Current Issue : July - September Volume : 2014 Issue Number : 3 Articles : 5 Articles
This study aimed to investigate the efficacy of gene therapy for treating autoimmune sensorineural hearing loss (ASHL) via local\nadministration of a recombinant adenovirus vector containing the Fas ligand or interleukin IL-10 gene. Guinea pigs were divided\ninto four groups, with different microinjections in the scala tympani. Group A were injected with FasL-EGFP, B with IL-10-EGFP,\nC with EGFP, and D with artificial perilymph. Seven days later, auditory brain-stem response (ABR) was tested, and the temporal\nbone was stained and observed by light microscopy.The spiral ligament and basementmembranewere observed using transmission\nelectron microscopy. FasL and IL-10 expression were examined using immunofluorescence histochemistry. Immunohistochemical\nanalysis showed that the recombinant adenovirus vector in Groups A, B, and C can transfect the stria vascularis, the spiral ligament,\nthe organ of Corti, the spiral ganglion, the region surrounding the small blood vessel in the modiolus, and the cochlear bone\nwall. Compared with those in Groups C and D, the ABR wave III mean thresholds were significantly lower and the inner ear\nimmunoinflammatory responses in Groups A and B were significantly alleviated. Inhibition of immunoinflammatory response\nalleviated immunoinflammatory injury and auditory dysfunction. This technique shows potential as a novel therapy for ASHL....
Tumour cells create their own microenvironment where they closely interact with a variety of soluble and non-soluble\nmolecules, different cells and numerous other components within the extracellular matrix (ECM). Interaction between\ntumour cells and the ECM is bidirectional leading to either progression or inhibition of tumourigenesis. Therefore,\ndevelopment of novel therapies targeted primarily to tumour microenvironment (TME) is highly rational. Here, we give\na short overview of different macromolecules of the ECM and introduce mechanisms whereby they contribute to\ntumourigenesis within the TME. Furthermore, we present examples of individual ECM macromolecules as regulators of\ncell behaviour during tumourigenesis. Finally, we focus on novel strategies of using ECM macromolecules as tools or\ntargets in cancer gene therapy in the future....
Background: Advanced squamous cervical cancer, one of the most commonly diagnosed cancers in women, still\nremains a major problem in oncology due to treatment failure and distant metastasis. Antitumor therapy failure is\ndue to both intrinsic and acquired resistance; intrinsic resistance is often decisive for treatment response. In this\nstudy, we investigated the specific pathways and molecules responsible for baseline therapy failure in locally\nadvanced squamous cervical cancer.\nMethods: Twenty-one patients with locally advanced squamous cell carcinoma were enrolled in this study. Primary\nbiopsies harvested prior to therapy were analyzed for whole human gene [removed]Agilent) based on the\npatientââ?¬â?¢s 6 months clinical response. Ingenuity Pathway Analysis was used to investigate the altered molecular\nfunction and canonical pathways between the responding and non-responding patients. The microarray results\nwere validated by qRT-PCR and immunohistochemistry. An additional set of 24 formalin-fixed paraffin-embedded\ncervical cancer samples was used for independent validation of the proteins of interest.\nResults: A 2859-gene signature was identified to distinguish between responder and non-responder patients.\nââ?¬Ë?DNA Replication, Recombination and Repairââ?¬â?¢ represented one of the most important mechanisms activated in\nnon-responsive cervical tumors, and the ââ?¬Ë?Role of BRCA1 in DNA Damage Responseââ?¬â?¢ was predicted to be the most\nsignificantly altered canonical pathway involved in intrinsic resistance (p = 1.86E-04, ratio = 0.262). Immunohistological\nstaining confirmed increased expression of BRCA1, BRIP1, FANCD2 and RAD51 in non-responsive compared with\nresponsive advanced squamous cervical cancer, both in the initial set of 21 cervical cancer samples and the second set\nof 24 samples.\nConclusions: Our findings suggest that FA/BRCA pathway plays an important role in treatment failure in advanced\ncervical cancer. The assessment of FANCD2, RAD51, BRCA1 and BRIP1 nuclear proteins could provide important\ninformation about the patients at risk for treatment failure....
Background: Peri-spinal subarachnoid (intrathecal; i.t.) injection of non-viral naked plasmid DNA encoding the\nanti-inflammatory cytokine, IL-10 (pDNA-IL-10) suppresses chronic neuropathic pain in animal models. However, two\nsequential i.t. pDNA injections are required within a discrete 5 to 72-hour period for prolonged efficacy. Previous reports\nidentified phagocytic immune cells present in the peri-spinal milieu surrounding the i.t injection site that may play a\nrole in transgene uptake resulting in subsequent IL-10 transgene expression.\nMethods: In the present study, we aimed to examine whether factors known to induce pro-phagocytic\nanti-inflammatory properties of immune cells improve i.t. IL-10 transgene uptake using reduced naked pDNA-IL-10\ndoses previously determined ineffective. Both the synthetic glucocorticoid, dexamethasone, and the hexose sugar,\nD-mannose, were factors examined that could optimize i.t. pDNA-IL-10 uptake leading to enduring suppression of\nneuropathic pain as assessed by light touch sensitivity of the rat hindpaw (allodynia).\nResults: Compared to dexamethasone, i.t. mannose pretreatment significantly and dose-dependently prolonged\npDNA-IL-10 pain suppressive effects, reduced spinal IL-1�Ÿ and enhanced spinal and dorsal root ganglia IL-10\nimmunoreactivity. Macrophages exposed to D-mannose revealed reduced proinflammatory TNF-a, IL-1�Ÿ, and nitric\noxide, and increased IL-10 protein release, while IL-4 revealed no improvement in transgene uptake. Separately,\nD-mannose dramatically increased pDNA-derived IL-10 protein release in culture supernatants. Lastly, a single i.t.\nco-injection of mannose with a 25-fold lower pDNA-IL-10 dose produced prolonged pain suppression in neuropathic rats.\nConclusions: Peri-spinal treatment with D-mannose may optimize naked pDNA-IL-10 transgene uptake for suppression\nof allodynia, and is a novel approach to tune spinal immune cells toward pro-phagocytic phenotype for improved\nnon-viral gene therapy...
Objective. The goal of the present study was to investigate the effect of IL-12 expressed in plasmid on the Th1 cytokine profile in\nan experimental HPV16-positive murine tumor model and the association with the IL-12�s antitumor effect. Methods. Mice were\ninjected with BMK-16/myc cells to establish HPV16-positive tumor and then pNGVL3-mIL-12 plasmid; pcDNA3 plasmid or PBS\nwas injected directly into tumor site. The antitumor effect of the treatment was evaluated and the cytokines expression profile in\neach tumor tissue was analyzed. Results. Treatment with pNGVL3-mIL-12 plasmid had a significant antitumor effect, and a Th2-\nTh3-type cytokines prolife was detected in the murine tumor model with expression of the cytokines IL-10, IL-4, and TGF-??1.\nHowever, after the tumor was treated with three intratumoral injections of plasmid containing IL-12 cDNA, it showed a cytokine\nprofile associated withTh1 with expression of IL-2, IL-12, and IFN-?? cytokines and reduced expression of IL-10, IL-4, and TGF-??1.\nConclusions.The treatment with the IL-12 gene in the experimental HPV16-positive tumor model promoted the activation of the\ncellular immune response via expression of a Th1-type cytokine profile and was associated with the inhibition of tumor growth.\nThus, IL-12 treatment represents a novel approach for gene therapy against cervical cancer....
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