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1.  Accumulation of Oxidized LDL in the Tendon Tissues of C57BL/6 or Apolipoprotein E Knock-Out Mice That Consume a High Fat Diet: Potential Impact on Tendon Health 
PLoS ONE  2014;9(12):e114214.
Clinical studies have suggested an association between dyslipidemia and tendon injuries or chronic tendon pain; the mechanisms underlying this association are not yet known. The objectives of this study were (1) to evaluate the impact of a high fat diet on the function of load-bearing tendons and on the distribution in tendons of oxidized low density lipoprotein (oxLDL), and (2) to examine the effect of oxLDL on tendon fibroblast proliferation and gene expression.
Gene expression (Mmp2, Tgfb1, Col1a1, Col3a1), fat content (Oil Red O staining), oxLDL levels (immunohistochemistry) and tendon biomechanical properties were examined in mice (C57Bl/6 or ApoE -/-) receiving a standard or a high fat diet. Human tendon fibroblast proliferation and gene expression (COL1A1, COL3A1, MMP2) were examined following oxLDL exposure.
In both types of mice (C57Bl/6 or ApoE -/-), consumption of a high fat diet led to a marked increase in oxLDL deposition in the load-bearing extracellular matrix of the tendon. The consumption of a high fat diet also reduced the failure stress and load of the patellar tendon in both mouse types, and increased Mmp2 expression. ApoE -/- mice exhibited more pronounced reductions in tendon function than wild-type mice, and decreased expression of Col1a1 compared to wild type mice. Human tendon fibroblasts responded to oxLDL by increasing their proliferation and their mRNA levels of MMP2, while decreasing their mRNA levels for COL1A1 and COL3A1.
The consumption of a high fat diet resulted in deleterious changes in tendon function, and these changes may be explained in part by the effects of oxLDL, which induced a proliferative, matrix-degrading phenotype in human tenocytes.
PMCID: PMC4264764  PMID: 25502628
2.  The seasonal variation of Achilles tendon ruptures in Vancouver, Canada: a retrospective study 
BMJ Open  2014;4(2):e004320.
To examine the seasonal distribution of tendon ruptures in a large cohort of patients from Vancouver, Canada.
Retrospective chart review.
Acute Achilles tendon rupture cases that occurred from 1987 to 2010 at an academic hospital in Vancouver, Canada. Information was extracted from an orthopaedic database.
No direct contact was made with the participants. The following information was extracted from the OrthoTrauma database: age, sex, date of injury and season (winter, spring, summer and autumn), date of surgery if date of injury was unknown and type of injury (sport related or non-sport related/unspecified). Only acute Achilles tendon rupture cases were included; chronic cases were excluded along with those that were conservatively managed.
Primary and secondary outcomes
The primary outcome was to determine the seasonal pattern of Achilles tendon rupture. Secondary outcomes, such as differences in gender and mechanism of sport (non-sport vs sport related), were also assessed.
There were 543 cases in total; 83% of the cases were men (average age 39.3) and 17% were women (average age 37.3). In total, 76% of cases were specified as sport related. The distribution of injuries varied significantly across seasons (χ2, p<0.05), with significantly more cases occurring in spring. The increase in the number of cases in spring was due to sport-related injuries, whereas non-sport-related cases were distributed evenly throughout the year.
The seasonality of sport-related Achilles tendon ruptures should be considered when developing preventive strategies and when timing their delivery.
PMCID: PMC3927994  PMID: 24519875
4.  An autoimmune response to OBP1a is associated with dry eye in the Aire-deficient mouse 
Sjögren’s Syndrome is a human autoimmune disease characterized by immune-mediated destruction of the lacrimal and salivary glands. Here, we show that the Aire-deficient mouse represents a new tool to investigate autoimmune dacryoadenitis and keratoconjunctivitis sicca, features of Sjögren’s Syndrome. Previous work in the Aire-deficient mouse suggested a role for alpha-fodrin, a ubiquitous antigen, in the disease process. Using an unbiased biochemical approach, however, we have identified a novel lacrimal gland autoantigen, odorant binding protein 1a, targeted by the autoimmune response. This novel autoantigen is expressed in the thymus in an Aire-dependent manner. The results from our study suggest that defects in central tolerance may contribute to Sjögren’s Syndrome and provide a new and clinically relevant model to investigate the pathogenic mechanisms in lacrimal gland autoimmunity and associated ocular surface sequelae.
PMCID: PMC2851482  PMID: 20237294
T cells; Autoimmunity; Autoantibodies; Tolerance; Thymus
5.  Loss of Raf Kinase Inhibitory Protein (RKIP) induces radioresistance in prostate cancer 
External beam radiation therapy is often used as in an attempt to cure localized prostate cancer (PCa), but is only palliative against disseminated disease. Raf Kinase Inhibitory Protein (RKIP) is a metastasis suppressor whose expression is reduced in approximately 50% of localized PCa tissues and is absent in metastases. Chemotherapeutic agents have been shown to induce tumor apoptosis through induction of RKIP expression. Our goal was to test if radiation therapy similarly induces apoptosis through induction of RKIP expression.
The C4-2B PCa cell line was engineered to over express or under express RKIP. The engineered cells were tested for apoptosis in cell culture and tumor regression in mice following radiation treatment.
Radiation induced both RKIP expression and apoptosis of PCa cells. Over expression of RKIP sensitized PCa cells to radiation-induced apoptosis; whereas, short-hairpin targeting of RKIP, so that radiation could not induce RKIP expression, protected cells from radiation-induced apoptosis. In a murine model, knockdown of RKIP in PCa cells diminished radiation-induced apoptosis. Molecular concept mapping of genes altered upon manipulation of RKIP expression revealed that an inverse correlation with the concept of genes altered by irradiation.
The data presented here indicate that the loss of RKIP, as seen in primary PCa tumors and metastases, confers protection against radiation-induced apoptosis. Therefore, it is conceivable that loss of RKIP confers a growth advantage upon PCa cells at distant sites since loss of RKIP would decrease apoptosis, favoring proliferation.
PMCID: PMC2597029  PMID: 18722266
RKIP; ionizing radiation; apoptosis; prostate cancer; radioresistance
6.  p38MAPK Induces Cell Surface α4 Integrin Downregulation to Facilitate erbB-2-Mediated Invasion1 
Neoplasia (New York, N.Y.)  2003;5(2):128-134.
We have previously shown that human breast cancer cells that overexpress erbB-2 are growth factor-independent. In order to test the contribution of erbB-2 to this and other transformed phenotypes without the genetic instability of cancer cells, erbB-2 was overexpressed in human mammary epithelial (HME) cells. ErbB-2-overexpressing HME cells exhibit several transformed phenotypes including cell surface α4 integrin downregulation and invasiveness. We formulated a model for invasiveness that depends on a cell's ability to downregulate α4 integrin. As small G-proteins play a role in cytoskeleton remodeling and as this is a likely route for α4 integrin trafficking, we investigated the role of small G-proteins and their downstream signals in mediating α4 integrin downregulation and invasiveness using Rac 1. Dominant-negative Rac 1 blocked erbB-2-mediated invasion and reversed erbB-2-mediated α4 integrin downregulation. In addition, constitutively active Rac 1 induced Ó4 integrin downregulation and invasiveness. In erbB-2-overexpressing and in constitutively active Rac 1-expressing cells, a p38MAP kinase (p38MAPK) inhibitor blocked invasiveness and reversed α4 integrin downregulation. These data suggest a model in which erbB-2 signaling activates Rac 1, which, in turn, activates p38MAPK, leading to the downregulation of α4 integrin. These data strengthen the model where loss of α4 integrin at the cell surface, leading to reduced α4 integrin binding to plasma fibronectin, plays a role in erbB-2-mediated invasiveness.
PMCID: PMC1550346  PMID: 12659685
Rac 1; p38MAPK; α4 integrin; invasion; erbB-2

Results 1-6 (6)