bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative evaluation of the prognostic value of MUC1, MUC2, sialyl‐Lewisa and sialyl‐Lewisx antigens in colorectal adenocarcinoma
Authors: Baldus S E , Mönig S P , Hanisch F‐G , Zirbes T K , Flucke U , Oelert S , Zilkens G , Madejczik B , Thiele J , Schneider P M , Hölscher A H , Dienes H P 
Published: March 2003

Comparative evaluation of the prognostic value of MUC1, MUC2, sialyl‐Lewisa and sialyl‐Lewisx antigens in colorectal adenocarcinoma Aims: The significance of MUC1, MUC2 and sialylated Lewis blood group antigens as prognostic markers in colorectal adenocarcinoma was investigated in a large series of patients because previous investigations revealed inconsistent results due to unrelated tumour samples from different patient groups and methodological differences. Methods and results: Tissues from 243 patients with colorectal adenocarcinoma were stained immunohistochemically. MUC1 showed a strong immunoreactivity (in more than 35% of the tumour area) in 32.5%, MUC2 in 51.0%, sialyl‐Lewisx in 67.9% and sialyl‐Lewisa in 73.7% of the cases, respectively. MUC1 immunoreactivity displayed a significant correlation with tumour progression as reflected by advancing pTNM staging and poor differentiation. MUC2 expression was significantly stronger in mucinous adenocarcinomas. Sialyl‐Lewisx immunostaining correlated with the extent of lymph node metastasis as well as low cytological differentiation. According to univariate and multivariate analysis (P < 0.0001) only MUC1 reactivity represented a marker of worse survival probability, opposed to the sialylated Lewis antigens that did not exert a predictive value. Conclusions: According to our data, MUC1 and sialyl‐Lewisx immunoreactivity exhibit statistically significant correlations with established markers of tumour progression. However, only MUC1 presents as an independent prognostic factor of colorectal adenocarcinoma.
Frequent alteration of MDM2 and p53 in the molecular progression of recurring non‐Hodgkin's lymphoma
Authors: Møller M B , Nielsen O , Pedersen N T 
Published: March 2003

Aims: Recurrence of non‐Hodgkin's lymphoma with or without transformation is often associated with increased clinical drug resistance and poor prognosis indicating molecular progression. The study addresses the currently poorly understood molecular mechanisms underlying relapsing non‐Hodgkin's lymphoma.Methods and results: We have analysed sequential biopsies from 42 non‐Hodgkin's lymphoma patients immunohistochemically for p53 alterations (based on p53 and p21Waf1 expression), as well as for expression of MDM2, p27Kip1 and cyclin D3. Relapse of follicle centre lymphoma was associated with p53 alterations as 5/6 (83%) follicle centre lymphomas with normal p53 at diagnosis showed p53 alterations at relapse. Of these cases, three showed transformation to diffuse large B‐cell lymphoma. p53 alteration was also associated with relapse of de novo diffuse large B‐cell lymphoma and T‐cell non‐Hodgkin's lymphoma, as 2/5 (40%) diffuse large B‐cell lymphomas and 3/9 (33%) T‐cell non‐Hodgkin's lymphomas with normal p53 at diagnosis showed p53 alterations at relapse. No indolent non‐Hodgkin's lymphoma case showed MDM2 over‐expression at diagnosis, whereas 4/5 (80%) transformed diffuse large B‐cell lymphomas developed MDM2 over‐expression.Conclusion: Our data are consistent with the notion that p53 alterations are important for the histological transformation of follicle centre lymphoma. However, the data also suggest that relapsing follicle centre lymphomas without overt transformation often have p53 alterations and increased risk of transformation, and that relapse of de novo diffuse large B‐cell lymphomas and T‐cell non‐Hodgkin's lymphomas is associated with p53 alterations. Furthermore, our results are consistent with an association of MDM2 over‐expression with histological transformation of both follicle centre lymphoma and marginal zone B‐cell lymphoma.
Age‐related changes in dermal mast cell prevalence in BALB/c mice: functional importance and correlation with dermal mast cell expression of Kit
Authors: Hart P. H. , Grimbaldeston M. A. , Hosszu E. K. , Swift G. J. , Noonan F. P. , Finlay‐Jones J. J. 
Published: March 2003

SummaryDifferences in dermal mast cell prevalence for adult mice of different strains have been reported previously. In this study, the dermal mast cell prevalence for BALB/c and C57BL/6 mice at 6 weeks of age was similar but as BALB/c mice matured from 6 to 10 weeks of age, their dermal mast cell prevalence halved. In contrast, there was no significant difference in the dermal mast cell prevalence of 6‐ and 10‐week‐old C57BL/6 mice. These differences determined the degree of susceptibility of BALB/c and C57BL/6 mice of different ages to UVB (UV radiation of wavelength 280–320 nm)‐induced systemic immunosuppression. Expression of the receptor for stem cell factor, Kit protein, was examined on mast cells under conditions in which the dermal mast cell prevalence varied. A significant correlation was observed between Kit expression by mast cells from adult BALB/c, DBA/2 and C57BL/6 mice and dermal mast cell prevalence. In BALB/c mice, mast cell Kit expression decreased as the mice matured from 6 to 10 weeks of age and correlated with the reduction in dermal mast cell numbers. Kit levels on dermal mast cells from C57BL/6 mice were consistently higher than on mast cells from BALB/c mice although significant reductions in Kit were also measured with ageing from 6 to 10 weeks. We hypothesize that regardless of the extent of Kit expression, the dermal mast cell populations were maximally expanded in C57BL/6 mice. We suggest that BALB/c mice of 6 and 10 weeks of age are useful hosts in which to quantitatively evaluate mast cell involvement in a range of functional assays involving skin.
Simple chemicals can induce maturation and apoptosis of dendritic cells
Authors: Manome H. , Aiba S. , Tagami H. 
Published: March 2003

SummaryAs is well known in the case of Langerhans cells, dendritic cells (DCs) play a crucial role in the initiation of immunity to simple chemicals such as noted in the contact hypersensitivity. Because DCs are scattered in non‐lymphoid organs as immature cells, they must be activated to initiate primary antigen‐specific immune reactions. Therefore, we hypothesized that some simple chemicals must affect the function of DCs. In this paper, we first demonstrated that human monocyte‐derived DCs responded to such simple chemicals as 2,4‐dinitrochlorobenzene (DNCB), 2,4,6‐trinitrochlorobenzene (TNCB), 2,4‐dinitrofluorobenzene (DNFB), NiCl2, MnCl2, CoCl2, SnCl2, and CdSO4 by augmenting their expression of CD86 or human leucocyte antigen‐DR (HLA‐DR), down‐regulating c‐Fms expression or increasing their production of tumour necrosis factor‐α (TNF‐α). In addition, the DCs stimulated with the chemicals demonstrated increased allogeneic T‐cell stimulatory function. Next, we found that, among these chemicals, only NiCl2 and CoCl2 induced apoptosis in them. Finally, we examined the effects of these chemicals on CD86 expression by three different macrophage subsets and DCs induced from the cultures of human peripheral blood monocytes in the presence of macrophage colony‐stimulating factor (M‐CSF), M‐CSF + interleukin‐4 (IL‐4), granulocyte–macrophage colony‐stimulating factor (GM‐CSF), and GM‐CSF + IL‐4, respectively. Among them, only DCs dramatically augmented their expression of CD86. These observations have revealed unique characteristics of DCs, which convert chemical stimuli to augmentation of their antigen presenting function, although their responses to different chemicals were not necessarily uniform in the phenotypic changes, cytokine production or in the induction of apoptosis.
A mimotope peptide‐based vaccine against Schistosoma mansoni: synthesis and characterization
Authors: Arnon R. , Tarrab‐Hazdai R. , Steward M. 
Published: March 2003

SummaryA panel of four mimotopes of the epitope recognized by the highly protective monoclonal antibody against Schistosoma mansoni (152‐66‐9B) was obtained by screening a solid‐phase 8mer random peptide library. Three of the four mimotopes (p28, p29 and p30) were efficiently recognized in an in vitro radioimmunoassay by the monoclonal antibody and by sera from infected mice and one (p30) induced in vitro proliferation of primed lymphocytes. When the mimotopes were conjugated to bovine serum albumin (BSA) and the conjugates used to immunize C57BL/6J mice, only the p30–BSA‐induced antibodies which were effective at complement‐mediated killing of schistosomula. The level of complement‐mediated killing obtained with the anti‐p30 antibodies was comparable to that seen with serum from mice immunized with the protective 9B‐antigen. Furthermore, following challenge infection of mimotope–BSA‐immunized mice, a greater than 40% reduction in worm burden was observed in p30–BSA‐immunized mice, a level comparable to that seen following immunization with the intact 9B‐antigen. These results show that a simple synthetic peptide immunogen comprising an eight‐amino acid mimotope of a conformational epitope on the 9B‐antigen can induce protective immune responses against S. mansoni that are comparable to those obtained following immunization with the far more complex intact antigen. This mimotope may well represent a potential component of a synthetic peptide vaccine against S. mansoni. The inclusion of other B‐cell‐ and T‐cell‐stimulating synthetic epitopes in such a vaccine, together with a more appropriate carrier, adjuvant and delivery systems may well result in a level of protection even greater than that seen with the single mimotope.
CD95 ligand expression as a mechanism of immune escape in breast cancer
Authors: Müschen M. , Moers C. , Warskulat U. , Even J. , Niederacher D. , Beckmann M. W. 
Published: March 2003

SummaryInteraction of CD95 (Apo‐1/Fas) and its ligand (CD95L) plays an important role in the regulation of the immune response, since CD95+ lymphocytes may be killed after engagement of the CD95 receptor. Studying the CD95/CD95L system in 40 cases of breast cancer, the malignant cells expressed CD95L, but lost CD95 expression, when compared with non‐malignant mammary tissue. Jurkat T cells incubated on breast cancer sections underwent CD95L‐specific apoptosis. The rate of apoptosis correlated with the CD95L mRNA levels of the tissue samples. In four breast cancer cell lines, CD95L expression was increased by interferon‐γ (IFN‐γ), which resulted in higher levels of CD95L‐specific apoptosis in co‐cultured Jurkat T cells. Since IFN‐γ is mainly secreted by activated T cells, up‐regulation of CD95L in breast cancer cells in response to IFN‐γ may thus counterselect activated tumour‐infiltrating T cells and favour the immune escape of breast cancer. As demonstrated by inhibition of matrix metalloproteinases, CD95L expressed on breast cancer cells can also be shed from the cell membrane into the culture supernatant. Supernatants derived from cultured breast cancer cells induced apoptosis in Jurkat T cells via CD95L. In breast cancer patients, depletion of CD4+ and CD8+ peripheral blood lymphocytes was significantly correlated with CD95L expression in the tumours. This might be suggestive for a relationship between CD95L expression by breast cancer and systemic immunosuppression.
Forced expression of terminal deoxynucleotidyl transferase in fetal thymus resulted in a decrease in γδ T cells and random dissemination of Vγ3Vδ1 T cells in skin of newborn but not adult mice
Authors: Aono A. , Enomoto H. , Yoshida N. , Yoshizaki K. , Kishimoto T. , Komori T. 
Published: March 2003

SummaryThe repertoire of lymphocyte receptor genes encoded in a germline is further diversified by a number of processes, including the template‐independent addition of nucleotides (N regions) by means of terminal deoxynucleotidyl transferase (TdT). Normally, mouse γδ T cells in the early fetal thymus, whose T‐cell receptor (TCR) genes lack N regions and are encoded by Vγ3‐Jγ1 and Vδ1‐Dδ2‐Jδ2 with canonical junctions (invariant Vγ3Vδ1), are thought to be the precursors of dendritic epidermal T cells (DETC). We generated mutant mice whose endogenous TdT promoter was replaced with the lck promoter through homologous recombination. These mutant mice expressed TdT in fetal thymus, had abundant N regions and infrequent canonical junctions in γ and δ rearrangements, and showed a decreased number of γδ T cells. Various Vγ3Vδ1 T cells, most of which had N regions in their TCR genes, were found to disseminate in the skin of newborn mutant mice, whereas normal numbers of DETCs with the invariant Vγ3Vδ1 rearrangement were observed in adult mutants. These data demonstrate that the regulation of TdT expression during fetal development is important for the generation of γδ T cells, and that Vγ3Vδ1 T cells, which have various junctional sequences in their TCR genes, randomly disseminate in skin, but invariant Vγ3Vδ1 T cells have a great advantage for proliferation in skin.
Regulation of human neutrophil‐mediated cartilage proteoglycan degradation by phosphatidylinositol‐3‐kinase
Authors: Hii C. S. T. , Marin L. A. , Halliday D. , Roberton D. M. , Murray A. W. , Ferrante A. 
Published: March 2003

SummaryThe ability of neutrophils to degrade cartilage proteoglycan suggests that the neutrophils that accumulate in the joints of rheumatoid arthritis patients are mediators of tissue damage. The regulatory mechanisms which are relevant to the proteoglycan‐degrading activity of neutrophils are poorly understood. Since phosphatidylinositol 3‐kinase (PI3‐K), protein kinase C (PKC), the extracellular signal‐regulated protein kinase (ERK)1/ERK2 and cyclic adenosine monophosphate (cAMP) have been reported to regulate neutrophil respiratory burst and/or degranulation, a role for these signalling molecules in regulating proteoglycan degradation was investigated. Preincubation of human neutrophils with GF109203X (an inhibitor of PKC), PD98059 (an inhibitor of MEK, the upstream regulator of ERK1/ERK2) or with forskolin or dibutyryl cAMP, failed to suppress proteoglycan degradation of opsonized bovine cartilage. In contrast, preincubation of neutrophils with wortmannin or LY294002, specific inhibitors of PI3‐K, inhibited proteoglycan degradation. Incubation of neutrophils with cartilage resulted in the activation of PI3‐K in neutrophils, consistent with a role for PI3‐K in proteoglycan degradation. Activation of PI3‐K and proteoglycan degradation was enhanced by tumour necrosis factor‐α. Degradation caused by neutrophils from the synovial fluid of rheumatoid arthritis patients was also inhibited by wortmannin. These data demonstrate that the proteoglycan degradative activity of neutrophils required PI3‐K but not PKC or the ERK1/ERK2/ERK5 cascades and was insensitive to increases in intracellular cAMP concentrations.
Impaired protective immunity and T helper 2 responses in alymphoplasia (aly) mutant mice infected with Trichinella spiralis
Authors: Korenaga M. , Akimaru Y. , Shamsuzzaman S. M. , Hashiguchi Y. 
Published: March 2003

SummaryThe alymphoplasia (aly) mutation of mice prevents the development of systemic lymph nodes and Peyer's patches. The mutant homozygotes (aly/aly) are partially deficient in both humoral and cell‐mediated immune functions. In the present study, we show that adult worm expulsion was slightly delayed and that T helper 2 (Th2)‐type responses were partially defective in aly/aly mice after infection with Trichinella spiralis. Male aly/aly and aly/+ mice (8‐weeks old) were infected with 400 muscle larvae. There was no difference in worm recovery between the two groups on day 5. However, worm recovery in aly/aly mice was significantly higher than that in aly/+ mice on day 14. Mucosal mast cells increased in number and peaked 14 days after infection in aly/+ mice. aly/aly mice were deficient in their mucosal mast cell response through out the primary infection. To examine the existence of mast cell precursors, aly/aly mice were treated with recombinant interleukin‐3 (rIL‐3) before infection. The mast cell response was poorly induced in aly/aly mice treated with rIL‐3. An immunoglobulin E (IgE) response was not detected in aly/aly mice during the course of infection. Serum IgG1 levels in aly/aly mice were significantly lower than that of aly/+. The serum IgG2a levels increased in both strains of mice. However, IgG2a production in aly/aly mice on day 14 was half as much as that in aly/+mice. Stimulation of splenic T cells in vitro with anti‐CD3 monoclonal antibody (mAb) showed that spleen cells from aly/+ mice on day 5 produced more IL‐4 than spleen cells from aly/aly mice. IL‐4 production from aly/aly mice on day 14 was half that from aly/+ mice. Interferon‐γ (IFN‐γ) was produced in both aly/aly and aly/+ mice on day 14. Proliferation assay showed that T cells of aly/aly mice responded poorly when cultured with antigen‐presenting cells. These results suggest that aly gene is needed for the induction of protective immunity and Th2 responses in mice infected with T. spiralis.
Dendritic cells rapidly undergo apoptosis in vitro following culture with activated CD4+ Vα24 natural killer T cells expressing CD40L
Authors: Nieda M. , Kikuchi A. , Nicol A. , Koezuka Y. , Ando Y. , Ishihara S. , Lapteva N. , Yabe T. , Tokunaga K. , Tadokoro K. , Juji T. 
Published: March 2003

SummaryHuman Vα24 natural killer T (Vα24NKT) cells are activated by α‐glycosylceramide‐pulsed dendritic cells (DCs) in a CD1d‐dependent and T‐cell receptor‐mediated manner. There are two major subpopulations of Vα24NKT cells, CD4– CD8– Vα24NKT and CD4+ Vα24NKT cells. We have recently shown that activated CD4– CD8– Vα24NKT cells have cytotoxic activity against DCs, but knowledge of the molecules responsible for cytotoxicity of Vα24NKT cells is currently limited. We aimed to investigate whether CD4+ Vα24NKT cells also have cytotoxic activity against DCs and to determine the mechanisms underlying any observed cytotoxic activity. We demonstrated that activated CD4+ Vα24NKT cells [CD40 ligand (CD40L) ‐positive] have cytotoxic activity against DCs (strongly CD40‐positive), but not against monocytes (weakly CD40‐positive) or phytohaemagglutinin blast T cells (CD40‐negative), and that apoptosis of DCs significantly contributes to the observed cytotoxicity. The apoptosis of DCs following culture with activated CD4+ Vα24NKT cells, but not with resting CD4+ Vα24NKT cells (CD40L‐negative), was partially inhibited by anti‐CD40L mAb. Direct ligation of CD40 on the DCs by the anti‐CD40 antibody also induced apoptosis of DCs. Our results suggest that CD40–CD40L interaction plays an important role in the induction of apoptosis of DCs following culture with activated CD4+ Vα24NKT cells. The apoptosis of DCs from normal donors, triggered by the CD40–CD40L interaction, may contribute to the homeostatic regulation of the normal human immune system, preventing the interminable activation of activated CD4+ Vα24NKT cells by virtue of apoptosis of DCs.
Transforming growth factor‐β promotes ‘death by neglect’ in post‐activated human T cells
Authors: Sillett H. K. , Cruickshank S. M. , Southgate J. , Trejdosiewicz L. K. 
Published: March 2003

SummaryTransforming growth factor‐β (TGF‐β) is central to the wound repair processes that follow local trauma and inflammation. In order to mimic the early events of wound‐healing, we studied the effects of TGF‐β on mitogen‐stimulated peripheral blood cells. TGF‐β added at the initiation of mitogenesis did not significantly alter T‐cell activation, proliferation, CD45 isoform switching, or activation‐induced cell death. By contrast, TGF‐β added 72 hr post‐activation (or later) enhanced the cumulative increase in apoptotic T cells. TGF‐β had no effect on mitogen‐induced up‐regulation of Fas (CD95) or Fas ligand and did not enhance killing of the Fas‐sensitive Jurkat cell line by activated T cells. Furthermore, TGF‐β had no direct effect on levels of mRNA for members of the bcl family (bcl‐X, bfl‐1, bik, bak, bax, bcl‐2 and mcl‐1). These findings suggest that TGF‐β does not directly induce apoptosis via the Fas system or by direct effects on bcl proteins. However, interleukin‐2, which can ‘rescue’ lymphocytes from spontaneous apoptosis due to cytokine deprivation, abolished the pro‐apoptotic effects of TGF‐β on post‐activated T cells, thus demonstrating that TGF‐β increases the cytokine‐dependence of T cells for survival. We propose a novel role for TGF‐β in the suppression of inflammation by promoting the elimination of post‐activated T cells once the initiating stimulus has been resolved.
The role of hepatocyte growth factor and its receptor c‐met in interactions between lymphocytes and stromal cells in secondary human lymphoid organs
Authors: Skibinski G. , Skibinska A. , James K. 
Published: March 2003

SummarySecondary lymphoid tissue consists of two major populations of cells: lymphoid cells and stromal cells. It is generally accepted that these two cell populations influence each other however, factors mediating these processes are poorly understood. In this paper we characterize one of the possible means of communication between stroma and lymphocytes namely through hepatocyte growth factor/c‐met receptor interactions. Hepatocyte growth factor (HGF) is a pleiotropic factor that is mainly produced by mesenchymal cells and acts on cells of epithelial origin which express the HGF receptor c‐met. Here we demonstrate that biologically active HGF is constitutively produced by fibroblast‐like stromal cells from human lymphoid tissues. HGF secretion from stromal cells was increased by direct contact with activated T cells. This increase was abrogated when activated T cells were separated physically from stromal cells. Using neutralizing antibody or cytokine inhibitors we provide evidence that enhancement of HGF production was due to additive effects of T‐cell membrane‐associated interleukin‐1 (IL‐1) and CD40 ligand. Finally, we also show that B lymphocytes activated with CD40L/anti‐µ or phorbol 12‐myristate 13‐acetate (PMA) express c‐met receptor. Co‐culture of activated B cells with stromal cells from spleen leads to enhanced production of immunoglobulins. This can be partially inhibited by introduction of anti‐HGF neutralizing antibodies to the culture system. Substitution of stromal cells with recombinant HGF did not produce enhancement of immunoglobulin secretion. On the other hand stimulation of c‐met receptor with HGF leads to enhanced integrin‐mediated adhesion of activated B cells to vascular cell adhesion molecule (VCAM‐1) and fibronectin. On the basis of the above experiments we conclude that HGF production by fibroblast‐like stromal cells can be modulated by activated T cells, thus providing signals for the regulation of adhesion of c‐met expressing B cells to extracellular matrix proteins. In this way HGF may indirectly influence immunoglobulin secretion by B cells.