Modulation of the canonical Wnt signaling pathway in bone and cartilage

In view of the complex roles of the canonical Wnt signaling during skeletal devel-opment and disease, it is important to accurately distinguish the specific roles of this signaling cascade at specific time windows during embryogenesis as well as postnatally in the maintenance of the skeleton. Moreover, a proper understanding of these multi-faceted roles will ultimately aid us in identifying new therapeutic targets for the treat-ment of growth disorders, osteoporosis and osteoarthritis. Most of the animal models that furnish our knowledge of the effects of canonical Wnt signaling during skeletal development and maintenance use the forced expression of a stabilized and thereby oncogenic _-catenin. The roles of intracellular _-catenin regulators and thereby of wild type _-catenin levels during skeletogenesis, bone mass accrual or AC maintenance are largely unknown. The research described in this thesis aimed at describing the role of two major intracellular regulators of _-catenin, namely Apc and Gsk3_ in regulation of SPC differentiation, bone mass accrual and cartilage maintenance.UBL - phd migration 201

A Survey of Radiation Doses in CT Urography Before and After Implementation of Iterative Reconstruction

Radiolog

WNT Signaling and Cartilage: Of Mice and Men

In adult articular cartilage, the extracellular matrix is maintained by a balance between the degradation and the synthesis of matrix components. Chondrocytes that sparsely reside in the matrix and rarely proliferate are the key cellular mediators for cartilage homeostasis. There are indications for the involvement of the WNT signaling pathway in maintaining articular cartilage. Various WNTs are involved in the subsequent stages of chondrocyte differentiation during development, and deregulation of WNT signaling was observed in cartilage degeneration. Even though gene expression and protein synthesis can be activated upon injury, articular cartilage has a limited ability of self-repair and efforts to regenerate articular cartilage have so far not been successful. Because WNT signaling was found to be involved in the development and maintenance of cartilage as well as in the degeneration of cartilage, interfering with this pathway might contribute to improving cartilage regeneration. However, most of the studies on elucidating the role of WNT signaling in these processes were conducted using in vitro or in vivo animal models. Discrepancies have been found in the role of WNT signaling between chondrocytes of mouse and human origin, and extrapolation of results from mouse models to the human situation remains a challenge. Elucidation of detailed WNT signaling functions will provide knowledge to improve cartilage regeneratio

Apc bridges Wnt/beta-catenin and BMP signaling during osteoblast differentiation of 16483 cells

Developmen

APC Mutations Are Associated With Increased Bone Mineral Density in Patients With Familial Adenomatous Polyposis

The canonical Wnt pathway plays a key regulatory role in osteoblastogenesis and bone mass acquisition through its main effector, beta-catenin Adenomatous polyposis coli (APC) represents the key intracellular gatekeeper of beta-catenin turnover, and heterozygous germline mutations in the APC gene cause familial adenomatous polyposis (FAP) Whether APC mutations affect bone mass has not been previously investigated We conducted a cross-sectional study evaluating skeletal status in FAP patients with a documented APC mutation Twenty-two FAP patients with a mean age of 42 years (545% women) were included in this study Mean bone mineral density (BMD) Z-scores were significantly increased above normal at all measured sites lumbar spine (p < 01), total hip (p < 01), femoral neck (p < 05), and trochanter (p < 01) Z-scores were +1 or greater in 14 patients (63 6%) and +2 or greater in 5 (22 7%) Mean values of bone turnover markers were within normal ranges There was a significant positive correlation between procollagen type I N-terminal propeptide (P1NP) and beta-crosslaps (beta-CTX) (r = 0 70, p < 001) and between these markers and sclerostin and BMD measurements We demonstrate that FAP patients display a significantly higher than normal mean BMD compared with age- and sex-matched healthy controls in the presence of a balanced bone turnover Our data suggest a state of "controlled" activation of the Wnt signaling pathway in heterozygous carriers of APC mutations, most likely owing to upregulation of cytoplasmic beta-catenin levels (C) 2010 American Society for Bone and Mineral ResearchDiabetes mellitus: pathophysiological changes and therap

Intra-observer agreements in multidisciplinary team assessments of pancreatic cancer patients

Background and Methods Treatment strategies for pancreatic cancer patients are made by a multidisciplinary team (MDT) board. We aimed to assess intra-observer variance at MDT boards. Participating units staged, assessed resectability, and made treatment allocations for the same patients as they did two years earlier. We disseminated clinical information and CT images of pancreatic cancer patients judged by one MDT board to have nonmetastatic pancreatic cancer to the participating units. All units were asked to re-assess the TNM stage, resectability, and treatment allocation for each patient. To assess intra-observer variance, we computed %-agreements for each participating unit, defined as low (75%) agreement. Results Eighteen patients were re-assessed by six MDT boards. The overall agreement was moderate for TNM-stage (ranging from 50%-70%) and resectability assessment (53%) but low for treatment allocation (46%). Agreement on resectability assessments was low to moderate. Findings were similar but more pronounced for treatment allocation. We observed a shift in treatment strategy towards increasing use of neoadjuvant chemotherapy, particularly in patients with borderline resectable and locally advanced tumors. Conclusions We found substantial intra-observer agreement variations across six different MDT boards of 18 pancreatic cancer patients with two years between the first and second assessment