Lipogenesis mitigates dysregulated sarcoplasmic reticulum calcium uptake in muscular dystrophy.

Muscular dystrophy is accompanied by a reduction in activity of sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) that contributes to abnormal Ca(2+) homeostasis in sarco/endoplasmic reticulum (SR/ER). Recent findings suggest that skeletal muscle fatty acid synthase (FAS) modulates SERCA activity and muscle function via its effects on SR membrane phospholipids. In this study, we examined muscle's lipid metabolism in mdx mice, a mouse model for Duchenne muscular dystrophy (DMD).

Reduced efficiency of sarcolipin-dependent respiration in myocytes from humans with severe obesity.

Objective: Sarcolipin (SLN) regulates muscle energy expenditure through its action on sarco/endoplasmic reticulum Ca(2+) -ATPase (SERCA) pump. It is unknown whether SLN-dependent respiration has relevance to human obesity, but whole-transcriptome gene expression profiling revealed that SLN was more highly expressed in myocytes from individuals with severe obesity (OB) than in lean controls (LN). The purpose of this study was to examine SLN-dependent cellular respiratory rates in LN and OB human muscles.

Marmosets as a preclinical model for testing "off-label" use of doxycycline to turn on Flt3L expression from high-capacity adenovirus vectors.

We developed a combined conditional cytotoxic, , herpes simplex type 1-thymidine kinase (TK), plus immune-stimulatory, , fms-like tyrosine kinase ligand-3-mediated gene therapy for glioblastoma multiforme (GBM). Therapeutic transgenes were encoded within high-capacity adenoviral vectors (HC-Ad); TK was expressed constitutively, while Flt3L was under the control of the TetOn regulatable promoter. We previously assessed efficacy and safety in intracranial GBM rodent models.

Adenoviral vector-mediated gene therapy for gliomas: coming of age.

Introduction: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and it carries a dismal prognosis. Adenoviral vector (Ad)-mediated gene transfer is being developed as a promising therapeutic strategy for GBM. Preclinical studies have demonstrated safety and efficacy of adenovirus administration into the brain and tumor mass in rodents and into the non-human primates' brain.

Temozolomide does not impair gene therapy-mediated antitumor immunity in syngeneic brain tumor models.

Purpose: Glioblastoma multiforme is the most common primary brain cancer in adults. Chemotherapy with temozolomide (TMZ) significantly prolongs the survival of patients with glioblastoma multiforme. However, the three-year survival is still approximately 5%.

Effectiveness and preclinical safety profile of doxycycline to be used "off-label" to induce therapeutic transgene expression in a phase I clinical trial for glioma.

Glioblastoma multiforme (GBM) is the most common malignant primary brain cancer in adults; it carries a dismal prognosis despite improvements in standard of care. We developed a combined gene therapy strategy using (1) herpes simplex type 1-thymidine kinase in conjunction with the cytotoxic prodrug ganciclovir to kill actively proliferating tumor cells and (2) doxycycline (DOX)-inducible Fms-like tyrosine kinase 3 ligand (Flt3L), an immune stimulatory molecule that induces anti-GBM immunity. As a prelude to a phase I clinical trial, we examined the efficacy and safety of this approach (Muhammad et al.

Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma.

Adenoviral vectors (Ads) are promising gene delivery vehicles due to their high transduction efficiency; however, their clinical usefulness has been hampered by their immunogenicity and the presence of anti-Ad immunity in humans. We reported the efficacy of a gene therapy approach for glioma consisting of intratumoral injection of Ads encoding conditionally cytotoxic herpes simplex type 1 thymidine kinase (Ad-TK) and the immunostimulatory cytokine fms-like tyrosine kinase ligand 3 (Ad-Flt3L). Herein, we report the biodistribution, efficacy, and neurological and systemic effects of a bicistronic high-capacity Ad, i.

High muscle lipid content in obesity is not due to enhanced activation of key triglyceride esterification enzymes or the suppression of lipolytic proteins.

The mechanisms underlying alterations in muscle lipid metabolism in obesity are poorly understood. The primary aim of this study was to compare the abundance and/or activities of key proteins that regulate intramyocellular triglyceride (IMTG) concentration in the skeletal muscle obtained from obese (OB; n = 8, BMI 38 ± 1 kg/m(2)) and nonobese (NOB; n = 9, BMI 23 ± 1 kg/m(2)) women. IMTG concentration was nearly twofold greater in OB vs.