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Biomedical subjects

J Adolfsson

Publications and source records attributed to J Adolfsson.

At least 19 recordsLinked to original sources
PubMed2006

Genetic variation in the COX-2 gene and the association with prostate cancer risk.

COX-2 is a key enzyme in the conversion of arachidonic acid to prostaglandins. The prostaglandins produced by COX-2 are involved in inflammation and pain response in different tissues in the body. Accumulating evidence from epidemiologic studies, chemical carcinogen-induced rodent models and clinical trials indicate that COX-2 plays a role in human carcinogenesis and is overexpressed in prostate cancer tissue. We examined whether sequence variants in the COX-2 gene are associated with prostate cancer risk. We analyzed a large population-based case-control study, cancer prostate in Sweden (CAPS) consisting of 1,378 cases and 782 controls. We evaluated 16 single nucleotide polymorphisms (SNPs) spanning the entire COX-2 gene in 94 subjects of the control group. Five SNPs had a minor allele frequency of more than 5% in our study population and these were genotyped in all case patients and control subjects and gene-specific haplotypes were constructed. A statistically significant difference in allele frequency between cases and controls was observed for 2 of the SNPs (+3100 T/G and +8365 C/T), with an odds ratio of 0.78 (95% CI=0.64-0.96) and 0.65 (95% CI=0.45-0.94) respectively. In the haplotype analysis, 1 haplotype carrying the variant allele from both +3100 T/G and +8365 C/T, with a population frequency of 3%, was also significantly associated with decreased risk of prostate cancer (p=0.036, global simulated p-value=0.046). This study supports the hypothesis that inflammation is involved in prostate carcinogenesis and that sequence variation within the COX-2 gene influence the risk of prostate cancer.

Aged↗
PubMed2002

The unrecognised cost of cancer patients' unrelieved symptoms:a nationwide follow-up of their surviving partners.

We investigated if a cancer patient's unrelieved symptoms during the last 3 months of life increase the risk of long-term psychological morbidity of the surviving partner. All women (n=506) living in Sweden under 80 years of age, who lost their husband/partner owing to cancer of the prostate in 1996 or of the urinary bladder in 1995 or 1996 were asked to answer an anonymous postal questionnaire, 2-4 years after their loss. The widows' psychological morbidity was associated with the patient's unrelieved mental symptoms. When the patient was perceived to have been very anxious during last three months of life (compared to no observed symptoms) the relative risks for the widows' psychological morbidity were: 2.5 (1.4-4.3) for depression and 3.4 (1.4-8.2) for anxiety. When comparing reports of the patient's pain (much vs no), the relative risks were 0.8 (0.5-1.2) for widowhood depression, and 0.8 (0.4-1.7) for widowhood anxiety. The patients were found to have had adequate access to physical pain control but poor access to psychological symptom control. Efficiency in diagnosing and treating psychological complications of terminally ill cancer patients may not only improve their quality of life but possibly also prevent long-term psychological morbidity of their surviving partners.

Adult↗
PubMed2002

Treatment of patients with clinical T3 prostate cancer.

OBJECTIVE: To describe and evaluate treatment alternatives for patients with clinical T3 prostate cancer. MATERIAL AND METHODS: Literature review with main focus on recent studies in order to include the impact of prostate specific antigen (PSA). The possibility of using neoadjuvant/adjuvant hormonal therapy in combination with surgery or radiation was assessed. Results were related to life expectancy, tumour grade and serum PSA. RESULTS: M and N-staging is mandatory before treatment with curative intent. Watchful waiting is an option for selected patients but early hormonal therapy seems to offer some survival advantages. Standard 65-70Gy external beam radiation is not sufficient for these patients with extracapsular disease but better results are obtained with dose-escalation (beyond 70Gy) and/or adjuvant hormonal therapy. Radical prostatectomy may be an option for patients with long life expectancy and "early" tumours, neoadjuvant hormonal withdrawal is of no proven value. CONCLUSIONS: Patients with a long life expectancy should not be denied treatment with curative intent solely based on the finding of extracapsular disease.

Antineoplastic Agents, Hormonal↗
PubMed2001

Self-renewal of multipotent long-term repopulating hematopoietic stem cells is negatively regulated by Fas and tumor necrosis factor receptor activation.

Multipotent self-renewing hematopoietic stem cells (HSCs) are responsible for reconstitution of all blood cell lineages. Whereas growth stimulatory cytokines have been demonstrated to promote HSC self-renewal, the potential role of negative regulators remains elusive. Receptors for tumor necrosis factor (TNF) and Fas ligand have been implicated as regulators of steady-state hematopoiesis, and if overexpressed mediate bone marrow failure. However, it has been proposed that hematopoietic progenitors rather than stem cells might be targeted by Fas activation. Here, murine Lin(-)Sca1(+)c-kit(+) stem cells revealed little or no constitutive expression of Fas and failed to respond to an agonistic anti-Fas antibody. However, if induced to undergo self-renewal in the presence of TNF-alpha, the entire short and long-term repopulating HSC pool acquired Fas expression at high levels and concomitant activation of Fas suppressed in vitro growth of Lin(-)Sca1(+)c-kit(+) cells cultured at the single cell level. Moreover, Lin(-)Sca1(+)c-kit(+) stem cells undergoing self-renewal divisions in vitro were severely and irreversibly compromised in their short- and long-term multilineage reconstituting ability if activated by TNF-alpha or through Fas, providing the first evidence for negative regulators of HSC self-renewal.

Animals↗
PubMed2001

p53 mutations in urinary bladder cancer.

We have screened for mutations in exons 5-8 of the p53 gene in a series consisting of 189 patients with urinary bladder neoplasms. 82 (44%) neoplasms were lowly malignant (Ta, G1-G2a) and 106 (56%) were highly malignant (G2b-G4 or > or = T1). Only one mutation was in a lowly malignant urinary bladder neoplasm, in total we found p53 mutations in 26 (14%) of the 189 patients. 30% of the samples had loss of heterozygosity (LOH) for one or both of the p53 exogenic (CA)n repeat and the p53 intragenic (AAAAT)n repeat markers. 31 samples (21%) showed LOH but were not mutated, suggesting other mechanisms inactivating p53 than mutations. 4 mutations were found at codon 280 and 2 mutations were found at codon 285, 2 previously reported hot spots for urinary bladder cancer. The study indicate a boundary between G2a and G2b tumours concerning the occurrence of genetic events affecting p53 function; moderately differentiated (G2) urinary bladder neoplasms probably are genetically heterogeneous which supports the suggestion that they should not be grouped together but instead, for example, be categorized as either lowly or highly malignant.

Cell Differentiation↗
PubMed2001

Low interleukin-1alpha messenger RNA levels predict decreased overall survival time of patients with urinary bladder carcinoma.

Due to our inability to exactly characterize tumours, many patients with urinary bladder cancer undergo unnecessary surgery or cytostatic therapy. We have here studied the expression of the cytokine interleukin-1alpha (IL-1alpha ) in 73 human bladder carcinomas in relation to patient survival, and examined possible relationships between IL-1alpha and urokinase plasminogen activator (uPA) expression. Expression levels of IL-1alpha and uPA mRNA were determined by RT-PCR using the quantitative TaqMan technique. The levels of IL-1alpha mRNA expression did not differ significantly between tumours of different grade or stage. Calculation of the overall survival rates showed a decreased overall survival time for patients with low levels of IL-1alpha mRNA in their tumours (log rank; P = 0.0002, median follow up: 37 months). Low tumoral IL-1alpha expression predicted decreased survival of patients with poorly differentiated tumours (P< 0.005) and of patients with invasive tumours (P = 0.02). uPA expression was about 4-fold increased in poorly differentiated tumours. High levels of uPA mRNA were associated with decreased overall survival times (log rank; P = 0.032, n = 60). We conclude that IL-1alpha is important for bladder cancer biology, and that measurements of this cytokine may be useful in pre-treatment characterization of urinary bladder cancer.

Cohort Studies↗
PubMed2001

Quality of life.

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Brachytherapy↗
PubMed2001

Upregulation of Flt3 expression within the bone marrow Lin(-)Sca1(+)c-kit(+) stem cell compartment is accompanied by loss of self-renewal capacity.

Flt3 has emerged as a potential regulator of hematopoietic stem cells (HSC). Sixty percent of cells in the mouse marrow Lin(-)Sca1(+)c-kit(+) HSC pool expressed flt3. Although single cell cloning showed comparable high proliferative, myeloid, B, and T cell potentials of Lin(-)Sca1(+)c-kit(+)flt3(+) and Lin(-)Sca1(+)c-kit(+)flt3(-) cells, only Lin(-)Sca1(+)c-kit(+)flt3(-) cells supported sustained multilineage reconstitution. In striking contrast, Lin(-)Sca1(+)c-kit(+)flt3(+) cells rapidly and efficiently reconstituted B and T lymphopoiesis, whereas myeloid reconstitution was exclusively short term. Unlike c-kit, activation of flt3 failed to support survival of HSC, whereas only flt3 mediated survival of Lin(-)Sca1(+)c-kit(+)flt3(+) reconstituting cells. Phenotypic and functional analysis support that Lin(-)Sca1(+)c-kit(+)flt3(+) cells are progenitors for the common lymphoid progenitor. Thus, upregulation of flt3 expression on Lin(-)Sca1(+)c-kit(+) HSC cells is accompanied by loss of self-renewal capacity but sustained lymphoid-restricted reconstitution potential.

Animals↗
PubMed2001

The prevalence of loss of heterozygosity in chromosome 3, including FHIT, in bladder cancer, using the fluorescent multiplex polymerase chain reaction.

OBJECTIVE: To determine some of the genetic alterations involved in the pathogenesis and progression of transitional cell carcinoma of the bladder. Materials and methods In a population-based study, freshly frozen tissue was collected from all patients newly diagnosed with urinary bladder cancer in the Stockholm region during 1995-1996. The prevalence of loss of heterozygosity (LOH) was assessed at seven sites on chromosome 3, analysed in 151 patients, using a fluorescent multiplex polymerase chain reaction based on DNA from the tumour and peripheral blood. RESULTS: LOH was detected in 12.1% (at 3q25-26.2) to 22.1% (at 3p11-12) of the informative cases. Relatively frequent LOH was detected at 3p22-24.2 (21.6%), at 3p14.2 within FHIT (21.5%), and at 3p11-12 (22.1%). Of 151 tumours, 72 (47.7%) showed LOH at one or more loci on chromosome 3. LOH on chromosome 3 was weakly associated with tumour grade (P = 0.095), but not with tumour stage (P = 0.701). However, when the frequency of LOH was analysed individually at each site, the prevalence of LOH at 3p11-12 was closely correlated with higher tumour stage (P = 0.011). Replication errors were detected in only four of 151 (2.6%) tumours. Conclusion These findings suggest that the 3p11-12 locus may involve a putative candidate tumour-suppressor gene which might be associated with bladder tumour invasiveness. The FHIT gene locus showed a relatively high frequency of LOH even in Ta tumours.

Acid Anhydride Hydrolases↗
PubMed2001

Emotional isolation: prevalence and the effect on well-being among 50-80-year-old prostate cancer patients.

OBJECTIVE: To investigate to what extent prostate cancer patients confide their emotional concerns, and whether having no one to confide in affects well-being. MATERIAL AND METHODS: A population-based study using epidemiological methods. A questionnaire was mailed to all 431 living prostate cancer patients aged 50-80 at the time of selection, diagnosed 1.5-2 years previously in Stockholm County, and 435 randomly selected men in the same age group. The questionnaire was completed anonymously. The main outcome measures included questions assessing the extent to which the men could share emotionally taxing feelings with their partner or others and questions assessing well-being. RESULTS: The questionnaire was returned by 79% of the patients and by 73% of the randomly selected men. Approximately one in five patients had no one to confide in. Of patients living with a partner, only one in 10 confided in someone other than their partner. Three out of 10 patients living in a relationship could not confide in their partner. Men having no one to confide in were less content with their life and reported poorer psychological and overall well-being compared with other men. The prostate cancer patients were not more likely to have someone to confide in than men in general. CONCLUSIONS: The results indicate that a lack of emotional support may be a problem for many prostate cancer patients and that the traditional psychosocial support offered to most cancer patients in Sweden may not reach male patients. There may be a need for a gender-adapted approach to emotional support.

Aged↗
PubMed2001

Bacillus Calmette-Guerin induces long-term local formation of nitric oxide in the bladder via the induction of nitric oxide synthase activity in urothelial cells.

PURPOSE: Bladder instillation of bacillus Calmette-Guerin (BCG) is effective therapy for recurrent superficial bladder cancer and carcinoma in situ. BCG induces nitric oxide synthase activity in the bladder. Nitric oxide is formed from L-arginine by nitric oxide synthase. We investigated nitric oxide formation and its localization in bladder cancer patients treated with intravesical BCG instillation. MATERIALS AND METHODS: The L-citrulline conversion assay was done to assess nitric oxide synthase activity in BCG treated T24 human bladder cancer cells and cultured normal human urothelial cells. Nitrite and nitrate in cell culture medium, urine and plasma were measured by capillary electrophoresis. Nitric oxide formation in the bladder was measured by chemiluminescence. RESULTS: A 24-hour treatment with BCG induced calcium independent nitric oxide synthase activity in T24 cells in a dose dependent manner. Nitrite and nitrate production by T24 cells also increased in a dose dependent manner after 24-hour BCG treatment. BCG treatment of cultured normal human urothelial cells resulted in the induction of calcium dependent and independent nitric oxide synthase activity. Nitrite in the urine of patients receiving BCG for the first time was increased 5-fold 24 hours after instillation. Furthermore, BCG increased luminal nitric oxide in the bladder. The increase was noted after a single treatment and sustained for 6 months. No changes in plasma nitrite or nitrate were observed after BCG treatment. CONCLUSIONS: BCG induces the local formation of nitric oxide in the bladder, whereas no evidence for systemic nitric oxide formation was noted. Increased nitric oxide production in the bladder is likely due to the induction of nitric oxide synthase activity in urothelial cells.

Adjuvants, Immunologic↗
PubMed2001

Repetitive gait of passive bipedal mechanisms in a three-dimensional environment.

The inherent dynamics of bipedal, kneed mechanisms are studied with emphasis on the existence and stability, of repetitive gait in a three-dimensional environment, in the absence of external, active control. The investigation is motivated by observations that sustained anthropomorphic locomotion is largely a consequence of geometric and inertial properties of the mechanism. While the modeling excludes active control, the energy dissipated in ground and knee collisions is continuously re-injected by considering gait down slight inclines. The paper describes the dependence of the resulting passive gait in vertically constrained and unconstrained mechanisms on model parameters, such as ground compliance and ground slope. We also show the possibility of achieving statically unstable gait with appropriate parameter choices.

Ankle Joint↗
PubMed2001

Active monitoring (deferred treatment or watchful waiting) in the treatment of prostate cancer. A review.

OBJECTIVES: To evaluate the concept of active monitoring only in the management of patients with prostate cancer. METHODS: Literature review. RESULTS: Active monitoring may be recommended in patients with stage T1a, well- and moderately-differentiated disease. Patients with a life expectancy exceeding 10 years are recommended re-evaluation with PSA, TRUS and biopsies of the residual prostate. This treatment is also indicated in patients with stage T1b-T2b, well- and moderately-differentiated tumours and a life expectancy of less than 10 years. Active monitoring is optional in patients with stage T1b-T2b, Gleason 2-4 prostate cancer and a life expectancy of 10-15 years. It is also optional in asymptomatic patients with locally advanced disease, stage T3-T4 which are well- and moderately-differentiated and have a short life expectancy. A very rare asymptomatic patient with M1 disease and the possibility of close follow-up may be offered active monitoring. CONCLUSIONS: Active monitoring is still a viable option for selected patients diagnosed with prostate cancer.

Adenocarcinoma↗
PubMed2000

[Treatment of localized prostatic cancer--different alternatives. Patients with localized prostatic cancer must actively participate in the choice of therapy].

The treatment options currently available for patients with clinically localized prostate cancer are radical prostatectomy, irradiation and deferred symptom-guided treatment. Today we do not have any controlled data indicating that any of these treatments is better than the other. Management policies that have evolved are, at best, based on structured comparisons of data from uncontrolled treatment series. In such comparisons the differences between the various treatment options with respect to disease-specific survival up to 10 to 15 years after diagnosis are modest. These comparisons are based on patient series diagnosed 15 to 20 years ago, i.e. before prostate specific antigen (PSA) was available as a marker for prostate cancer. The utilization of PSA has dramatically changed the conditions for diagnosing prostate cancer, in that with PSA we find more men with prostate cancer with smaller tumors at diagnosis. Today we find many tumors because of an elevated PSA followed by systematic biopsies in men without palpable prostatic lesions. Thus it is difficult to translate long-term outcome data from older patient series to the current situation in which tumors are found under changed clinical conditions. Consequently, a patient can only be informed about the different treatment options and their side effects. In the treatment decision process he has to balance a possible benefit in survival against side effects, according to his own preferences. We need randomized studies comparing the different treatment options. Such research is under way in Scandinavia, but due to the long course of the disease we will probably have to wait many years before we can answer the questions which sparked these studies.

Antineoplastic Agents↗
PubMed2000

Leukotriene D(4) triggers an association between gbetagamma subunits and phospholipase C-gamma1 in intestinal epithelial cells.

The proinflammatory mediator leukotriene D(4) (LTD(4)) binds to the seven-transmembrane receptor CYSLT(1). Although this leukotriene plays an important biological role, its intracellular signaling pathways are only partly known. In previous experiments, we found that LTD(4) induced tyrosine phosphorylation and translocation of phospholipase (PLC)-gamma1 to a plasma membrane fraction in a human epithelial cell line (Int 407). In the present study, we further examined these signaling events and found that LTD(4) induced a rapid interaction between Gbetagamma subunits and PLC-gamma1; results obtained with GST fusion proteins of PLC-gamma1 suggest that this interaction is mediated via the pleckstrin homology domain of PLC-gamma1. Moreover, LTD(4) induced an increased association of c-Src with PLC-gamma1, and the selective Src family tyrosine kinase inhibitor PP1 blocked both LTD(4)-induced tyrosine phosphorylation of PLC-gamma1 and the association of PLC-gamma1 with Gbetagamma subunits. The relevance of these observations in intracellular calcium signaling was investigated by microinjecting cells with anti-Gbeta, anti-PLC-gamma1, or anti-c-Src antibodies and by pretreatment with PP1. LTD(4)-induced calcium mobilization was blocked by each of the indicated antibodies (but not isotype-matched control antibodies) and by PP1. Our data suggest that Gbetagamma subunits can, directly or indirectly, serve as membrane-bound partners for PLC-gamma1 and c-Src and that each of these proteins is essential for LTD(4)-induced downstream PLC-gamma1 signaling.

Calcium↗