Obesity may impair protein synthesis rates and cause anabolic resistance to growth factors, hormones, and exercise, ultimately affecting skeletal muscle mass and function. To better understand muscle wasting and anabolic resistance with obesity, we assessed protein 24-h fractional synthesis rates (24-h FSRs) in selected hind-limb muscles of sedentary and resistance-exercised lean and obese Zucker rats. Despite atrophied hind-limb muscles (-28% vs. lean rats), 24-h FSRs of mixed proteins were significantly higher in quadriceps (+18%) and red or white gastrocnemius (+22 or +38%, respectively) of obese animals when compared to lean littermates. Basal synthesis rates of myofibrillar (+8%) and mitochondrial proteins (-1%) in quadriceps were not different between phenotypes, while manufacture of cytosolic proteins (+12%) was moderately elevated in obese cohorts. Western blot analyses revealed a robust activation of p70S6k (+178%) and a lower expression of the endogenous mTOR inhibitor DEPTOR (-28%) in obese rats, collectively suggesting that there is an obesity-induced increase in net protein turnover favoring degradation. Lastly, the protein synthetic response to exercise of mixed (-7%), myofibrillar (+6%), and cytosolic (+7%) quadriceps subfractions was blunted compared to the lean phenotype (+34, +40, and +17%, respectively), indicating a muscle- and subfraction-specific desensitization to the anabolic stimulus of exercise in obese animals.

Considering that protein-based assays may yield false negative test results and that dysferlin aggregation may be present in other LGMDs, mutational screening is necessary for specific diagnosis in primary dysferlinopathy patients exhibiting this phenotype.

E rythrocytosis refers to an erythrocyte count above the sexspecific normal range and can be subclassified into relative erythrocytosis, caused by a reduction in plasma volume (hemoconcentration), or absolute erythrocytosis, caused by increased erythrocyte mass. Primary erythrocytosis refers to autonomous production of erythrocytes, typically from a myeloproliferative neoplasm (polycythemia vera [PV]). In contrast, second ary erythrocytosis is caused by a physiologically appropriate response to elevated serum erythropoietin levels. Up to 4% of ambulatory men and 0.4% of ambulatory women in Canada have erythrocytosis, based on hemoglobin levels greater than 165 g/L or 160 g/L, respectively. 1 Differentiating PV from other causes of erythrocytosis is critical because early recognition and treatment of PV can prevent many of its vasomotor and thrombotic complications. Polycythemia vera is rare, with an incidence and prevalence of 0.84 and 22 per 100 000, respectively. 2,3 Although the prevalence of secondary erythrocytosis is difficult to estimate, it is higher than that of PV. Secondary erythrocytosis affects 6%-8% of patients with chronic obstructive pulmonary disease 4 and 2%-8% of patients with obstructive sleep apnea. 5,6 In this review, we summarize a contemporary approach to differentiating PV from other causes of erythrocytosis, and review the natural history, diagnosis and management of PV (Box 1). What is the differential diagnosis for erythrocytosis? Relative erythrocytosis results from any condition that reduces plasma volume, such as gastrointestinal fluid losses or diuretic use. Absolute erythrocytosis can be driven by a clonal bone marrow disease (PV) or be secondary to another disease, including a physiologic response to increased erythropoietin secondary to hypoxia, drugs 11 or erythropoietin-producing solid tumours 12,13 (Box 2). Congenital causes of erythrocytosis include high-oxygenaffinity hemoglobins, erythropoietin receptor mutations and alterations in oxygen-sensing molecular pathways. Polycythemia vera is a myeloproliferative neoplasm characterized by increased erythrocyte mass, thrombosis and vasomotor symptoms. A gain-of-function mutation in Janus kinase 2 (JAK2) underlies 98% of PV cases. 15

a HPV-positive oropharyngeal carcinoma (OPC) patients have superior outcomes relative to HPV-negative patients, but the underlying mechanisms remain poorly understood. We conducted a proteomic investigation of HPV-positive (n ‫؍‬ 27) and HPV-negative (n ‫؍‬ 26) formalinfixed paraffin-embedded OPC biopsies to acquire insights into the biological pathways that correlate with clinical behavior. Among the 2,633 proteins identified, 174 were differentially abundant. These were enriched for proteins related to cell cycle, DNA replication, apoptosis, and immune response. The differential abundances of cortactin and methylthioadenosine phosphorylase were validated by immunohistochemistry in an independent cohort of 29 OPC samples (p ‫؍‬ 0.023 and p ‫؍‬ 0.009, respectively). An additional 1,124 proteins were independently corroborated through comparison to a published proteomic dataset of OPC. Furthermore, utilizing the Cancer Genome Atlas, we conducted an integrated investigation of OPC, attributing mechanisms underlying differential protein abundances to alterations in mutation, copy number, methylation, and mRNA profiles. A key finding of this integration was the identification of elevated cortactin oncoprotein levels in HPV-negative OPCs. These proteins might contribute to reduced survival in these patients via their established role in radiation resistance. Through interrogation of Cancer Genome Atlas data, we demonstrated that activation of the ␤1-integrin/FAK/cortactin/