Angiotensin‐converting enzyme inhibition increases glucose‐induced insulin secretion in response to acute restraint

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Genome-wide association study identifies breast cancer risk variant at 10q21.2: results from the Asia Breast Cancer Consortium

Although approximately 20 common genetic susceptibility loci have been identified for breast cancer risk through genome-wide association studies (GWASs), genetic risk variants reported to date explain only a small fraction of heritability for this common cancer. We conducted a four-stage GWAS including 17 153 cases and 16 943 controls among East-Asian women to search for new genetic risk factors for breast cancer. After analyzing 684 457 SNPs in 2062 cases and 2066 controls (Stage I), we selected for replication among 5969 Chinese women (4146 cases and 1823 controls) the top 49 SNPs that had neither been reported previously nor were in strong linkage disequilibrium with reported SNPs (Stage II). Three SNPs were further evaluated in up to 13 152 Chinese and Japanese women (6436 cases and 6716 controls) (Stage III). Finally, two SNPs were evaluated in 10 847 Korean women (4509 cases and 6338 controls) (Stage IV). SNP rs10822013 on chromosome 10q21.2, located in the zinc finger protein 365 (ZNF365) gene, showed a consistent association with breast cancer risk in all four stages with a combined per-risk allele odds ratio of 1.10 (95% CI: 1.07-1.14) (P-value for trend = 5.87 × 10(-9)). In vitro electrophoretic mobility shift assays demonstrated the potential functional significance of rs10822013. Our results strongly implicate rs10822013 at 10q21.2 as a genetic risk variant for breast cancer among East-Asian women.     

Cardiac CT and MRI guide surgery in impending left ventricular rupture after acute myocardial infarction

We report the case of a 67 year-old patient who presented with worsening chest pain and shortness of breath, four days post acute myocardial infarction. Contrast enhanced computed tomography of the chest ruled out a pulmonary embolus but revealed an unexpected small subepicardial aneurysm (SEA) in the lateral left ventricular wall which was confirmed on cardiac magnetic resonance imaging. Intraoperative palpation of the left lateral wall was guided by the cardiac MRI and CT findings and confirmed the presence of focally thinned and weakened myocardium, covered by epicardial fat. An aneurysmorrhaphy was subsequently performed in addition to coronary bypass surgery and a mitral valve repair. The patient was discharged home on post operative day eight in good condition and is feeling well 2 years after surgery.     

Acoustic monitoring (RFM) of total hip arthroplasty results of a cadaver study

Introduction

At present there are no reliable non-traumatic and non-invasive methods to analyse the healing process and loosening status after total hip replacement. Therefore early as well as late loosening of prosthesis and interface component problems are difficult to be found or diagnosed at any time.

Methods

In a cadaver study the potential application of Resonance Frequency Monitoring (RFM) will be evaluated as a non-invasive and non-traumatic method to monitor loosening and interface problems in hip replacement. In a 65 year old female cadaver different stability scenarios for a total hip replacement (shaft, head/modular head and cup, ESKA, Luebeck, Germany) are simulated in cemented and cement less prosthesis and then analysed with RFM. The types of stability vary from secure/press-fit to interface-shaft disruption.

Results

The RFM shows in cemented as well as cement less prosthesis significant intra-individual differences in the spectral measurements with a high dynamic (20 dB difference corresponding to the factor 100 (10000%)), regarding the simulated status of stability in the prosthesis system.

Conclusion

The results of the study demonstrate RFM as a highly sensitive non-invasive and non-traumatic method to support the application of RFM as a hip prosthesis monitoring procedure. The data obtained shows the possibility to use RFM for osteointegration surveillance and early detection of interface problems, but will require further evaluation in clinical and experimental studies.     

Paclitaxel interrupts TGF-beta1 signaling between gallbladder epithelial cells and myofibroblasts

BACKGROUND: The cellular and molecular mechanisms of fibrogenesis in the extrahepatic biliary epithelium are not known. Transforming growth factor-beta1 (TGF-beta1) is a cytokine implicated in signaling pathways that mediate collagen formation. An observation that paclitaxel (PT), applied topically into the rat common bile duct, inhibited stricture formation led us to hypothesize that PT's effects might be due to interruption of TGF-beta1 signaling between biliary epithelial cells and subepithelial myofibroblasts. MATERIALS AND METHODS: We tested this hypothesis using an in vitro cell-culture model in which murine gallbladder epithelial cells (GBEC) are cultured separately or cocultured with human gallbladder myofibroblasts (GBMF). RESULTS: Exposure to Escherichia coli lipopolysaccharide (LPS) enhanced TGF-beta1 mRNA expression and stimulated TGF-beta1 protein secretion into both apical and basolateral compartments in GBEC. This effect was more prominent with basolateral secretion and was also more pronounced in the coculture system. In GBMF, collagen I mRNA expression and protein secretion were stimulated by treatment with LPS or TGF-beta1. GBMF also expressed TGF-beta1 mRNA, whose levels were enhanced by exposure to either LPS or exogenous TGF-beta1. PT inhibited LPS-induced TGF-beta1 mRNA expression and protein secretion in GBEC in both culture systems. Tumor necrosis factor-alpha mRNA expression and protein secretion were not affected by PT in GBEC, demonstrating that the effects were specific for TGF-beta1. PT also inhibited LPS- and TGF-beta1-induced collagen I mRNA expression and protein secretion in GBMF. CONCLUSIONS: These findings support a model in which GBEC communicate with subepithelial GBMF via TGF-beta1, leading to collagen deposition and fibrosis, and in which GBMF possess autocrine mechanisms involving TGF-beta1 that could regulate collagen production. PT inhibits these fibrogenic pathways.     

Peroxidasin Is Secreted and Incorporated into the Extracellular Matrix of Myofibroblasts and Fibrotic Kidney

Mammalian peroxidases are heme-containing enzymes that serve diverse biological roles, such as host defense and hormone biosynthesis. A mammalian homolog of Drosophila peroxidasin belongs to the peroxidase family; however, its function is currently unknown. In this study, we show that peroxidasin is present in the endoplasmic reticulum of human primary pulmonary and dermal fibroblasts, and the expression of this protein is increased during transforming growth factor-β1-induced myofibroblast differentiation. Myofibroblasts secrete peroxidasin into the extracellular space where it becomes organized into a fibril-like network and colocalizes with fibronectin, thus helping to form the extracellular matrix. We also demonstrate that peroxidasin expression is increased in a murine model of kidney fibrosis and that peroxidasin localizes to the peritubular space in fibrotic kidneys. In addition, we show that this novel pathway of extracellular matrix formation is unlikely mediated by the peroxidase activity of the protein. Our data indicate that peroxidasin secretion represents a previously unknown pathway in extracellular matrix formation with a potentially important role in the physiological and pathological fibrogenic response.Peroxidases are heme-containing enzymes with highly conserved structure, serving diverse functions in the plant and animal kingdom.¹ Peroxidases catalyze the oxidation of various substrates in the presence of H₂O₂. Mammalian peroxidases have an important role in several physiological processes including host defense and hormone biosynthesis. The family of mammalian peroxidases consists of myeloperoxidase, eosinophil peroxidase, lactoperoxidase, thyroid peroxidase, and the mammalian peroxidasin. Myeloperoxidase, eosinophil peroxidase, and lactoperoxidase have antimicrobial activity and serve in the first line of host defense, while thyroid peroxidase has an essential role in the biosynthesis of thyroid hormones.^2,3,4 The function of the mammalian peroxidasin is currently unknown. Peroxidases in plants and in lower animal species frequently participate in extracellular matrix (ECM) formation. In the presence of H₂O₂, peroxidases enzymatically cross-link extracellular proteins through tyrosine residues.⁵ ECM stabilization by dityrosine bridges is well-documented during sea urchin fertilization, where secreted ovoperoxidase is responsible for the formation of cross-links.⁶ Dityrosine formation is also involved in the stabilization of C. elegans cuticle, where dual oxidases, carrying both NADPH oxidase and peroxidase-like domains, provide hydrogen peroxide for the crosslinking reaction.⁷Peroxidasin (PXDN), a unique form of peroxidase was first identified in Drosophila melanogaster.⁸ Beside containing a peroxidase domain, which is highly homologous to other animal peroxidases, peroxidasin also contains protein domains characteristic for proteins of the ECM. Drosophila PXDN was found to be expressed in several stages of development, but the exact function remained unknown.⁸ Little is still known about the mammalian PXDN protein. A human homolog of Drosophila PXDN was originally identified as a p53-responsive gene product from a colon cancer cell line, but it was not characterized in detail.⁹ An independent cloning effort, using subtractive hybridization also led to the identification of the mammalian PXDN gene, which was originally named melanoma gene 50, based on the expression in melanoma samples.¹⁰ This latter study has characterized PXDN as a possible potent melanoma-associated antigen, but it did not examine the possible physiological role of the protein.Here we demonstrate that peroxidasin is expressed by human primary cells, including fibroblasts of different origin, where the protein is localized to the endoplasmic reticulum. On stimulation by transforming growth factor (TGF)-β1, differentiating myofibroblasts show increased expression of peroxidasin. The protein becomes secreted to the extracellular space where it is organized into a fibril-like network. We also show that this pathway of ECM formation is probably not mediated by the peroxidase activity of the protein. Our results suggest that beside the secretion of well-known constituents of the ECM, PXDN secretion by myofibroblasts is a novel way of ECM modification in wound repair and tissue fibrosis.     

Validation of MCADD newborn screening

Medium‐chain acyl‐CoA dehydrogenase deficiency (MCADD) represents a potentially fatal fatty acid β‐oxidation disorder. Newborn screening (NBS) by tandem mass spectrometry (MS/MS) has been implemented worldwide, but is associated with unresolved questions regarding population heterogeneity, burden on healthy carriers, cut‐off policies, false‐positive and negative rates. In a retrospective case‐control study, 333 NBS samples showing borderline acylcarnitine patterns but not reaching recall criteria were genotyped for the two most common mutations (c.985A>G/c.199C>T) and compared with genotypes and acylcarnitines of 333 controls, 68 false‐positives, and 34 patients. c.985A>G was more frequently identified in the study group and false‐positives compared to controls (1:4.3/1:2.3 vs. 1:42), whereas c.199C>T was found more frequently only within the false‐positives (1:23). Biochemical criteria were devised to differentiate homozygous (c.985A>G), compound heterozygous (c.985A>G/c.199C>T), and heterozygous individuals. Four false‐negatives were identified because our initial algorithm required an elevation of octanoylcarnitine (C₈) and three secondary markers in the initial and follow‐up sample. The new approach allowed a reduction of false‐positives (by defining high cut‐offs: 1.4 μmol/l for C₈; 7 for C₈/C₁₂) and false‐negatives (by sequencing the ACADM gene of few suspicious samples). Our validation strategy is able to differentiate healthy carriers from patients doubling the positive predictive value (42→88%) and to target NBS to MCADD‐subsets with potentially higher risk of adverse outcome. It remains controversial, if NBS programs should aim at identifying all subsets of all diseases included. Because the natural course of milder variants cannot be assessed by observational studies, our strategy could serve as a general model for evaluation of MS/MS‐based NBS.     

HER-2 positive and p53 negative breast cancers are associated with poor prognosis

p53 and HER-2 coexpression in breast cancer has been controversial. These markers were tested using immunohistochemistry and HercepTest. HER-2 expression is related to reduced breast cancer survival (p = .02) . p53 expression relates to HER-2 expression (p = .029). Coexpression between p53 and HER-2 has no relation to prognosis. On univariate and multivariate analysis, combination of HER-2 positive and p53 negative expression was associated with a poor prognosis (p = .018 and p = .027, respectively), while the combination of HER-2 negative and p53 positive expression was associated with a favorable prognosis (p = .022 and p = .010, respectively). Therefore the expression of these markers should be considered collectively.