TS inhibition able to improve the anticancer effect and to overcome drug resistance...
2018: Vitamins and Hormones
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