Overview of latest articles and publications on gene therapy in PubMed, including Human Gene Therapy, Journal of Molecular Medicine and Journal of Gene Medicine. PubMed is a service of the US National Library of Medicine that includes over 18 million citations from MEDLINE and other life science journals.
- Data Mining Approaches for Genomic Biomarker Development: Applications Using Drug Screening Data from the Cancer Genome Project and the Cancer Cell Line Encyclopedia.
Covell DG Data Mining Approaches for Genomic Biomarker Development: Applications Using Drug Screening Data from the Cancer Genome Project and the Cancer Cell Line Encyclopedia. [JOURNAL ARTICLE]PLoS One 2015; 10(7):e0127433.Developing reliable biomarkers of tumor cell drug sensitivity and resistance can guide hypothesis-driven basic science research and influence pre-therapy clinical decisions. A popular strategy for developing biomarkers uses characterizations of human tumor samples against a range of cancer drug responses that correlate with genomic change; developed largely from the efforts of the Cancer Cell Line Encyclopedia (CCLE) and Sanger Cancer Genome Project (CGP). The purpose of this study is to provide an independent analysis of this data that aims to vet existing and add novel perspectives to biomarker discoveries and applications. Existing and alternative data mining and statistical methods will be used to a) evaluate drug responses of compounds with similar mechanism of action (MOA), b) examine measures of gene expression (GE), copy number (CN) and mutation status (MUT) biomarkers, combined with gene set enrichment analysis (GSEA), for hypothesizing biological processes important for drug response, c) conduct global comparisons of GE, CN and MUT as biomarkers across all drugs screened in the CGP dataset, and d) assess the positive predictive power of CGP-derived GE biomarkers as predictors of drug response in CCLE tumor cells. The perspectives derived from individual and global examinations of GEs, MUTs and CNs confirm existing and reveal unique and shared roles for these biomarkers in tumor cell drug sensitivity and resistance. Applications of CGP-derived genomic biomarkers to predict the drug response of CCLE tumor cells finds a highly significant ROC, with a positive predictive power of 0.78. The results of this study expand the available data mining and analysis methods for genomic biomarker development and provide additional support for using biomarkers to guide hypothesis-driven basic science research and pre-therapy clinical decisions.
- Potentiation of Glibenclamide Hypoglycaemia in Mice by MK-467, a Peripherally Acting Alpha2-Adrenoceptor Antagonist.
Ruohonen ST, Ranta-Panula V, Bastman S, et al. Potentiation of Glibenclamide Hypoglycaemia in Mice by MK-467, a Peripherally Acting Alpha2-Adrenoceptor Antagonist. [JOURNAL ARTICLE]Basic Clin Pharmacol Toxicol 2015 Jul 1.Pharmacological antagonism and genetic depletion of pancreatic α2A -adrenoceptors increase insulin secretion in mice, and enhance the insulinotropic action of glibenclamide, a representative of the sulphonylurea class of insulin secretagogues used in the therapy of type 2 diabetes. Antagonism of α2 -adrenoceptors in the central nervous system (CNS) causes tachycardia and hypertension, making generalized α2 -adrenoceptor blockade unfavourable for clinical use despite its potential to decrease blood glucose levels. The purpose of this study was to test the acute effects of the peripherally acting α2 -adrenoceptor antagonist MK-467 alone and in combination with glibenclamide in non-diabetic C57BL/6N mice. Cardiovascular safety was assessed in freely moving mice with radiotelemetry. Dose-dependent decreases in blood glucose and increases in plasma insulin concentrations were seen with the combination of MK-467 and glibenclamide; the combinations were much more potent than glibenclamide or MK-467 alone. Furthermore, MK-467 had no effect on mean arterial pressure or heart rate in freely moving mice, and did not prevent the centrally mediated hypotensive effect of the α2 -adrenoceptor agonist medetomidine. Thus, peripheral blockade of α2 -adrenoceptors does not evoke the same cardiovascular adverse effects as antagonism of CNS α2 -adrenoceptors. The current results indicate that the combined use of small doses of a peripherally acting α2 -adrenoceptor antagonist with a sulphonylurea drug could provide a novel option for the treatment of type 2 diabetes, especially in patients with increased tonic α2 -adrenoceptor-mediated inhibition of insulin secretion. This article is protected by copyright. All rights reserved.
- Comprehensive Glycomics of a Multistep Human Brain Tumor Model Reveals Specific Glycosylation Patterns Related to Malignancy.
Furukawa JI, Tsuda M, Okada K, et al. Comprehensive Glycomics of a Multistep Human Brain Tumor Model Reveals Specific Glycosylation Patterns Related to Malignancy. [JOURNAL ARTICLE]PLoS One 2015; 10(7):e0128300.Cancer cells frequently express glycans at different levels and/or with fundamentally different structures from those expressed by normal cells, and therefore elucidation and manipulation of these glycosylations may provide a beneficial approach to cancer therapy. However, the relationship between altered glycosylation and causal genetic alteration(s) is only partially understood. Here, we employed a unique approach that applies comprehensive glycomic analysis to a previously described multistep tumorigenesis model. Normal human astrocytes were transformed via the serial introduction of hTERT, SV40ER, H-RasV12, and myrAKT, thereby mimicking human brain tumor grades I-IV. More than 160 glycans derived from three major classes of cell surface glycoconjugates (N- and O-glycans on glycoproteins, and glycosphingolipids) were quantitatively explored, and specific glycosylation patterns related to malignancy were systematically identified. The sequential introduction of hTERT, SV40ER, H-RasV12, and myrAKT led to (i) temporal expression of pauci-mannose/mono-antennary type N-glycans and GD3 (hTERT); (ii) switching from ganglio- to globo-series glycosphingolipids and the appearance of Neu5Gc (hTERT and SV40ER); (iii) temporal expression of bisecting GlcNAc residues, α2,6-sialylation, and stage-specific embryonic antigen-4, accompanied by suppression of core 2 O-glycan biosynthesis (hTERT, SV40ER and Ras); and (iv) increased expression of (neo)lacto-series glycosphingolipids and fucosylated N-glycans (hTERT, SV40ER, Ras and AKT). These sequential and transient glycomic alterations may be useful for tumor grade diagnosis and tumor prognosis, and also for the prediction of treatment response.
- Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS.
Krönke J, Fink EC, Hollenbach PW, et al. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. [JOURNAL ARTICLE]Nature 2015 Jul 1.Lenalidomide is a highly effective treatment for myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)). Here, we demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1α) by the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)), resulting in CK1α degradation. CK1α is encoded by a gene within the common deleted region for del(5q) MDS and haploinsufficient expression sensitizes cells to lenalidomide therapy, providing a mechanistic basis for the therapeutic window of lenalidomide in del(5q) MDS. We found that mouse cells are resistant to lenalidomide but that changing a single amino acid in mouse Crbn to the corresponding human residue enables lenalidomide-dependent degradation of CK1α. We further demonstrate that minor side chain modifications in thalidomide and a novel analogue, CC-122, can modulate the spectrum of substrates targeted by CRL4(CRBN). These findings have implications for the clinical activity of lenalidomide and related compounds, and demonstrate the therapeutic potential of novel modulators of E3 ubiquitin ligases.
- Perspective of future drugs targeting sterile 20/SPS1-related proline/alanine-rich kinase for blood pressure control.
Lin GM, Liu PY, Wu CF, et al. Perspective of future drugs targeting sterile 20/SPS1-related proline/alanine-rich kinase for blood pressure control. [Journal Article]World J Cardiol 2015 Jun 26; 7(6):306-10.According to a genome-wide association study, intronic SNPs within the human sterile 20/SPS1-related proline/alanine-rich kinase (SPAK) gene was linked to 20% of the general population and may be associated with elevated blood pressure. As cell volume changes, mammalian SPAK kinases respond to phosphorylate and regulate cation-coupled chloride co-transporter activity. To our knowledge, phosphorylation of upstream with-no-lysine (K) (WNK) kinases would activate SPAK kinases. The activation of WNK-OSR1/SPAK cascade on the kidneys and aortic tissue is related to the development of hypertension. Several regulators of the WNK pathway such as the Kelch kinase protein 3 - Cullin 3 E3 ligase, hyperinsulinemia, and low potassium intake to mediate hypertension have been identified. In addition, the SPAK kinases may affect the action of renin-angiotensin-aldosterone system on blood pressure as well. In 2010, two SPAK knock-in and knock-out mouse models have clarified the pathogenesis of lowering blood pressure by influencing the receptors on the kidneys and aortic smooth muscle. More recently, two novel SPAK inhibitors for mice, Stock 1S-14279 and Closantel were discovered in 2014. Targeting of SPAK seems to be promising for future antihypertensive therapy. Therefore we raised some viewpoints for the issue for the antihypertensive therapy on the SPAK (gene or kinase).
- Adenocarcinoma arising at ileostomy sites: Two cases and a review of the literature.
Procaccino L, Rehman S, Abdurakhmanov A, et al. Adenocarcinoma arising at ileostomy sites: Two cases and a review of the literature. [Journal Article]World J Gastrointest Surg 2015 Jun 27; 7(6):94-7.Total colectomy with ileostomy placement is a treatment for patients with inflammatory bowel disease or familial adenomatous polyposis (FAP). A rare and late complication of this treatment is carcinoma arising at the ileostomy site. We describe two such cases: a 78-year-old male 30 years after subtotal colectomy and ileostomy for FAP, and an 85-year-old male 50 years after colectomy and ileostomy for ulcerative colitis. The long latency period between creation of the ileostomies and development of carcinoma suggests a chronic metaplasia due to an irritating/inflammatory causative factor. Surgical excision of the mass and relocation of the stoma is the mainstay of therapy, with possible benefits from adjuvant chemotherapy. Newly developed lesions at stoma sites should be biopsied to rule out the possibility of this rare ileostomy complication.
- Mesenchymal stem cells: A new diagnostic tool?
Valenti MT, Mori A, Malerba G, et al. Mesenchymal stem cells: A new diagnostic tool? [Journal Article]World J Stem Cells 2015 Jun 26; 7(5):789-92.Mesenchymal stem cells (MSCs) are progenitor cells capable of self-renewal that can differentiate in multiple tissues and, under specific and standardized culture conditions, expand in vitro with little phenotypic alterations. In recent years, preclinical and clinical studies have focused on MSC analysis and understanding the potential use of these cells as a therapy in a wide range of pathologies, and many applications have been tested. Clinical trials using MSCs have been performed (e.g., for cardiac events, stroke, multiple sclerosis, blood diseases, auto-immune disorders, ischemia, and articular cartilage and bone pathologies), and for many genetic diseases, these cells are considered an important resource. Considering of the biology of MSCs, these cells may also be useful tools for understanding the physiopathology of different diseases, and they can be used to develop specific biomarkers for a broad range of diseases. In this editorial, we discuss the literature related to the use of MSCs for diagnostic applications and we suggest new technologies to improve their employment.
- Construction of the recombinant vaccine based on T-cell epitope encoding Der p1 and evaluation on its specific immunotherapy efficacy.
Zhao J, Li C, Zhao B, et al. Construction of the recombinant vaccine based on T-cell epitope encoding Der p1 and evaluation on its specific immunotherapy efficacy. [Journal Article]Int J Clin Exp Med 2015; 8(4):6436-43.Specific immunotherapy (SIT) is currently recognized as the only etiological therapy to ameliorate asthmatic symptom. The current study was aimed at evaluating the immune effect of vaccine MAT3T designed on MHCII pathway, which includes T cell fusion peptide encoding Dermatophagoides pteronyssinus class 1 allergen (Der p1). We initially cloned the nucleotide sequences of TAT, IhC and 3 segments of T cell epitope coding for Der p1, and reassembled these sequences in linear manner to form fusion gene named MAT3T, which was applied to immunize the asthmatic models of mice induced by Der p1 allergen for tentative SIT. ELISA results showed that MAT3T was able to increase the level of IFN-γ in BALF and allergen specific antibody IgG2a in serum, while decrease the level of IL-13 in BALF and allergen specific antibody IgE and IgG1. Pathological confirmation further revealed that the inflammatory reactions and inflammatory cell infiltration were totally reduced in lung tissue of mice after MAT3T treatment. Our results show that the recombinant allergen MAT3T can effectively correct the imbalance of Th1/Th2, and MAT3T may be used as candidate vaccine against asthma on SIT basis.
- Association of SLCO1B1 gene polymorphisms with toxicity response of high dose methotrexate chemotherapy in childhood acute lymphoblastic leukemia.
Li J, Wang XR, Zhai XW, et al. Association of SLCO1B1 gene polymorphisms with toxicity response of high dose methotrexate chemotherapy in childhood acute lymphoblastic leukemia. [Journal Article]Int J Clin Exp Med 2015; 8(4):6109-13.The present study aims to investigate the correlation of polymorphisms of SLCO1B1 gene with the toxicity during therapy with the high-dose methotrexate (MTX) chemotherapy in childhood acute lymphoblastic leukemia.We analyzed 2 polymorphisms (rs4149081 and rs11045897) in SLCO1B1 gene in 280 Chinese pediatric B-ALL patients, using MTX plasma concentration as an objective and quantifiable marker of toxicity. We utilized Enzyme-multiplied immunoassay technique (EMIT) to measure the plasma concentration of MTX. The polymerase chain reaction-allele specific (PCR-AS) method was utilized to perform the genotyping.We found there was a statistically significant association between MTX plasma concentration and the SLCO1B1 rs11045879 CC genotype (P<0.05). We also found the rs4149081 AA genotype was associated with high-MTX plasma concentrations. A-C haplotype carriers have a higher risk for MTX delayed clearance but G-T haplotype was associated with a lower risk for MTX delayed clearance.The rs4149081 AA genotype and the rs11045897 CC genotype could be indicators for high-MTX plasma concentrations in children with ALL.
- Cytokine-induced killer cells combined with dendritic cells inhibited liver cancer cells.
Li QY, Shi Y, Huang DH, et al. Cytokine-induced killer cells combined with dendritic cells inhibited liver cancer cells. [Journal Article]Int J Clin Exp Med 2015; 8(4):5601-10.To investigate the prognosis of advanced liver cancer patients treated with CIK-DCs and the mechanism of apoptosis of HEPG 2 cells.67 patients were enrolled in the study. Peripheral blood mononuclear cells (PBMCs) were separated, of which adherent PBMCs used granulocyte 2 macrophage colony2 stimulating factor (GM2CSF), tumor necrosis factor 2α (TNF2α), and interleukin 24 (IL24) to induce DCs, which were sensitized with antigen of autologous or exogenous cancer cells to obtain Ag-DCs; suspended PBMCs used interferon 2γ (IFN2γ), IL-2, and CD 3 monoclonal antibody (CD3mAb) respectively, to induce CIK cells. DCs and CIK cells were cultured together. Flow cytometry was used to detect the phenotypes of DCs and CIK cells, and the blood retransfused into patients. Western blot and flow cytometer were used to analyze the growth cycle of HepG 2 cells and the expression of BAX and PCNA.No patients underwent complete remission, 5 obtained partial remission and 29 had stable disease. Of the 31 patients whose lesions could not be evaluated, 17 received effective treatment, showing that the immune response was enhanced. In vitro laboratory experiments revealed that DC-CIK cells markedly affected the growth cycle of HepG 2 cells. Analysis showed that DC-CIK cells enhanced the gene expression of BAX and inhibited the activity of PCNA.Co-cultured DCs and CIK cells inhibit the proliferation and migration of liver cancer cells by down-regulating PCNA and up-regulating BAX. This approach may be an effective method to treat advanced liver cancer.