The paradoxical expression of maspin in ovarian carcinoma.

Maspin is a noninhibitory member of the serpin family that is down-regulated in breast carcinoma but overexpressed in pancreatic carcinoma. There are no published data regarding the role of maspin in ovarian carcinoma, which is the focus of the present study. Ovarian cell lines (normal and cancer) and tumors (80 invasive, 14 benign, and 10 low malignant potential) were evaluated for maspin expression and localization. Normal ovarian surface epithelial cells had low levels of maspin. Two of four ovarian cancer cell lines (OVCAR3 and SKOV3) expressed maspin, whereas the cell line EG had weak expression, and 222 had no detectable maspin. Subcellular fractionation studies revealed that the two maspin-positive ovarian cancer cell lines contained maspin in both the nuclear and cytosolic compartments. Wild-type maspin was transfected into the aggressive ovarian cancer cell lines SKOV3 and 222. The in vitro invasive activity of the maspin-transfected cell lines was 44-68% lower than respective controls. The histopathology analysis revealed that among the ovarian tumors examined, 57 (71%) were ranked positive for maspin. Thirty (37%) of the invasive tumors overexpressed maspin. Invasive cancers were more likely to have predominantly cytoplasmic staining compared with benign and low-malignant-potential tumors. Maspin overexpression was significantly associated with a high tumor grade (P = 0.004), the presence of ascites (P = 0.02), a lower likelihood of optimal surgical cytoreduction (P = 0.04), and a shorter duration of overall survival (median survival, 6.33 versus 2.67 years; P = 0.003). The Cox proportional hazards multivariate model revealed that maspin overexpression and high stage were independent predictors of survival. Thus, maspin was found to be overexpressed in a substantial proportion of ovarian tumors, which may serve as an adverse prognostic factor; however, its localization may provide new clues as to its activity and function. These paradoxical results may offer new insights regarding the role of maspin in ovarian cancer progression that may also impact diagnosis and treatment strategies.     

Elucidating the function of secreted maspin: inhibiting cathepsin D-mediated matrix degradation

Cellular interaction with the extracellular milieu plays a significant role in normal biological and pathologic processes. Excessive degradation of basement membrane matrix by proteolytic enzymes is a hallmark of tumor invasion and metastasis, and aspartyl proteinase cathepsin D is implicated as a major contributor to this process. Maspin, a non-inhibitory serpin, plays an important role in mammary gland development and remodeling. Expression of Maspin is decreased in primary tumors and lost in metastatic lesions. Maspin is mostly cytoplasmic and is partially secreted; however, the fate and function of secreted Maspin has remained mostly unexplored. We hypothesized that secreted Maspin is incorporated into the matrix deposited by normal mammary epithelial cells and thus could play a critical role in cathepsin D-mediated matrix degradation and remodeling of mammary tissue. In the absence of Maspin, as is the case with most cancer cells, matrix degradation proceeds unrestricted, thus facilitating the progression to metastasis. To test this, we employed an in vitro model where gels containing both types I and IV collagen were preconditioned with normal mammary epithelial cells to allow the incorporation of secreted Maspin. This conditioned matrix was used to examine cathepsin D-mediated collagen degradation by human breast cancer cell lines. Our results indicate that secretion of Maspin and its deposition into the extracellular milieu play an important role in matrix degradation. In this capacity, Maspin could potentially regulate mammary tissue remodeling occurring under normal and pathologic conditions. In addition, these findings could have a potential effect on future therapeutic intervention strategies for breast cancer.     

Numerical fatigue analysis of premolars restored by CAD/CAM ceramic crowns

Objectives

The purpose of this study was to estimate the fatigue life of premolars restored with two dental ceramics, lithium disilicate (LD) and polymer infiltrated ceramic (PIC) using the numerical method and compare it with the published in vitro data.

Serum immunoglobulin A concentration is a reliable biomarker for liver fibrosis in non-alcoholic fatty liver disease

AIM: To evaluate the diagnostic accuracy of serum Immunoglobulin A (IgA) for differentiating early stage nonalcoholic fatty liver disease (NAFLD) from nonalcoholic steatohepatitis (NASH).METHODS: All cases had fatty liver change confirmed by ultrasound and aminotransferases of at least twice the normal level. Clinical and biochemical data, including serum IgA, were obtained from 50 histologically proven NAFLD cases and 54 healthy controls. Fasting whole blood samples were obtained from the study population. Immunoturbidimetric methods were used to measure the IgA levels. All NAFLD cases were hospitalized for liver biopsy. Liver specimens were examined for steatosis, steatohepatitis and fibrosis within hepatocytes. Patients were categorized into two groups: NASH and non-NASH. Variables were compared within cases (NASH vs non-NASH) and controls. Cut-off values of serum IgA were evaluated using analysis of receiver operating characteristic (ROC curves). Associations between the variables were tested using calculations of correlation coefficients. Statistical significances were assigned to P values < 0.05.RESULTS: The extent of liver fibrosis correlated positively with IgA levels. Subjects with no fibrosis in their liver biopsies had a lower IgA level (301.5 ± 91.2 mg/dL) than subjects with any degree of fibrosis (388.8 ± 140.8 mg/dL), (P = 0.01). IgA levels were higher in NASH cases, and its value was significantly higher for higher degrees of fibrosis. Patients with perisinusoidal or pericellular fibrosis had significantly higher levels of IgA (403.5 ± 133.9 mg/dL, 418.2 ± 129.5 mg/dL) compared to those without it (301.8 ± 94.9 mg/dL, 297.7 ± 91.5 mg/dL), respectively. No significant correlation was found between steatosis grade and serum IgA levels. Based on ROC analysis, the best predictive IgA cutoff value for detecting liver fibrosis was 360 mg/dL (61% sensitivity, 81% specificity).CONCLUSION: The serum IgA level is useful to evaluate the severity of liver fibrosis and can be used serially for evaluation and follow-up of NAFLD cases.     

Function and Structure of Resistance Vessels in Black and White People

J Clin Hypertens (Greenwich). 2010;12:431–438. ^©2010 Wiley Periodicals, Inc. The risk of development of hypertension is greater in black people compared to white people through mechanisms that are poorly understood. Several biological and environmental factors have been proposed. Based on the role of an increased peripheral resistance in the pathogenesis of hypertension, the authors focus in this systematic review on ethnic differences in function and mechanical properties of resistance arteries in normotensive participants. PubMed was systematically searched for papers on ethnic differences in vascular function and structure. A total of 620 papers were retrieved, of which 31 papers were included in the analysis. The available data indicate that compared to normotensive whites, normotensive black people have enhanced vascular reactivity to sympathetic stimulation, attenuated responses to vasodilators, and a relatively narrow vascular lumen diameter. Of these mechanisms, the reduced vasodilation and reduced nitric oxide bioavailability in the vascular wall seem to form the most important distinction between resistance vessel properties of black and white participants.     

Could Hormones Make a Difference in the Treatment of Juvenile Rheumatoid Arthritis?

Adrenal androgens dehydroepiandrosterone (DHEA; prasterone) and its sulphated form (DHEA-S) are among the most abundant hormonal steroids in men and nonpregnant women. Deficiencies of these adrenal androgens are associated with autoimmune disorders such as rheumatoid arthritis (RA). Recent studies from our laboratory have also identified low levels of adrenal androgens in the serum and synovial fluid of patients with juvenile rheumatoid arthritis (JRA). These findings support and complement those already published for RA and other autoimmune diseases. Because of the paucity of data on the hormonal status of patients with JRA, studies on the relationship between hypoandrogenicity and predisposition to develop JRA, and/or disease progression have not been conducted. In addition, despite the rapid expansion of research in the clinical use of these adrenal androgens in hyperlipidaemia, atherosclerosis, obesity, diabetes mellitus, insulin resistance and hypertension, their potential beneficial effects in JRA/RA have not been fully investigated. In fact, clinical trials of adrenal androgens in RA have only been conducted for the treatment of systemic lupus erythematosus. Further studies using prospective approaches are necessary to provide a unified consensus on the hormonal status of patients with JRA (as well as those with RA). This overview of our knowledge of the putative role(s) of hormones in arthritis will hopefully stimulate researchers in basic science and rheumatologists to synergistically collaborate in the effective translation of such knowledge to new clinical approaches.     

The nature of the homeostatic changes in nephrolithiasis patients

Rheorenographic findings, activities of 4 major glycolytic enzymes and 3 Krebs cycle ones in serum and blood, urinary fibrinolytic activity were analyzed in 117 patients with coral nephrolithiasis (the pelvis was drained after calculus removal) in 114 patients with non-coral calculi (the pelvis was sutured) before and 7, 14 days after surgery. Rheography revealed a significant decrease in arterial vascular tone and blood filling and an impairment in venous return in the diseased kidney. In the patients with nephrolithiasis, the enzymatic activity showed 3.5-10.5- and 4.5-11.5-fold increase (p less than 0.001) in the Krebs cycle and glycolysis, respectively, suggesting activation of not only oxidative phosphorylation, but anaerobic glycolysis. Tubular metabolic acidosis occurred, which made the enzymes enter blood and urine from the epithelial cells. On days 7-14 of postoperation, rheographic parameters, enzymatic and fibrinolytic activities of the urine remained virtually unchanged as compared to the values observed in the preoperative period. Moreover, the patients with a sutured pelvis showed highly accelerated glycolysis during the surgery against prior to the procedure. Urinary mitochondrial enzyme release increased, which reflected an enhancement of degenerative changes in nephron cells. Urinary fibrinolytic activity remained lower. In the patients with a drained pelvis, all the parameters in question became better.