Prospective evaluation of prognostic factors uPA/PAI-1 in node-negative breast cancer: Phase III NNBC3-Europe trial (AGO, GBG, EORTC-PBG) comparing 6 × FEC versus 3 × FEC/3 × Docetaxel

Contains fulltext : 98255.pdf (publisher's version ) (Open Access)BACKGROUND: Today, more than 70% of patients with primary node-negative breast cancer are cured by local therapy alone. Many patients receive overtreatment by adjuvant chemotherapy due to inadequate risk assessment. So far, few clinical trials have prospectively evaluated tumor biology based prognostic factors. Risk assessment by a biological algorithm including invasion factors urokinase-type plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor type 1 (PAI-1) will assess up to 35-55% of node-negative patients as low-risk and thus avoid chemotherapy. In contrast, a clinical-pathological algorithm will only classify 20-40% of patients as low-risk. High-risk node-negative patients should receive chemotherapy. Anthracycline-based regimens are accepted as a standard, the additional benefit of taxanes remains an open question. METHODS/DESIGN: The international NNBC3 ("Node Negative Breast Cancer 3-Europe") trial compares biological risk assessment (UP) using invasion factors uPA/PAI-1 with a clinical-pathological algorithm (CP). In this trial, the type of risk assessment (CP or UP) was chosen upfront by each center for its patients. Fresh frozen tissue was obtained to determine uPA/PAI-1 using an enzyme-linked immunosorbent assay (ELISA). Patients assessed as high-risk were stratified by human epidermal growth factor receptor 2 (HER2) status and then randomised to receive anthracycline-containing chemotherapy 5-Fluorouracil (F)/Epirubicin (E)/Cyclophosphymide (C) or an anthracycline-taxane sequence (FE(100)C*6 versus FE(100)C*3 followed by Docetaxel(100)*3). DISCUSSION: In this trial, 4,149 node-negative patients with operable breast cancer from 153 centers in Germany and France were included since 2002. Measurement of uPA/PAI-1 by ELISA was performed with standardised central quality assurance for 2,497 patients (60%) from 56 "UP"-centers. The NNBC 3-Europe trial showed that inclusion of patients into a clinical phase III trial is feasible based on biological testing of fresh frozen tumor material. In addition, 2,661 patients were classified as high-risk and thus received chemotherapy. As adjuvant chemotherapy, 1,334 high-risk patients received FE(100)C-Docetaxel(100), and 1,327 received French FE(100)C. No unexpected toxicities were observed. Chemotherapy efficacy and comparison of UP with CP will be evaluated after longer follow-up. TRIAL REGISTRATION: clinical Trials.gov NCT01222052

Підручник зі слов’янського фольклору в Канаді

Рецензія на підручник: Kononenko N. Slavic Folklore: a Handbook. - Westport (Connecticut); London: Greenwood Press, 2007. - 209 pp

Direct search for light gluinos

We present the results for a direct search for light gluinos through the appearance of $\eta\rightarrow 3\pi^{0}$ with high transverse momentum in the vacuum tank of the NA48 experiment at CERN. We find one event within a lifetime range of $10^{-9}-10^{-3}$s and another one between $10^{-10}-10^{-9}$s. Both events are consistent with the expected background from neutrons in the beam, produced by 450 GeV protons impinging on the Be targets, which interact with the residual air in the tank. From these data we give limits on the production of the hypothetical $g\widetilde{g}$ bound state, the $R^0$ hadron, and its $R^0\rightarrow\eta\widetilde{\gamma}$ decay in the $R^0$ mass range between 1 and 5~GeV

Intestinal B-cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signalling

BACKGROUND & AIMS The progression of nonalcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis contributes to NASH, but the mechanisms involved and the consequences for NASH-induced fibrosis and liver cancer remain unknown. We investigated the role of gastrointestinal B cells in the development of NASH, fibrosis and NASH-induced HCC. METHODS C57BL/6J wild-type (WT), B cell-deficient and different immunoglobulin-deficient or transgenic mice were fed distinct NASH diets (for example, choline-deficient high-fat diet, CD-HFD) or chow diet for 6 or 12 months, whereafter NASH, fibrosis, and NASH-induced HCC were assessed and analysed. Specific pathogen-free/germ-free WT and μMT mice (containing B cells only in the gastrointestinal tract) were fed a CD-HFD, and treated with an anti-CD20 antibody, whereafter NASH and fibrosis were assessed. Tissue biopsy samples from patients with NAFL, NASH and cirrhosis were analysed to correlate the secretion of immunoglobulins to clinicopathological features. Flow cytometry, immunohistochemistry and scRNA-Seq analysis were performed in liver and gastrointestinal tissue for immune cells in mice and humans. RESULTS Activated intestinal B cells were increased in mouse and human NASH samples and licensed metabolic T-cell activation to induce NASH independently of antigen-specificity and gut microbiota. Genetic or therapeutic depletion of systemic or gastrointestinal B cells prevented or reverted NASH and liver fibrosis. IgA secretion was necessary for fibrosis induction by activating CD11b+CCR2+F4/80+CD11c-FCGR1+ hepatic myeloid cells through an IgA-FcR signalling axis. Similarly, patients with NASH had increased numbers of activated intestinal B-cells and showed a positive correlation between IgA levels and activated FcRγ+ hepatic myeloid cells as well extent of liver fibrosis. CONCLUSIONS Intestinal B cells and the IgA-FcR signalling axis represent potential therapeutic targets for treating NASH. IMPACT AND IMPLICATIONS Nonalcoholic steatohepatitis (NASH) is a chronic inflammatory condition on the rise and can lead to hepatocellular carcinoma (HCC), the 3rd most common cause of cancer-related death worldwide. Currently, there is no effective treatment for this progressive disease that correlates with a marked risk of HCC mortality and carries a substantial healthcare burden. To date, among all the solid tumours, especially in HCC, the incidence and mortality rates are almost the same, making it crucial to find curative treatments for chronic diseases, such as NASH, which highly predispose to tumorigenesis. We have previously shown that NASH is an auto-aggressive condition aggravated, amongst others, by T cells. Therefore, we hypothesized that B cells might have a role in disease induction and progression. Our present work highlights that B cells have a dual role in NASH pathogenesis, being implicated in the activation of auto-aggressive T cells and the development of fibrosis via activation of monocyte-derived macrophages by secreted immunoglobulins (e.g., IgA). Furthermore, we could show that the absence of B cells prevented HCC development. B-cell intrinsic signalling pathways, secreted immunoglobulins, and interactions of B cells with other immune cells are potential targets in combinatorial NASH therapies against inflammation and fibrosis

Measurements of the leptonic branching fractions of the τ\tau

Data collected with the DELPHI detector from 1993 to 1995 combined with previous DELPHI results for data from 1991 and 1992 yield the branching fractions B({\tau \rightarrow \mbox{\rm e} \nu \bar{\nu}}) = (17.877 \pm 0.109_{stat} \pm 0.110_{sys} )\% and $B({\tau \rightarrow \mu \nu \bar{\nu}}) = (17.325 \pm 0.095_{stat} \pm 0.077_{sys} )\%$