| 41. |
- Bjartell, Anders, et al.
(author)
-
Distribution and tissue expression of semenogelin I and II in man as demonstrated by in situ hybridization and immunocytochemistry
- 1996
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In: Journal of Andrology. - 0196-3635. ; 17, s. 17-26
-
Journal article (peer-reviewed)abstract
- Semenogelin I and II (Sgl, Sgll) are two separate gene products of chromosome 20 with extensive (80%) identity in primary structure. They are mainly responsible for immediate gel formation of freshly ejaculated semen. Degradation of Sgl and Sgll is due to the proteolytic action of prostate-specific antigen (PSA); it results within 5-15 minutes in liquefaction of semen and release of progressively motile spermatozoa. By means of cDNA cloning and Northern blots, Sgl and Sgll transcripts have previously been shown to be abundant in human seminal vesicles, but Sgll alone is suggested to be expressed at low levels in the epididymis. To characterize the expression and tissue distribution of Sgl and Sgll in greater detail, we produced monoclonal immunoglobulin Gs (lgGs for immunocytochemistry (lCC) and specific [35S]-, digoxigenin-, or alkaline phosphatase-labeled 30-mer antisense probes to Sgl and Sgll for in situ hybridization (lSH). Immunocytochemical staining for both Sgl and Sgll, and lSH detection of both Sgl and Sgll transcripts, were demonstrated in the cytoplasm of seminal vesicle epithelium. lSH showed Sgll alone to be expressed in the epithelium of the epididymal cauda. Neither lCC nor lSH yielded any evidence of Sgl or Sgll expression in caput or corpus epithelium or in any stromal cells of the epididymis. Consistent with our previous findings using polyclonal lgG, monoclonal anti-Sgll Sgll lgGs identified epitopes on the posterior head, midpiece, and tail of ejaculated spermatozoa. Spermatozoa in the epididymal cauda were also immunoreactive, but those in the caput or corpus region of the epididymis as well as those in the testis were negative. As shown by lCC, neither Sgl nor Sgll were expressed in the testis, the prostate, the female genital tract, or other normal human tissue specimens. Although the significance of Sg attachment to epididymal and ejaculated spermatozoa remains to be established, monoclonal anti-Sg lgG might prove useful in establishing the origin of seminal vesicle tissue components in prostate core biopsies or other biopsy specimens.
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| 42. |
- Benda, Birgitta
(author)
-
Islet xenotransplantation : An immunological study in the pig-to-mouse model
- 1999
-
Doctoral thesis (other academic/artistic)abstract
- Successful clinical xenotransplantation, i.e., transplantation between species, would eliminate the shortage of donor organs. In order to study the acute cellular rejection reaction following discordant xenogeneic transplantation, an experimental pig-to- mouse islet xenotransplantation model was established. Further, immunological processes were evaluated using genetically deficient (knock-out) recipient mice and pharmacological agents exerting cytokine-modulatory actions.Xenogeneic islet transplantation persists in mice deficient in antibodies, interleukin-6, perforin or granzyme B, suggesting that neither xenoreactive antibodies or interleukin-6 nor granule-mediated lysis are of critical importance to the rejection process. Instead, the immune response following pig-to-mouse islet xenotransplantation bears a close morphological resemblance to a T helper (Th) 1-dependent delayed-type hypersensitivity-reaction with a massive infiltration of macrophages and comparatively small amounts of peripherally accumulated T cells. It may be speculated that islet xenograft destruction is a macrophage-mediated process regulated by T cells. Indeed, Th1-associated cytokines with macrophage-activating properties (interferon-γ and tumor necrosis factor-α) and interleukin-2 seem to be important to islet xenograft rejection, even though other cytokines eventually substitute for the lack of those in a majority of animals.Key words: xenotransplantation, porcine, islet, in vivo, knock-out mouse,immunohistochemistry, CsA, MDL 201,449A, Ig, FcR, IL-6, perforin, granzyme B,macrophage, eosinophilic granulocyte, T cell, TCR, IFN- g, TNF- a, IL-2.
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| 43. |
- Christiansen, Ilse
(author)
-
Soluble intercellular and vascular cell adhesion molecules-1 in lymphoid neoplasms : A clinical and prognostic study of Hodgkin's disease, non-Hodgkin's lymphomas and chronic B-lymphocytic leukaemia
- 1998
-
Doctoral thesis (other academic/artistic)abstract
- The interaction of soluble adhesion molecules with adhesion ligands expressed by immunological cells interfere with the cell-cell adhesion essential for the signal transductions that initiate immunological responses. Preliminary data suggest that soluble adhesion molecules also promote angiogenesis. Thus dysregulated production of soluble adhesion molecules may emerge as participants of disturbed immuno- surveillance, lymphocyte trafficking and dissemination of cancer cells. Vascular cell adhesion molecule-l (VCAM-1) and intercellular adhesion molecule-l (ICAM-1) are inducible and/or upregulated by cytokines in different cells types such as endothelial cells, follicular dendritic cells, and stromal cells. Lymphoid neoplasms, representing malignant counterparts of immunological cells, are characterised by heterogeneous histopathologies and clinical manifestations.Serum levels of soluble ICAM-1 (sICAM-1) and soluble VCAM-1 (sVCAM-1) were elevated in Hodgkin's disease (HD) and chronic B-lymphocytic leukaemia (B-CLL), while only sICAM-1 was elevated in non-Hodgkin's lymphomas (NHL). Serum levels of sICAM-1 and sVCAM-1 correlated with tumour burden and other known prognostic markers. sICAM-1 was an independent prognostic variable in HD and B-CLL. sVCAM-1 was an independent prognostic variable in HD. The discriminative power of serum levels of sVCAM-1 in smouldering and non-smouldering B-CLL could prove clinically valuable.Both ICAM-1 and VCAM-1 were overexpressed by vascular endothelium and stroma in biopsies of HD, B-CLL and NHL. No correlation between tissue expression of the adhesion molecules and the serum levels of sICAM-1 and sVCAM-1 appeared. VCAM-1 was expressed by two of seven HD cell lines, and sVCAM-1 was detectable in supernatants from these two cell lines. ICAM-1 was expressed by all I-ID cell lines and detectable in supernatants. In the majority of B-CLL and NHL cultures, ICAM-1 expression was upregulated by tumour cells, resulting in detectable sICAM-1 in supernatants.In conclusion, serum levels of both sICAM-1 and sVCAM-1 had prognostic powers equalling or surpassing known prognostic markers in lymphoid neoplasms. The functional consequences of dysregulated serum levels of sICAM-1 and sVCAM-1 in lymphoid neoplasms is at present largely unknown.
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| 44. |
- Fulda, S., et al.
(author)
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Betulinic acid triggers CD95 (APO-1/Fas)- and p53-independent apoptosis via activation of caspases in neuroectodermal tumors
- 1997
-
In: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 57:21, s. 4956-4964
-
Journal article (peer-reviewed)abstract
- Betulinic acid CBA), a melanoma-specific cytotoxic agent, induced apoptosis in neuroectodermal tumors, such as neuroblastoma, medulloblastoma, and Ewing's sarcoma, representing the most common solid tumors of childhood. BA triggered an apoptosis pathway different from the one previously identified for standard chemotherapeutic drugs. BA-induced apoptosis was independent of CD95-ligand/receptor interaction and accumulation of wild-type p53 protein, but it critically depended on activation of caspases (interleukin 1 beta-converting enzyme/Ced-3-like proteases), FLICE/MACH (caspase-8), considered to be an upstream protease in the caspase cascade, and the downstream caspase CPP32/YAMA/Apopain (caspase-3) were activated, resulting in cleavage of the prototype substrate of caspases PARP. The broad-spectrum peptide inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, which blocked cleavage of FLICE and PARP, also completely abrogated BA-triggered apoptosis. Cleavage of caspases was preceded by disturbance of mitochondrial membrane potential and by generation of reactive oxygen species. Overexpression of Bcl-2 and Bcl-x(L) conferred resistance to BA at the level of mitochondrial dysfunction, protease activation, and nuclear fragmentation. This suggested that mitochondrial alterations were involved in BA-induced activation of caspases. Furthermore, pax and Bcl-x(s), two death-promoting proteins of the Bcl-2 family, were up-regulated following BA treatment. Most importantly, neuroblastoma cells resistant to CD95- and doxorubicin-mediated apoptosis were sensitive to treatment with BA, suggesting that BA may bypass some forms of drug resistance. Because BA exhibited significant antitumor activity on patients' derived neuroblastoma cells ex vivo, BA may be a promising new agent for the treatment of neuroectodermal tumors in vivo.
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| 45. |
- Hansson, Tony
(author)
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Coeliac disease : Clinical and immunological aspects
- 1999
-
Doctoral thesis (other academic/artistic)abstract
- A better immunological definition of coeliac disease and highly discriminatory serum markers are needed to identify children with early mucosal lesions and for rapid follow-up and a better knowledge of antigen reactivity and cytokine production will be needed to clarify the pathogenic mechanisms.The numbers of circulating IgAanti-gliadin antibody-producing (IgAAGA SFC) cells were increased in patients with untreated coeliac disease compared to controls and treated coeliac disease patients. In children with coeliac disease the numbers of IgAAGA SFC increased rapidly after gluten challenge. The levels of IgA specific for human as well as guinea-pig tissue transglutaminase (tTG) were increased in the untreated coeliac diseasechildren compared to the control groups. A human erythrocyte tTG ELISAassay had the highest sensitivity (100%) and a specificity of 98%.The numbers of IFN-γ producing cells in the peripheral blood was increased in children with untreated celiac disease as compared to healthy controls. The IL-4 production correlated with the serum levels of total IgE. The numbers of IFN-γ producing cells increased after gluten challenge, whereas no such change was evident for IL-4 or IL-10 producing cells. Children with coeliac disease had more mononuclear cells expressing TGF-β1, TNF-αand IFN-γ in the lamina propria as compared to disease controls. TGFβ3 and IL-4 expressing cells were present in the lamina propria as well as in the epithelial layer in children with coeliac disease.In conclusion, our results indicate that: (1) the ELISPOT assay or other methods for detection of antibody production may be helpful in assessing the optimal timing of the biopsy to shorten the duration of gluten challenge, (2) anti-tTG IgA antibodies can be used as a sensitive and specific complement to existing serological tests for coeliac disease, (3) circulating mononuclear cells in children with active coeliac disease secrete cytokines compatible with a type 1 response, (4) mononuclear cells in the gut of children with activecoeliac disease produce type 1 cytokines as well asTGF-β and IL-4.
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| 46. |
- Jansson, Tomas
(author)
-
Methods for selection and optimisation of radiotherapy and early therapy evaluation in breast cancer
- 1998
-
Doctoral thesis (other academic/artistic)abstract
- Adjuvant systemic therapy for breast cancer, the most common malignancy in females, increases survival and this has recently also been demonstrated for postoperative radiotherapy. The aims of this study were to develop an optimised radiotherapeutic technique for postoperative treatment, to analyse the association between p53 status in node-negative patients and radiotherapy, to investigate the incidence of in-breast relapses after conservative surgery and radiotherapy and to determine if positron emissiontomography could be useful for early evaluation of polychemotherapy.A technique with mixed photon and electron beams from an accelerator equipped with a multileaf collimator was developed for irradiation of the breast parenchyma and regional lymph nodes after breast-conserving surgery.Lymph node negative patients with p53 mutated cancers treated with radiotherapy to either the ipsilateral breast parenchyma after sector resection, or the parasternal and supraclavicular fossa after modified radical mastectomy due to medial or central tumours had a statistically significant longer relapse-free, breast cancer-corrected, and overall survival (p=0.0007, p=0.001, p=0.02, respectively) compared with non-irradiated patients.In 672 patients with pT1N0M0 cancers treated with radiotherapy (54 Gy) after breast-conserving surgery 2.5% in-breast relapses appeared after a mean follow-up of 6.8 years.Positron emission tomography with 18FDG and 11C-methionine revealed a decrease in tumour metabolism one to two weeks after the first course of polychemotherapy in 11 of 12 clinically responding patients.
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| 47. |
- Lindholm, C-E, et al.
(author)
-
Prognostic factors for tumour response and skin damage to combined radiotherapy and hyperthermia in superficial recurrent breast carcinomas
- 1995
-
In: International Journal of Hyperthermia. - : Informa UK Limited. - 0265-6736 .- 1464-5157. ; 11:3, s. 337-355
-
Journal article (peer-reviewed)abstract
- Prognostic factors for complete tumour response and acute skin damage to combined hyperthermia and radiotherapy were analysed in material of patients with breast cancer, recurrent in previously irradiated areas. Radiotherapy was given daily to a total absorbed dose of 30.0 Gy in 2 weeks or 34.5 Gy in 3 weeks. The first radiotherapy schedule was combined with heat twice weekly, a total of four heat treatments (schedule A). The second radiotherapy schedule was combined with heat either once or twice a week resulting in a total of three (schedule B) or six (schedule C) heat treatments. Heat was induced with microwaves (2450, 915 or 434 MHz) via external applicators and always given after the radiotherapy fraction. The complete response (CR) rate in evaluable patients was 71% (49/69). There was no significant difference in CR rate between the three different hyperthermia schedules. The CR rates were 74% (14/19), 65% (15/23) and 74% (20/27) for schedules A, B and C respectively. The only factor predicting CR, evaluated both uni- and multivariately, was the CRE-value for the present radiotherapy dose (p = 0.02). If only tumours treated with 915 MHz were taken into account, however, then the highest minimum temperature at a given heat session predicted complete response (p = 0.03). This was true also in a multivariate analysis of this subgroup of tumours. A Kaplan-Meier analysis (log rank test) showed no significant difference in duration of CR between the different treatment schedules. Cox's proportional hazards method revealed three significant factors: tumour size (negatively correlated, p = 0.007), the time interval between the diagnosis of the primary tumour and the present treatment (p = 0.02) and the average temperature (0.03). Maximum acute skin reactions in the treatment field were scored according to an ordinal scale of 0-8, modified after WHO 1979. Twenty-six treatment areas (32%) expressed more severe skin damage (score > or = 5) in terms of desquamation with blisters (14%) and necrosis or ulceration (19%). Factors correlated with skin damage were the size of the lesion area (p = 0.011), the highest average maximum temperature during a given heat session (p = 0.03) and the fractionation schedule of hyperthermia (p = 0.05). The extent of previous radiotherapy absorbed dose, previous surgery in the treated area or previous chemotherapy had no significant influence on the acute skin reactions.
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| 48. |
- Nordin, Karin
(author)
-
Psychological responses to gastrointestinal cancer
- 1998
-
Doctoral thesis (other academic/artistic)abstract
- The overall aim of the present thesis is to gain knowledge about psychological distress and adjustment in gastrointestinal cancer patients (colon, rectum, gastric, pancreatic or biliary) at various phases of their disease.Reactions to the diagnosis, anxiety, depression and coping were investigated in newly diagnosed patients (n=139). Repeated assessments were performed throughout the fast year after the diagnosis. Only a limited group reported high levels of anxiety (17%) and depression (21%) close to the diagnosis. Patients with colon or rectal cancer, most of whom were potentially cured, had a more confronting attitude to their diagnosis and reported more 'Fighting Spirit' than patients with gastric and pancreatic/biliary cancer. These responses were associated with better emotional well-being. The former group also reported less `Hopeless/helplessness' and 'Anxious preoccupation', which were related to higher levels of psychological distress. There were no changes over time in mean levels of anxiety and depression and virtually no changes in mean values of the coping subscales. In a separate group (n=141), overall levels of anxiety, depression and worry were low in conjunction to a medical follow-up control visit approximately two years after diagnosis.Levels of anxiety and depression at diagnosis predicted a similar status six months later. A model based on standardised cut-off scores of moderate or high levels of anxiety or depression and intrusive thoughts close to the diagnosis was used to identity patients with prolonged psychological distress.A psychometric analysis was performed of the Mental Adjustment to Cancer (MAC) scale (n=868 patients with various cancers). The reliability of the original subscales was satisfying. A confirmatory factor analysis revealed a factor structure including 28 of the original 40 items in four factors. Both versions of the MAC confound coping efforts and emotional outcomes, preventing analyses of coping-outcome relations.The main conclusion is that a majority of gastrointestinal cancer patients cope well with their disease in the short as well as in the long run.
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| 49. |
- Weigelt, Cecilia
(author)
-
Tumor-targeted superantigens for experimental immunotherapy of human leukemia/lymphoma
- 1998
-
Doctoral thesis (other academic/artistic)abstract
- Bacterial superantigens (SAgs) have the property of stimulating high proportions of T cells expressing certain TCR Vβ sequences. The SAg first binds with high affinity to HLA class II molecules on the target cell and then stimulates the T cell to produce cytokines and to become cytotoxic. HLA class II+ target cells may be lysed by cytotoxic T cell cytokines such as TNFα and IFNγ but also by direct cell contact. Staphylococcus enterotoxin A (SEA) is a bacterial SAg produced by certain Staphylococcus areus strains. The HLA class II binding affinity of SEA was reduced by a point mutation (D227A, generating SEAm) not affecting T cell activating properties. This SEAm was first fused to protein A (PA) and later to the Fab-part of an anti-CD19 mAb. Using either fusion protein, cytotoxic T cells (CTLs) were successfully redirected from HLA class II molecules to a defined target structure.Cells from patients with chronic B-lymphocytic leukemia (B-CLL) were highly sensitive for SAg-dependent cell-mediated cytotoxicity (SDCC) using allogeneic SEA-reactive T cells in vitro. T cells targeted by the PA-SEAm fusion protein (FP) and B-cell reactive mAbs also killed the malignant cells. Activation of target cells with a phorbol ester, increased surface ICAM-1, LFA-1, LFA-3 and HLA-DR expression and enhanced their sensitivity for SDCC. The PA-SEAm FP was also used together with myeloid cell reactive mAbs and CTLs to kill 10 different acute or chronic myeloid leukemic (AML or CML) cell line cells in vitro.High concentrations of TNFα and IFNγ in vitro were not directly toxic to target cells exposed for 4h, arguing for other killing mechanisms. One likely mechanism was lytic killing by perforin and granzymes, since inhibition of granulae abolished the cytotoxic effect. MAbs against the Fas antigen did not interfere with killing.The anti-CD19-Fab-SEAm FP used together with CTLs efficiently killed CD19+ normal and malignant B cells. Malignant cells included both tumor B cell lines and tumor cells from patients with B non-Hodgkin's lymphoma (B-NHL). The sensitivity of target cells varied and was correlated to surface ICAM-1 expression. In vivo therapeutic effects were monitored in a humanized severe combined immunodeficiency disease (SCID) model. A significant reduction of tumor weight was registered in treated animals.In conclusion, antibody-superantigen FPs are attractive agents for treating human hematopoietic tumors resistant to conventional therapy. There are abundant numbers of potential effector T cells in lymphoma tissue and the bioaccessibility is good. The SAg activates about 1/5 of all T cells, leaving the majority unaffected. In this thesis, different immunotherapeutic concepts are discussed and compared with targeted SAg-therapy.
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| 50. |
- Karlsson, Mats G., 1960-, et al.
(author)
-
No association between immunohistochemical expression of p53, c-erbB-2, Ki-67, estrogen and progesterone receptors in female papillary thyroid cancer and ionizing radiation
- 1997
-
In: Cancer Letters. - Clare, Ireland : Elsevier. - 0304-3835 .- 1872-7980. ; 120:2, s. 173-177
-
Journal article (peer-reviewed)abstract
- An association has previously been reported between exposure to medical diagnostic ionizing radiation and papillary thyroid cancer in women. To further evaluate potential mechanisms in carcinogenesis, the expression of p53, c-erbB-2, as well as Ki-67, estrogen and progesterone receptors were analyzed by immunohistochemistry in 19 women exposed to X-rays and for comparison in nine women without such reported exposure. They all had papillary thyroid cancer. No difference was found between these groups. The results of this study showed that p53, c-erbB-2, Ki-67, estrogen and progesterone receptors are not involved in papillary thyroid cancer associated with exposure to medical diagnostic ionizing radiation.
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