Gene therapy

Clarithromycin is a 14-membered macrolide antibiotic. Low-dose, long-term macrolide therapy is effective in patients with chronic airway diseases, such as diffuse panbronchitis, chronic bronchitis, and chronic sinusitis. However, the mechanism underlying this clinical efficacy remains unclear. The dual specificity phosphatase MKP-1 (MAPK phosphatase-1), also called DUSP (dual specificity phosphatase-1), was initially identified as an in vitro ERK-specific phosphatase, but depending on the cell type, it can also dephosphorylate other members of the MAPK family, such as p38 and JNK, and thus suppress downstream signaling of these kinases...

Thoracic aortic aneurysm (TAA) is a genetic disease predisposing to aortic dissection. It is important to identify the genetic modifiers controlling penetrance and expressivity to improve clinical prognostication. Exome sequencing was performed in 27 subjects with syndromic or familial TAA presenting with extreme phenotypes (15 with severe TAA; 12 with mild or absent TAA). Family-based analysis of a subset of the cohort identified variants, genes, and pathways segregating with TAA severity among three families...

Major histocompatibility complex class I chain-related gene B (MICB) is expressed on tumor cells and participates in natural killer (NK) cell-mediated antitumor immune response through engagement with the NKG2D receptor. This study was undertaken to identify novel microRNA (miRNA) regulators of MICB and clarify their functions in NK cell-mediated cytotoxicity to hepatocellular carcinoma (HCC) cells. Bioinformatic analysis and luciferase reporter assay were conducted to search for MICB-targeting miRNAs. Overexpression and knockdown experiments were performed to determine the roles of candidate miRNAs in the susceptibility of HCC cells to NK lysis...

Thrombotic thrombocytopenic purpura (TTP) can rapidly progress into a life-threatening condition, thus the importance of appropriate diagnosis and treatment cannot be overstated. Until recently, TTP has mainly been diagnosed by clinical findings such as thrombocytopenia and non-immune hemolytic anemia. In addition to these clinical findings, however, reduced activity of a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) below 10% has been accepted internationally as a diagnostic criterion for TTP...

DNA breaks can be induced by exogenous stimuli or by endogenous stress, but are also generated during recombination of V, D, and J genes (V(D)J recombination), immunoglobulin class switch recombination (CSR). Among various DNA breaks generated, DNA double strand break (DSB) is the most deleterious one. DNA damage response (DDR) is initiated when DSBs are detected, leading to DNA break repair by non-homologous end joining (NHEJ). The process is critically important for the generation of diversity for foreign antigens; and failure to exert DNA repair leads to immunodeficiency such as severe combined immunodeficiency and hyper-IgM syndrome...

Metastatic triple negative breast cancer comprises 12-17% of breast cancers and carries a poor prognosis relative to other breast cancer subtypes. Treatment options in this disease are largely limited to systemic chemotherapy. A majority of clinical studies assessing efficacy of targeted therapeutics (e.g. the mTOR inhibitor everolimus) in advanced breast cancer patients have not utilized predictive genomic biomarker-based selection and have reported only modest improvement in clinical outcome relative to standard of care...

Neuroendocrine carcinoma of the cervix is an ultra-rare malignancy with a poor prognosis and limited treatment options. Checkpoint blockade immunotherapy has rapidly developed into an emerging standard of care for several common disease types. Interestingly, in preclinical and retrospective clinical data, radiation therapy has been demonstrated to synergize with checkpoint inhibitors. Here we report a patient with metastatic, chemotherapy-refractory neuroendocrine carcinoma who presented with partial bowel obstruction due to a large tumor burden...

BACKGROUND: Immune-checkpoint inhibitors against programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) have shown remarkable therapeutic activity in non-small-cell lung cancer (NSCLC). However, biomarker-based patient selection remains a challenge. Our aim was to assess the heterogeneity of various immune markers between different tumor areas of surgically resected NSCLC specimens. MATERIALS AND METHODS: We included 94 adenocarcinoma (ADC) and 50 squamous cell carcinoma (SCC) specimens...

OBJECTIVE: To identify novel genetic and epigenetic factors associated with Myasthenia gravis (MG) using an identical twins experimental study design. METHODS: The transcriptome and methylome of peripheral monocytes were compared between monozygotic (MZ) twins discordant and concordant for MG, as well as with MG singletons and healthy controls, all females. Sets of differentially expressed genes and differentially methylated CpGs were validated using RT-PCR for expression and target bisulfite sequencing for methylation on additional samples...

X-linked retinitis pigmentosa (XLRP) is generally a severe form of retinitis pigmentosa, a neurodegenerative, blinding disorder of the retina. 70% of XLRP cases are due to mutations in the retina-specific isoform of the gene encoding retinitis pigmentosa GTPase regulator (RPGR(ORF15)). Despite successful RPGR(ORF15) gene replacement with adeno-associated viral (AAV) vectors being established in a number of animal models of XLRP, progression to human trials has not yet been possible. The inherent sequence instability in the purine-rich region of RPGR(ORF15) (which contains highly repetitive nucleotide sequences) leads to unpredictable recombination errors during viral vector cloning...

BACKGROUND: No satisfactory treatment exists for chronic rejection (CR) after lung transplantation (LT). Our objective was to assess whether ozone (O3) treatment could ameliorate CR. METHODS: Male Sprague-Dawley inbred rats (n = 36) were randomly assigned into four groups: (1) control (n = 6), (2) sham (n = 6), (3) LT (n = 12), and (4) O3-LT (n = 12). Animals underwent left LT. O3 was rectally administered daily for 2 weeks before LT (from 20 to 50 μg) and 3 times/wk (50 μg/dose) up to 3 months...

In the era of precision medicine, the identification of new targets is a constant challenge to improve cancer therapy. Preclinical investigations, epidemiological studies and analyses of tissue specimens from patients strongly support the contribution of prolactin receptor (PRLR) signaling to breast and prostate tumorigenesis and cancer progression. Although a clear causative link with mutations of the genes encoding prolactin or its receptor is lacking, increased PRLR signaling in these cancers can be assessed by the overexpression of cognate proteins and is often confirmed by over-activation of downstream signaling effectors...

The spread of P. falciparum resistant strain has led to a significant resurgence of malaria morbidity and mortality. The current cornerstone in malaria treatment in India is Artemisinin based Combination (Artesunate + Sulphadoxine-Pyrimethamine) Therapy (ACT) for treatment of uncomplicated P. falciparum malaria since 2010. In the present study we assessed the therapeutic efficacy of ACT and molecular monitoring of antimalarial resistance. Therapeutic efficacy was determined by in vivo method using 28 days follow-up...

To elucidate the anti-tumor effects and molecular mechanisms of ING5 on glioma cells, we overexpressed it in U87 cells, and examined the phenotypes and their relevant molecules. It was found that ING5 overexpression suppressed proliferation, energy metabolism, migration, invasion, and induced G2/M arrest, apoptosis, dedifferentiation, senescence, mesenchymal- epithelial transition and chemoresistance to cisplatin, MG132, paclitaxel and SAHA in U87 cells. There appeared a lower expression of N-cadherin, Twist, Slug, Zeb1, Zeb2, Snail, Ac-H3, Ac-H4, Cdc2, Cdk4 and XIAP, but a higher expression of Claudin 1, Histones 3 and 4, p21, p53, Bax, β-catenin, PI3K, Akt, and p-Akt in ING5 transfectants...

Metformin is most widely prescribed for type 2 diabetes. Recently, evidences have shown that metformin has anticancer effects on pancreatic-, colorectal-, ovarian-, and other cancers. Because metformin has less adverse effects and is inexpensive, it could be a useful chemo-therapeutic agent with anticancer effects. In this study, we demonstrated metformin inhibited by cell proliferation, cell migration ability, clonogenic ability, and cancer stem cell population. Metformin also induced cell cycle arrest in parental-(SNU-C5), and 5-Fu resistant-colorectal cancer cell line (SNU-C5_5FuR)...

Inter- and intra-tumour molecular heterogeneity is increasingly recognized in clear cell renal cell carcinoma (ccRCC). It may partially explain the diversity of responses to targeted therapies and the various clinical outcomes. In this study, a 56-year-old male ccRCC patient with multiple metastases received radical nephrectomy and resection of the metastatic tumour in chest wall. The surgical specimens were implanted into nude mice to establish patient-derived xenograft (PDX) models with KI2367 model derived from the primary tumour and KI2368 model from the metastastic tumour...

As an intermediate metabolite of the tricarboxylic acid cycle in mitochondria, succinate is widely investigated for its role in metabolism. In recent years, an increasing number of studies have concentrated on the unanticipated role of succinate outside metabolism, acting as, for instance, an inflammatory signal or a carcinogenic initiator. Actually, succinate dehydrogenase gene mutations and abnormal succinate accumulation have been observed in a battery of hereditary and sporadic malignancies. In this review, we discuss the unexpected role of succinate and possible mechanisms that may contribute to its accumulation...

BACKGROUND: Posterior fossa (PF) ependymomas (EPNs) in infants less than 1 year of age (iEPN-PF) have a poorer clinical outcome than EPNs in older children. While radiation therapy is the standard of care for the latter, it is withheld in infants to avoid neurotoxicity to immature brain. It is unknown whether the adverse outcome in iEPN-PFs is due to treatment differences or aggressive biology. We examined this question using molecular profiling. METHODS: Six anaplastic iEPN-PFs were subjected to transcriptomic analysis and FISH for p16 loss and gains of 1q, and compared with anaplastic PF EPNs from older children...

The regulation of RNA interference (RNAi) could be a powerful method for the study of temporal and dose dependent effects of gene expression. In this study, we designed the hepatitis delta virus (HDV) ribozyme with an embedded theophylline aptamer as the sensor domain and the pri-miRNA of endogenous gene Bcl-2 as the effector domain to engineer an RNAi-regulatory device in MCF-7 cells. The system allowed us to control gene expression by adding theophylline into the culture media in a dose dependent fashion...

Large bone defects often pose major difficulties in orthopedic surgery. The application of long term cultured stem cells combined with a scaffold lead to a significant improvement of bone healing in recent experiments but is strongly restricted by EU-law. Bone marrow mononuclear cells (BMC), however, can be isolated and transplanted within few hours and have been proven effective in experimental models of bone healing. The effectivity of the BMC supported therapy might be influenced by the type of scaffold...