Autophagy modulates articular cartilage vesicle formation in primary articular chondrocytes.

Chondrocyte-derived extracellular organelles known as articular cartilage vesicles (ACVs) participate in non-classical protein secretion, intercellular communication, and pathologic calcification. Factors affecting ACV formation and release remain poorly characterized; although in some cell types, the generation of extracellular vesicles is associated with up-regulation of autophagy. We sought to determine the role of autophagy in ACV production by primary articular chondrocytes. Using an innovative dynamic model with a light scatter nanoparticle counting apparatus, we determined the effects of autophagy modulators on ACV number and content in conditioned medium from normal adult porcine and human osteoarthritic chondrocytes. Healthy articular chondrocytes release ACVs into conditioned medium and show significant levels of ongoing autophagy. Rapamycin, which promotes autophagy, increased ACV numbers in a dose- and time-dependent manner associated with increased levels of autophagy markers and autophagosome formation. These effects were suppressed by pharmacologic autophagy inhibitors and short interfering RNA for ATG5. Caspase-3 inhibition and a Rho/ROCK inhibitor prevented rapamycin-induced increases in ACV number. Osteoarthritic chondrocytes, which are deficient in autophagy, did not increase ACV number in response to rapamycin. SMER28, which induces autophagy via an mTOR-independent mechanism, also increased ACV number. ACVs induced under all conditions had similar ecto-enzyme specific activities and types of RNA, and all ACVs contained LC3, an autophagosome-resident protein. These findings identify autophagy as a critical participant in ACV formation, and augment our understanding of ACVs in cartilage disease and repair.

Drug-sensitive FGFR2 mutations in endometrial carcinoma.

Oncogenic activation of tyrosine kinases is a common mechanism of carcinogenesis and, given the druggable nature of these enzymes, an attractive target for anticancer therapy. Here, we show that somatic mutations of the fibroblast growth factor receptor 2 (FGFR2) tyrosine kinase gene, FGFR2, are present in 12% of endometrial carcinomas, with additional instances found in lung squamous cell carcinoma and cervical carcinoma. These FGFR2 mutations, many of which are identical to mutations associated with congenital craniofacial developmental disorders, are constitutively activated and oncogenic when ectopically expressed in NIH 3T3 cells. Inhibition of FGFR2 kinase activity in endometrial carcinoma cell lines bearing such FGFR2 mutations inhibits transformation and survival, implicating FGFR2 as a novel therapeutic target in endometrial carcinoma.

SOS1 mutations are rare in human malignancies: implications for Noonan Syndrome patients.

Germ line gain-of-function mutations in several members of the RAS/ERK pathway, including PTPN11, KRAS, and RAF1, cause the autosomal dominant genetic disorder Noonan Syndrome (NS). NS patients are at increased risk of leukemia/myeloproliferative disease and possibly some solid tumors, such as neuroblastoma. Recently, SOS1 gain of function mutations have also been shown to cause NS. Somatic PTPN11, KRAS, and RAF1 mutations occur (although at different frequencies) in a variety of sporadic neoplasms, but whether SOS1 mutations are associated with human cancer has not been evaluated. We sequenced DNA from a total of 810 primary malignancies, including pancreatic, lung, breast, and colon carcinomas, and acute myelogenous leukemia, as well as several neuroblastoma cell lines. From this large, diverse series, missense SOS1 mutations were identified in a single pancreatic tumor, one lung adenocarcinoma, and a T-cell acute lymphoblastic leukemia cell line. Our findings suggest that SOS1 is not a significant human oncogene in most cancers. Furthermore, NS patients with SOS1 mutations may not be at increased risk of developing cancer.

Mental health indicators in APEC.

BACKGROUND: The World Economic Forum (2011) concluded that the economic impact of mental illness is the single most important contributor among all non-communicable diseases to loss of productivity. The 21 economies represented by Asia Pacific Economic Cooperation (APEC) responded to that information with efforts to address mental health as an integral component of economic development. AIM: In order to help assess the progress of APEC region compared to other regions of the world, the World Health Organization (WHO) granted us access to a subset of the 2014 Mental Health Atlas database containing health indicators from all 21 APEC economies. METHODS: APEC-specific data were extracted using the same format used by WHO in its Mental Health Atlas to compare/contrast data in APEC versus the six WHO regions of the world. RESULTS: It was observed that mental health workforces in APEC include a higher number of psychiatrist providers compared with WHO regions. Suicide rates reported in three APEC economies are among the highest in the world. All APEC economies continue their individual and coordinated efforts to support their ' APEC Roadmap to Promote Mental Wellness in a Healthy Asia Pacific (2014-2020)'. CONCLUSION: Significant challenges for APEC members exist to coordinate regional efforts to improve mental health due to highly variable income levels, existing health infrastructures and social preferences. The findings in this report may serve as a helpful baseline for measuring success within the APEC region by 2020, the year in which progress in support of economic development will be reassessed.

Evaluation of passive and active rehabilitation and of tendon repair for partial tendon lacerations after three weeks of healing in canines.

BACKGROUND: Both passive and active rehabilitation have been shown to be superior to immobilization following partial tendon laceration, but few studies have directly compared these two rehabilitation protocols. In addition, controversy still remains over whether a partial tendon laceration should be repaired. METHODS: We evaluated gap formation, adhesions, gliding function and structural properties of repaired and unrepaired tendons following 3 weeks of unrestricted active rehabilitation versus passive mobilization for partial laceration of canine flexor digitorum profundus tendons. An ex vivo radiographic method was used to measure tendon excursion and rotation at each finger joint. The tendon was examined for adhesions, and gapping was measured with calipers. The tendons were tensile tested to failure. FINDINGS: We found no significant differences in tendon excursion, total joint rotation, or adhesions between any groups. Gap size was higher with active mobilization. We found no effect of rehabilitation protocol on the strength or stiffness of healing tendons at 3 weeks. Tendon repair did not affect tendon strength, but did produce higher stiffness in healing tendons at 3 weeks. INTERPRETATION: The results indicate that active rehabilitation appears safe for partial lacerations less than 60 percent. Though repair appears to weaken the tendon in the early stages of healing, it may provide some biomechanical benefit by the middle stages of healing.