Nonsteroidal anti-inflammatory drug use associated with reduced incidence of adenocarcinomas of the esophagus and gastric cardia that overexpress cyclin D1: a population-based study.

This study was undertaken to determine whether selected risk factors for esophageal and gastric cancer are associated with tumors that overexpress cyclin D1. Archived tumor tissue was available for 630 esophageal and gastric cancer patients who participated in a population-based case-control study. Patients were categorized into case groups based on whether protein overexpression of the cyclin D1 gene, as assessed by immunohistochemistry, was present (cyclin D1+, n = 285) or not (cyclin D1-, n = 345) in the tumor. The distribution of risk factors in each of these case groups was then compared with the distribution among the 695 controls. Multivariate-adjusted odds ratios (OR) for esophageal adenocarcinoma were reduced in relation to use of aspirin and other nonsteroidal anti-inflammatory drug (NSAID) use but only among patients with cyclin D1+ tumors (0.45, 95% confidence interval [CI] = 0.26, 0.79) and not among those with cyclin D1- tumors (1.12, 95% CI = 0.67, 1.86). A similar pattern was observed for gastric cardia adenocarcinomas. In contrast, ORs for esophageal squamous cell carcinoma and noncardia gastric adenocarcinomas in relation to NSAID use were reduced, regardless of cyclin D1 status. ORs did not vary with cyclin D1 status in relation to alcohol, body size, or cigarette smoking, with the following exception; for noncardia gastric adenocarcinomas the cyclin D1- tumors showed a 2-fold elevation in the OR with ever smoking. These data suggest that the reduction in risk associated with NSAID use may be restricted to those esophageal and gastric cardia adenocarcinomas that overexpress cyclin D1.     

Characteristic expression profiles induced by genotoxic carcinogens in rat liver.

When applied in toxicological studies, the recently developed gene expression profiling techniques using microarrays, which brought forth the new field of toxicogenomics, facilitate the interpretation of a toxic compound's mechanism of action. In this study, we investigated whether genotoxic carcinogens at doses known to induce liver tumors in the 2-year rat bioassay deregulate a common set of genes in a short-term in vivo study and, if so, whether these deregulated genes represent defined biological pathways. Rats were dosed with the four genotoxic hepatocarcinogens dimethylnitrosamine (4 mg/kg/day), 2-nitrofluorene (44 mg/kg/day), aflatoxin B1 (0.24 mg/kg/day), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, 20 mg/kg/day). After treatment for up to 14 days, the expression profiles of the livers were analyzed on Affymetrix RG_U34A microarrays. Among the significantly upregulated genes were a set of target genes of the tumor suppressor protein p53, indicating a DNA damage response. Such a response was expected and, therefore, confirmed the validity of our approach. In addition, the gene expression changes suggest a specific detoxification response, the activation of proliferative and survival signaling pathways, and some cell structural changes. These responses were strong throughout the 14 day time course for 2-nitrofluorene and aflatoxin B1; in the case of dimethylnitrosamine and NNK, the effects were weakly detectable at day 1 and then increased with time. For dimethylnitrosamine and aflatoxin B1, which caused observable inflammation in vivo, we found a corresponding upregulation of inflammatory genes at the same time points. Thus, by the toxicogenomic analysis of short-term in vivo studies, we identified genes and pathways commonly deregulated by genotoxic carcinogens, which may be indicative for the early events in tumorigenesis and, thus, predictive of later tumor development.     

Über Lipoidose,Atheromatose und Sklerose der Aorta und deren Beziehungen zur Endaortitis

Ohne Zusammenfassung Mit 23 gro?enteils mehrteiligen und einer farbigen Abbildung im Text (42 Einzelbilder).     

Update Granulomatose mit Polyangiitis (GPA, Wegener-Granulomatose)

Granulomatosis with polyangitis (GPA, Wegener’s granulomatosis) is characterized by a granulomatous inflammation of the respiratory tract and a necrotizing ANCA-associated small to medium-size vessel vasculitis with a predilection for the lungs (pulmonary capillaritis) and kidneys (necrotizing glomerulonephritis). The disease evolves stage-wise and typically starts as inflammation of the respiratory tract followed by development of systemic vasculitis manifestations. Today, treatment is evidence-based and adapted according to activity and disease stage which has resulted in a significant improvement in long-term outcome. Early mortality during the first year of treatment poses one of the main problems and is a result of infections under immunosuppressive treatment. Furthermore, treatment of refractory disease activity which is often represented by granulomatous manifestations is still a challenge and may result in significant organ damage if not treated successfully.     

Prophylactic total gastrectomy in the management of hereditary tumor syndromes

Purpose

Germline mutations in several genes confer a relevant lifetime risk of gastric cancer. In this context, an increasing involvement of a surgeon can be seen, mainly with the question of performing a prophylactic operation.

Methods

Patients with hereditary tumor syndromes predisposing for gastric cancer who received care leading to prophylactic total gastrectomy in our Center for Hereditary Tumor Syndromes were analyzed. For each patient, the multidisciplinary decision-making process, the perioperative course, and the histopathologic findings were assessed. Short-term morbidity was evaluated based on the medical reports.

Results

The analysis includes nine patients (six female, three male) with a median age of 41.6 (range 23–60) years. Indication for prophylactic total gastrectomy was based on family history and genetic analysis (eight patients with a germline mutation of the CDH1 gene and one patient with a SMAD4 mutation). Removal of the entire gastric mucosa was documented intraoperatively by fresh frozen section examination. Extended (DII) lymphadenectomy was performed in four patients. Histopathologic examination of gastrectomy specimens revealed six patients (6/9, 67 %) with multifocal signet ring cell carcinomas. In our series, prophylactic total gastrectomy was a safe procedure without mortality and low morbidity.

Conclusions

Patients with hereditary syndromes predisposing for gastric cancer should be evaluated for this curative procedure in a specialized center. Further research is necessary, and the implementation of nationwide registers including patients with prophylactic gastrointestinal operations due to hereditary tumor syndrome is advisable.

     

Differential immune imprinting by influenza virus vaccination and infection in nonhuman primates

Immune memory of a first infection with influenza virus establishes a lasting imprint. Recall of that memory dominates the response to later infections or vaccinations by antigenically drifted strains. Early childhood immunization before infection may leave an imprint with different characteristics. We report here a comparison of imprinting by vaccination and infection in a small cohort of nonhuman primates (NHPs). We assayed serum antibody responses for binding with hemaglutinnins (HAs) both from the infecting or immunizing strain (H3 A/Aichi 02/1968) and from strains representing later H3 antigenic clusters (“forward breadth”) and examined the effects of defined HA mutations on serum titers. Initial exposure by infection elicited strong HA-binding and neutralizing serum antibody responses but with little forward breadth; initial vaccination with HA from the same strain elicited a weaker response with little neutralizing activity but considerable breadth of binding, not only for later H3 HAs but also for HA of the 2009 H1 new pandemic virus. Memory imprinted by infection, reflected in the response to two immunizing boosts, was largely restricted (as in humans) to the outward-facing HA surface, the principal region of historical variation. Memory imprinted by immunization showed exposure to more widely distributed epitopes, including sites that have not varied during evolution of the H3 HA but that yield nonneutralizing responses. The mode of initial exposure thus affects both the strength of the response and the breadth of the imprint; design of next-generation vaccines will need to take the differences into account.

Antigenic exposures determine the acquisition and development of adaptive immunity. The humoral response in a naive individual yields both antibody-secreting plasma cells that recognize the new antigen and memory B cells that can respond to future encounters with related antigens. The combination of these two components can confer long-lasting protection against antigenically stable pathogens. For antigenically diverse pathogens and those that evolve to evade immune pressure (e.g., influenza virus and HIV), serum responses often confer incomplete immunity to future variants (1, 2).The hemagglutinin (HA) and neuraminidase (NA) define the serotype of an influenza virus isolate (3). Antigenic shifts occur when novel animal influenza viruses can transmit to humans, spread rapidly, and initiate pandemics, owing to absence of any preexisting immunity (4, 5). Historically, the descendants of pandemic viruses have become endemic seasonal variants that undergo antigenic drift as they evolve over time to evade dominant human herd immunity (6, 7). For most adults, both processes have shaped human immunity to influenza.Immune memory causes a primary infection to impart an enduring imprint (8–11). Despite a lifetime of repeated exposures to divergent influenza viruses, the relative strength of an individual’s immune response to vaccination or infection correlates with the antigenic similarity of the vaccine or infecting strain to that person’s initial exposure. Until recently, the first encounter was invariably an infection. Because of recent changes in vaccine policy in the United States and Europe, infants and toddlers are now encouraged to receive influenza vaccines before they experience an influenza infection (12, 13). We have little information, however, about the immunological memory to influenza virus established when the primary exposure is vaccination rather than infection.Using nonhuman primates (rhesus macaques) as a model, we have examined how the mode of influenza exposure affects both primary and secondary antibody responses. We found that an initial exposure by infection elicited strong, strain-specific, HA-binding, and neutralizing serum antibody responses. Initial exposure by immunization with the HA protein from the strain used in the infection arm of the study elicited relatively weaker HA-binding responses that lacked neutralization potency but had greater interseasonal forward breadth. Subsequent exposures, by immunization, generated antibodies with increased interseasonal breadth in infected animals and neutralizing activity in the initially immunized monkeys. Initially infected macaques maintained responses that were strongly imprinted by the infecting strain, while those initially immunized with protein retained a serum repertoire that cross-reacted with heterologous HAs. Moreover, the distribution of epitopes bound by serum IgG was different in the two cases. These data suggest that the mode of HA exposure influences its immune imprint and that next-generation vaccine design will need to take this influence into account.