The biophysical environment of membrane phospholipids affects structure, function, and stability of membrane-bound proteins. 1,2 Obesity can disrupt membrane lipids, and in particular, alter the activity of sarco/endoplasmic reticulum (ER/SR) Ca 2+ -ATPase (SERCA) to affect cellular Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Objective Sarcolipin (SLN) regulates muscle energy expenditure through its action on sarco/endoplasmic reticulum Ca2+-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. Design and Methods Primary myocytes were isolated from muscle biopsy from seven LN and OB Caucasian females. Cellular respiration was assessed with and without lentivirus-mediated SLN knockdown in LN and OB myocytes. Results SLN mRNA and protein abundance was greater in OB compared to LN cells. Despite elevated SLN levels in wildtype OB cells, respiratory rates among SLN-deficient cells were higher in OB compared to LN. Obesity-induced reduction in efficiency of SLN-dependent respiration was associated with altered SR phospholipidome. Conclusions SLN-dependent respiration is reduced in muscles from humans with severe obesity compared to lean controls. Identification of molecular mechanism that affects SLN-efficiency might promote an increase in skeletal muscle energy expenditure.

Introduction Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults; 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. Importantly Ads have been safely administered within the tumor resection cavity in humans. Areas Covered Background on GBM and Ad vectors; we describe gene therapy strategies for GBM and discuss the value of combination approaches. Finally we discuss the results of the human clinical trials for GBM that have used adenoviral vectors. Expert Opinion The transduction characteristics of Ad vectors, and their safety profile, added to their capacity to achieve high levels of transgene expression have made them powerful vectors for the treatment of GBM. Recent gene therapy successes in the treatment of retinal diseases and systemic brain metabolic diseases, encourages the development of gene therapy for malignant glioma. Exciting clinical trials are currently recruiting patients; although it is large randomized phase III controlled clinical trials that will provide the final decision on the success of gene therapy for the treatment of GBM.

Signal transducer and activator of transcription 3 (STAT3) has been implicated as a hub for multiple oncogenic pathways. The constitutive activation of STAT3 is present in several cancers, including gliomas (GBMs), and is associated with poor therapeutic responses. Phosphorylation of STAT3 triggers its dimerization and nuclear transport, where it promotes the transcription of genes that stimulate tumor growth. In light of this role, inhibitors of the STAT3 pathway are attractive therapeutic targets for cancer. To this end, we evaluated the STAT3-inhibitory activities of three compounds a concomitant induction of cell death. Although these compounds were effective at inhibiting STAT3 phosphorylation, they also displayed variable dose-dependent inhibition of STAT1, STAT5, and nuclear factor k light-chain enhancer of activated B cells. The therapeutic efficacy of these compounds was further evaluated in peripheral and intracranial mouse tumor models. Whereas CPA-7 elicited regression of peripheral tumors, both melanoma and GBM, its efficacy was not evident when the tumors were implanted within the brain. Our data suggest poor permeability of this compound to tumors located within the central nervous system. WP1066 and ML116 exhibited poor in vivo efficacy. In summary, CPA-7 constitutes a powerful anticancer agent in models of peripheral solid cancers. Our data strongly support further development of CPA-7-derived compounds with increased permeability to enhance their efficacy in primary and metastatic brain tumors.