| 51. |
- Zelvyté, Inga
(författare)
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Alpha 1-antitrypsin: A Role in Cancer Progression
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alpha1-antitrypsin (AAT), a circulating single-chain glycoprotein is the most abundant serine proteinase inhibitor in human plasma. AAT is an acute phase protein, its levels increase rapidly to concentrations exceeding 50mM in response to inflammation, infection and malignant diseases. Since AAT is a powerful inhibitor of neutrophil elastase and proteinase 3, it is generally assumed that its physiological function is to protect host tissue from the proteolytic actions of these proteinases. However, in vivo AAT is found not only in the native, inhibitory form, but also modified non-inhibitory forms including polymerized, cleaved and/or degraded. Recent findings suggest that non-inhibitory forms of AAT may also express biological activity, un-related to serine proteinase inhibition. The overall aim of the studies upon which this thesis is based was to test a hypothesis that AAT in native and modified molecular forms may exert multiple biological effects on tumor cell behaviour, in vitro. Cancer patients with high levels of proteinase inhibitors are often characterized by a more disseminated disease and worse prognosis. We have found that plasma levels of AAT, alpha1-antichymotrypsin and secreted leukocyte proteinase inhibitor are significantly higher in newly diagnosed lung cancer patients, particularly in cases with metastases, compared to the age and gender matched controls. These results support the view that proteinase inhibitor levels may reflect or contribute to tumor progression. We next examined the effects of inhibitory (native) and non-inhibitory (polymerized and/or C-terminal fragment, C-36) forms of AAT on human neutrophil and lung cancer cell functional activities separately and in co-culture models, in vitro. Our data show that the C-36 peptide of AAT, in a concentration-dependent manner, induces neutrophil chemotaxis, adhesion, degranulation and superoxide generation, while native and polymerized AAT at similar and higher concentrations were without effect. In co-culture experiments we observed that interactions between neutrophil released content and lung cancer cells were modulated by exogenously added AAT and C-36 peptide. Similar experiments performed in vitro on lung, breast and pancreatic cancer cells showed that AAT, depending on its molecular form, may either promote or inhibit cancer cell proliferation, invasiveness and the ability to release certain biomarkers, such as growth factors, cytokines and matrix metalloproteinases. Together our findings support the hypothesis that AAT’s role in cancer progression might not only be limited to its property of inhibiting overexpressed proteinases but also to direct effects on inflammatory and tumor cells.
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| 52. |
- Eberhard, Jakob, et al.
(författare)
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Impact of therapy and androgen receptor polymorphism on sperm concentration in men treated for testicular germ cell cancer: a longitudinal study.
- 2004
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Ingår i: Human Reproduction. - : Oxford University Press (OUP). - 0268-1161 .- 1460-2350. ; 19:6, s. 1418-1425
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Tidskriftsartikel (refereegranskat)abstract
- Abstract in Undetermined BACKGROUND: Testicular cancer (TC) patients have a high survival rate, and the question of post-therapy recovery of sperm production and its dependence on genetic predisposition is of major interest. METHODS: Ejaculates were obtained from 112 TC patients at one or more of the following time points: post-orchidectomy, or 6, 12, 24, 36 and 60 months post-therapy. The lengths of the androgen receptor (AR) function modulating CAG and GGN repeats in leukocyte DNA were also analysed. RESULTS: No significant decrease in sperm concentration was seen in men who received 1-2 cycles of adjuvant chemotherapy (ACT). Radiotherapy (RT) or more than two cycles of chemotherapy (HCT) caused an initial decline in sperm concentration, which returned to pre-treatment levels 2-5 years after therapy. In the HCT group, sperm concentration 12-24 months post-treatment (T(12-24)) was inversely correlated with CAG length (rho = -0.72, P = 0.03). The type of treatment, but not the concentration at T(0), was an independent predictor of sperm concentration at T(6) (P < 0.0005) and T(12-24) (P = 0.004). CONCLUSION: ACT did not induce a significant decline in sperm concentration. After HCT and RT, a significant reduction of sperm concentration was observed, recovering to pre-treatment levels 2-5 years post-treatment. In HCT-treated patients, the AR CAG length influenced the recovery of spermatogenesis.
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| 53. |
- Dahlén, A, et al.
(författare)
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Analysis of the distribution and frequency of trisomy 7 in vivo in synovia from patients with osteoarthritis and pigmented villonodular synovitis
- 2001
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Ingår i: Cancer Genetics and Cytogenetics. - 0165-4608. ; 131:1, s. 19-24
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Tidskriftsartikel (refereegranskat)abstract
- Osteoarthritis (OA) and pigmented villonodular synovitis (PVNS) are disorders associated with trisomy 7. The aim of the present study was to determine the frequency and distribution of the cells with +7 in vivo by analyzing sections of paraffin-embedded synovia from patients affected by OA, PVNS, other forms of synovitis [hemorragic synovitis (HS) and chronic synovitis (CS)], and from individuals without joint disease. Fluorescence in situ hybridization (FISH), using a centromeric probe for chromosome 7, showed that the mean frequency of trisomic nuclei in 5-microm sections was highest in PVNS (9.0%), followed by CS (5.9%), OA (5.6%), and HS (4.6%), whereas trisomic nuclei were rare (0.7%) in normal tissue. When 8-microm sections were studied, the frequencies of trisomic cells in OA and control synovia increased to 6.7% and 1.5%, respectively. Trisomic nuclei were found in all cases, including those for which cytogenetic analysis of short-term cultures had not disclosed any trisomic cells. Overall, the trisomic cells were scattered within the tissue. However, small clusters of cells with +7 were found in three cases. By hematoxylin-eosin staining of the slides used for FISH analysis it could be shown that the clustered trisomic cells were proliferating synoviocytes within villous extensions of the synovial membrane.
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| 54. |
- Hedström, Mariann, et al.
(författare)
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Distressing and positive experiences and important aspects of care for adolescents treated for cancer : adolescent and nurse perceptions
- 2004
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Ingår i: European Journal of Oncology Nursing. - : Elsevier BV. - 1462-3889 .- 1532-2122. ; 8:1, s. 6-17
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Tidskriftsartikel (refereegranskat)abstract
- Distressing and positive experiences for adolescents with cancer with regard to being told the diagnosis, receiving chemotherapy and being admitted to the ward, and important aspects of care for adolescents with cancer was investigated. Data were gathered through semi-structured interviews with 23 adolescents and 21 nurses, and analysed by content analysis. The findings indicate that cancer during adolescence is connected with a range of negative experiences such as fears of alienation, fears of altered appearance, fears of dying, and various physical concerns. Positive experiences include positive relations to staff and being well cared for. Important care for adolescents treated for cancer consists mainly of meeting nice, friendly, supportive, and competent staff, who provide them with age-appropriate information. The findings indicate that adolescents with cancer experience a range of negative and positive experiences related to disease and treatment and that good care for adolescents with cancer is a broad, complex, and multidimensional phenomenon.
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| 55. |
- Jin, Yuesheng, et al.
(författare)
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Clonal chromosome abnormalities in premalignant lesions of the skin.
- 2002
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Ingår i: Cancer Genetics and Cytogenetics. - 0165-4608. ; 136:1, s. 48-52
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Tidskriftsartikel (refereegranskat)abstract
- Two lesions, actinic keratosis (AK) and squamous cell carcinoma in situ (CIS), are believed to be precursors of squamous cell carcinoma (SCC) of the skin. These lesions can serve as an excellent model system for studying genetic changes associated with the inception of skin SCC. In the present study, five such lesions of the skin, three AKs and two AK+CIS, from three patients were short-term cultured and analyzed cytogenetically. One of the patients (case 3) had also an SCC in addition to three premalignant lesions. All lesions, but one, showed clonal karyotypic abnormalities. The recurrent changes identified were numerical, that is, +7 and +20. The structural rearrangements found in three AK were different, but it could be noted that the distal part of the long arm of chromosome 4 was involved in two AK and the SCC of case 3A. It was also interesting that chromosome 1 participated in structural rearrangements in three AK with band 1p31 being involved in two tumors. The karyotypic profile of these lesions is compared with that of skin SCC; it turns out that the general patterns are different in the sense that the SCC more often have complex karyotypes and display unbalanced aberrations involving the centromeric regions. Some karyotypic similarities between the SCC and their precursors are revealed. The fact that the structural rearrangements involving chromosomal band 3p13 and the centromeric region of chromosome 3 in AK are common features for many types of malignant tumors, including skin SCC, indicates that these changes are early genetic events associated with malignant transformation.
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| 56. |
- Guerin, S, et al.
(författare)
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Radiation dose as a risk factor for malignant melanoma following childhood cancer
- 2003
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Ingår i: European Journal of Cancer. - 1879-0852. ; 39:16, s. 2379-2386
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to determine therapy-related risk factors for the development of melanoma after childhood cancer. Among 4401 3-year survivors of a childhood cancer in eight French and British centres and 25 120 patients younger than 20 years old at first malignant neoplasm (FMN) extracted from the Nordic Cancer Registries, 16 patients developed a melanoma as a second malignant neoplasm (SMN). A cohort study of the French and British cohorts was performed. In a nested case-control study, the 16 patients who developed a melanoma as a SMN (cases) were matched with 3-5 controls in their respective cohort according to gender, age at the first cancer, the calendar year of occurrence of the first cancer and follow-up. Radiotherapy appeared to increase the risk of melanoma for local doses > 15 Gy, Odds Ratio (OR)= 13 (95% Confidence Interval (CI): 0.94-174). Regarding chemotherapy, we observed an increased OR for both alkylating agents and spindle inhibitors, OR 2.7 (95% CI: 0.5-14). Children treated for a gonadal tumour as a FMN were found to be at a higher risk of melanoma, OR 8.7 (95% CI: 0.9-86). The adjusted OR for the local radiation dose was 1.07 (95% CI: 1.00-1.15). In conclusion, radiotherapy may contribute to an increased risk of melanoma as a SMN, but only at very high doses of low linear energy transfer radiation. Common genetic origins between gonadal tumours and malignant melanomas are likely. (C) 2003 Elsevier Ltd. All rights reserved.
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| 57. |
- Ohlsson, Bodil, et al.
(författare)
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Acute taurodeoxycholate-induced pancreatitis in the rat is associated with hyperCCKemia
- 2000
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Ingår i: International Journal of Pancreatology. - 0169-4197. ; 27:3, s. 195-201
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cholecystokinin (CCK) has been suggested to be involved in the development and course of acute pancreatitis. In the present study we measured plasma CCK concentrations in acute experimental pancreatitis (AEP) in the rat, and evaluated the role of circulating CCK levels on the initial pancreatic damage in pancreatitis. METHODS: Endogenous hyperCCKemia was induced by surgical biliodigestive shunt (BDS) and exogenous hyperCCKemia by infusion of CCK-8S. The CCK-A receptor antagonist devazepide was used to antagonize the effect of CCK. Pancreatitis was induced by pancreatic duct infusion of sodium taurodeoxycholate 4 wk after the BDS operation or 1 wk after the start of the infusions. Nonpancreatitic sham- and BDS-operated rats, respectively, were used as control animals as were groups of otherwise untreated rats with pancreatitis. The animals were sacrificed 6 h after induction of pancreatitis. Concentrations of CCK were determined in plasma as were protein and amylase levels in the pancreas and peritoneal exudates. The extent of pancreatic necroses was assessed microscopically. RESULTS: Pancreatitis caused an 11-20-fold increase of circulating CCK as measured after 6 h. In pancreatitic rats with induced hyperCCKemia, there was a further marked increase of plasma CCK. Pancreatic weight and edema, protein and amylase contents, and extent of necroses were the same regardless of the level of plasma CCK. Devazepide had no influence on the studied pancreatic parameters. CONCLUSION: We conclude that acute taurodeoxycholate-induced pancreatitis in the rat is associated with elevated plasma CCK concentrations. There seems, however, not to be any correlation between the degree of hyperCCKemia and the extent of initial pancreatic damage.
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| 58. |
- Räihä, Niels, et al.
(författare)
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Letters to the editor.
- 2004
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Ingår i: Journal of Pediatric Gastroenterology and Nutrition - Jpgn. - : Elsevier BV. - 1536-4801. ; 18:4, s. 453-453
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 59. |
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| 60. |
- Smeland, S, et al.
(författare)
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Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII: prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders
- 2003
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Ingår i: European Journal of Cancer. - 1879-0852. ; 39:4, s. 488-494
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Tidskriftsartikel (refereegranskat)abstract
- From 1990 to 1997, 113 eligible patients with classical osteosarcoma received neo-adjuvant chemotherapy consisting of high-dose methotrexate, cisplatin and doxorubicin. Good histological responders continued to receive the same therapy postoperatively, while poor responders received salvage therapy with an etoposide/ifosfamide combination. With a median follow-up of 83 months, the projected metastasis-free and overall survival rates at 5 years are 63 and 74%, respectively. Independent favourable prognostic factors for outcome were tumour volume < 190 ml, 24-h serum methotrexate > 4.5 muM and female gender. The etoposide/ifosfamide replacement combination did not improve outcome in the poor histological responders. In conclusion, this intensive multi-agent chemotherapy results in > 70% of patients with classical osteosarcoma surviving for 5 years. The data obtained from this non-randomised study do not support discontinuation and exchange of all drugs used preoperatively in histological poor responders. As observed in previous Scandinavian osteosarcoma studies, female gender appears to be a strong predictor of a favourable outcome. (C) 2003 Elsevier Science Ltd. All rights reserved.
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