bluuebunny/crossref_metadata_2025_split huggingface dataset:
Malignant epithelioid mesothelioma: anti‐mesothelial marker expression correlates with histological pattern
Authors: Attanoos R L , Webb R , Dojcinov S D , Gibbs A R 
Published: March 2003

Malignant epithelioid mesothelioma: anti‐mesothelial marker expression correlates with histological pattern Aims: Malignant epithelioid mesothelioma shows marked cytoarchitectural diversity. The aim of the study was to evaluate how immunoreactivity with mesothelial markers related to histological pattern. Methods and results: Ninety‐two cases of malignant epithelioid mesothelioma (60 pleural, 32 peritoneal) were examined and classified as exhibiting tubulopapillary, adenomatoid, solid, small cell or pleomorphic patterns. All cases were immunohistochemically stained with thrombomodulin, calretinin, CD44H, and cytokeratin 5/6. Cases of malignant mesothelioma exhibited a number of different histological forms. Immunohistochemical expression of each mesothelial marker tested was not homogeneous across different histological patterns of malignant epithelioid mesothelioma, even within the same tumour section. Calretinin (with nuclear expression) was identified to show the highest overall sensitivity and lowest range variation in staining (67% sensitivity in small cell areas to 100% expression in pleomorphic areas). Cytokeratin 5/6 and thrombomodulin yielded similar overall sensitivity. Thrombomodulin appeared to demonstrate higher sensitivity for small cell variant tumour (83% sensitivity). A notable advantage with cytokeratin 5/6 was that expression was more diffuse in nature rather than the focal membranous elaboration seen in thrombomodulin. The widest range of staining was seen in small cell mesothelioma (83% sensitivity with thrombomodulin to 17% sensitivity with cytokeratin 5/6) and in tubulopapillary areas (90% sensitivity with calretinin to 38% sensitivity with CD44H). Conclusions: Calretinin appears most useful and shows the highest overall sensitivity for malignant epithelioid mesothelioma, with good expression in areas displaying a tubulopapillary, adenomatoid, solid and pleomorphic pattern. For small cell mesothelioma, thrombomodulin appears to confer higher sensitivity and is advocated, in this setting, as the first line mesothelial marker. Cytokeratin 5/6 is a useful and easily interpretable mesothelial marker. CD44H is not of particular use in the diagnosis of malignant epithelioid mesothelioma. Accurate interpretation of immunohistochemistry in mesothelioma requires an awareness of the immunophenotypic heterogeneity identified in different histological forms of the tumour, and this is of particular importance in small biopsies.
Genomic imbalances detected by comparative genomic hybridization are prognostic markers in invasive ductal breast carcinomas
Authors: Zudaire I , Odero M D , Caballero C , Valenti C , Martínez‐Penuela J M , Isola J , Calasanz M J 
Published: March 2003

Genomic imbalances detected by comparative genomic hybridization are prognostic markers in invasive ductal breast carcinomas Aims: The aim of this work is the study of the prognostic significance of the chromosomal aberrations described in a series of invasive ductal breast carcinomas. Methods and results: We analysed by comparative genomic hybridization a group of 70 formalin‐fixed paraffin‐embedded invasive ductal breast carcinomas. Aberrations showed a frequency similar to previous studies using frozen tumours. Interestingly, we identified gains involving 6q16‐q24 more frequently than in other series. We analysed the association among the chromosomal imbalances, 11 histopathological factors, relapse rate and overall survival of patients. Associations showed 16q losses as a potential marker of good prognosis, as they were more frequent in node‐negative (P=0.025) and in oestrogen‐positive tumours (P < 0.001). Furthermore, 100% of bcl‐2+ tumours presented this aberration compared with 29.3% in bcl‐2– (P=0.014). 1q, 11q, 17q and 20q gains were associated with poor prognosis: 95% of cases with 1q gains were bigger than 20 mm (P=0.041). Tumours with 1q and 11q gains showed a higher relapse rate (P=0.063; P=0.066). Within the good prognosis group of lymph node‐negative patients, 17q and 20q gains identify a subgroup with increased relapse rate (P=0.039). Conclusions: Chromosomal imbalances, together with histopathological factors, may help to predict outcome in breast cancer patients.
Immunohistochemical detection of 8‐hydroxydeoxyguanosine, a marker of oxidative DNA damage, in human chronic cholecystitis
Authors: Seki S , Kitada T , Yamada T , Sakaguchi H , Nakatani K , Onoda N , Satake K 
Published: March 2003

Immunohistochemical detection of 8‐hydroxydeoxyguanosine, a marker of oxidative DNA damage, in human chronic cholecystitis Aims: Recent studies suggest that oxidative DNA damage induced during chronic inflammation may play a role in carcinogenesis in some organs. Although gallbladder carcinomas are frequently observed with a background of chronic cholecystitis, little is known about oxidative DNA damage in chronic cholecystitis. The aims of this study were to investigate the expression of 8‐hydroxydeoxyguanosine (8‐OHdG), a biomarker of oxidative DNA damage, in normal and chronically inflamed human gallbladder mucosa and compare its expression with clinicopathological findings. Methods and results: 8‐OHdG expression was immunohistochemically examined using a monoclonal antibody against 8‐OHdG in human gallbladder specimens. In normal gallbladder (n=5), no 8‐OHdG expression was observed. In contrast, nuclear expression of 8‐OHdG was detected in 28 of 31cases (90.3%) in gallbladder epithelial cells with chronic cholecystitis. The positive cells were predominantly observed in the areas of active inflammation with prominent cell infiltration. Quantitative analysis revealed that the number of 8‐OHdG+ cells (labelling index) significantly (rs=0.671, P < 0.05) correlated with the degree of the activity of mucosal inflammation, while gender, age, and the presence of gallstones did not influence the index. Conclusions: Oxidative DNA damage is common in chronic cholecystitis, suggesting a possible link between chronic inflammation and gallbladder carcinogenesis.
Acidic pH increases the avidity of FcγR for immune complexes
Authors: López D. H. , Trevani A. S. , Salamone G. , Andonegui G. , Raiden S. , Giordano M. , Geffner J. R. 
Published: March 2003

SummaryThe interaction of immunoglobulin G (IgG) antibodies with FcγR constitutes a critical mechanism through which IgG antibody effector functions are mediated. In the current work we have examined whether human neutrophil FcγR exhibit pH dependence in their association with IgG. Binding assays were performed in culture medium adjusted to different pH values. It was found that the binding of either heat‐aggregated human IgG (AIgG), soluble immune complexes (sIC) or IgG‐coated erythrocytes (IgG‐E) was markedly higher at pH 6·5 than at pH 7·3. This effect was not observed when saturation of FcγR was achieved, suggesting that acidic pH increases the avidity of FcγR for IC without modifying the total binding capacity. Similar results were observed for the binding of AIgG to either monocytes, natural killer (NK) or K562 cells, suggesting that acidic pH increases the avidity of both, FcγRII and FcγRIII. Additional experiments were performed to analyse whether the binding of IgG to FcγRI also showed pH dependence. To this aim, we employed interferon‐γ‐treated human neutrophils and mouse inflammatory macrophages, previously incubated with blocking antibodies directed to FcγRII and FcγRIII. Acidic pH did not enhance the binding of AIgG nor monomeric IgG under these experimental conditions. Further studies are required to determine whether the enhancement of FcγR avidity for IC could be attributed to titration of histidine(s) residues on the Fc fragment of IgG.
Histidine‐rich glycoprotein prevents the formation of insoluble immune complexes by rheumatoid factor
Authors: Gorgani N. N. , Altin J. G. , Parish C. R. 
Published: March 2003

SummaryIn previous studies we have shown that histidine‐rich glycoprotein (HRG), a relatively abundant plasma protein, can bind to immunoglobulin G (IgG) and inhibit the insolubilization of IgG‐containing immune complexes (IC). It was of interest, therefore, to determine whether HRG can inhibit the formation of insoluble IC (IIC) resulting from the interaction of rheumatoid factor (RF) with human IgG‐containing IC. Light scattering techniques were used to examine the effect of HRG on the formation of IIC between RF and IC containing human IgG according to three different models. In all three models physiological concentrations of HRG could block the formation of IIC induced by RF. Optical biosensor studies of the RF–IgG interaction also revealed that HRG can mask the epitopes on IgG recognized by RF. Additional studies examined whether HRG can solubilize already formed IIC and demonstrated that HRG can, in fact, partially solubilized IIC. These data indicate that HRG can regulate the formation of IIC induced by RF at three levels: namely by inhibiting the initial recognition of IgG containing IC by RF, by inhibiting the subsequent insolubilization of IgG containing IC by RF and by solubilizing already formed IIC. Collectively, these findings suggest that HRG may be an important inhibitor of the formation of pathogenic IC in diseases such as systemic lupus erythematosus and rheumatoid arthritis.
The effect on immunoglobulin glycosylation of altering in vivo production of immunoglobulin G
Authors: Jeddi P. , Keusch J. , Lydyard P. M. , Bodman‐Smith K. B. , Chesnutt M. S. , Wofsy D. , Hirota H. , Taga T. , Delves P. J. 
Published: March 2003

SummaryThe effect on murine immunoglobulin G (IgG) glycosylation of altering IgG production in vivo was assessed in interleukin (IL)‐6 transgenic and CD4 knockout mice. C57BL/6 mice carrying the IL‐6 transgene showed increased levels of circulating IgG. This was associated with decreased levels of galactose on the IgG oligosaccharides. No decrease in β4‐galactosyltransferase mRNA or in enzyme activity was seen in IL‐6 transgenic mice. MRL‐lpr/lpr mice normally have elevated levels of circulating IgG, again accompanied by decreased levels of IgG galactose. Disruption of the CD4 gene in MRL‐lpr/lpr mice led to a substantial decrease in the concentration of circulating IgG, but IgG galactose levels remained low. Thus, an enforced decrease in IgG levels in the lymphoproliferative MRL‐lpr/lpr mice did not alter the percentage of agalactosyl IgG in these mice, suggesting that agalactosyl IgG production is not simply caused by excessive IgG synthesis leading to an insufficient transit time in the trans‐Golgi, but rather to a molecular defect in the interaction between galactosyltransferase and the immunoglobulin heavy chain.
Differential expression of inducible nitric oxide synthase gene by alveolar and peritoneal macrophages in lipopolysaccharide‐hyporesponsive C3H/HeJ mice
Authors: Wang M. J. , Jeng K. C. G. , Shih P. C. 
Published: March 2003

SummaryIn lipopolysaccharide (LPS)‐hyporesponsive C3H/HeJ mice, alveolar macrophages (AMφ) produce much more tumour necrosis factor‐α than peritoneal macrophages (PMφ) when stimulated with LPS (10 µg/ml), but the induction of inducible nitric oxide synthase (iNOS) gene expression and production of nitric oxide (NO) in AMφ are not found. In the present study, we determined the induction of iNOS gene expression, using semi‐quantitative reverse transcription–polymerase chain reaction, and the release of NO in AMφ and PMφ from C3H/HeJ and C3H/HeN mice. The results showed the induction of iNOS mRNA accumulation in a dose‐dependent manner by LPS alone or in combination with interferon‐γ in both macrophages. The effects of the stimuli on iNOS gene expression and NO production were significantly higher in AMφ than in the PMφ of C3H/HeJ mice. The response of macrophages from C3H/HeN mice was similar to those from C3H/HeJ mice, but the difference of iNOS gene expression between AMφ and PMφ in C3H/HeN mice was not as striking as in C3H/HeJ mice. The results show that the iNOS gene expression and NO production were activated differently in AMφ and PMφ and suggest that the functional properties of macrophages isolated from distinct origins are different.
Impaired delayed‐type hypersensitivity response in mutant mice secreting soluble CD4 without expression of membrane‐bound CD4
Authors: Wang C.‐R. , Hino A. , Yoshimoto T. , Nagase H. , Kato T. , Hirokawa K. , Matsuzawa A. , Nariuchi H. 
Published: March 2003

SummaryDelayed‐type hypersensitivity (DTH) is an important in vivo manifestation of cell‐mediated immunity. We examined the DTH response to methylated bovine serum albumin of a novel mutant strain of mice that have soluble CD4 (sCD4) in their circulation without expression of CD4 on the cell surface. The DTH response of the mutant mice was severely impaired, although the response of CD4 knockout (KO) mice, generated by homologous recombination, was comparable to that of wild‐type mice. The response of the mutant mice was restored by the neutralization of sCD4 with anti‐CD4, and that of CD4KO mice was markedly reduced by the implantation of a diffusion chamber containing sCD4 cDNA transfectant cells. The restored DTH response of the mutant mice treated with anti‐CD4 was abolished by treatment with anti‐interferon‐γ (IFN‐γ). IFN‐γ production by CD4 mutant and CD4KO mice was consistent with their DTH response and inversely related to the presence of sCD4 in their circulation, indicating that sCD4 impairs the DTH response by blocking the production of IFN‐γ in our mutant mice. These results raise the possibility that sCD4 could impair cell‐mediated immunity. Our mutant mice would provide a useful tool with which to analyse the mechanisms of the DTH reaction.
The role of endogenous steroid hormones in the generation of T helper 2‐mediated autoimmunity in mercuric chloride‐treated Brown–Norway rats
Authors: Macphee I. A. M. , Turner D. R. , Oliveira D. B. G. 
Published: March 2003

SummaryInjection of Brown–Norway rats with mercuric chloride (HgCl2) activates a T helper type 2 (Th2) autoimmune response, with production of a number of autoantibodies and vasculitis primarily affecting the gut. Glucocorticoids have been shown to suppress Th1 and to promote the development of Th2‐type responses. Conversely dehydroepiandrosterone (DHEA) promotes Th1 responses with suppression of Th2 responses. This study set out to define the role of these hormones in this animal model. Rats were adrenalectomized (Adx) with no steroid replacement (n = 11), Adx with basal steroid replacement given by a 25 mg corticosterone pellet inserted subcutaneously (n = 13), or sham‐Adx (n = 14) prior to administration of HgCl2. In both groups of Adx animals there was a delay in the production of immunoglobulin E (IgE) and serum concentrations on day 9 were marginally lower (P = 0·035, repeated measures
anova). All of the animals Adx with no steroid replacement and two Adx animals with steroid replacement died between 10 and 14 days after HgCl2 challenge. There was no difference in the severity of caecal vasculitis between the groups. A significant increase in adrenal size was noted following administration of HgCl2. Administration of subcutaneous DHEA implants (100 mg and 200 mg) had no significant effect on IgE concentrations or severity of vasculitis. These observations do not support the hypothesis that corticosterone and DHEA play a central role in setting the Th1/Th2 balance in this experimental Th2‐mediated autoimmune disease; in contrast with the Th1‐mediated autoimmune disease experimental allergic encephalomyelitis where corticosterone plays a key role in immunoregulation.
Mucosal immunogenicity of plant lectins in mice
Authors: Lavelle E. C. , Grant G. , Pusztai A. , Pfüller U. , O’Hagan D. T. 
Published: March 2003

SummaryThe mucosal immunogenicity of a number of plant lectins with different sugar specificities was investigated in mice. Following intranasal (i.n.) or oral administration, the systemic and mucosal antibody responses elicited were compared with those induced by a potent mucosal immunogen (cholera toxin; CT) and a poorly immunogenic protein (ovalbumin; OVA). After three oral or i.n. doses of CT, high levels of specific serum antibodies were measured and specific IgA was detected in the serum, saliva, vaginal wash, nasal wash and gut wash of mice. Immunization with OVA elicited low titres of serum IgG but specific IgA was not detected in mucosal secretions. Both oral and i.n. delivery of all five plant lectins investigated [Viscum album (mistletoe lectin 1; ML‐1), Lycospersicum esculentum (tomato lectin; LEA), Phaseolus vulgaris (PHA), Triticum vulgaris (wheat germ agglutinin (WGA), Ulex europaeus I (UEA‐1)] stimulated the production of specific serum IgG and IgA antibody after three i.n. or oral doses. Immunization with ML‐1 induced high titres of serum IgG and IgA in addition to specific IgA in mucosal secretions. The response to orally delivered ML‐1 was comparable to that induced by CT, although a 10‐fold higher dose was administered. Immunization with LEA also induced high titres of serum IgG, particularly after i.n. delivery. Low specific IgA titres were also detected to LEA in mucosal secretions. Responses to PHA, WGA and UEA‐1 were measured at a relatively low level in the serum, and little or no specific mucosal IgA was detected.
Studies on delayed systemic effects of ultraviolet B radiation on the induction of contact hypersensitivity, 3. Dendritic cells from secondary lymphoid organs are deficient in interleukin‐12 production and capacity to promote activation and differentiation of T helper type 1 cells
Authors: Kitazawa T. , Streilein J. W. 
Published: March 2003

SummaryUltraviolet‐B radiation (UVR) of mouse skin promotes both local and systemic immune aberrations that are thought to be important in the pathogenesis of cutaneous malignancies. Acute, low‐dose UVR regimens inhibit the induction of contact hypersensitivity (CH) in genetically susceptible mice by TNF‐α‐dependent mechanisms. In addition, these regimens also promote the development of tolerance when hapten is applied to the UVR‐exposed site at the completion of the radiation treatment protocol. A third immune abnormality is also observed in mice exposed to acute, low‐dose UVR. This abnormality, which develops within 48–72 hr of the completion of the UVR regimen, has been described among antigen‐presenting cells within secondary lymphoid organs, including lymph nodes that do not drain the site of irradiation. Dendritic cells (DCs) from lymph nodes and spleens of mice exposed to UVR lack the capacity to induce CH if they are derivatized with hapten and injected intracutaneously into naive mice. The DC defect is related to the production of and systemic dissemination of interleukin‐10 (IL‐10) by keratinocytes within the epidermis of the UVR‐exposed skin. We have now examined the nature of the functional aberration that exists among DCs within the secondary lymphoid organs of UVR‐exposed mice by examining the capacity of DCs to express co‐stimulatory molecules, and their ability to activate ovalbumin (OVA) ‐specific DO11.10 T‐cell receptor transgenic T cells in vitro. Our results indicate that DCs from UVR‐exposed mice produced insufficient amounts of IL‐12. When pulsed with OVA, these cells were capable of inducing proliferation among DO11.10 T cells in vitro, but the responding cells produced neither IFN‐γ nor IL‐10 and IL‐4. A similar antigen‐presenting cell defect was generated in mice treated with a subcutaneous injection of IL‐10. We conclude that acute, low‐dose UVR creates an IL‐10‐dependent functional deficit in DCs in secondary lymphoid organs, and that this defect robs UVR‐exposed mice of the capacity to develop CH when hapten is painted epicutaneously.
Antibody cross‐linking of human CD9 and the high‐affinity immunoglobulin E receptor stimulates secretion from transfected rat basophilic leukaemia cells
Authors: Higginbottom A. , Wilkinson I. , McCullough B. , Lanza F. , Azorsa D. O. , Partridge L. J. , Monk P. N. 
Published: March 2003

SummaryPrevious studies have shown that antibody cross‐linking of the tetraspanin protein CD9 stimulates the degranulation of platelets and eosinophils, although the mechanism of activation is unclear. In this work we transfected human CD9 into the rat basophilic leukaemia (RBL‐2H3) cell line and studied the stimulation of secretion from these cells in response to a panel of anti‐CD9 antibodies. Intact immunoglobulin G1 (IgG1) antibodies activated transfected cells whereas F(ab′)2 fragments of antibody and an intact IgG2a did not. Stimulation of secretion was inhibited by co‐incubation with monomer murine immunoglobulin E (IgE) but not with an IgG1 isotype control, indicating that the response involves the endogenous high‐affinity IgE receptor (FcεRI). The anti‐CD9 antibody activation curve was biphasic, and supraoptimal antibody concentrations stimulated little or no degranulation, indicating that multivalent binding of human CD9 molecules is necessary for the formation of an active complex with rat FcεRI. Immunoprecipitation of FcεRI under mild detergent conditions co‐precipitated CD9, suggesting the presence of pre‐existing complexes of CD9 and FcεRI that could be activated by antibody cross‐linking. These data are further evidence that tetraspanins are involved in FcεRI signalling and may reflect the participation of tetraspanins in the formation of complexes with other membrane proteins that use components of Fc receptors for signal transduction.
Pentoxifylline treatment of mice with chronic pulmonary tuberculosis accelerates the development of destructive pathology
Authors: Turner J. , Frank A. A. , Brooks J. V. , Marietta P. M. , Orme I. M. 
Published: March 2003

SummaryIt is well established in animal models that production of the cytokine tumour necrosis factor‐α (TNF‐α) is essential to the proper expression of acquired specific resistance following infection with Mycobacterium tuberculosis. This gives rise to an apparent state of chronic disease which over the next 100–200 days is characterized by slowly worsening pathological changes in the lung. To determine whether continued TNF‐α production was harmful during this phase mice were treated with a TNF‐α inhibitor, pentoxifylline. It was observed that although this therapy did not alter the numbers of bacteria recovered from the lungs of the infected mice, tissue damage within the lung was accelerated. These data thus demonstrate that production of TNF‐α, already known to be important during the early expression of resistance to tuberculosis, remains important and beneficial during the chronic stage of the disease.