Polymorphisms and Biologic Effects of Acidic Mammalian Chitinase in Asthma

In this study, we hypothesize that human acidic mammalian chitinase (AMCase) binds and is regulated by the epidermal growth factor receptor (EGFR), and that AMCase interacts with Galectin-3 (Gal-3) to mediate anti-apoptotic functions. We further hypothesize that asthma-associated polymorphisms of AMCase alter chitinase activity and modulate anti-apoptotic effects. We investigated the interactions between AMCase, Gal-3 and EGFR by establishing binding and co-expression in vitro; apoptotic effects were evaluated via Annexin V/Propidium Iodide staining. Molecular cloning was performed to generate single nucleotide polymorphisms (SNPs) of AMCase associated with asthma. Our data showed that co-expression of AMCase and EGFR induces chitinase activity; we found that AMCase and Gal-3 bind each other in vitro, and that they co-localize in the cytoplasm of cells. Co-transfection of AMCase and Gal-3 demonstrates greater anti-apoptotic effect than Gal-3 alone, while recombinant Gal-3 induces apoptosis, which is not blocked by incubation with recombinant AMCase. From these data, we conclude that AMCase is regulated by EGFR, and that AMCase and Gal-3 physically interact, however contrary to our hypothesis, the anti-apoptotic effects of AMCase are unlikely to be mediated by Gal-3. Further exploration of this pathway using SNP constructs generated in this study will shed light on the mechanism of AMCase in asthma

Discs large (Dlg1) complexes in lymphocyte activation

T cell antigen recognition involves the formation of a structured interface between antigen-presenting and T cells that facilitates the specific transmission of activating and desensitizing stimuli. The molecular machinery that organizes the signaling molecules and controls their disposition in response to activation remains poorly understood. We show here that in T cells Discs large (Dlg1), a PDZ domain-containing protein, is recruited upon activation to cortical actin and forms complexes with early participants in T cell activation. Transient overexpression of Dlg1 attenuates basal and Vav1-induced NFAT reporter activation. Reduction of Dlg1 expression by RNA interference enhances both CD3- and superantigen-mediated NFAT activation. Attenuation of antigen receptor signaling appears to be a complex, highly orchestrated event that involves the mutual segregation of important elements of the early signaling complex

A molecular-properties-based approach to understanding PDZ domain proteins and PDZ ligands

PDZ domain-containing proteins and their interaction partners are mutated in numerous human diseases and function in complexes regulating epithelial polarity, ion channels, cochlear hair cell development, vesicular sorting, and neuronal synaptic communication. Among several properties of a collection of documented PDZ domain–ligand interactions, we discovered embedded in a large-scale expression data set the existence of a significant level of co-regulation between PDZ domain-encoding genes and these ligands. From this observation, we show how integration of expression data, a comparative genomics catalog of 899 mammalian genes with conserved PDZ-binding motifs, phylogenetic analysis, and literature mining can be utilized to infer PDZ complexes. Using molecular studies we map novel interaction partners for the PDZ proteins DLG1 and CARD11. These results provide insight into the diverse roles of PDZ–ligand complexes in cellular signaling and provide a computational framework for the genome-wide evaluation of PDZ complexes

Resection of primary leiomyosarcoma of the inferior vena cava (IVC) with reconstruction: a case series and review of the literature.

BACKGROUND: Leiomyosarcoma of the inferior vena cava (IVC) is a rare tumor which presents a unique surgical challenge. We present a series of six cases of leiomyosarcoma resection performed with IVC reconstruction. METHODS: Retrospective chart review was performed for patients undergoing initial operative resection of primary leiomyosarcoma with IVC reconstruction, at a tertiary care center. RESULTS: Between 2005-2013, six patients underwent resection with reconstruction. Half were female, and the mean age at presentation was 57 ± 15.4 years. Three patients required en bloc resection with adjacent organs. Three patients were resected on venovenous bypass, and one on cardiopulmonary bypass. Three underwent IVC patch repair (bovine pericardium, n = 2; saphenous vein, n = 1), and three had IVC reconstruction with graft (Dacron, n = 1; PTFE, n = 1; aortic homograft, n = 1). All achieved grossly negative margins. Median disease-free survival was 34 months (IQR 7-52 months), and median disease-specific survival was 51 months (IQR 20-108). Five year disease-free and disease-specific survival rates were 30% and 66.7%, respectively. CONCLUSIONS: Leiomyosarcomas of the IVC present a technical challenge to the surgeon. Careful preoperative workup and a collaborative team consisting of experienced cardiac and vascular surgeons and surgical oncologists can allow for a safe and successful operation despite extensive tumor involvement

Outcomes after resection of leiomyosarcomas of the inferior vena cava: a pooled data analysis of 377 cases.

BACKGROUND: Primary leiomyosarcomas of the inferior vena cava (IVC) pose unique surgical challenges. Due to the rarity of the disease, little definitive data exists on prognosis and treatment options. METHODS: A pooled data analysis was performed on all cases of initial IVC leiomyosarcoma resection identified by literature search (n = 371) and our institutional database (n = 6). Kaplan-Meier and Cox regression analyses were performed to identify factors associated with disease-free survival (DFS) and overall survival (OS). RESULTS: Patients were predominantly female (76%, n = 286); the median age of presentation was 55 years. Five-year DFS and OS were 6% and 55%, respectively. Preoperative factors independently associated with decreased OS included older age (HR:1.05, 95% CI:1.00-1.09), larger tumor size (HR:1.14, 95% CI:1.04-1.24), resection of adjacent organ(s) (HR:3.62, 95% CI:1.34-9.77), and R2 resection (HR:7.80, 95% CI:1.94-32.05). Isolated involvement of the suprarenal infrahepatic IVC was associated with longer OS (HR:0.22, 95% CI:0.06-0.78). A scoring system incorporating independent predictors of OS stratified outcomes: score 4-5 (n = 10, median OS 6 months), score 2-3 (n = 88, median OS 23 months) compared to a score of 0-1 (n = 44, median OS 29 months). CONCLUSIONS: Following resection of IVC leiomyosarcomas, recurrence is a near certainty; long-term survival, however is possible. The dominant predictors of survival include margin status, tumor size and radical resection. These can be combined into a risk score that has prognostic value