Aberrant energy metabolism is a hallmark of cancer. To fulfill the increased energy requirements, tumor cells secrete cytokines/factors inducing muscle and fat degradation in cancer patients, a condition known as cancer cachexia. It accounts for nearly 20% of all cancer-related deaths. However, the mechanistic basis of cancer cachexia and therapies targeting cancer cachexia thus far remain elusive. A ketogenic diet, a high-fat and low-carbohydrate diet that elevates circulating levels of ketone bodies (i.e., acetoacetate, β-hydroxybutyrate, and acetone), serves as an alternative energy source. It has also been proposed that a ketogenic diet leads to systemic metabolic changes. Keeping in view the significant role of metabolic alterations in cancer, we hypothesized that a ketogenic diet may diminish glycolytic flux in tumor cells to alleviate cachexia syndrome and, hence, may provide an efficient therapeutic strategy. We observed reduced glycolytic flux in tumor cells upon treatment with ketone bodies. Ketone bodies also diminished glutamine uptake, overall ATP content, and survival in multiple pancreatic cancer cell lines, while inducing apoptosis. A decrease in levels of c-Myc, a metabolic master regulator, and its recruitment on glycolytic gene promoters, was in part responsible for the metabolic phenotype in tumor cells. Ketone body-induced intracellular metabolomic reprogramming in pancreatic cancer cells also leads to a significantly diminished cachexia in cell line models. Our mouse orthotopic xenograft models further confirmed the effect of a ketogenic diet in diminishing tumor growth and cachexia. Thus, our studies demonstrate that the cachectic phenotype is in part due to metabolic alterations in tumor cells, which can be reverted by a ketogenic diet, causing reduced tumor growth and inhibition of muscle and body weight loss.

In recent years, an increasing number of studies have demonstrated that a myopathy is present, contributes, and, to a certain extent, determines the pathogenesis of peripheral arterial occlusive disease (PAD). These works provide evidence that a state of repetitive cycles of exercise-induced ischemia followed by reperfusion at rest operates in PAD patients and mediates a large number of structural and metabolic changes in the muscle, resulting in reduced strength and function. The key players in this process appear to be defective mitochondria that, through multilevel failure in their roles as energy, oxygen radical species, and apoptosis regulators, produce and sustain a progressive decline in muscle performance. In this 2-part review, we highlight the currently available evidence that characterizes the nature and mechanisms responsible for this myopathy. In part 1, the authors review the functional and histomorphological characteristics of the myopathy and focus on the biochemistry and bioenergetics of its mitochondriopathy. In part 2, they then review accumulating evidence that oxidative stress related to ischemia reperfusion is probably the major operating mechanism of PAD myopathy. Important new findings of a possible neuropathy and a shift in muscle fiber type are also reviewed. Learning more about these mechanisms will enhance our understanding of the degree to which they are preventable and treatable.

In recent years, an increasing number of studies have demonstrated that a myopathy is present, contributes, and, to a certain extent, determines the pathogenesis of peripheral arterial occlusive disease. These works provide evidence that a state of repetitive cycles of exercise-induced ischemia followed by reperfusion at rest operates in patients with peripheral arterial occlusive disease and mediates a large number of structural and metabolic changes in the muscle, resulting in reduced strength and function. The key players in this process appear to be defective mitochondria that, through multilevel failure in their roles as energy, oxygen radical species, and apoptosis regulators, produce and sustain a progressive decline in muscle performance. In this 2-part review, the currently available evidence that characterizes the nature and mechanisms responsible for this myopathy is highlighted. In part 1, the functional and histomorphological characteristics of the myopathy were reviewed, and the main focus was on the biochemistry and bioenergetics of its mitochondriopathy. In part 2, accumulating evidence that oxidative stress related to ischemia reperfusion is probably the major operating mechanism of peripheral arterial occlusive disease myopathy is reviewed. Important new findings of a possible neuropathy and a shift in muscle fiber type are also reviewed. Learning more about these mechanisms will enhance our understanding of the degree to which they are preventable and treatable.

Purpose: To compare through a systematic review of published literature the stroke outcomes in protected and unprotected carotid artery stenting (CAS). Methods: PubMed and Cochrane electronic databases were queried to identify peer-reviewed publications from 1995 to 2007 meeting our pre-defined criteria for inclusion (English language, human only, at least 20 patients reported) and exclusion (procedures performed for the treatment of total occlusion, dissection, or aneurysmal disease; urgently performed procedures; use of covered stents; access other than transfemoral). Information was collected on a standardized data abstraction form for pooled analysis of total strokes within 30 days of procedure in all patients and in symptomatic and asymptomatic subgroups. A random effects meta-analysis of studies with concurrently reported data on protected and unprotected CAS was performed. Results: Initial database query resulted in 2485 articles, of which 134 were included in the final analyses (12,263 protected CAS patients and 11,198 unprotected CAS patients). Twenty-four studies included data on both protected and unprotected CAS. Using pooled analysis of all 134 reports, the relative risk (RR) for stroke was 0.62 (95% CI 0.54 to 0.72) in favor of protected CAS. Subgroup analysis revealed a significant benefit for protected CAS in both symptomatic (RR 0.67; 95% CI 0.52 to 0.56) and asymptomatic (RR 0.61; 95% CI 0.41 to 0.90) patients (p<0.05). Meta-analysis of the 24 studies reporting data on both protected and unprotected stenting demonstrated a relative risk of 0.59 (95% CI 0.47 to 0.73) for stroke, again favoring protected CAS (p<0.001). Conclusion: Our systematic review indicated that the use of cerebral protection devices decreased the risk of perioperative stroke with CAS. A well designed randomized trial can further confirm our findings and possibly indicate the device with the best outcomes.