| 111. |
- Koul, Anjila, et al.
(författare)
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TP53 protein expression analysis by luminometric immunoassay in comparison with gene mutation status and prognostic factors in early stage endometrial cancer
- 2002
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Ingår i: International Journal of Gynecological Cancer. - : BMJ. - 1048-891X .- 1525-1438. ; 12:4, s. 362-371
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the TP53 tumor suppressor gene have been shown to significantly correlate with poor prognosis in endometrial cancer. In the present study we have evaluated a luminometric immunoassay (LIA) for quantitative estimation of TP53 protein expression in 65 cytosol preparations from endometrial cancer, previously analyzed for mutations in TP53 exons 4-10. LIA showed high (greater than or equal to 0.6 ng/mg protein) expression of TP53 protein in all eight tumors with missense mutation, but high protein levels were also detected in 15 tumors with normal TP53 sequence. All four tumors with nonsense or frameshift mutations had low or no TP53 protein expression. LIA was further evaluated in a retrospective study of 201 cytosol samples from endometrial cancer. TP53 overexpression (>= 0.6 ng/mg protein) was observed in 22% of the tumors and correlated with nonendometrioid histology types (P = 0.005), poorly differentiated tumors (P = 0.001), higher FIGO grade (P = 0.001), DNA nondiploidy (P = 0.002), and high S-phase fraction (P = 0.03). After a median follow-up time of 6.8 years (range 0.7-9.9 years), 22 (13%) progressions were observed in the 175 patients with early stage (I-II) disease. TP53 overexpression (P = 0.04), FIGO grade 3 vs. 1 + 2 (P = 0.01), higher age (P = 0.02), and DNA nondiploidy (P < 0.001) showed significant correlation to shorter progression-free survival in these patients. We conclude that TP53 protein analysis by LIA provides an incomplete correlation to mutation status and cannot substitute for mutation analysis in assessment of prognosis in endometrial carcinoma. In comparison to TP53 overexpression and higher FIGO grades, DNA nonploidy status seems to be a better prognostic indicator to define a subset of early stage endometrial cancer patients who may benefit by adjuvant chemotherapy/radiotherapy.
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| 112. |
- Krook, Henrik
(författare)
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Xenograft Rejection : A Study of Cytokine mRNA Expression in Experimental Models
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Acute cellular xenograft rejection of ICCs triggered mRNA expression of proinflammatory cytokines (IL-1b and TNF-a), Th1 associated cytokines (IL-12p40, IL-2 and IFN-g) and Th2 associated cytokines (IL-4 and IL-10). The peak values and the kinetics of the mRNA expression indicated that acute cellular xenograft rejection is enhanced by the proinflammatory response and mediated by the Th1 associated response, whereas the function of the Th2 associated response most likely is to counteract the Th1 associated cytokines and thereby inhibit bystander damage by the delayed type hypersensitivity like rejection process. Tacrolimus was shown to have a protective effect on the ICC xenografts, which was linked with inhibition of Th1 associated cytokines. This beneficial effect was paradoxically abrogated by prednisolone. The cytokines were interpreted to mediate the same response during cellular rejection of vascularized xenografts in the mouse-to-rat heart transplant model as in the non vascularized ICC model, even though the the response includes intragraft antibody deposits. Also the xenogeneic neural grafts implanted into the CNS displayed a similar cytokine response, but this process was slower and had less distinguished peak values compared to the ICC xenografts.The shortage of organs is the major limitation for clinical allotransplantation. For making clinical xenotransplantation possible and thereby eliminate the organ shortage, issues regarding ethical dilemmas, microbiological hazards, physiological incompatibilities and immunological problems need to be addressed. The aim of the studies in this thesis was to investigate the mechanisms behind acute cellular xenograft rejection. The immunological response, with a focus on the cytokine mRNA expression, was analysed at different time points in rats transplanted with fetal porcine islet like cell clusters (ICCs), mouse hearts, or syngeneic, allogeneic, concordant or discordant xenogeneic neural tissue grafts.In conclusion, both the cytokine mRNA expression and the morphology of acute cellular xenograft rejection bear a close resemblance to a delayed type hypersensitivity reaction, primarily mediated by indirect antigen presentation. This might explain why clinically used immunosuppressive protocols normally are inefficient for use in xenotransplantation, since these are presumed to primarily suppress T cell response triggered direct antigen presentation, which dominates during allogeneic acute rejection.
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| 113. |
- Lambe, M., et al.
(författare)
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Pregnancy and risk of renal cell cancer : a population-based study in Sweden
- 2002
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Ingår i: British Journal of Cancer. - London, United Kingdom : Nature Publishing Group. - 0007-0920 .- 1532-1827. ; 86:9, s. 1425-1429
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiological findings indicate that hormonal influences may play a role in the etiology of renal cell cancer (RCC). The possible effect of childbearing remains enigmatic; while some investigators have reported a positive association between number of births and renal cell cancer risk, others have not. A case-control study, nested within a nation-wide Fertility Register covering Swedish women born 1925 and later, was undertaken to explore possible associations between parity and age at first birth and the risk of renal cell cancer. Among these women a total of 1465 cases of RCC were identified in the Swedish Cancer Register between 1958 and 1992 and information on the number of live childbirths and age at each birth was obtained by linkage to the Fertility Database. For each case, five age-matched controls were randomly selected from the same register. Compared to nulliparous women, ever-parous women were at a 40% increased risk of RCC (Odds Ratio [OR]=1.42; 95% CI 1.19-1.69). The corresponding OR for women of high parity (five or more live births) was 1.91 (95% CI 1.40-2.62). After controlling for age at first birth among parous women, each additional birth was associated with a 15% increase in risk (OR=1.15; 95% CI 1.08-1.22). The observed positive association between parity and renal cell cancer risk is unlikely to be fully explained by uncontrolled confounding, but warrants further evaluation in large studies, with allowance for body mass index.
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| 114. |
- Landberg, Göran
(författare)
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Multiparameter analyses of cell cycle regulatory proteins in human breast cancer: a key to definition of separate pathways in tumorigenesis.
- 2002
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Ingår i: Adv Cancer Res. - 0065-230X. - 9780120066841 ; 84, s. 35-56
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Breast cancer is one of the most common cancer forms affecting many women. The disease nevertheless has widely varying behavior and therefore patient outcome, and an important undertaking is to define and understand the molecular mechanisms behind these actions. Defects in the G1/S transition in the cell cycle affect both tumor proliferation and the fidelity of check points responsible for chromosomal integrity and DNA damage response and has lately been shown to represent one of a rather limited set of key aberrations in the transformation process. Many cell cycle regulatory proteins are either oncogenes or suppressor genes or are closely associated to the transformation process. The types of aberrations in the G1/S transition seem to be different in various cancers but are nevertheless often linked to clinical behaviors. In this review the role of multiparameter analyses of cell cycle regulatory proteins in breast cancer will be outlined with special attention to pattern analyses as well as the definition of two contrasting pathways in tumorigenesis defined by either cyclin D1 or cyclin F overexpression.
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| 115. |
- Larsen, EC, et al.
(författare)
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A role for PKC-epsilon in Fc gamma R-mediated phagocytosis by RAW 264.7 cells
- 2002
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Ingår i: Journal of Cell Biology. - : Rockefeller University Press. - 0021-9525 .- 1540-8140. ; 159:6, s. 939-944
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Tidskriftsartikel (refereegranskat)abstract
- Protein kinase C (PKC) plays a prominent role in immune signaling, and the paradigms for isoform selective signaling are beginning to be elucidated. Real-time microscopy was combined with molecular and biochemical approaches to demonstrate a role for PKC-epsilon in Fcgamma receptor (FcgammaR)-dependent phagocytosis. RAW 264.7 macrophages were transfected with GFP-conjugated PKC isoforms, and GFP movement was followed during phagocytosis of fluorescent IgG-opsonized beads. PKC-epsilon, but not PKC-delta, concentrated around the beads. PKC-epsilon accumulation was transient; apparent as a "flash" on target ingestion. Similarly, endogenous PKC-epsilon was specifically recruited to the nascent phagosomes in a time-dependent manner. Overexpression of PKC-epsilon, but not PKC-alpha, PKC-delta, or PKC-gamma enhanced bead uptake 1.8-fold. Additionally, the rate of phagocytosis in GFP PKC-epsilon expressors was twice that of cells expressing GFP PKC-delta. Expression of the regulatory domain (ERD) and the first variable region (epsilonV1) of PKC-epsilon inhibited uptake, whereas the corresponding PKC-delta region had no effect. Actin polymerization was enhanced on expression of GFP PKC-epsilon and ERD, but decreased in cells expressing epsilonV1, suggesting that the epsilonRD and epsilonV1 inhibition of phagocytosis is not due to effects on actin polymerization. These results demonstrate a role for PKC-epsilon in FcgammaR-mediated phagocytosis that is independent of its effects on actin assembly.
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| 116. |
- Leek, Håkan, et al.
(författare)
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Pilocarpine treatment of xerostomia in head and neck patients
- 2002
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Ingår i: Micron. - 0968-4328. ; 33:2, s. 153-155
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Forskningsöversikt (refereegranskat)abstract
- We studied the effect of pilocarpine hydrochloride, a parasympathicomimewtic agent, on major salivary gland output and subjective responses in 40 patients with salivary hypofunction. Pilocarpine increased salivary output or gave significant symptomatic relief in 21 of the 40 patients. The women fared better than the men. Side effects were uncommon, were generally mild, and caused no treatment interruption. These results indicate that pilocarpine is effective in relieving the signs and symptoms of postradiation xerostomia. (C) 2001 Elsevier Science Ltd. All rights reserved.
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| 117. |
- Lehmann, Sören
(författare)
-
In vitro studies of retinoids and arsenic in non-M3 acute myeloid leukemia
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Despite advances in the treatment of patients with acute myeloid leukemia (AML), the majority of the patients will die from their disease. The current intensive therapy for AML is also complicated my substantial morbidity and mortality and, as a result, many patients cannot be given the most effective therapy. Therefore, the need for more effective as well as less toxic treatment approaches for AML is urgent. Retinoids and arsenic has recently shown impressive results in the treatment of acute promyelocytic leukemia (APL) and both drugs exhibit less toxic effects than the commonly used chemotherapeutic drugs. In these studies we have investigated the effects of retinoids and arsenic in cells from patients with non-APL (or non-M3) AML. Furthermore, we have investigated what mechanisms that could be of importance for the sensitivity to these drugs. The results showed that there is a pronounced heterogeneity in the sensitivity to the retinoids all-trans-retinoic acid (ATRA) and 9-cis-RA but cells from the majority of the patients were sensitive and some cases exhibited a pronounced sensitivity to retinoids. There was no cross-resistance between the retinoids and daunorubicin (DNR) and cells that were more resistant to DNR tended to be more retinoidsensitive. Also, CD34-positive AML cells were more sensitive than the CD34-negative. In order to find markers for retinoid sensitivity we correlated the expression of retinoid receptors (RARs and RXR alpha) and retinoid bindings proteins (CRBPI and CRABPs) to the sensitivity to ATRA in the patient samples. No correlation between the sensitivity to the retinoids and the basal mRNA expression of any of these proteins was found. However, upregulation of RAR beta and CRABPII after ATRA exposure did significantly correlate to retinoid sensitivity. For arsenic, a significant dose dependent sensitivity was found in all the patient samples even at concentrations below those that are seen in plasma during APL treatment. The sensitivity to arsenic was then compared to that of common AML drugs such as anthracyclines, etoposide, AMSA and Ara-C. There was a significant correlation in the sensitivity between the different anthracyclines as well as between the anthracyclines and etoposide and AMSA. However, all correlation coefficients were negative for the comparisons between arsenic and the other drugs and most so between arsenic and idarubicin. We then investigated the sensitivity to arsenic in P-gp-expressing cell lines showing that P-gp expression does not affect the sensitivity to arsenic. We also investigated the sensitivity in cell lines with either increased expression of MRP 1, downregulated topoisomerase II or in cells that were FAS-resistant. None of these resistant cell lines were shown to exhibit any decrease in sensitivity to arsenic compared to its non-resistant cell line. The only cell line that showed a decreased arsenic sensitivity was the lung cancer cell line GLC4/ADR. In addition to the overexpression of the lung resistance protein (LRP), these cells exhibited higher concentrations of GSH than the wild type GLG4. The multidrug resistant reverser and pyridine analogue PAK-104P exerted a powerful sensitizing effect on the cells together with arsenic, both in resistant and nonresistant cells. This sensitizing effect was accompanied by a slight decrease in GSH but this effect was moderate compared to the strong effect on cell toxicity. Therefore, we suggest that the sensitizing effect of PAK-104P should be further studied as well as its potential as a sensitizer to arsenic in vivo.
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| 118. |
- Lennartsson, Johan, 1972-
(författare)
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Stem Cell Factor Induced Signal Transduction
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Stem Cell Factor (SCF) can function as a survival factor, a mitogen or a chemoattractant depending on cell type. Binding of SCF to c-Kit induces dimerization and subsequent autophosphorylation of the receptor. This thesis describes the intracellular signal transduction elicited by c-Kit. In the search for signal transduction molecules binding to activated c-Kit, we identified the adaptor proteins Grb2 and Grb7 as interacting partners. Grb2 could associate to Tyr-703 in the kinase insert as well as to Tyr-936 in the C-terminal tail of c-Kit. However, Grb7 could only bind to Tyr-936. Tyr-568 in c-Kit is essential for SCF induced association and activation of Src family kinases (SFK). A mutated receptor that could not activate SFK (Y568F or Y568/570F) showed reduced Shc phosphorylation, Ras GTP loading, Erk activation and induction of c-fos. However, activation of SFK is not essential for the mitogenic response as measured by DNA synthesis.Tyr-900 in c-Kit was identified as a SFK dependent phosphorylation site. The adaptor protein Crk and the p85 subunit of PI3’-kinase could associate with phosphorylated Tyr-900. In addition, we could demonstrate a constitutive complex between Crk and p85, suggesting indirect binding of Crk to Tyr-900 via p85. Mutation of Tyr-900 (Y900F) led to a reduced phosphorylation of Crk-II, loss of the second wave of Erk phosphorylation and a reduced mitogenic response. In addition the mutated receptor showed an increased ligand-induced degradation as compared to the wild-type receptor.There exist two splice forms of c-Kit that differ in the presence or absence of four amino acids in the extracellular juxtamembrane region. These splice forms bind SCF with similar affinity but display striking differences in signaling characteristics, e.g. in phosphorylation kinetics, ligand-induced c-Kit degradation and activation of Erks. However, other pathways are activated similarly by both splice forms, such as the Ser/Thr kinase Akt which lies downstream of PI3’-kinase. In this study we show that differential phosphorylation of the various tyrosine residues occurs. Interestingly, Tyr-568 is more efficiently phosphorylated in the shorter form leading to stronger binding of SFK, whereas the PI3’-kinase binding site showed a similar degree of phosphorylation consistent with the data on Akt activation.
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| 119. |
- Lennernäs, Bo, 1963, et al.
(författare)
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Anorectal function after modern conformal radiation therapy for prostate cancer: a pilot study
- 2002
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Ingår i: Tech Coloproctol. - 1123-6337. ; 6:2, s. 101-4
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated whether, and if so to what extent, radiotherapy applied on a series of patients with prostate cancer influenced the patient's bowel habits and anorectal function. Ten consecutive patients participated in the study. The median age of the patients was 74 years (range, 61-71) and the average follow-up period was 22 (range, 15-28) months. Four patients were irradiated using external beam radiotherapy (2 Gy/day for a total of 70 Gy); 6 patients were irradiated with a combination of external beam radiotherapy (50 Gy, 2 Gy/day) and high dose rate brachytherapy (two 10-Gy fractions). Upon interview, patients disclosed characteristic functional disturbances such as urgency with occasional accidents, faecal soiling and spotting of underwear. Involuntary release of gas was another embarrassing problem. One or more of these problems were present in half of the patients. Endoscopy disclosed signs of mild proctitis. Sphincter pressure, rectal capacity and the volume threshold for appreciation of defecation urge were all significantly lower in patients than in 10 age-matched controls. In conclusion, disturbances of anorectal function with imperfection of incontinence still occur so some extent despite improved precision, and reduced margins offered by the modern conformal radiation therapy of prostate cancer. Anal sphincter function, the reservoir capacity of the rectum and its sensory function are adversely affected and radiation proctitis with rectal fibrosis and damage of the extrinsic innervations of the anal sphincters appear to be the principal causative factors. Although conformal radiotherapy together with better positioning may be two substantial improvements of modern radiotherapy, further improvements are needed.
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| 120. |
- Levin Jakobsen, Anne-Marie, 1955, et al.
(författare)
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Expression of synaptic vesicle protein 2 (SV2) in neuroendocrine tumours of the gastrointestinal tract and pancreas.
- 2002
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Ingår i: The Journal of pathology. - : Wiley. - 0022-3417. ; 196:1, s. 44-50
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Tidskriftsartikel (refereegranskat)abstract
- Identification of neuroendocrine differentiation in tumours has important implications for prognosis and therapy. The aim of the present study was to evaluate monoclonal antibodies against synaptic vesicle protein 2 (SV2) as histopathological markers for neuroendocrine differentiation in tumours of the gastrointestinal tract and pancreas. Paraffin blocks from 211 gastrointestinal tumours were examined by immunocytochemistry, using a monoclonal antibody against SV2. Virtually all endocrine tumours of the gastrointestinal tract (11/11 gastric, 53/53 ileal, 16/21 appendiceal, and 22/22 rectal) and pancreas (24/24) were positively labelled. SV2 labelling was also demonstrated in gastrointestinal pacemaker cell tumours (8/8), while adenocarcinomas of the gastrointestinal tract and pancreas were negative, with the exception of occasional adenocarcinomas demonstrating weak SV2 labelling (stomach 1/22, rectum 1/29, and pancreas 0/21). Western blotting of tumour biopsies confirmed expression of SV2 in endocrine tumours of the gastrointestinal tract and pancreas. No relationship was observed between SV2 expression in tumours and hormone production or malignant potential. In conclusion, SV2 is expressed in neuroendocrine tumours of the gastrointestinal tract and pancreas, but not in non-endocrine tumours. The SV2 monoclonal antibody can therefore be used as a general marker for neuroendocrine differentiation in gastrointestinal and pancreatic tumours.
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