The transporter associated with antigen processing: function and implications in human diseases.

The adaptive immune systems have evolved to protect the organism against pathogens encountering the host. Extracellular occurring viruses or bacteria are mainly bound by antibodies from the humoral branch of the immune response, whereas infected or malignant cells are identified and eliminated by the cellular immune system. To enable the recognition, proteins are cleaved into peptides in the cytosol and are presented on the cell surface by class I molecules of the major histocompatibility complex (MHC). The transport of the antigenic peptides into the lumen of the endoplasmic reticulum (ER) and loading onto the MHC class I molecules is an essential process for the presentation to cytotoxic T lymphocytes. The delivery of these peptides is performed by the transporter associated with antigen processing (TAP). TAP is a heterodimer of TAP1 and TAP2, each subunit containing transmembrane domains and an ATP-binding motif. Sequence homology analysis revealed that TAP belongs to the superfamily of ATP-binding cassette transporters. Loss of TAP function leads to a loss of cell surface expression of MHC class I molecules. This may be a strategy for tumors and virus-infected cells to escape immune surveillance. Structure and function of the TAP complex as well as the implications of loss or downregulation of TAP is the topic of this review.     

Asthma und asthmatypische Beschwerden bei Schulkindern: Vergleich von Gebieten in Deutschland und Osterreich

Conclusion

Geographical differences in morbidity of asthma and asthmalike complaints were ascertained and remained stable after adjustment for potential confounders. However, the choice of the way of presentation (relative risk versus deviation from the weighted mean of the prevalences) can provoke different suggestive effects.     

Divergent regulation of cell surface protease expression in HL-60 cells differentiated into macrophages with granulocyte macrophage colony stimulating factor or neutrophils with retinoic acid

Taking advantage of the recently demonstrated presence of N-aminopeptidasesand the serine protease dipeptidyi aminopeptidase IV (DPP IV)at the surface of human myeloblastic HL-60 cells, the regulationof these protease activities in HL-60 cell differentiation hasbeen assessed using combined spectrophotometric and flow cytometricassays. Addition of human recombinant granulocyte macrophagecolony stimulating factor (rHu-GM-CSF) to HL-60 cells to inducedifferentiation into macrophages led to a time and dose-dependentincrease in both cell surface N-aminopeptidase and DPP IV activities.Protease up-regulation was due to an enhancement in cell surfaceprotease number, associated with a slight rise in apparent affinitiesof the enzymes for their substrates. In contrast, in HL-60 cellsinduced to differentiate into neutrophils in the presenceofretinoic acid, expression of cell surface N-amlnopeptidaseswas almost completely abolished in a time-and dose-dependentfashion, and this down-regulation was accompanied by a weakbut significant decrease in affinity. However, no noticeabledifference was seen in serine DPP IV expression between retinoicacid-treated and untreated HL-60 cells. Retinoic acid treatmentalso reduced soluble protease activity in vitro indicating thatdown-regulation of membrane aminopeptldases was not due to theirproteolytic clip. No modulation in the activity of any of theenzymes tested was seen with human recombinant tumor necrosisfactor- or retinol which do not induce HL-60 cell differentiation.The up-regulation of cell surface protease expression in HL-60cells differentiated into macrophages was similar to that observedin monocytes isolated from peripheral blood: both DPP IV andN-aminopeptidase activities strictly increased on cells thatundergo macrophage maturation (up to 5-fold) and independentlyof the nature of the differentiation inducer. Thus, the distinctivepatterns of N-aminopeptidase and DPP IV expression that areseen in differentiating neutrophils and macrophages appear tobe relatedto differences in stage of myeloid maturation. Becausecell surface proteases are crucially involved in leukocyte functions,the data presented suggest that alterations in cell surfaceprotease expression are associated with events controlling thedifferentiation of immature cells.     

Reproductive toxicity and toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin

Possible effects on the next generation after long-term exposure (subcutaneous administration) of male rats to very high doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were studied. Two dose regimes were applied: TCDD-25 (initial dose: 25 g/kg body wt; maintenance dose: 5 g/kg body wt, once weekly) and TCDD-75 (initial dose: 75 g/kg body wt; maintenance dose: 15 g/kg body wt). Male rats were treated for 10 weeks before mating and then throughout the entire 12 week mating period. They were mated to unexposed virgin females. One group of pregnant females was used for teratological evaluations, and another group was allowed to deliver. No significant differences were observed in the number of implantations or fetuses per litter, and resorption rate, and fetal weight between the controls and TCDD-treated groups. No gross-structural anomalies occurred in any of the fetuses sired by TCDD-treated males. In the TCDD-25 group an increased frequency of two types of variations was observed which also occur in controls: incompletely ossified fingers (TCDD-25=5.1%, controls=2.6%), and incompletely ossified ossa zygomatica (TCDD-25=1.8%, controls=0.5%). In the TCDD-25 group a slight but statistically significant increase was observed in the rate of stillbirths (TCDD-25=1.3%, controls=0.1%), apparently due to an unusually low frequency occurring in the controls (overall historical controls=0.6%). There was no difference in postnatal mortality (TCDD-25=1.3%, controls=1.3%). Taken together, despite the very high doses of TCDD used, the data do not provide evidence for biologically significant paternally-mediated developmental toxicity in the fetuses and newborn.     

Cytotoxic Effect of Brain Macrophages on Developing

Brain macrophages are transiently present in different regions of the central nervous system during development or in the course of tissue remodelling following various types of injuries. To investigate the influence of these phagocytes on neuronal growth and survival, brain macrophages stemming from the cerebral cortex of rat embryos were added to neuronal primary cultures. A neurotoxic effect of brain macrophages was demonstrated by the reduction of the number of neurons bearing neurites within two days of contact between the two cell types. Neuronal death and phagocytosis were also directly observed in video recordings of living cultures. This toxicity involved the production by brain macrophages of reactive oxygen intermediates, as shown by the protective effect of catalase, a scavenger of H2O2. In addition, the respiratory bursts of brain macrophages were stimulated in the presence of neurons. These results suggest that brain macrophages could favour the appearance of neuroregressive events which occur either during neurogenesis or in neurodegenerative diseases, implying intracerebral recruitment of mononuclear phagocytes.     

Catalysis of nitrosation in vitro and in vivo in rats by catechin and resorcinol and inhibition by chlorogenic acid

Measurements were made of the effects of phenolic compounds,some of which are present in the human diet, on the nitrosationof proline by nitrite to give N-nitrosoproline (NPRO). In vitro,resorcinol, catechin, p-nitrosophenol and phenol were catalystsand chlorogenic acid an inhibitor; guaiacol showed a marginalcatalytic effect. Both the catalytic and the inhibiting effectswere dependent on pH and on the concentration of phenolic compounds;catalysis by resorcinol and catechin was increased at optimalratios of [nitrite]: [phenolic compound]. Endogenous nitrosationwas examined in vivo by co-administration of nitrite, prolineand a phenolic compound to rats and by monitoring the amountof NPRO excreted in the urine. Under similar experimental conditions,the catalytic effects observed in vivo decreased in the sameorder as those observed in vitro: resorcinol > p-nitrosophenol> catechin > phenol guaiacol; chlorogenic acid acted asan inhibitor. Catalysis and inhibition of N-nitrosation in ratsin vivo appears to occur via mechanisms similar to those invitro, although the effects in vivo were smaller. The implicationsof our findings for the endogenous formation of N-nitroso compoundsand for variations in exposure due to different dietary constituentsin humans are discussed.     

High prognostic value of p16INK4 alterations in gastrointestinal stromal tumors.

PURPOSE: Gastrointestinal stromal tumors (GISTs) represent a distinctive (but histologically heterogeneous) group of neoplasms, the malignant potential of which is often uncertain. To determine the prognostic relevance of p16INK4 alterations in GISTs, we investigated a larger group of GISTs and correlated the genetic findings with clinicopathological factors and patient survival. MATERIAL AND METHODS: We evaluated the methylation status of the promotor by methylation-specific polymerase chain reaction (PCR), the presence of mutations by PCR-SSCP-sequencing, the loss of heterozygosity at the p16INK4 locus (using the c5.1 marker), and the immunohistochemical expression of p16INK4 protein in 43 GISTs in 39 patients. RESULTS: p16INK4 alterations were found in 25 of 43 GISTs (58.1%), with benign, borderline, or malignant GISTs showing no differences in the type and frequency of alteration. p16INK4 alterations were correlated with a loss of p16INK4 protein expression (P <.01). Patients who had tumors with p16INK4 alterations had a poorer prognosis than patients with tumors without such alterations (P =.02). There was a high predictive value for p16INK4 alterations only in the group of benign and borderline GISTs (P <.01) with regard to clinical outcome. Univariate Cox's proportional hazard regression analysis revealed a strong correlation between p16INK4 alterations, tumor size, mitotic index, and overall survival (P <.02), whereas multivariate Cox's analysis confirmed only p16INK4 alterations as an independent prognostic factor. CONCLUSION: We believe that the evaluation of p16INK4 alteration status is a helpful prognosticator, particularly in the benign and borderline groups of GISTs.     

Phase I trial and pharmacokinetic study of BMS-247550, an epothilone B analog, administered intravenously on a daily schedule for five days.

PURPOSE: The epothilones are a novel class of nontaxane microtubule-stabilizing agents. BMS-247550 is a semisynthetic analog of the natural product epothilone B. We conducted a phase I study administering BMS-247550 as a 1-hour intravenous infusion daily for 5 consecutive days every 21 days. PATIENTS AND METHODS: Twenty-one patients received BMS-247550 without filgrastim in the first cycle. An additional six patients were enrolled at a starting dose of 8 mg/m2/d with filgrastim support. Twenty-one of the 27 patients had received prior paclitaxel, docetaxel, or both. RESULTS: One hundred seven cycles were administered to 27 patients. The maximum-tolerated dose was 6 mg/m2 of BMS-247550 administered as a 1-hour intravenous infusion daily for 5 consecutive days every 21 days. Dose-limiting toxicity at a dose of 8 mg/m2/d was neutropenia with or without filgrastim support. Nonhematologic grade 3 toxicities included fatigue (seven cycles), stomatitis (two cycles), and anorexia (one cycle). The mean terminal half-life of BMS-247550 was 16.8 +/- 6.0 hours, the volume of distribution at steady-state was 798 +/- 375 L, and the clearance was 712 +/- 247 mL/min. Objective responses were observed in patients with breast, cervical, and basal cell cancer. Reductions in CA-125 levels were noted in patients with ovarian cancer. CONCLUSION: The recommended phase II dose of BMS-247550 on the daily schedule for 5 days is 6 mg/m2/d. Neutropenia was dose limiting, but higher doses were tolerated by a large fraction of patients with filgrastim support. Peripheral neuropathy was mild, even after multiple cycles of therapy, and was not dose limiting.     

Morphologic dysplasia in de novo acute myeloid leukemia (AML) is related to unfavorable cytogenetics but has no independent prognostic relevance under the conditions of intensive induction therapy: results of a multiparameter analysis from the German AML Cooperative Group studies.

PURPOSE: On the basis of cytomorphology according to the French-American-British (FAB) classification, we evaluated the prognostic impact of dysplastic features and other parameters in de novo acute myeloid leukemia (AML). We also assessed the clinical significance of the recently introduced World Health Organization (WHO) classification for AML, which proposed dysplasia as a new parameter for classification. PATIENTS AND METHODS: We analyzed prospectively 614 patients with de novo AML, all of whom were diagnosed by central morphologic analysis and treated within the German AML Cooperative Group (AMLCG)-92 or the AMLCG-acute promyalocytic leukemia study. RESULTS: Patients with AML M3, M3v, or M4eo demonstrated a better outcome compared with all other FAB subtypes (P <.001); no prognostic difference was observed among other FAB subtypes. The presence or absence of dysplasia failed to demonstrate prognostic relevance. Other prognostic markers, such as age, cytogenetics, presence of Auer rods, and lactate dehydrogenase (LDH) level at diagnosis, all showed significant impact on overall and event-free survival in univariate analyses (P <.001 for all parameters tested). However, in a multivariate analysis, only cytogenetics (unfavorable or favorable), age, and high LDH maintained their prognostic impact. Dysplasia was not found to be an independent prognostic parameter, but the detection of trilineage dysplasia correlated with unfavorable cytogenetics. CONCLUSION: Our results indicate that cytomorphology and classification according to FAB criteria are still necessary for the diagnosis of AML but have no relevance for prognosis in addition to cytogenetics. Our results suggest that the WHO classification should be further developed by using cytogenetics as the main determinant of biology. Dysplastic features, in particular, have no additional impact on predicting prognosis when cytogenetics are taken into account.     

Family history of autoimmune thyroid disease and childhood acute leukemia.

The association between a familial history of autoimmune disease and childhood acute leukemia was investigated in a French case-control study that, overall, was designed to assess the role of perinatal, infectious, environmental, and genetic factors in the etiology of childhood acute leukemia. Familial histories of autoimmune disease in first- and second-degree relatives were compared in 279 incident cases, 240 cases of acute lymphocytic leukemia (ALL) and 39 cases of acute non-lymphoblastic leukemia (ANLL), and 285 controls. Recruitment was frequency matched by age, gender, hospital, and ethnic origin. Odds ratios (OR) were estimated using an unconditional regression model taking into account the stratification variables, socioeconomic status, and familial structure. A statistically significant association between a history of autoimmune disease in first- or second-degree relatives and ALL (OR, 1.7; 95% confidence interval (CI), 1.0-2.8) was found. A relationship between thyroid diseases overall and ALL (OR, 2.0; 95% CI, 1.0-3.9) was observed. This association was more pronounced for potentially autoimmune thyroid diseases (Grave's disease and/or hyperthyroidism and Hashimoto's disease and/or hypothyroidism) (OR, 3.5; 95% CI, 1.1-10.7 and OR, 5.6; 95% CI, 1.0-31.1, respectively for ALL and ANLL), whereas it was not statistically significant for the other thyroid diseases (thyroid goiter, thyroid nodule, and unspecified thyroid disorders) (OR, 1.6; 95% CI, 0.7-3.5 and OR, 1.3; 95% CI, 0.2-7.0, respectively, for ALL and ANLL). The results suggest that a familial history of autoimmune thyroid disease may be associated with childhood acute leukemia.