Preferential Langerhans cell differentiation from CD34(+) precursors upon introduction of ABCG2 (BCRP)

Epidermal Langerhans cells (LC) and dermal interstitial dendritic cells (IDC) were found to express the ATP-binding cassette (ABC) transporter breast cancer resistance protein (BCRP; ABCG2). Also, low BCRP expression was present on CD34(+) blood DC precursors and expression was increased upon their differentiation to LC. The CD34(+) acute myeloid leukemia-derived DC cell line MUTZ3 can be cultured into LC or IDC, depending on the cytokine cocktail used. Introduction of functional BCRP in MUTZ3 progenitor cells through retroviral transduction resulted in the emergence of typical LC-characteristics in IDC cultures; the majority of cells remained negative for the IDC-specific C-type lectin DC-SIGN, but rather displayed enhanced expression of the LC-specific C-type lectin Langerin and characteristic high expression levels of CD1a. BCRP-induced skewing toward LC-like differentiation coincided with early RelB expression in 'IDC', derived from MUTZ3-BCRP, and depended on endogenous transforming growth factor beta (TGF-β) production. Intriguingly, cellular BCRP localization differed between skin LC and IDC, and a more cytoplasmic BCRP localization, as observed in primary skin LC, seemed to relate to LC-like differentiation in IDC cultures upon BCRP introduction in MUTZ3 progenitors. Together these data support a role for BCRP in preferential LC differentiation from CD34(+) myeloid DC progenitors.     

Calcium regulation in the human myocardium affected by dilated cardiomyopathy: A structural basis for impaired Ca2+-sensitivity

Calcium regulation in the human heart is impaired during idiopathic dilated cardiomyopathy (IDC). Here, we analyze the structural basis for impairment in the regulatory mechanism. Regulation of contractility was monitored by MgATPase and Ca2+-binding assays as a function of calcium. Myofibrillar proteolysis and expression of troponin T isoforms were established by gel electrophoresis and by Western blots. Myofibrillar ATPase assays in low salt however, revealed a drastic lowering of calcium sensitivity in IDC myofibrils as indicated by reductions in both activation by high calcium and in EGTA-mediated inhibition of MgATPase. Structural changes in myofilament proteins were found in most IDC hearts, specifically proteolysis of myosin light chain 2 (LC2), troponin T and I (TnT and TnI), and sometimes large isoform shift in TnT. IDC did not induce mutations in LC2 and troponin C (TnC), as established by cDNA sequence data from IDC cases, thus, calcium binding to IDC myofibrils was unaffected. Reassociation of IDC myofibrils with native LC2 raised MgATPase activation at high Ca2+ to control levels, while repletion with intact, canine TnI/TnT restored inhibition at low Ca2+. A model, identifying possible steps in the steric blocking mechanism of regulation, is proposed to explain IDC-induced changes in Ca2+-regulation. Moreover, shifts in TnT isoforms may imply either a genetic or a compensatory factor in the development and pathogenesis of some forms of IDC.     

The development of the human lymph node

Summary Lymph nodes of human fetuses from the 11th to the 20th gestational week (g.w.) were investigated by light- and electron microscopy under particular consideration of the development of the T-cell and the B-cell regions and their specific reticulum cells. Lymph node development begins as a mesenchymal condensation, containing capillaries and mesenchymal cells; this primordium bulges into a lymph sac. Within the primordium of the lymph node granulopoiesis and erythropoiesis occur temporarily from the 12th to the 14th g.w. The first lymphoid cells and undifferentiated blast cells are seen in the 12th g.w.; monocytes and macrophages can be found from the 13th g.w. onward.The development of the T-cell regions begins during the 13th g.w., before differentiation into cortex and medulla becomes obvious in the 14th g.w. Near the marginal sinus, cells displaying features of interdigitating reticulum cells (IDC) show similarities to monocytes. The morphological differentiation of the IDC is complete in the 17th g.w. when they are found in the paracortical region. Among the IDC, lymphoid cells with features of thymocytes are arranged in small groups.The first indication of the development of B-cell regions can be recognized in the 14th g.w. when precursors of dendritic reticulum cells (DRC) are seen near the marginal sinus; this area also displays lymphoblasts, immunoblasts, and plasmoblasts. During the 20th g.w. small primary follicles are discernible in the outer cortex; in addition to blast cells they contain small lymphocytes, none of which show features of thymocytes. The morphological development of DRCs is not entirely complete until the 20th g.w.; however, some cells already show a characteristic network of interwoven processes.The probable origin of (i) the IDC from monocytes, and (ii) the DRC and fibroblastic reticulum cells from a common type of mesenchymal precursor cells, as well as their significance for a specific micromilieu in the T-cell and the B-cell regions, are discussed.This investigation was supported by grants from the Deutsche Forschungsgemeinschaft and the Sonderforschungsbereich 111 of the Deutsche ForschungsgemeinschaftThe authors appreciate the contribution of human fetal material from Dr. J. von Hollweg and Dr. J. Körner, Hospital Heidberg, Hamburg, and the excellent technical assistance of Mrs. O.M. Bracker, Mrs. H. Hansen, Mrs. R. Köpke, Mrs. I. Knauer, Mrs. F. Müller, Mrs. H. Siebke, and Mrs. H. Waluk     

An analytical comparison of cobalt cardiomyopathy and idiopathic dilated cardiomyopathy

Toxic cardiomyopathy (TC) has a rapid clinical course and morphologically resembles idiopathic dilated cardiomyopathy (IDC). To further characterize TC, we used light microscopy to compare lesions caused by cobalt (Co) to those of IDC. Cobalt levels were also measured as a chemical marker to differentiate TC from IDC. We reviewed cases with TC and IDC and excluded all cases with chemotherapy-induced myopathy and catecholamine toxicity as well as cases with possible infectious, ischemic, or hypersensitivity-induced myopathies. We compared the light microscopic findings of 12 TC cases to 12 cases of IDC, and measured trace Co levels on digested heart tissue samples. The TC cases had prominent myofibrillar loss and atrophy; no cases had neutrophil infiltration or frank myocyte necrosis. In contrast, IDC had minimal myofibril loss and atrophy. Cobalt levels in the range of 0.6 to 5.45 μg/g of dry tissue were obtained for the TC cases, while IDC demonstrated Co levels of 0.01–0.2 μg/g. Distinction between TC and IDC is predominantly a function of myocyte change, with TC showing myofibrillar loss and atrophy in the absence of inflammatory infiltrates and fibrosis; IDC is predominantly associated with myocyte hypertrophy, atrophy, and fibrosis. The opinions or assertions expressed herein are the private views of the authors and are not to be construed as official or as representing the views of the Armed Forces Institute of Pathology, the Department of the Army or the Department of Defense.     

The role of micronucleus scoring in fine needle aspirates of ductal carcinoma of the breast

S. Samanta, P. Dey and R. Nijhawan The role of micronucleus scoring in fine needle aspirates of ductal carcinoma of the breast Aims and objectives: Micronucleus (MN) scoring was carried out in benign (fibroadenoma) and malignant (infiltrating ductal carcinoma) breast lesions to evaluate the role of MN as a biomarker in breast carcinomas. We also compared MN scores among different cytological grades of breast carcinoma. Materials and methods: A total of 31 archival cases of fibroadenoma (FA) and 40 cases of infiltrating ductal carcinoma (IDC) were selected. The best May‐Grünwald–Giemsa (MGG) stained fine needle aspiration cytology (FNAC) smear of each case was selected. The MN scoring was carried out independently by two observers on 1000 epithelial cells in oil immersion magnification (100× objective). The MN scores in FA and IDC were compared. The IDC cases were graded and the MN scores in different cytological grades of IDC were compared. Results: The mean MN scores (± standard deviation) in FA and IDC were 0.6 (± 1.1) and 13.6 (± 12.8), respectively, which were significantly different (P < 0.0001). There were seven grade 1, 13 grade 2, and 20 grade 3 IDCs. The mean MN scores (± standard deviation) of grade 1, 2 and 3 IDC were 4.3 (± 2.3), 11.95 (± 9.2) and 21.1 (± 16.7), respectively. An analysis of variance (anova ) test showed a significant difference in MN score between all the grades of IDC (P < 0.05). However, there was no significant difference between fibroadenoma and grade 1 IDC. The Pearson’s correlation coefficient showed positive correlations between MN scoring in the different grades of IDC. Conclusions: MN scoring on routinely stained smears of IDCs was significantly higher than in fibroadenoma and was relatively easy, reliable and reproducible. As MN scoring of grade 1 IDC was similar to fibroadenoma, a larger study should be conducted to compare grade 1 IDC with other benign breast lesions.     

IDC1, a pezizomycotina-specific gene that belongs to the PaMpk1 MAP kinase transduction cascade of the filamentous fungus Podospora anserina

Components involved in the activation of the MAPK cascades in filamentous fungi are not well known. Here, we provide evidence that IDC1, a pezizomycotina-specific gene is involved along with the PaNox1 NADPH oxidase in the nuclear localization of the PaMpk1 MAP kinase, a prerequisite for MAPK activity. Mutants of IDC1 display the same phenotypes as mutants in PaNox1 and PaMpk1, i.e., lack of pigment and of aerial hyphae, female sterility, impairment in hyphal interference and inability to develop Crippled Growth cell degeneration. As observed for the PaNox1 mutant, IDC1 mutants are hypostatic to PaMpk1 mutants. IDC1 seems to play a key role in sexual reproduction. Indeed, fertility is diminished in strains with lower level of IDC1. In strains over-expressing IDC1, protoperithecia reach a later stage of development towards perithecia without fertilization; however, upon fertilization maturation of fertile perithecia is diminished and delayed. In addition, heterokaryon construction shows that IDC1 is necessary together with PaNox1 in the perithecial envelope but not in the dikaryon resulting from fertilization.     

Characterization of the human nebulette gene: a polymorphism in an actin-binding motif is associated with nonfamilial idiopathic dilated cardiomyopathy

Idiopathic dilated cardiomyopathy (IDC) is characterized by a thin-walled heart with systolic dysfunction of unknown etiology. Because abnormalities in genes for cytoskeletal proteins related to Z-disc function have recently been reported to cause IDC, genomic organization of the gene for nebulette, a novel actin-binding Z-disc protein, was determined and its sequence variations were searched for in Japanese patients with IDC and healthy controls. The nebulette gene consists of 28 exons, and four sequence variations leading to amino acid replacement (Gln187His, Met351Val, Asn654Lys, and Thr728Ala) were identified in the patients. These variations were also found in the healthy controls and hence they were polymorphisms and not disease-specific mutations. Frequencies of Gln187His, Met351Val, and Thr728Ala variants were similar in the patients and controls. However, the frequency of homozygotes for Lys at codon 654, a variant at a relatively conserved residue in an actinbinding motif, was significantly increased in nonfamilial IDC patients (n=106) as compared with healthy control subjects (n=331) (7.54% vs 1.21%, OR=6.25, P=0.002, 95% CI=1.92-20.29), while this association was not found in familial IDC patients (n=24). These observations suggest that the nebulette polymorphism in the actin-binding motif was a novel genetic marker of susceptibility to nonfamilial IDC.     

Expression of the serine protease, matriptase, in breast ductal carcinoma of Chinese women: correlation with clinicopathological parameters

Matriptase is a serine protease expressed by cells of surface epithelial origin, including epithelial breast tumor cells. Matriptase cleaves and activates proteins implicated in the progression of cancer and represents a potential prognostic and therapeutic target. The aim of this study was to examine matriptase expression in breast tumors of Chinese women and to identify its clinicopathological correlations. Immunohistochemical analysis of matriptase was performed in tissue microarrays of 251 breast tumors including 30 fibroadenomas, 59 ductal carcinomas in situ (DCIS), 38 grade I invasive ductal carcinomas (IDC), 79 grade II IDC, and 45 grade III IDC. The matriptase scores were significantly higher in the tumors than their non-tumor counterparts (178+/-12 for fibroadenoma; 275+/-11 for DCIS; 299+/-10 for grade I IDC; 251+/-10 for grade II IDC; and 314+/-11 for grade III IDC). In cases of IDC, matriptase scores were significantly correlated with tumor staging and nodal staging. Our findings demonstrate that matriptase is over-expressed in breast ductal carcinoma of Chinese women. It therefore may be a good biomarker for diagnosis and treatment of malignant breast tumors.     

The effects of genetics and age on expression of MHC class II and CD4 antigens on rat cardiac interstitial dendritic cells

Interstitial dendritic cells (IDC) in normal hearts of inbred rat strains and congenic and congenic recombinant lines were identified and quantitated by immunohistologic methods, on the basis of cellular reactivity with MRC-OX6, a monoclonal antibody (MAb) directed against MHC class II determinants, and with W3/25, a MAb directed against a CD4 epitope. In all strains and lines examined, the W3/25+ IDC frequency was uniformly high with little interstrain variation. In contrast, all rat strains and lines examined showed either high or low OX6+ IDC frequency. Double staining by two color immunofluorescence indicated that strains with a low OX6+ IDC frequency were characterized by a high frequency of W3/25+ OX6- IDC and a low frequency of W3/25+ OX6+ IDC. In strains with high OX6+ IDC frequency, the majority of IDC coexpressed both markers. Comparative analysis of (i) MHC identical background disparate strains and lines, (ii) MHC disparate background identical strains and lines, and (iii) F2 segregation analysis of intercrosses and backcrosses derived from an original cross between high and low frequency OX6+ IDC strains, all indicated that OX6+ IDC frequency is dependent upon both MHC- and non-MHC-linked genetic factors. It is suggested that rat cardiac OX6+ IDC frequency is influenced by a minimum of two autosomal genes, one of which is MHC linked. The frequencies of both W3/25+ IDC frequency reached adult levels by 10 days of age; adult levels of OX6+ IDC were not attained until Day 21. It is postulated that in the rat heart, W3/25+ OX6- IDC are potential precursors of W3/25+ OX6+ IDC, and that the cellular frequency of coexpression in the adult is under genetic influence. Whether these genetic factors modify constitutive or physiologic levels of class II-inducing lymphokine activity, or influence cellular susceptibility of IDC to induced class II expression is unclear.     

Interdigitating reticulum cells in lymph nodes of Sézary syndrome. Freeze-fracture and ultrathin-section morphology

Lymph nodes with extensive leukemic infiltration from three patients with the Sézary syndrome were examined in ultrathin sections and in freeze-fracture replicas. Sézary cells (SC) and interdigitating reticulum cells (IDC) were the predominant cell types in the lymph nodes. Both were closely connected with each other by apparently interdigitating cytoplasmic processes. The projections between these cells were, in the main, processes from the IDC. In freeze-fracture replicas these cellular processes did not appear as interdigitations but were more bubble-like, and for this reason these cells are imprecisely described by the term "interdigitating." The SC were seen to possess only short cytoplasmic processes. The frequent polar grouping of cell organelles in SC in the region of the contact zone with IDC and the high organelle content of IDC ('activated IDC') could be the morphologic expression of intense interaction between IDC and SC. IDC displayed three features in freeze-fracture which are not specific to the Sézary syndrome, but should be applicable to IDC in general: (1) they exhibited an approximately equal density of intramembrane particles in both the E-face and the P-face, (2) some of the intramembrane particles in the P-face were assembled in clusters and (3) the surface showed bubble-like formations of the cytoplasmic processes. On the basis of these properties it was possible to distinguish IDC from macrophages and lymphocytes in freeze-fracture replicas.     

Investigation of altered urinary metabolomic profiles of invasive ductal carcinoma of breast using targeted and untargeted approaches

Introduction

Invasive ductal carcinoma (IDC) is a type of breast cancer, usually detected in advanced stages due to its asymptomatic nature which ultimately leads to low survival rate. Identification of urinary metabolic adaptations induced by IDC to understand the disease pathophysiology and monitor therapy response would be a helpful approach in clinical settings. Moreover, its non-invasive and cost effective strategy better suited to minimize apprehension among high risk population.

Objective

This study aims toward investigating the urinary metabolic alterations of IDC by targeted (LC-MRM/MS) and untargeted (GC–MS) approaches for the better understanding of the disease pathophysiology and monitoring therapy response.

Methods

Urinary metabolic alterations of IDC subjects (63) and control subjects (63) were explored by targeted (LC-MRM/MS) and untargeted (GC–MS) approaches. IDC specific urinary metabolomics signature was extracted by applying both univariate and multivariate statistical tools.

Results

Statistical analysis identified 39 urinary metabolites with the highest contribution to metabolomic alterations specific to IDC. Out of which, 19 metabolites were identified from targeted LC-MRM/MS analysis, while 20 were identified from the untargeted GC–MS analysis. Receiver operator characteristic (ROC) curve analysis evidenced 6 most discriminatory metabolites from each type of approach that could differentiate between IDC subjects and controls with higher sensitivity and specificity. Furthermore, metabolic pathway analysis depicted several dysregulated pathways in IDC including sugar, amino acid, nucleotide metabolism, TCA cycle etc.

Conclusions

Overall, this study provides valuable inputs regarding altered urinary metabolites which improved our knowledge on urinary metabolomic alterations induced by IDC. Moreover, this study identified several dysregulated metabolic pathways which offer further insight into the disease pathophysiology.

     

Tumor characteristics and the clinical outcome of invasive lobular carcinoma compared to infiltrating ductal carcinoma in a Chinese population

ABSTRACT: BACKGROUND: We sought to compare the baseline demographics, standard pathologic factors and long-term clinical outcomes between ILC and infiltrating ductal carcinoma (IDC) using a large database. METHODS: Clinicopathologic features, overall survival (OS), and recurrence/metastasis-free survival (RFS) were compared between 2,202 patients with IDC and 215 patients with ILC. RESULTS: ILC was significantly more likely to be associated with a favorable phenotype, but the incidence of contralateral breast cancer was higher for ILC patients than for IDC patients (8.4% vs. 3.9%; P =0.001). The frequencies of recurrence/metastasis (P = 0.980) and death (P = 0.064) were similar among patients with IDC and patients with ILC after adjustment for tumor size and nodal status. The median follow-up was 42.8 months. CONCLUSIONS: Chinese women with ILCs do not have better clinical outcomes than their counterparts with IDC. Management decisions should be based on individual patient and tumor biologic characteristics, and not on lobular histology.     

Immunohistochemical co-expression of c-erbb-2/Neu oncoprotein, altered tumour suppressor (p53) protein, EGF-R and EMA in histological subtypes of infiltrating duct carcinoma of the breast

Carcinoma of the breast has an unpredictable biological behaviour. Several oncogenes have been implicated in the progression of breast cancer. Immunohistochemical staining of c-erbB-2 (Neu) oncoprotein and mutant p53 protein on 45 cases of infiltrating duct carcinoma (IDC) of the breast revealed 33% membrane positivity of c-erbB-2 oncoprotein, 46% nuclear positivity of mutated p53 protein, 33% and 84% membrane positivity of EGF-R and EMA respectively. Staining profile of c-erb-B2 oncoprotein in various histological subtypes of IDC of the breast indicated a high positivity rate in comedo followed by NOS and cibriform subtype. Similarly, high incidence of immunopositivity of mutated p53 protein was observed in comedo and cibriform subtypes while papillary carcinoma were found exclusively positive for mutated p53 protein. Interestingly, tubular subtype of IDC was not positive for c-erbB-2 oncoprotein as well as p53 mutant protein. Further, comedo and cibriform subtypes of IDC revealed 'high grade' histological features of tumour of the breast with high mitotic count, presence of marked pleomorphism and multinucleation thus, reflecting a positive relationship with overexpression of c-erbB-2 (Neu) oncoprotein as well as mutant p53 protein. The results on immunoexpression of c-erbB-2 oncoprotein and mutated p53 protein in various histological subtypes of IDC of the breast demonstrated c-erbB-2 status as an important predictor and also indicated that oncogene product may be involved in growth factor response pathway.     

Molecular differences between ductal carcinoma in situ and adjacent invasive breast carcinoma: a multiplex ligation-dependent probe amplification study

Ductal carcinoma in situ (DCIS) accounts for approximately 20% of mammographically detected breast cancers. Although DCIS is generally highly curable, some women with DCIS will develop life-threatening invasive breast cancer, but the determinants of progression to infiltrating ductal cancer (IDC) are largely unknown. In the current study, we used multiplex ligation-dependent probe amplification (MLPA), a multiplex PCR-based test, to compare copy numbers of 21 breast cancer related genes between laser-microdissected DCIS and adjacent IDC lesions in 39 patients. Genes included in this study were ESR1, EGFR, FGFR1, ADAM9, IKBKB, PRDM14, MTDH, MYC, CCND1, EMSY, CDH1, TRAF4, CPD, MED1, HER2, CDC6, TOP2A, MAPT, BIRC5, CCNE1 and AURKA.There were no significant differences in copy number for the 21 genes between DCIS and adjacent IDC. Low/intermediate-grade DCIS showed on average 6 gains/amplifications versus 8 in high-grade DCIS (p=0.158). Furthermore, alterations of AURKA and CCNE1 were exclusively found in high-grade DCIS, and HER2, PRDM14 and EMSY amplification was more frequent in high-grade DCIS than in low/intermediate-grade DCIS. In contrast, the average number of alterations in low/intermediate and high-grade IDC was similar, and although EGFR alterations were exclusively found in high-grade IDC compared to low/intermediate-grade IDC, there were generally fewer differences between low/intermediate-grade and high-grade IDC than between low/intermediate-grade and high-grade DCIS.In conclusion, there were no significant differences in copy number for 21 breast cancer related genes between DCIS and adjacent IDC, indicating that DCIS is genetically as advanced as its invasive counterpart. However, high-grade DCIS showed more copy number changes than low/intermediate-grade DCIS with specifically involved genes, supporting a model in which different histological grades of DCIS are associated with distinct genomic changes that progress to IDC in different routes. These high-grade DCIS specific genes may be potential targets for treatment and/or predict progression.     

Protection against Retrovirus Pathogenesis by SR Protein Inhibitors

Indole derivatives compounds (IDC) are a new class of splicing inhibitors that have a selective action on exonic splicing enhancers (ESE)-dependent activity of individual serine-arginine-rich (SR) proteins. Some of these molecules have been shown to compromise assembly of HIV infectious particles in cell cultures by interfering with the activity of the SR protein SF2/ASF and by subsequently suppressing production of splicing-dependent retroviral accessory proteins. For all replication-competent retroviruses, a limiting requirement for infection and pathogenesis is the expression of the envelope glycoprotein which strictly depends on the host splicing machinery. Here, we have evaluated the efficiency of IDC on an animal model of retroviral pathogenesis using a fully replication-competent retrovirus. In this model, all newborn mice infected with a fully replicative murine leukemia virus (MLV) develop erythroleukemia within 6 to 8 weeks of age. We tested several IDC for their ability to interfere ex vivo with MLV splicing and virus spreading as well as for their protective effect in vivo. We show here that two of these IDC, IDC13 and IDC78, selectively altered splicing-dependent production of the retroviral envelope gene, thus inhibiting early viral replication in vivo, sufficiently to protect mice from MLV-induced pathogenesis. The apparent specificity and clinical safety observed here for both IDC13 and IDC78 strongly support further assessment of inhibitors of SR protein splicing factors as a new class of antiretroviral therapeutic agents.     

Interdigitating reticulum cells in the popliteal lymph node of the rat

Summary Electronmicroscopic and cytochemical studies were performed to localize interdigitating reticulum cells (IDC) in the popliteal lymph node of the rat.The morphological features of the IDC of the rat correspond to those described for other species, but also show similarities to normal macrophages in the rat. This is considered to be an argument in favour of the common origin of IDC's and macrophages.Ultrahistochemical studies with horseradish peroxidase (HRP) reveal no phagocytotic capacity of IDC's. After perfusion fixation containing ruthenium red (RR) the surface coat stains heavily: RR is also found deep in the membrane invaginations of the IDC, indicating the presence of polyanionic sialoglyco-proteins. The post-capillary-venules (PVC) are very permeable to both HRP and RR.The phosphotungstic acid-chromic acid stain (PTA-CrA) also reveals glycoproteins in the surface coat; these glycoproteins are susceptible to -neuraminidase, whereas glycoproteins in the Golgi complexes, lysosomes and in the vesicular complexes of IDC are not. The glycoproteins of the latter are susceptible to 0.1 N NaOH. These findings indicate that IDC produce different kinds of glycoprotein, one of which may be secreted and act as a factor for stimulating peripheral T-lymphocytes.Intimate contact between IDC's and PCV's could be observed. It is therefore conceivable that IDC's play an important role in the homing of T-lymphocytes.     

Interactions between iron-deficiency chlorosis and soybean cyst nematode in Minnesota soybean fields

Experiments were conducted in four commercial fields differing in severity of iron-deficiency chlorosis (IDC), and soybean cyst nematode (SCN) in Waseca and Lamberton, Minnesota to determine the interaction between the IDC and SCN. Each experiment was a randomized complete block with a factorial treatment design including 23 cultivars with or without traits of resistance to SCN, and IDC. The study illustrated the interactive effects of the two defensive traits on the diseases and soybean yields. IDC rating was higher in SCN-susceptible than SCN-resistant soybean, suggesting SCN infection increased IDC. Resistance to IDC apparently increased SCN reproduction due to better soybean plant growth. Yield response to the defensive traits depended on the disease pressures in a field. When both IDC and SCN were present in a field, deploying SCN-resistance was the best solution to the problems. However, SCN-resistance suppressed soybean yields when used in fields without the disease problems. IDC-resistance increased yield of SCN-susceptible cultivars, but it did not result in detectable yield benefit of SCN-resistant cultivars in SCN-infested sites. Effective use of the defensive traits for management of IDC and SCN requires specific knowledge of the disease problems present in a field. Mention of trade names or commercial products in this publication is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the U. S. Department of Agriculture and the University of Minnesota.     

A meta-analysis of HLA-DR polymorphism and genetic susceptibility to idiopathic dilated cardiomyopathy

Idiopathic dilated cardiomyopathy (IDC) has been hypothesized as a multifactorial disorder initiated by an environment trigger in individuals with predisposing human leukocyte antigen (HLA) alleles. Published data on the association between HLA-DR polymorphism and IDC risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of 19 case–control studies including 1,378 cases and 10,383 controls provided data on the association between HLA-DR polymorphism and genetic susceptibility to IDC. Overall, statistically elevated frequencies of HLA-DR4 (OR 1.58; 95% CI 1.21–2.07; P = 0.0009) and HLA-DR5 (OR 1.35; 95% CI 1.05–1.73; P = 0.02) alleles were found in patients with IDC compared with controls. Individuals with HLA-DR3 antigen have a protective effect against IDC (OR 0.72; 95% CI 0.58–0.90; P = 0.004). In summary, this meta-analysis indicated that certain HLA-DR alleles may be genetic markers for susceptibility and resistance to IDC.     

Inducing antitumor T cell immunity: comparative functional analysis of interstitial versus Langerhans dendritic cells in a human cell line model

Dendritic cells (DC) are increasingly applied as a cellular adjuvant in immunotherapy of cancer. Two major myeloid DC subsets are recognized: interstitial DC (IDC) that infiltrate connective tissues and Langerhans cells (LC) that line epithelial surfaces. Yet, functional differences between IDC and LC remain to be defined. We recently showed that the CD34(+) acute myeloid leukemia cell line MUTZ-3 supports differentiation of both DC-SIGN(+) IDC and Langerin-positive Birbeck granule-expressing LC. By comparative functional characterization of MUTZ-3 IDC and MUTZ-3 LC, we aimed to elucidate the relative abilities of these two DC subsets to induce a specific T cell response and reveal the more suitable candidate for use as a clinical vehicle of tumor vaccines. Although mature LC and IDC displayed comparable lymph node-homing potential, mature LC showed higher allogeneic T cell stimulatory capacity. Nevertheless, IDC supported the induction of tumor Ag-specific CD8(+) T cells at an overall higher efficiency. This might be related to the observed inability of LC to release T cell stimulatory cytokines such as IL-12p70, IL-23, and IL-15. Although this inability did not result in a detectable deviation in the cytokine expression profile of primed T cells, transduction with IL-12p70 significantly improved priming efficiency of LC, and ensured a functional equivalence with IDC in this regard. In conclusion, except for the inability of LC to release distinct type 1 T cell stimulatory cytokines, in vitro function of LC and IDC suggests comparable abilities of both subsets for the in vivo induction of antitumor T cells.