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961.
Matthias Christgen Henriette Bruchhardt Catarina Hadamitzky Cornelia Rudolph Doris Steinemann Dorothea Gadzicki Britta Hasemeier Daniel Rmermann Tim Focken Till Krech Matthias Ballmaier Brigitte Schlegelberger Hans Kreipe Ulrich Lehmann 《The Journal of pathology》2009,217(5):620-632
Infiltrating lobular breast cancer (ILBC) is a clinically and biologically distinct tumour entity defined by a characteristic linear cord invasion pattern and inactivation of the CDH1 tumour suppressor gene encoding for E‐cadherin. ILBCs also lack β‐catenin expression and show aberrant cytoplasmic localization of the E‐cadherin binding protein p120‐catenin. The lack of a well‐characterized ILBC cell line has hampered the functional characterization of ILBC cells in vitro. We report the establishment of a permanent ILBC cell line, named IPH‐926, which was derived from a patient with metastatic ILBC. The DNA fingerprint of IPH‐926 verified genetic identity with the patient and had no match among the human cell line collections of several international biological resource banks. IPH‐926 expressed various epithelial cell markers but lacked expression of E‐cadherin due to a previously unreported, homozygous CDH1 241ins4 frameshift mutation. Detection of the same CDH1 241ins4 mutation in archival tumour tissue of the corresponding primary ILBC proved the clonal origin of IPH‐926 from this particular tumour. IPH‐926 also lacked β‐catenin expression and showed aberrant cytoplasmic localization of p120‐catenin. Array‐CGH analysis of IPH‐926 revealed a profile of genomic imbalances that included many distinct alterations previously observed in primary ILBCs. Spectral karyotyping of IPH‐926 showed a hyperdiploid chromosome complement and numerous clonal, structural aberrations. IPH‐926 cells were anti‐cancer drug‐resistant, clonogenic in soft agar, and tumourigenic in SCID mice. In xenograft tumours, IPH‐926 cells recapitulated the linear cord invasion pattern that defines ILBCs. In summary, IPH‐926 significantly extends the biological spectrum of the established breast cancer cell lines and will facilitate functional analyses of genuine human ILBC cells in vitro and in vivo. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 相似文献
962.
Sandra Pereson Hans Wils Gernot Kleinberger Eileen McGowan Mado Vandewoestyne Bianca Van Broeck Geert Joris Ivy Cuijt Dieter Deforce Michael Hutton Christine Van Broeckhoven Professor Samir Kumar‐Singh 《The Journal of pathology》2009,219(2):173-181
Amyloid‐β (Aβ) plaques are pathological hallmarks of Alzheimer disease (AD). In addition, innate inflammatory responses, such as those mediated by microglia, are integral to the pathogenesis of AD. Interestingly, only dense‐core plaques and not diffuse plaques are associated with neuritic and inflammatory pathology in AD patients as well as in mouse AD models. However, the precise neuropathological changes that occur in the brain in response to amyloid deposition are largely unknown. To study the molecular mechanism(s) responsible for Aβ‐mediated neuropathology, we performed a gene expression analysis on laser‐microdissected brain tissue of Tg2576 and APPPS1 mice that are characterized by different types of amyloid plaques and genetic backgrounds. Data were validated by image and biochemical analyses on different ages of Tg2576, APPPS1, and Aβ42‐depositing BRI‐Aβ42 mice. Consistent with an important role of inflammatory responses in AD, we identified progranulin (mouse Grn; human GRN) as one of the top ten up‐regulated molecules in Tg2576 (≈8‐fold increased) and APPPS1 (≈2‐fold increased) mice compared to littermate controls, and among the eight significantly up‐regulated molecules common to both mouse models. In addition, Grn levels correlated significantly with amyloid load, especially the dense‐core plaque pathology (p < 0.001). We further showed that Grn is up‐regulated in microglia and neurons and neurites around dense‐core plaques, but not in astrocytes or oligodendrocytes, as has been shown in AD patients. Our data therefore support the ongoing use of these mouse models in drug trials, especially those with anti‐inflammatory compounds. Moreover, the correlation of Grn with increasing disease severity in AD mouse models prompts human studies exploring the viability of GRN as a disease biomarker. Because loss of GRN has recently been shown to cause frontotemporal dementia and serves as a risk factor for AD, the strong GRN reactivity around dense‐core plaques is consistent with an important role of this factor in AD pathogenesis. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 相似文献
963.
Magnus Isaksson Brita Ardesj Lars Rnnblom Olle Kmpe Hans Lassmann Maija‐Leena Eloranta Anna Lobell 《European journal of immunology》2009,39(10):2925-2935
EAE, an animal model for MS, is a Th17 and Th1‐cell‐mediated autoimmune disease, but the mechanisms leading to priming of encephalitogenic T cells in autoimmune neuroinflammation are poorly understood. To investigate the role of plasmacytoid DC (pDC) in the initiation of autoimmune Th17‐ and Th1‐cell responses and EAE, we depleted pDC with anti‐pDC Ag‐1 (anti‐PDCA1) mAb prior to immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein (MOG). pDC‐depleted mice developed less severe clinical and histopathological signs of EAE than control mice, which demonstrates a promoting role for pDC in the initiation of EAE. The levels of type I IFN were much lower in the sera from anti‐PDCA1‐treated mice. However, neutralization of type I IFN ameliorated the early phase of EAE but did not alter the severity of disease. Thus, only a minor part of the EAE‐promoting effect of pDC appears to be mediated by IFN‐α/β secretion. The numbers of MOG‐specific Th17 cells, but not Th1 cells, were lower in spleen from anti‐PDCA1‐treated mice compared with controls. In contrast, pDC depletion a week after MOG immunization resulted in more severe clinical signs of EAE. In conclusion, we demonstrate that pDC promote initiation of MOG‐induced Th17‐cell responses and EAE. 相似文献
964.
Christoph S. Clemen Dirk Fischer Jens Reimann Ludwig Eichinger Clemens R. Müller Harald D. Müller Hans H. Goebel Rolf Schrder 《Human mutation》2009,30(3):E490-E499
Myofibrillar myopathies are caused by mutations in desmin, B‐crystallin, myotilin, ZASP, and filamin genes. Since the vast majority of myofibrillar myopathy causing mutations are heterozygous single amino acid substitutions or small in‐frame deletions, the pathogenic role of mutant versus wild‐type protein cannot be assessed in human skeletal muscle by standard immunodetection techniques. We report on an exceptional desminopathy due to a heterozygous c.735G>C mutation. Immunoblotting detected full‐length 53desmin and a truncated 50variant in skeletal muscle from three affected patients of two different families. RT‐PCR identified three desmin mRNA species encoding for wild‐type and two mutant proteins, p.Glu245Asp and p.Asp214_Glu245del. Since previous functional studies on the p.Glu245Asp mutant showed biological properties identical to wild‐type desmin, the truncated p.Asp214_Glu245del desmin is the disease‐causing mutant. Semiquantitative RT‐PCR established a fraction of the truncated desmin mRNA species in a range from 24% to 37%. Initial quantification of corresponding desmin proteins in the muscle biopsy of the index patient of one family indicated a fraction of only 10% of the truncated species. However, serial analyses of different sections from each muscle biopsy revealed a high intra‐ and interindividual variability of the truncated desmin protein level within a range from 5% to 43%. Desmin assembly studies in vitro have established clear‐cut pathogenic ratios of mutant versus wild‐type proteins. However, our findings point out a far more complex situation in human skeletal muscle. The heterogeneously distributed mutation load within and between individual specimens, which reflects local differences in the expression and/or turnover of the mutant protein in different areas containing multiple myonuclear domains, renders it impossible to define an exact pathogenic threshold of a specific mutant in vivo. © 2008 Wiley‐Liss, Inc. 相似文献
965.
Remko Hersmus Bertie HCGM de Leeuw Hans Stoop Pascal Bernard Helena C van Doorn Hennie T Brüggenwirth Stenvert LS Drop J Wolter Oosterhuis Vincent R Harley Leendert HJ Looijenga 《European journal of human genetics : EJHG》2009,17(12):1642-1649
Patients with disorders of sex development (DSD), especially those with gonadal dysgenesis and hypovirilization, are at risk of developing the so-called type II germ cell tumors (GCTs). Both carcinoma in situ and gonadoblastoma (GB) can be the precursor lesion, resulting in a seminomatous or non-seminomatous invasive cancer. SRY mutations residing in the HMG domain are found in 10–15% of 46,XY gonadal dysgenesis cases. This domain contains two nuclear localization signals (NLSs). In this study, we report a unique case of a phenotypical normal woman, diagnosed as a patient with 46,XY gonadal dysgenesis, with an NLS missense mutation, on the basis of the histological diagnosis of a unilateral GB. The normal role of SRY in gonadal development is the upregulation of SOX9 expression. The premalignant lesion of the initially removed gonad was positive for OCT3/4, TSPY and stem cell factor in germ cells, and for FOXL2 in the stromal component (ie, granulosa cells), but not for SOX9. On the basis of these findings, prophylactical gonadectomy of the other gonad was performed, also showing a GB lesion positive for both FOXL2 (ovary) and SOX9 (testis). The identified W70L mutation in the SRY gene resulted in a 50% reduction in the nuclear accumulation of the mutant protein compared with wild type. This likely explains the diminished SOX9 expression, and therefore the lack of proper Sertoli cell differentiation during development. This case shows the value of the proper diagnosis of human GCTs in identification of patients with DSD, which allows subsequent early diagnosis and prevention of the development of an invasive cancer, likely to be treated by chemotherapy at young age. 相似文献
966.
Chiu CC Huang YT Chuang HL Chen HH Chung TC 《Immunopharmacology and immunotoxicology》2009,31(1):75-82
Pseudomonas aeruginosa Exotoxin A (PEA) induces hepatotoxicity in experimental animals. Lipopolysaccharide (LPS) interacts synergistically with xenotoxics to induce severe organ injury. We examined the combination of non-injurious doses of LPS and sub-hepatotoxic PEA in the induction of multiple organ injury (MOI). Rats treated with 20 or 40 microg/kg LPS plus 10 microg/kg PEA developed severe liver, kidney, and lung injury; elevation of TNF-alpha, IFN-gamma, and IL-2; and high mortality. Depletion of Kupffer cells or T-cells by pretreatment with Gadolinium Chloride or FK506, respectively, attenuated MOI. Thus LPS + PEA acted synergistically on Kupffer and T-cells to induce proinflammatory cytokines contributing to MOI. 相似文献
967.
Micah Gross Chris Boesch Christine S. Bolliger Barbara Norman Thomas Gustafsson Hans Hoppeler Michael Vogt 《European journal of applied physiology》2014,114(2):221-234
Introduction
We aimed to manipulate physiological determinants of severe exercise performance. We hypothesized that (1) beta-alanine supplementation would increase intramuscular carnosine and buffering capacity and dampen acidosis during severe cycling, (2) that high-intensity interval training (HIT) would enhance aerobic energy contribution during severe cycling, and (3) that HIT preceded by beta-alanine supplementation would have greater benefits.Methods
Sixteen active men performed incremental cycling tests and 90-s severe (110 % peak power) cycling tests at three time points: before and after oral supplementation with either beta-alanine or placebo, and after an 11-days HIT block (9 sessions, 4 × 4 min), which followed supplementation. Carnosine was assessed via MR spectroscopy. Energy contribution during 90-s severe cycling was estimated from the O2 deficit. Biopsies from m. vastus lateralis were taken before and after the test.Results
Beta-alanine increased leg muscle carnosine (32 ± 13 %, d = 3.1). Buffering capacity and incremental cycling were unaffected, but during 90-s severe cycling, beta-alanine increased aerobic energy contribution (1.4 ± 1.3 %, d = 0.5), concurrent with reduced O2 deficit (?5.0 ± 5.0 %, d = 0.6) and muscle lactate accumulation (?23 ± 30 %, d = 0.9), while having no effect on pH. Beta-alanine also enhanced motivation and perceived state during the HIT block. There were no between-group differences in adaptations to the training block, namely increased buffering capacity (+7.9 ± 11.9 %, p = 0.04, d = 0.6, n = 14) and glycogen storage (+30 ± 47 %, p = 0.04, d = 0.5, n = 16).Conclusions
Beta-alanine did not affect buffering considerably, but has beneficial effects on severe exercise metabolism as well as psychological parameters during intense training phases. 相似文献968.
Ingmar Mederacke Heiner Wedemeyer Sandra Ciesek Eike Steinmann Regina Raupach Karsten Wursthorn Michael P. Manns Hans Ludger Tillmann 《Journal of clinical virology》2009,46(3):210-215
BackgroundRecently, a novel quantitative HCVcoreAg immunoassay developed for commercialisation by Abbott has become available in Europe and Asia.ObjectivesWe evaluated the correlation of HCV-RNA and HCVcoreAg and investigated the stability of HCVcoreAg and HCV-RNA.Study designHCVcoreAg was quantified by a novel fully automated immunoassay (Architect HCVAg, Abbott, Germany). HCV-RNA quantification was performed either using the Cobas-TaqMan assay or Amplicor-HCV-Monitor (Roche-Diagnostics, Germany). Correlation of HCVcoreAg with HCV-RNA was studied cross-sectionally and longitudinally in untreated patients followed for up to 8 years. Stability of HCVcoreAg and HCV-RNA was evaluated in plasma and whole blood stored for up to 96 h at different conditions.ResultsHCVcoreAg showed good correlation with HCV-RNA in all 118 cross-sectional tested samples irrespective of the HCV genotype (r = 0.75). In the majority but not all of the 10 longitudinally studied patients HCVcoreAg also demonstrated a good correlation with HCV-RNA. HCVcoreAg was stable in plasma at 4, 20, and 37 °C for up to 96 h, whereas HCV-RNA significantly declined at 37 °C. In whole blood, HCVcoreAg and HCV-RNA levels declined at all conditions with exception of HCVcoreAg at 37 °C. HCVcoreAg was stable after 1–5 freezing/thawing cycles and not light-sensitive.ConclusionsHCVcoreAg represents a stable and reliable marker of viral replication showing a good correlation with HCV-RNA irrespective of the HCV genotype. HCVcoreAg determination can be used to confirm viral replication and monitor viral load or acquisition of HCV over time. 相似文献
969.
Rong Chen Gunnar O Klein Erik Sundvall Daniel Karlsson Hans ?hlfeldt 《BMC medical informatics and decision making》2009,9(1):33-13
Background
Exchange of Electronic Health Record (EHR) data between systems from different suppliers is a major challenge. EHR communication based on archetype methodology has been developed by openEHR and CEN/ISO. The experience of using archetypes in deployed EHR systems is quite limited today. Currently deployed EHR systems with large user bases have their own proprietary way of representing clinical content using various models. This study was designed to investigate the feasibility of representing EHR content models from a regional EHR system as openEHR archetypes and inversely to convert archetypes to the proprietary format. 相似文献970.
Mikael Lundin Janusz Szymas Ewert Linder Hans Beck Peter de Wilde Han van Krieken Marcial García Rojo Ignacio Moreno Aurelio Ariza Sitki Tuzlali Sergülen Derviolu Heikki Helin Veli-Pekka Lehto Johan Lundin 《Virchows Archiv : an international journal of pathology》2009,454(4):421-429
Web-based virtual microscopy has enabled new applications within pathology. Here, we introduce and evaluate a network of academic
servers, designed to maximize image accessibility to users from all regions of Europe. Whole-slide imaging was utilized to
digitize the entire slide set (n = 154) for the slide seminars of the 21st European Congress of Pathology. The virtual slides were mirrored to five academic
servers across Europe using a novel propagation method. Functionality was implemented that automatically selects the fastest
server connection in order to optimize the slide-viewing speed (). Results show that during 6 months of monitoring the uptime of the network was 100%. The average viewing speed with the
network was 3.1 Mbit/s, as compared to 1.9 Mbit/s using single servers. A good viewing speed (>2Mbit/s) was observed in 32
of 37 countries (86%), compared to 25 of 37 (68%) using single servers. Our study shows that implementing a virtual microscopy
network spanning a large geographical area is technically feasible. By utilizing existing academic networks and cost-minimizing
image compression, it is also economically feasible.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献