mTORC1 underlies ageâ related muscle fiber damage and loss by inducing oxidative stress and catabolism

Aging leads to skeletal muscle atrophy (i.e., sarcopenia), and muscle fiber loss is a critical component of this process. The mechanisms underlying these ageâ related changes, however, remain unclear. We show here that mTORC1 signaling is activated in a subset of skeletal muscle fibers in aging mouse and human, colocalized with fiber damage. Activation of mTORC1 in TSC1 knockout mouse muscle fibers increases the content of morphologically abnormal mitochondria and causes progressive oxidative stress, fiber damage, and fiber loss over the lifespan. Transcriptomic profiling reveals that mTORC1’s activation increases the expression of growth differentiation factors (GDF3, 5, and 15), and of genes involved in mitochondrial oxidative stress and catabolism. We show that increased GDF15 is sufficient to induce oxidative stress and catabolic changes, and that mTORC1 increases the expression of GDF15 via phosphorylation of STAT3. Inhibition of mTORC1 in aging mouse decreases the expression of GDFs and STAT3’s phosphorylation in skeletal muscle, reducing oxidative stress and muscle fiber damage and loss. Thus, chronically increased mTORC1 activity contributes to ageâ related muscle atrophy, and GDF signaling is a proposed mechanism.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149208/1/acel12943-sup-0002-TableS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149208/2/acel12943.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149208/3/acel12943-sup-0001-FigS1-S14.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149208/4/acel12943_am.pd

CRISPR/Cas‐mediated genome editing to treat EGFR‐mutant lung cancer: a personalized molecular surgical therapy

While substantial progress has been made in the treatment of lung cancer with the development of tyrosine kinase inhibitors (TKIs) that target tumor‐driving mutations in the epidermal growth factor receptor (EGFR), nearly all patients treated with TKIs ultimately develop drug resistance due to resistance‐conferring genomic mutations. CRISPR/Cas9‐mediated genome editing is a powerful new technique that allows precise changes to be made to cells’ genomes. This technology is currently used widely in research laboratories, but it has yet to make an impact in the clinics. We suggest a potential exciting clinical application for this technical advance—allowing personalized, molecular surgery to correct or destroy the mutated EGFR. After detection of EGFR mutations in individual patients’ cancers from biopsy samples, the EGFR‐mutant genes will be repaired or destroyed with virus‐delivered CRISPR/Cas system. We demonstrate the feasibility of such an approach with examples from the most common primary and secondary EGFR mutations that are encountered. These proposed “molecular surgeries” on genomic DNA directly target the cause of the disease in a personalized and possibly permanent manner. This approach could be combined with traditional surgery, radiation therapy, or chemo/targeted therapy

Thoracoscopic lobectomy is associated with acceptable morbidity and mortality in patients with predicted postoperative forced expiratory volume in 1 second or diffusing capacity for carbon monoxide less than 40% of normal.

OBJECTIVE: A predicted postoperative (ppo) forced expiratory volume in 1 second (FEV1%) or diffusing capacity of the lung for carbon monoxide (DLCO%) of METHODS: PpoFEV1% and ppoDLCO% were calculated for patients undergoing open or VATS lobectomy for lung cancer in the Society of Thoracic Surgeons General Thoracic database from 2009 to 2011. Univariate comparisons, multivariate analyses, and 1:1 propensity matching were performed. RESULTS: A total of 13,376 patients underwent lobectomy (50.9% open, 49.1% VATS). A decreased ppoFEV1% and ppoDLCO% were each independent predictors for both cardiopulmonary complications and mortality in the open group (all P ≤ .008). In the VATS group, ppoFEV1% was an independent predictor of complications (P = .001) but not mortality (P = .77), and ppoDLCO% was an independent predictor of complications (P = .046) and mortality (P = .008). With decreasing ppoFEV1% or ppoDLCO%, complications and mortality increased at a greater rate in the open lobectomy than in a propensity-matched VATS group (n = 4215 each). For patients with ppoFEV1% \u3c 40%, mortality was greater in the open (4.8%) than in the matched VATS group (0.7%, P = .003). Similar results were seen for ppoDLCO% \u3c 40% (5.2% open, 2.0% VATS, P = .003). The rate of complications was significantly greater at ppoFEV1% \u3c 40% in the open (21.9%) than in the matched VATS (12.8%, P = .005) group and similar results were seen with ppoDLCO% \u3c 40% (14.9% open, 10.4% VATS, P = .016). CONCLUSIONS: VATS lobectomy can be performed with acceptable rates of morbidity and mortality in patients with reduced ppoFEV1% or ppoDLCO%