Pancreatic Duct Glands Are Distinct Ductal Compartments That React to Chronic Injury and Mediate Shh-Induced Metaplasia

BACKGROUND & AIMS: Pancreatic intraepithelial neoplasia (PanIN) are pancreatic cancer precursor lesions of unclear origin and significance. PanIN aberrantly express sonic hedgehog (Shh), an initiator of pancreatic cancer, and gastrointestinal mucins. A majority of PanIN are thought to arise from ducts. We identified a novel ductal compartment that is gathered in gland-like outpouches (pancreatic duct glands [PDG]) of major ducts and characterized its role in injury and metaplasia. METHODS: The ductal system was analyzed in normal pancreata and chronic pancreatitis in humans and mice. Anatomy was assessed by serial hematoxylin and eosin sections and scanning electron microscopy of corrosion casts. Expression of mucins and developmental genes and proliferation were assessed by immunohistochemistry or real-time quantitative polymerase chain reaction. Effects of Shh on ductal cells were investigated by exposure to Shh in vitro and transgenic misexpression in vivo. RESULTS: Three-dimensional analysis revealed blind-ending outpouches of ducts in murine and human pancreata. These PDG are morphologically and molecularly distinct from normal ducts; even in normal pancreata they display PanIN and metaplastic features, such as expression of Shh and gastric mucins. They express other developmental genes, such as Pdx-1 and Hes-1. In injury, Shh is up-regulated along with gastric mucins. Expansion of the PDG compartment results in a mucinous metaplasia. Shh promotes this transformation in vitro and in vivo. CONCLUSIONS: PDG are distinct gland-like mucinous compartments with a distinct molecular signature. In response to injury, PDG undergo an Shh-mediated mucinous gastrointestinal metaplasia with PanIN-like features. PDG may provide a link between Shh, mucinous metaplasia, and neoplasia

Dietary Vitamin D Intake and Muscle Mass in Older Women. Results from a Cross-Sectional Analysis of the Epidos Study

Objectives: Vitamin D intake may prevent physical performance decline through prevention of muscle mass loss. Our objective was to determine whether low dietary intakes were associated with low muscle mass (MM). Design and participants: Cross-sectional analysis of 1989 community-dwelling women (mean age 80.5 +/- 3.8years) from the EPIDemiologie de l\u27OSteoporose (EPIDOS) study were assessed at baseline. Measurements: Low intakes of vitamin D (<70 mu g/week) were estimated from the weekly dietary vitamin D intakes (self-administered food frequency questionnaire). Low MM was defined according to the appendicular skeletal muscle mass index assessed using Dual Energy X-ray Absorptiometry, divided by square height of less than 5.45 kg/m(2). Usual gait speed defined physical performance. Age, sun exposure, co-morbidities, education level, living arrangements, recreational physical activity, dietary protein and calcium intakes, bone mineral density, handgrip strength, and body mass index were considered as potential confounders. Multivariate logistic regression analyses assessed the association between low vitamin D intakes and low MM. Results: Two-hundred and nine (10.5%) women with low MM were compared to 1,780 women with normal MM. In final model, obesity/overweight (Adjusted Odds Ratios, aOR=0.09; 95%CI [0.05-0.17]), malnutrition (aOR=3.90; 95%CI [2.74-5.54]) and low handgrip strength (aOR=2.33; 95%CI [1.44-3.77]; p<0.001) were statistically associated with a low MM status. Conclusion: No association with low MM has been reported regarding low dietary intakes of vitamin D

Topological aggregation, the twin paradox and the No Show paradox

International audienceConsider the framework of topological aggregation introduced by Chichilnisky (1980). We prove that in this framework the Twin Paradox and the No Show Paradox cannot be avoided. Anonymity and unanimity are not needed to obtain these results

Systematic Mutational Analysis of the Intracellular Regions of Yeast Gap1 Permease

The yeast general amino acid permease Gap1 is a convenient model for studying the intracellular trafficking of membrane proteins. Present at the plasma membrane when the nitrogen source is poor, it undergoes ubiquitin-dependent endocytosis and degradation upon addition of a good nitrogen source, e.g. ammonium. It comprises 12 transmembrane domains (TM) flanked by cytosol-facing N- and C-terminal tails (NT, CT). The NT of Gap1 contains the acceptor lysines for ubiquitylation and its CT includes a sequence essential to exit from the endoplasmic reticulum (ER).Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Direct Evidence that Bevacizumab, an Anti-VEGF Antibody, Up-regulates SDF1 , CXCR4, CXCL6, and Neuropilin 1 in Tumors from Patients with Rectal Cancer

Clinical studies converge on the observation that circulating cytokines are elevated in most cancer patients by anti-vascular endothelial growth factor (VEGF) therapy. However, the source of these molecules and their relevance in tumor escape remain unknown. We examined the gene expression profiles of cancer cells and tumor-associated macrophages in tumor biopsies before and 12 days after monotherapy with the anti-VEGF antibody bevacizumab in patients with rectal carcinoma. Bevacizumab up-regulated stromal cell-derived factor 1alpha (SDF1alpha), its receptor CXCR4, and CXCL6, and down-regulated PlGF, Ang1, and Ang2 in cancer cells. In addition, bevacizumab decreased Ang1 and induced neuropilin 1 (NRP1) expression in tumor-associated macrophages. Higher SDF1alpha plasma levels during bevacizumab treatment significantly associated with distant metastasis at three years. These data show that VEGF blockade up-regulates inflammatory pathways and NRP1, which should be evaluated as potential targets for improving anti-VEGF therapy

Clinicopathologic and Molecular Profiles of Microsatellite Unstable Barrett Esophagus-associated Adenocarcinoma

Microsatellite instability (MSI) has been reported in various tumors, with colon cancer as the prototype. However, little is known about MSI in Barrett esophagus (BE)-associated adenocarcinoma. Thus, the aim of this study was to compare the clinicopathologic and molecular features of BE-associated adenocarcinomas with and without MSI. The study cohort consisted of 76 patients with BE-associated adenocarcinomas (66 male, 10 female), with a mean age of 65.1 years. Immunohistochemistry (IHC) for MLH1, MSH2, MSH6, PMS2, and CD3 and in situ hybridization for Epstein-Barr virus-encoded RNA were performed. MLH1 and PMS2 expression was lost by IHC in 5 cases (6.6%); of these, 5 showed high-level MSI (MSI-H) by polymerase chain reaction assay, and 4 showed hMLH1 promoter methylation. Histologically, tumors with MSI-H were heterogenous and included conventional adenocarcinomas with tumor-infiltrating lymphocytes (n=1), medullary carcinoma (n=2), signet ring cells (n=1), and signet ring cell and mucinous components (n=1). Compared with tumors negative for MSI by IHC, BE-associated adenocarcinomas with MSI-H were associated with older patient age (P=0.0060), lymphovascular invasion (P=0.027), and significantly larger numbers of tumor-infiltrating lymphocytes (P<0.0001). However, there was no statistical difference in overall survival between the 2 groups (P=0.285). In conclusion, MSI-H is uncommon in BE-associated adenocarcinomas, but is associated with clinicopathologic features fairly similar to sporadic microsatellite unstable colorectal cancers. Given the growing evidence that indicates lack of benefits from adjuvant therapy with fluorouracil in the colonic counterpart, it may be important to identify MSI-H in BE-associated adenocarcinomas

Scaling Limit of the Ising Model in a Field

The dilute A_3 model is a solvable IRF (interaction round a face) model with three local states and adjacency conditions encoded by the Dynkin diagram of the Lie algebra A_3. It can be regarded as a solvable version of an Ising model at the critical temperature in a magnetic field. One therefore expects the scaling limit to be governed by Zamolodchikov's integrable perturbation of the c=1/2 conformal field theory. Indeed, a recent thermodynamic Bethe Ansatz approach succeeded to unveil the corresponding E_8 structure under certain assumptions on the nature of the Bethe Ansatz solutions. In order to check these conjectures, we perform a detailed numerical investigation of the solutions of the Bethe Ansatz equations for the critical and off-critical model. Scaling functions for the ground-state corrections and for the lowest spectral gaps are obtained, which give very precise numerical results for the lowest mass ratios in the massive scaling limit. While these agree perfectly with the E_8 mass ratios, we observe one state which seems to violate the assumptions underlying the thermodynamic Bethe Ansatz calculation. We also analyze the critical spectrum of the dilute A_3 model, which exhibits massive excitations on top of the massless states of the Ising conformal field theory.Comment: 29 pages, RevTeX, 11 PostScript figures included by epsf, using amssymb.sty (v2.2