Serum proteome profiling identifies novel and powerful markers of cystic fibrosis liver disease.

Cystic Fibrosis associated liver disease (CFLD) develops in approximately 30% of CF patients. However, routine sensitive diagnostic tools for CFLD are lacking. Within this study, we aimed to identify new experimental biomarkers for the detection of CFLD. 45 CF patients were included in the study and received transient elastography. Differential regulation of 220 different serum proteins was assessed in a subgroup of patients with and without CFLD. Most interesting candidate proteins were further quantified and validated by ELISA in the whole patient cohort. To assess a potential relation of biomarker expression to the degree of hepatic fibrosis, serum biomarkers were further determined in 18 HCV patients where liver histology was available. 43 serum proteins differed at least 2-fold in patients with CFLD compared to those without liver disease as identified in proteome profiling. In ELISA quantifications, TIMP-4 and Endoglin were significantly up-regulated in patients with CFLD as diagnosed by clinical guidelines or increased liver stiffness. Pentraxin-3 was significantly decreased in patients with CFLD. Serum TIMP-4 and Endoglin showed highest values in HCV patients with liver cirrhosis compared to those with fibrosis but without cirrhosis. At a cut-off value of 6.3 kPa, transient elastography compassed a very high diagnostic accuracy and specificity for the detection of CFLD. Among the biomarkers, TIMP-4 and Endoglin exhibited a high diagnostic accuracy for CFLD. Diagnostic sensitivities and negative predictive values were increased when elastography and TIMP-4 and Endoglin were combined for the detection of CFLD. Serum TIMP-4 and Endoglin are increased in CFLD and their expression correlates with hepatic staging. Determination of TIMP-4 and Endoglin together with transient elastography can increase the sensitivity for the non-invasive diagnosis of CFLD

Matrix metalloproteinase-13 refines pathological staging of precancerous colorectal lesions

An exact classification of precancerous stages of colorectal polyps might improve therapy and patients´ outcome. Here we investigate the association between grade of dysplasia and Matrix metalloproteinase-13 (MMP-13) expression in 137 biopsies from patients with cancerous and non-cancerous colorectal adenomas. A reproducible staining procedure for histologic MMP-13 analysis in routinely fixed colorectal biopsy specimens has been established. A newly adopted immunoreactive scoring system for MMP-13 was demonstrated as reliable readout. The strength of the association between pathologic stage and immunoreactive MMP-13 scoring emphasizes its eligibility for diagnosis in precancerous colorectal lesions

Bioaktive Kollagenfragmente : Neue strukturbiologische Studien an Kollagen-Integrin-Komplexen belegen Justus Liebigs wegweisende Ideen

In seinem bahnbrechenden Werk „Thierchemie“ von 1843 beschreibt Justus Liebig Ge latine, das Abbauprodukt von Kollagen, als Leim gebendes Gebilde. Bis heute ist in der Human- wie in der Veterinärmedizin umstritten, ob die Verabreichung von Kollagenfragmenten in Form von Nahrungsergänzungsmitteln eine wirksame Strategie darstellt, um einem Gelenkverschleiß vorzubeugen, der sich z.B. in einer Arthrose manifestieren kann. Die Arbeitsgruppe von Prof. Hans-Christian Siebert kombiniert nanotechnologische Analysemethoden mit Bioinformatikalgorithmen, um die submolekularen Mechanismen zu ergründen, die die hochkomplexen Wechselwirkungen bestimmter Rezeptoren in der extra-zellulären Matrix mit unterschiedlichen bioaktiven Kollagenfragmenten ermöglichen

Matrix metalloproteinase-19 inhibits growth of endothelial cells by generating angiostatin-like fragments from plasminogen

<p>Abstract</p> <p>Background</p> <p>Angiogenesis is the process of forming new blood vessels from existing ones and requires degradation of the vascular basement membrane and remodeling of extracellular matrix (ECM) in order to allow endothelial cells to migrate and invade into the surrounding tissue. Matrix metalloproteinases (MMPs) are considered to play a central role in the remodeling of basement membranes and ECM. However, MMPs contribute to vascular remodeling not only by degrading ECM components. Specific MMPs enhance angiogenesis via several ways; they help pericytes to detach from vessels undergoing angiogenesis, release ECM-bound angiogenic growth factors, expose cryptic pro-angiogenic integrin binding sites in the ECM, generate promigratory ECM component fragments, and cleave endothelial cell-cell adhesions. MMPs can also negatively influence the angiogenic process through generating endogenous angiogenesis inhibitors by proteolytic cleavage. Angiostatin, a proteolytic fragment of plasminogen, is one of the most potent antagonists of angiogenesis that inhibits migration and proliferation of endothelial cells. Reports have shown that metalloelastase, pancreas elastase, plasmin reductase, and plasmin convert plasminogen to angiostatin.</p> <p>Results</p> <p>We report here that MMP-19 processes human plasminogen in a characteristic cleavage pattern to generate three angiostatin-like fragments with a molecular weight of 35, 38, and 42 kDa. These fragments released by MMP-19 significantly inhibited the proliferation of HMEC cells by 27% (p = 0.01) and reduced formation of capillary-like structures by 45% (p = 0.05) compared with control cells. As it is known that angiostatin blocks hepatocyte growth factor (HGF)-induced pro-angiogenic signaling in endothelial cells due to structural similarities to HGF, we have analyzed if the plasminogen fragments generated by MMP-19 interfere with this pathway. As it involves the activation of c-met, the receptor of HGF, we could show that MMP-19-dependent processing of plasminogen decreases the phosphorylation of c-met.</p> <p>Conclusion</p> <p>Altogether, MMP-19 exhibits an anti-angiogenic effect on endothelial cells via generation of angiostatin-like fragments.</p

Marketing As Tool of Resource Efficiency

This paper shows the role of marketing in ensuring resource efficiency. It is found that the marketing is one of the methods of saving resources, making them effective in use. The conclusion about the need to use marketing to increase the efficiency of resource management in the organization is justified. It is suggested to use SWOT-analysis as a marketing technique for choosing a particular strategy, significant for the company in the management of resource efficiency. The forecasting of demand allows receiving evidence-based options in tendencies of change, indicators of quality, expenses and other indicators. Therefore, the system of the resource efficiency at an enterprise has to be guided by forecasting the demand and its task. Improved analysis cost methods (such as the factorial analysis, the functional and cost analysis) help to solve a problem of resource efficiency at the stage of design or production improvement. It is proved that application of the concept of social and ethic marketing promotes development of the resource efficiency program in management

Hepatitis B virus surface proteins accelerate cholestatic injury and tumor progression in Abcb4-knockout mice

Understanding of the pathophysiology of cholestasis associated carcinogenesis could challenge the development of new personalized therapeutic approaches and thus improve prognosis. Simultaneous damage might aggravate hepatic injury, induce chronic liver disease and even promote carcinogenesis. We aimed to study the effect of Hepatitis B virus surface protein (HBsAg) on cholestatic liver disease and associated carcinogenesis in a mouse model combining both impairments. Hybrids of Abcb4-/- and HBsAg transgenic mice were bred on fibrosis susceptible background BALB/c. Liver injury, serum bile acid concentration, hepatic fibrosis, and carcinogenesis were enhanced by the combination of simultaneous damage in line with activation of c-Jun N-terminal kinase (JNK), proto-oncogene c-Jun, and Signal transducer and activator of transcription 3 (STAT3). Activation of Protein Kinase RNA-like Endoplasmic Reticulum Kinase (PERK) and Eukaryotic translation initiation factor 2A (eIF2a) indicated unfolded protein response (UPR) in HBsAg-expressing mice and even in Abcb4-/- without HBsAg-expression. CONCLUSION: Cholestasis-induced STAT3- and JNK-pathways may predispose HBsAg-associated tumorigenesis. Since STAT3- and JNK-activation are well characterized critical regulators for tumor promotion, the potentiation of their activation in hybrids suggests an additive mechanism enhancing tumor incidence

Transfusion of Target Antigens to Pre-Immunized Recipients:A New Mechanism in Transfusion-Related Acute Lung Injury

Transfusion-related lung injury (TRALI) is a serious side effect of blood transfusion. Exclusion of antibody carriers from the donor pool has significantly decreased the number of cases, but TRALI remains the leading cause of transfusion-related morbidity and mortality in industrialized countries. Here, we show that proteins released from donor cells during processing of blood components are capable of inducing a new type of reverse TRALI when transfused to preimmunized recipients. First, we show that soluble neutrophil surface protein CD177 in complex with proteinase 3 (sCD177/PR3) is not only present in human plasma but also in packed red blood cell (PRBC) supernatant. Filtration or storage enhances the concentration of sCD177/PR3 in PRBCs. Second, we show that sCD177/PR3 specifically binds to PECAM-1 on stimulated (but not on unstimulated) endothelial cells (ECs). Third, we provide evidence that the sCD177/PR3/PECAM-1 complex is functional. In the presence of monoclonal or human antibodies against CD177 or PR3, ECs produce reactive oxygen species and become apoptotic. Albumin flux through an EC monolayer increases significantly whenever antibodies and the cognate antigens are present. Finally, we describe a clinical case in which anti-CD177 present in a transfusion recipient precipitated TRALI after the transfusion of CD177-positive, but not CD177-negative, PRBCs. In conclusion, we introduce a new TRALI mechanism based on the specific binding of transfused, soluble antigens to activated ECs in preimmunized recipients. We suggest that further studies and clinical work-up of TRALI should also include antibody investigation of the recipient

Gauge copies in the Landau-DeWitt gauge: a background invariant restriction

The Landau background gauge, also known as the Landau-DeWitt gauge, has found renewed interest during the past decade given its usefulness in accessing the confinement-deconfinement transition via the vacuum expectation value of the Polyakov loop, describable via an appropriate background. In this Letter, we revisit this gauge from the viewpoint of it displaying gauge (Gribov) copies. We generalize the Gribov-Zwanziger effective action in a BRST and background invariant way; this action leads to a restriction on the allowed gauge fluctuations, thereby eliminating the infinitesimal background gauge copies. The explicit background invariance of our action is in contrast with earlier attempts to write down and use an effective Gribov-Zwanziger action. It allows to address certain subtleties arising in these earlier works, such as a spontaneous and thus spurious Lorentz symmetry breaking, something which is now averted.Comment: 14 pages. v2: version to appear in Phys.Lett.B, with minor modifications and extra reference