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.
- Mitochondrial Ribosomes in Cancer.
Mitochondrial Ribosomes in Cancer. [Journal Article, Review]Semin Cancer Biol 2017 Apr 23.SCKim HJ, Maiti P, Barrientos A Mitochondria play fundamental roles in the regulation of life and death of eukaryotic cells. They mediate aerobic energy conversion through the oxidative phosphorylation (OXPHOS) system, and harbor and...Mitochondria play fundamental roles in the regulation of life and death of eukaryotic cells. They mediate aerobic energy conversion through the oxidative phosphorylation (OXPHOS) system, and harbor and control the intrinsic pathway of apoptosis. As a descendant of a bacterial endosymbiont, mitochondria retain a vestige of their original genome (mtDNA), and its corresponding full gene expression machinery. Proteins encoded in the mtDNA, all components of the multimeric OXPHOS enzymes, are synthesized in specialized mitochondrial ribosomes (mitoribosomes). Mitoribosomes are therefore essential in the regulation of cellular respiration. Additionally, an increasing body of literature has been reporting an alternative role for several mitochondrial ribosomal proteins as apoptosis-inducing factors. No surprisingly, the expression of genes encoding for mitoribosomal proteins, mitoribosome assembly factors and mitochondrial translation factors is modified in numerous cancers, a trait that has been linked to tumorigenesis and metastasis. In this article, we will review the current knowledge regarding the dual function of mitoribosome components in protein synthesis and apoptosis and their association with cancer susceptibility and development. We will also highlight recent developments in targeting mitochondrial ribosomes for the treatment of cancer.
- Next generation sequencing to dissect the genetic architecture of KNG1 and F11 loci using factor XI levels as an intermediate phenotype of thrombosis.
Next generation sequencing to dissect the genetic architecture of KNG1 and F11 loci using factor XI levels as an intermediate phenotype of thrombosis. [Journal Article]PLoS One 2017; 12(4):e0176301.PlosMartin-Fernandez L, Gavidia-Bovadilla G, Corrales I, et al. Venous thromboembolism is a complex disease with a high heritability. There are significant associations among Factor XI (FXI) levels and SNPs in the KNG1 and F11 loci. Our aim was to identify the gene...Venous thromboembolism is a complex disease with a high heritability. There are significant associations among Factor XI (FXI) levels and SNPs in the KNG1 and F11 loci. Our aim was to identify the genetic variation of KNG1 and F11 that might account for the variability of FXI levels. The KNG1 and F11 loci were sequenced completely in 110 unrelated individuals from the GAIT-2 (Genetic Analysis of Idiopathic Thrombophilia 2) Project using Next Generation Sequencing on an Illumina MiSeq. The GAIT-2 Project is a study of 935 individuals in 35 extended Spanish families selected through a proband with idiopathic thrombophilia. Among the 110 individuals, a subset of 40 individuals was chosen as a discovery sample for identifying variants. A total of 762 genetic variants were detected. Several significant associations were established among common variants and low-frequency variants sets in KNG1 and F11 with FXI levels using the PLINK and SKAT packages. Among these associations, those of rs710446 and five low-frequency variant sets in KNG1 with FXI level variation were significant after multiple testing correction and permutation. Also, two putative pathogenic mutations related to high and low FXI levels were identified by data filtering and in silico predictions. This study of KNG1 and F11 loci should help to understand the connection between genotypic variation and variation in FXI levels. The functional genetic variants should be useful as markers of thromboembolic risk.
- Detection of Hepatitis B Virus M204I Mutation by Quantum Dot-Labeled DNA Probe.
Detection of Hepatitis B Virus M204I Mutation by Quantum Dot-Labeled DNA Probe. [Journal Article]Sensors (Basel) 2017 Apr 26; 17(5)SZhang C, Chen Y, Liang X, et al. Quantum dots (QDs) are semiconductor nanoparticles with a diameter of less than 10 nm, which have been widely used as fluorescent probes in biochemical analysis and vivo imaging because of their excell...Quantum dots (QDs) are semiconductor nanoparticles with a diameter of less than 10 nm, which have been widely used as fluorescent probes in biochemical analysis and vivo imaging because of their excellent optical properties. Sensitive and convenient detection of hepatitis B virus (HBV) gene mutations is important in clinical diagnosis. Therefore, we developed a sensitive, low-cost and convenient QDs-mediated fluorescent method for the detection of HBV gene mutations in real serum samples from chronic hepatitis B (CHB) patients who had received lamivudine or telbivudine antiviral therapy. We also evaluated the efficiency of this method for the detection of drug-resistant mutations compared with direct sequencing. In CHB, HBV DNA from the serum samples of patients with poor response or virological breakthrough can be hybridized to probes containing the M204I mutation to visualize fluorescence under fluorescence microscopy, where fluorescence intensity is related to the virus load, in our method. At present, the limits of the method used to detect HBV genetic variations by fluorescence quantum dots is 10³ IU/mL. These results show that QDs can be used as fluorescent probes to detect viral HBV DNA polymerase gene variation, and is a simple readout system without complex and expensive instruments, which provides an attractive platform for the detection of HBV M204I mutation.
- Improvement of Flap Necrosis in a Rat Random Skin Flap Model by In Vivo Electroporation-Mediated HGF Gene Transfer.
Improvement of Flap Necrosis in a Rat Random Skin Flap Model by In Vivo Electroporation-Mediated HGF Gene Transfer. [Journal Article]Plast Reconstr Surg 2017 May; 139(5):1116e-1127e.PRSeyed Jafari SM, Shafighi M, Beltraminelli H, et al. These findings suggested in vivo electroporation-mediated HGF gene delivery enhanced viability and vascularity of the ischemic skin flap.Despite great understanding of underlying mechanisms for flap necrosis and advances in surgical techniques, flap necrosis remains a critical issue. In the present study, the authors investigated the efficacy of electroporation-mediated hepatocyte growth factor (HGF) gene delivery to random dorsal skin flaps (McFarlane) to accelerate wound healing and reduce flap necrosis.Fifteen male Wistar rats (290 to 320 g) were divided randomly into three groups. Group a, the control group (n = 5), underwent surgery and received no gene transfer. Group b received electroporation-mediated HGF gene delivery 24 hours after surgery as a treatment. Group c received electroporation-mediated HGF gene delivery 24 hours before surgery as prophylaxis (n = 5). Planimetry, laser Doppler imaging, and immunohistochemistry were used to assess the efficacy of HGF gene therapy among the groups.Electroporation-mediated HGF gene delivery significantly decreased flap necrosis percentage compared with the control group in prophylactic and treatment groups (p = 0.0317 and p = 0.0079, respectively) and significantly increased cutaneous perfusion compared with the control group (p = 0.0317 and p = 0.0159, respectively). Moreover, Spearman rank correlation showed a significant negative correlation between flap necrosis percentage and laser index (p = 0.0213 and r = -0.5964, respectively). Furthermore, significantly higher mean CD31 vessel density was detected in treatment and prophylactic groups (p = 0.0079 and p = 0.0159, respectively). In addition, quantitative image analysis revealed significantly higher HGF protein expression in groups b and c (p = 0.0079 and p = 0.0079, respectively).These findings suggested in vivo electroporation-mediated HGF gene delivery enhanced viability and vascularity of the ischemic skin flap.
- The Mucosal Antibacterial Response Profile and Fecal Microbiota Composition Are Linked to the Disease Course in Patients with Newly Diagnosed Ulcerative Colitis.
The Mucosal Antibacterial Response Profile and Fecal Microbiota Composition Are Linked to the Disease Course in Patients with Newly Diagnosed Ulcerative Colitis. [Journal Article]Inflamm Bowel Dis 2017 Apr 25.IBMagnusson MK, Strid H, Isaksson S, et al. In patients with newly diagnosed UC, fecal microbiota composition and mucosal antibacterial response profile, especially bactericidal/permeability-increasing protein, are linked to disease course.The clinical disease course of ulcerative colitis (UC) varies substantially between individuals and can currently not be reliably predicted. The gut microbiota and the host's immune defense are key players for gut homeostasis and may be linked to disease outcome. The aim of this study was to determine fecal microbiota composition and mucosal antibacterial response profile in untreated patients with newly diagnosed UC and the impact of these factors on disease course.Stool samples and intestinal biopsies were obtained from therapy-naive newly diagnosed patients with UC. Patients were defined to have mild or moderate/severe disease course assessed by disease activity during the 3 years follow-up. Fecal microbiota was analyzed by the GA-map Dysbiosis test (n = 18), and gene expression in intestinal biopsies was analyzed by RT Profiler polymerase chain reaction array (n = 13) and real-time polymerase chain reaction (n = 44).At the time of diagnosis of UC, the fecal microbiota composition discriminated between patients with mild versus moderate/severe disease course. Also, the mucosal antibacterial gene expression response profile differed between patients with mild versus moderate/severe disease course with bactericidal/permeability-increasing protein (BPI) being most important for the discrimination. Mucosal bactericidal/permeability-increasing protein gene expression at diagnosis was higher in patients with mild versus moderate/severe disease course when confirmed in a larger patient cohort (P = 0.0004, n = 44) and was a good predictor for the number of flares during the 3 years follow-up (R = 0.395, P < 0.0001).In patients with newly diagnosed UC, fecal microbiota composition and mucosal antibacterial response profile, especially bactericidal/permeability-increasing protein, are linked to disease course.
- Proton pump inhibitor-responsive esophageal eosinophilia: still a valid diagnosis?
Proton pump inhibitor-responsive esophageal eosinophilia: still a valid diagnosis? [Journal Article]Curr Opin Gastroenterol 2017 Apr 25.COMolina-Infante J, Gonzalez-Cordero PL, Lucendo AJ Proton pump inhibitor-responsive esophageal eosinophilia is an inappropriate disease descriptor, arbitrarily based on a response to a single drug, and should be abandoned. Patients who have esophageal ...To update rapidly evolving concepts regarding the controversial entity of 'proton pump inhibitor (PPI)-responsive esophageal eosinophilia,' referring to patients with clinical, endoscopic and histologic features of eosinophilic esophagitis (EoE) who achieve remission on PPI therapy.Up to half of pediatric and adult patients with typical EoE symptoms and histology achieve clinico-pathologic remission on PPI therapy, irrespective of whether esophageal pH monitoring demonstrates abnormal acid reflux. In patients with clinical and histologic features of EoE, genotypic and phenotypic features of PPI responders and nonresponders are virtually indistinguishable, and different from those of patients with gastroesophageal reflux disease. In PPI responders, PPIs effects on esophageal Th2 inflammation and gene expression are similar to those of topical steroids in PPI nonresponders. These therapies, along with diets, recently have been shown to be potentially interchangeable in two small series.Proton pump inhibitor-responsive esophageal eosinophilia is an inappropriate disease descriptor, arbitrarily based on a response to a single drug, and should be abandoned. Patients who have esophageal eosinophilia and esophageal symptoms that resolve with PPI therapy have phenotypic, molecular, mechanistic, and therapeutic features indistinguishable from similar patients who do not respond to PPIs. These patients with PPI responsiveness should be considered within the spectrum of EoE.
- Retinoblastoma cells activate the AKT pathway and are vulnerable to the PI3K/mTOR inhibitor NVP-BEZ235.
Retinoblastoma cells activate the AKT pathway and are vulnerable to the PI3K/mTOR inhibitor NVP-BEZ235. [Journal Article]Oncotarget 2017 Apr 08.OXie C, Freeman MJ, Lu H, et al. Retinoblastoma is a pediatric cancer of the retina most often caused by inactivation of the retinoblastoma (RB1) tumor suppressor gene. We previously showed that Rb1 loss cooperates with either co-acti...Retinoblastoma is a pediatric cancer of the retina most often caused by inactivation of the retinoblastoma (RB1) tumor suppressor gene. We previously showed that Rb1 loss cooperates with either co-activating the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, or co-deleting Pten, to initiate retinoblastoma tumors in mice. The objectives of this study were to determine if the AKT pathway is activated in human retinoblastomas and the extent that anti-PI3K therapy induces apoptosis in retinoblastoma cells, alone or in combination with the DNA damaging drugs carboplatin and topotecan. Serial sections from human retinoblastoma tissue microarrays containing 27 tumors were stained with antibodies specific to p-AKT, Ki-67, forkhead box O1 (p-FOXO1), and ribosomal protein S6 (p-S6) using immunohistochemistry and each tumor sample scored for intensity. Human retinoblastoma tumors displayed significant correlation between p-AKT intensity with highly proliferative tumors (p = 0.008) that were also highly positive for p-FOXO1 (p = 0.002). Treatment with BEZ235, a dual PI3K/mTOR inhibitor, reduced phosphorylation levels of the AKT targets p-FOXO and p-S6 and effectively induced apoptosis the Y79 and Weri-1 human retinoblastoma cell lines and in vivo in our retinoblastoma mouse model. Long-term treatment with BEZ235 in vivo using our retinoblastoma-bearing mice induced apoptosis but did not significantly extend the lifespan of the mice. We then co-administered BEZ235 with topotecan and carboplatin chemotherapeutics in vivo, which more effectively induced apoptosis of retinoblastoma, but not normal retinal cells than either treatment alone. Our study has increased the variety of potentially effective targeted treatments that can be considered for human retinoblastoma.
- Potential biomarkers of DNA replication stress in cancer.
Potential biomarkers of DNA replication stress in cancer. [Journal Article]Oncotarget 2017 Apr 07.ORen L, Chen L, Wu W, et al. Oncogene activation is an established driver of tumorigenesis. An apparently inevitable consequence of oncogene activation is the generation of DNA replication stress (RS), a feature common to most can...Oncogene activation is an established driver of tumorigenesis. An apparently inevitable consequence of oncogene activation is the generation of DNA replication stress (RS), a feature common to most cancer cells. RS, in turn, is a causal factor in the development of chromosome instability (CIN), a near universal feature of solid tumors. It is likely that CIN and RS are mutually reinforcing drivers that not only accelerate tumorigenesis, but also permit cancer cells to adapt to diverse and hostile environments. This article reviews the genetic changes present in cancer cells that influence oncogene-induced RS and CIN, with a particular emphasis on regions of the human genome that show enhanced sensitivity to the destabilizing effects of RS, such as common fragile sites. Because RS exists in a wide range of cancer types, we propose that the proteins involved counteracting this stress are potential biomarkers for indicating the degree of RS in cancer specimens. To test this hypothesis, we conducted a pilot study to validate whether some of proteins that are known from in vitro studies to play an essential role in the RS pathway could be suitable as a biomarker. Our results indicated that this is possible. With this review and pilot study, we aim to accelerate the development of a biomarker for analysis of RS in tumor biopsy specimens, which could ultimately help to stratify patients for different forms of therapy such as the RS inhibitors already undergoing clinical trials.
- Selective eradication of cancer cells by delivery of adenovirus-based toxins.
Selective eradication of cancer cells by delivery of adenovirus-based toxins. [Journal Article]Oncotarget 2017 Apr 07.OShapira S, Shapira A, Kazanov D, et al. A proof of concept for a novel cancer safe and effective gene therapy exploiting an aberrant hyperactive pathway is achievable.KRAS mutation is an early event in colorectal cancer carcinogenesis. We previously reported that a recombinant adenovirus, carrying a pro-apoptotic gene (PUMA) under the regulation of Ets/AP1 (RAS-responsive elements) suppressed the growth of cancer cells harboring hyperactive KRAS. We propose to exploit the hyperactive RAS pathway, rather than to inhibit it as was previously tried and failed repeatedly. We aim to improve efficacy by substituting PUMA with a more potent toxin, the bacterial MazF-MazE toxin-antitoxin system, under a very tight regulation.A massive cell death, in a dose-dependent manner, reaching 73% at MOI 10 was seen in KRAS cells as compared to 22% in WT cells. Increase expression of MazE (the anti-toxin) protected normal cells from any possible internal or external leakage of the system and confirmed the selectivity, specificity and safety of the targeting system. Considerable tumor shrinkage (61%) was demonstrated in vivo following MazEF-encoding adenovirus treatment without any side effects.Efficient vectors for cancer-directed gene delivery were constructed; "pAdEasy-Py4-SV40mP-mCherry-MazF"pAdEasy-Py4-SV40mP-mCherry-MazF-IRES-TetR-CMVmp-MazE-IRES-EGFP","pAdEasy-ΔPy4-SV40mP-mCherry-MazF-IRES-TetR-CMVmp-MazE-IRES-EGFP "and "pAdEasy-mCherry". Virus particles were produced and their potency was tested. Cell death was measured qualitatively by using the fluorescent microscopy and colony formation assay, and was quantified by MTT. FACS analysis using annexin V and RedDot2 dyes was performed for measuring apoptotic and dead cells, respectively. In vivo tumor formation was measured in a xenograft model.A proof of concept for a novel cancer safe and effective gene therapy exploiting an aberrant hyperactive pathway is achievable.
- Co-delivery of microRNA-21 antisense oligonucleotides and Gemcitabine using nanomedicine for pancreatic cancer therapy.
Co-delivery of microRNA-21 antisense oligonucleotides and Gemcitabine using nanomedicine for pancreatic cancer therapy. [Journal Article]Cancer Sci 2017 Apr 26.CSLi Y, Chen Y, Li J, et al. Tumor metastasis occurs naturally in pancreatic cancer, and the efficacy of chemotherapy is usually poor. Precision medicine, combining down-regulation of target genes with chemotherapy drugs, is expec...Tumor metastasis occurs naturally in pancreatic cancer, and the efficacy of chemotherapy is usually poor. Precision medicine, combining down-regulation of target genes with chemotherapy drugs, is expected to improve the therapeutic effects. Therefore, we developed a combined therapy of microRNA-21 antisense oligonucleotides (ASO-miR-21) and Gemcitabine (Gem) using a targeted co-delivery nanoparticle (NP) carrier and investigated the synergistic inhibitory effects on pancreatic cancer cells metastasis and growth. PEG-Polyethyleneimine (PEI)-Magnetic iron oxide nanoparticles (PEG-PEI-IONPs) were employed to co-deliver ASO-miR-21 and Gem. An anti-CD44v6 single chain variable fragment (scFvCD44v6 ) was used to coat the particles to obtain active and targeted delivery. Our results showed that the downregulation of the oncogenic miR-21 by ASO resulted in up-regulation of the tumor-suppressor genes PDCD4 and PTEN and the suppression of the epithelial-mesenchymal transformation (EMT), which inhibited the proliferation and induced the clonal formation, migration and invasion of pancreatic cancer cells in vitro. The co-delivery of ASO-miR-21 and Gem induced more cell apoptosis and inhibited the growth of pancreatic cancer cells to a greater extent than the single ASO-miR-21 or Gem treatment in vitro. In animal tests, more scFvCD44v6 -PEG-PEI/ASO-IONP/Gem (scFv-ASO-Gem-NPs) accumulated at the tumor site than non-targeted NPs and induced a potent inhibition of tumor proliferation and metastasis. MR imaging was used to observed tumor homing of nanoparticles. These results imply that the combination of miR-21 gene silencing and Gem therapy using scFv-functionalized nanoparticle carrier exerted synergistic anti-tumour effects on pancreatic cancer cells, which is a promising strategy for pancreatic cancer therapy. This article is protected by copyright. All rights reserved.