Peripheral myelin protein-22 (PMP22) modulates alpha 6 integrin expression in the human endometrium

<p>Abstract</p> <p>Background</p> <p>PMP22, a member of the GAS3 family of tetraspan proteins, is associated with a variety of neurological diseases. Previous studies have shown that PMP22 is expressed in proliferative endometrium, but its function within this tissue is poorly understood. In this study, we first characterized the expression of PMP22 in the human menstrual cycle and began to characterize its function in the endometrium.</p> <p>Methods</p> <p>Using a combination of immunohistochemistry and quantitative PCR, we characterized the expression of PMP22 in both proliferative and secretory endometrium. Differences in PMP22 expression between proliferative and secretory endometrium were determined using a Mann-Whitney U test. In order to investigate the influence of PMP22 on α6 integrin expression, cells were created that ectopically overexpressed PMP22 or expressed a siRNA to inhibit its expression. These cells were analyzed for changes in integrins and binding to extracellular matrices.</p> <p>Results</p> <p>In this study, we show that PMP22 expression is higher in proliferative phase than secretory phase. Functionally, we have begun to characterize the functional significance of this expression. Previous studies have suggested a link between PMP22 and α6 integrin, and therefore we asked whether PMP22 could associate or potentially modulate the expression of α6 integrin. Expression of both PMP22 and α6 integrin were detectable in endometrial epithelial and stromal cells, and we show that both proteins can associate and colocalize with each other. To understand if PMP22 directly altered the expression of a6 integrin, we examined cell lines with modulated levels of the protein. Overexpression of PMP22 was sufficient to increase α6 integrin surface expression with a concominant increase in binding to the extracellular matrix laminin, while a reduction in PMP22 suppressed α6 integrin surface expression.</p> <p>Conclusion</p> <p>These findings suggest a physiologic role for PMP22 on the expression of α6 integrin. We predict that this may be important for the maintainence of endometrial integrity and to the disease biology associated with altered levels of α6 integrin expression in the endometrium.</p

Epithelial Membrane Protein-2 Promotes Endometrial Tumor Formation through Activation of FAK and Src

Endometrial cancer is the most common gynecologic malignancy diagnosed among women in developed countries. One recent biomarker strongly associated with disease progression and survival is epithelial membrane protein-2 (EMP2), a tetraspan protein known to associate with and modify surface expression of certain integrin isoforms. In this study, we show using a xenograft model system that EMP2 expression is necessary for efficient endometrial tumor formation, and we have started to characterize the mechanism by which EMP2 contributes to this malignant phenotype. In endometrial cancer cells, the focal adhesion kinase (FAK)/Src pathway appears to regulate migration as measured through wound healing assays. Manipulation of EMP2 levels in endometrial cancer cells regulates the phosphorylation of FAK and Src, and promotes their distribution into lipid raft domains. Notably, cells with low levels of EMP2 fail to migrate and poorly form tumors in vivo. These findings reveal the pivotal role of EMP2 in endometrial cancer carcinogenesis, and suggest that the association of elevated EMP2 levels with endometrial cancer prognosis may be causally linked to its effect on integrin-mediated signaling

Complex Left Atrial Appendage Morphology Is an Independent Risk Factor for Cryptogenic Ischemic Stroke

Importance: Ischemic strokes pose a significant health burden. However, the etiology of between 20 and 40% of these events remains unknown. Left atrial appendage morphology may influence the occurrence of thromboembolic events.Design: A retrospective cross-sectional study was conducted to investigate the role of LAA morphology in patients with atrial fibrillation (AF) and cardioembolic-associated stroke and patients with cryptogenic stroke without atrial fibrillation. LAA morphology is classified into two groups: (1) simple (chicken-wing) vs. (2) complex (non-chicken wing) based on transesophageal echocardiography (TEE) findings. In addition to the LAA morphology, left atrial parameters, including orifice diameter, depth, emptying velocity, and filling velocity, were collected for both groups. Mathematical, computational models were constructed to investigate flow velocities in chicken-wing and non-chicken wing morphological patterns to assess LAA function further.Findings: TEE values for volume, size, emptying, and filling velocities were similar between simple and complex LAA morphology groups. Patients with cryptogenic stroke without coexisting AF were noted to have significantly higher rates of complex LAA morphology. Chicken-wing LAA morphology was associated with four-fold higher flow rate (kg/s) in computational simulations.Conclusions: Complex LAA morphology may be an independent contributing factor for cryptogenic strokes. Further studies are warranted to investigate the mechanism involved in LAA morphology and thromboembolic events

Chest Wall Malignant Peripheral Nerve Sheath Tumor In A 21-Year Old Female

Malignant peripheral nerve sheath tumors are aggressive sarcomas that derive from peripheral nerve cells and are associated with a poor prognosis. We report a rare case of malignant peripheral nerve sheath tumor in the anterior chest wall of a 21-year-old female. The patient underwent induction chemotherapy, and resection of the mass with negative margins. She subsequently underwent radiation therapy

Chest wall malignant peripheral nerve sheath tumor in a 21-year old female

Malignant peripheral nerve sheath tumors are aggressive sarcomas that derive from peripheral nerve cells and are associated with a poor prognosis. We report a rare case of malignant peripheral nerve sheath tumor in the anterior chest wall of a 21-year-old female. The patient underwent induction chemotherapy, and resection of the mass with negative margins. She subsequently underwent radiation therapy

Targeting inflammation after myocardial infarction

Purpose of review: Inflammation plays a key role in clearing cellular debris and recovery after acute myocardial infarction (AMI). Dysregulation of or prolonged inflammation may result in adverse cardiac remodeling and major adverse clinical events (MACE). Several pre-clinical studies and moderate sized clinical trials have investigated the role of immunomodulation in improving clinical outcomes in patients with AMI.Recent findings: Clinical data from the Canakinumab Atherothrombosis Outcome (CANTOS) and Colchicine Cardiovascular Outcomes Trial (COLCOT) have provided encouraging results among patients with AMI. Several other clinical and pre-clinical trials have brought about the prospect of modulating inflammation at various junctures of the inflammatory cascade including inhibition of complement cascade, interleukins, and matrix metalloproteinases. In patients with AMI, modulation of residual inflammation via various inflammatory pathways and mediators may hold promise for further reducing MACE. Learning from current data and understanding the nuances of immunomodulation in AMI are key for future trials and before widespread dissemination of such therapies

Epithelial membrane protein-2 promotes endometrial tumor formation through activation of FAK and Src.

Endometrial cancer is the most common gynecologic malignancy diagnosed among women in developed countries. One recent biomarker strongly associated with disease progression and survival is epithelial membrane protein-2 (EMP2), a tetraspan protein known to associate with and modify surface expression of certain integrin isoforms. In this study, we show using a xenograft model system that EMP2 expression is necessary for efficient endometrial tumor formation, and we have started to characterize the mechanism by which EMP2 contributes to this malignant phenotype. In endometrial cancer cells, the focal adhesion kinase (FAK)/Src pathway appears to regulate migration as measured through wound healing assays. Manipulation of EMP2 levels in endometrial cancer cells regulates the phosphorylation of FAK and Src, and promotes their distribution into lipid raft domains. Notably, cells with low levels of EMP2 fail to migrate and poorly form tumors in vivo. These findings reveal the pivotal role of EMP2 in endometrial cancer carcinogenesis, and suggest that the association of elevated EMP2 levels with endometrial cancer prognosis may be causally linked to its effect on integrin-mediated signaling