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Biomedical subjects

R Holm

Publications and source records attributed to R Holm.

At least 19 recordsLinked to original sources
PubMed2006

Expression of EphA2 and EphrinA-1 in vulvar carcinomas and its relation to prognosis.

AIMS: To examine the expression of EphA2 and EphrinA-1 in vulvar squamous cell carcinomas and investigate their prognostic relevance. METHODS: Tumours from 224 patients with vulvar squamous cell carcinomas were investigated for expression of EphA2 and EphrinA-1 using single and double immunostaining methods. RESULTS: High expression (strong/moderate staining intensity) of EphA2 and EphrinA-1 was observed in 114 (51%) and 126 (56%) vulvar carcinomas, respectively. In the three cases tested using the double immunostaining method, colocalisation of EphA2 and EphrinA-1 proteins was identified in the same neoplastic cells. High EphA2 expression was significantly correlated to high expression of EphrinA-1 (p<0.01) and cyclin A (p<0.01), large tumour size (p = 0.03), deep invasion (p<0.01) and higher FIGO stage (p = 0.05). A correlation between high EphrinA-1 expression and high levels of cyclin A (p<0.01) and p21 (p<0.01), deep invasion (p<0.01) and higher FIGO stage (p = 0.01) was also seen. In univariate analysis, high expression of EphrinA-1 was associated with poor survival (p = 0.03). However, in the multivariate analysis neither EphrinA-1 nor EphA2 were significantly correlated to survival. CONCLUSIONS: EphA2 and EphrinA-1 were overexpressed in 51% and 56% of the vulvar squamous cell carcinomas, respectively, and high levels of EphA2 and EphrinA-1 proteins were associated with deep tumour invasion and high FIGO stage. However, EphA2 and EphrinA-1 were not independently associated with clinical outcome in vulvar carcinomas.

Adult↗
PubMed2006

Optimization of self-microemulsifying drug delivery systems (SMEDDS) using a D-optimal design and the desirability function.

D-optimal design and the desirability function were applied to optimize a self-microemulsifying drug delivery system (SMEDDS). The optimized key parameters were the following: 1) particle size of the dispersed emulsion, 2) solubility of the drug in the vehicle, and 3) the vehicle compatibility with the hard gelatin capsule. Three formulation variables, PEG200, a surfactant mixture, and an oil mixture, were included in the experimental design. The results of the mathematical analysis of the data demonstrated significant interactions among the formulation variables, and the desirability function was demonstrated to be a powerful tool to predict the optimal formulation for the explored system.

Capsules↗
PubMed2005

Markers of apoptosis in stage IB squamous cervical carcinoma.

AIMS: To examine the prognostic relevance of the expression of the Bcl-2, Bcl-xL, and Bax proteins in stage IB squamous cervical carcinoma (SCC). METHODS: In total, 220 patients who underwent radical hysterectomy and bilateral lymphadenectomy at the Norwegian Radium Hospital for stage IB SCC between 1987 and 1993 were studied. Immunohistochemistry using monoclonal antibodies against Bcl-2, Bcl-xL, and Bax was used to examine protein expression. Ten patients who underwent hysterectomy for uterine prolapse served as controls. RESULTS: Cytoplasmic expression of Bcl-2, Bcl-xL, and Bax was low (< 5% positive cells) in 159 of 220 (73%), 193 of 220 (87%), and 39 of 220 (18%) tumours, respectively, and high (> or = 5% positive cells) in 61 of 220 (27%), 27 of 220 (13%), and 181 of 220 (82%) tumours, respectively. In univariate analysis, all classic clinicopathological parameters but none of the investigated proteins were associated with prognosis. In multivariate analysis, only deep stromal invasion was independently related to survival. CONCLUSION: Bcl-2, Bcl-xL, and Bax were not independently associated with prognosis in stage IB SCC.

Adult↗
PubMed2004

TP53 mutations in early-stage ovarian carcinoma, relation to long-term survival.

We conducted the present study to evaluate the frequency and prognostic importance on long-term survival of TP53 mutations and TP53 protein accumulation in a cohort of 178 patients with early-stage ovarian carcinomas. TP53 mutations scored as aberrant temporal temperature gradient gel electrophoresis pattern from all exons were observed in 39.9% of the tumours. Full screening of exons 5-8, followed by sequencing, was successful in 135 cases, and 48 mutations altering the protein were detected in 39 cases (28.9%). TP53 mutations were slightly less common in the Federation of Gynecologists and Obstetricians stage IA than in IB/IC (P=0.05). No significant correlations with histological type, grade of differentiation, DNA ploidy status or age at diagnosis were found. TP53 protein accumulation analysed by immunohistochemistry was found in 32.6% of all tumours, and was a poor predictor of TP53 mutations with 56.4% sensitivity, 77.1% specificity, 50% positive predictive value and 81.3% negative predictive value. Neither TP53 mutations nor TP53 protein accumulation influenced the prognosis significantly in this group of patients.

Aged↗
PubMed2003

Comparison of two intervention programmes in young female players in European handball--with and without ankle disc.

INTRODUCTION: The prevention of injuries in all sports calls for a structured plan. The plan consists, as earlier described, of four steps. We have previously presented studies incorporating all four steps. The studies have shown that it is possible to prevent most injuries in young female players in European handball by applying a training programme combining the use of an ankle disc with functional strength training. In the previous studies we were not able to discriminate whether the preventive effect was due to the functional strength training or the training with the ankle disc. The aim of this study was to compare a programme with ankle disc and functional strength training with a programme with functional strength training only. METHODS: Twenty handball teams were asked to participate, and 16 of 20 handball teams agreed to participate. The teams were cluster randomised to either the programme with or without an ankle disc. RESULTS: The group using the programme without the ankle disc had a significantly higher number of traumatic injuries (16 vs. 6). The incidences of traumatic injuries in the ankle disc group were 2.4 (95% CI 0.7; 6.2) injuries per 1000 h of match and 0.2 (95% CI 0.02; 0.7) injuries per 1000 h of practice. In the group without ankle disc the incidences were 6.9 (95% CI 3.3; 12.7) injuries per 1000 h of match and 0.6 (95% CI 0.2; 1.3) injuries per 1000 h of practice. A significantly higher multivariate odds ratio (4.8) was found in the group not using the ankle disc. In addition the group using the ankle disc had significantly fewer moderate and major injuries. CONCLUSION: By adding ankle disc training to a training programme with functional strength training, it is possible to reduce the number of injuries significantly, especially the number of moderate and major injuries.

Adolescent↗
PubMed2003

Association between histology grade, expression of HsMCM2, and cyclin A in human invasive breast carcinomas.

AIM: Increased proliferation of tumour cells has prognostic value in human invasive breast carcinomas (IBCs), and high histology grade and cyclin A expression, which may reflect high proliferation rate, are associated with poor prognosis. Expression of HsMCM2 is related to cell proliferation. This study evaluates the correlation between the expression of cyclins A, D1, D3, and E, Ki-67, proliferating cell nuclear antigen (PCNA), histology grade, and HsMCM2 expression, in addition to the independent prognostic value of HsMCM2 expression in human IBCs. METHODS: Immunohistochemistry to evaluate HsMCM2, Ki-67, and PCNA expression in tumours from 147 patients with IBC. RESULTS: Nuclear staining for HsMCM2 was seen in 10-30% of the tumour cells in 30 samples, in 30-70% in 40 samples, in > 70% in 44 samples, and in < 10% in 33 samples. One way ANOVA showed a significant association between expression of HsMCM2 and cyclin A, D3, E, histology grade, and Ki-67. A borderline correlation was seen between HsMCM2 and PCNA. In multivariate analysis, the only association was with cyclin A, in addition to a borderline association with histology grade. In a Cox regression hazards model, expression of HsMCM2 was associated with poor patient survival, although it lost its independent prognostic value when cyclin A expression was included. Ki-67 and PCNA expression were not associated with patient survival. CONCLUSION: Cyclin A expression is independently associated with HsMCM2 expression, histology grade, and Ki-67. HsMCM2 expression is associated with poor patient survival, although it loses prognostic value when adjusted for cyclin A.

Biomarkers, Tumor↗
PubMed2002

Differential Ki67 and bcl-2 immunoexpression in solid-glandular and spindle cell components of biphasic synovial sarcoma: a double immunostaining assessment with cytokeratin and vimentin.

AIMS: Synovial sarcoma is a malignant soft tissue of uncertain histogenesis that may show a biphasic (spindle and solid/glandular components) or a monophasic histological appearance. In previous studies, we demonstrated that the solid/glandular component possesses higher proliferation rates than the spindle cell component of biphasic synovial sarcomas and that the spindle cell component may exhibit a progressive transition from or to the solid-glandular component in biphasic synovial sarcoma. To evaluate this hypothesis further, we designed a novel approach to correlate immunoexpression of Ki67, bcl-2 and bax in the spindle cell and in the solid-glandular component of biphasic synovial sarcomas. We also performed a double-immunohistochemical assessment of the Ki67 proliferative indices and the immunoexpression of anti-apoptotic protein bcl-2 in neoplastic cells expressing either vimentin or cytokeratin. METHODS AND RESULTS: Immunohistochemistry for vimentin (10 cases), bcl-2 (10 cases), Ki67(10 cases), cytokeratin (10 cases), and bax (eight cases), and double-immunostaining for vimentin/Ki67 (10 cases), vimentin/bcl-2 (nine cases), cytokeratin/Ki67 (10 cases), and cytokeratin/bcl-2 (10 cases) assays were performed in 10 cases of primary biphasic synovial sarcoma. Semiquantitative assessment was adopted for each case in both components. Statistical analysis was performed using Fisher's exact test or chi2 test. On conventional immunohistochemistry, the solid/glandular component revealed more expression of Ki67, bax and cytokeratin than the spindle cell component (P=0.0004, P=0.082, and P < 0.0001, respectively); on the other hand, the latter showed higher expression of bcl-2 and vimentin than the former (P=0.0281 and P=0.059, respectively). Double immunohistochemistry analysis revealed higher co-expression levels of cytokeratin/Ki67 and cytokeratin/bcl-2 than the spindle cell component (P=0.015 and P < 0.0001, respectively); conversely, the latter presented higher co-expression of vimentin/bcl-2 than the former (P=0.0007). All cases showed no more than 10% of cells coexpressing cytokeratin/bcl-2, cytokeratin/Ki67, and no case revealed cells coexpressing vimentin/Ki67. CONCLUSION: Our findings indicate that in biphasic synovial sarcoma the acquisition of epithelial phenotype (solid/glandular component) is associated with a high expression of pro-apoptotic proteins and a high proliferative differentiation status, and conversely, mesenchymal phenotype (spindle cell component) is associated with a high expression of apoptosis-inhibitor bcl-2 and a low proliferative terminal-type differentiation status.

Adult↗
PubMed2001

Cyclin A expression in superficial spreading malignant melanomas correlates with clinical outcome.

The present study analysed by immunohistochemistry the protein level of cyclin A and Ki-67 in a panel of paraffin-embedded tissue obtained from 172 primary (110 superficial and 62 nodular) and 73 metastatic melanomas, and ten benign naevi. Since cyclin A exists in the same quaternary complex in the S-phase of the cell cycle as the cdk inhibitor p21WAF1/CIP1, the levels of the two proteins were compared. Cyclin A and Ki-67 were heterogeneously expressed in the malignant tumours, whereas in benign naevi, only rare positive cells were detected. In superficial spreading melanomas, the cyclin A level was related to tumour thickness, with less expression in thinner lesions (p<0.00001), and to Ki-67 (p<0.00001) and p21WAF1/CIP1 (p=0.01) scores. Multivariate analysis showed that in addition to the depth of the primary tumour, the protein level of cyclin A was an independent indicator of relapse-free period (thickness, p<0.00001; cyclin A, p=0.0003). In contrast, in nodular melanoma, the cyclin A level was associated with Ki-67 expression, but neither cyclin A nor Ki-67 was related to tumour thickness (cyclin A, p=0.06; Ki-67, p=0.61) and neither had any impact on relapse-free (cyclin A, p=0.64; Ki-67, p=0.32) or overall (cyclinA, p=0.94; Ki-67, p=0.45) survival. In conclusion, the results indicate that cyclin A is a strong prognostic factor for patients with superficial spreading melanomas. In nodular melanomas, the proliferation rate seems to have little impact on disease progression.

Adult↗
PubMed2001

Comparison of total oral bioavailability and the lymphatic transport of halofantrine from three different unsaturated triglycerides in lymph-cannulated conscious rats.

The lymphatic transport and the portal absorption of the lipophilic drug halofantrine were investigated in a conscious rat model. The rats were dosed with 0.1 g with triolein, trilinolein or trilinolenin containing 2 mg halofantrine. Following oral administration of the triglycerides, the mesenteric lymph and plasma samples were collected. The lymphatic transport for halofantrine was 11.1+/-1.2 after administration of trilinolein, 9.0+/-3.5 for trilinolenin and 8.6+/-2.2 for triolein and the total amount of halofantrine transported in the lymph was linear proportional with the amount of triglyceride in the lymph. The absorption of halofantrine directly into the blood showed a trend towards a higher AUC for trilinolien and trilinolenin compared to triolein, but no statistical difference could be found. The statistically analysis of the mean total bioavailability therefore shows that the absorption of halofantrine was largely independent on triglyceride unsaturation.

Administration, Oral↗
PubMed2001

Comparison of the lymphatic transport of halofantrine administered in disperse systems containing three different unsaturated fatty acids.

PURPOSE: To compare the influence of the degree of fatty acid unsaturation (oleic [C18:], linoleic [C18:2], or linolenic acid [C18:3]), with the intestinal lymphatic transport of halofantrine free base from disperse systems in anesthetized rats. METHODS: The mesenteric lymph duct was cannulated in anesthetized rats. Lipid vehicle containing halofantrine was administered by intraduodenal infusion. The concentration of halofantrine in blood and lymph samples was analyzed. RESULTS: The rank order of the lymphatic transport of halofantrine was C18:2 > C18:1 > C18:3. Comparison of the area under the curve (AUC) from the three fatty acids showed no statistically significant differences between the AUCs from the lymph cannulated rats. In terms of rank order effects, the plasma concentrations of halofantrine were highest for the rats dosed C18:2 followed by C18:3 and C18:1. CONCLUSIONS: Using C18:2 as a vehicle increased the lymphatic transport of halofantrine 16.6-fold over that observed for the system containing C18:3. The extent of lymphatic transport for the C18:1 system did not differ from the other two formulations, but the combined lymph and plasma data indicated that the C18:2 was the most suitable lipid vehicle for the oral delivery of halofantrine.

Animals↗
PubMed2001

Reduced expression of p21WAF1 is an indicator of malignant behaviour in anal carcinomas.

AIMS: p21 and p27 protein expression were examined in a comparatively large series of patients with squamous cell carcinoma of the anal canal and compared with clinical and histopathological data (tumour stage, nodal status and differentiation). METHODS AND RESULTS: We analysed the expression of p21 and p27 protein in 94 anal carcinomas by immunohistochemistry. Nuclear p21 and p27 staining were detected in 71% (67/94) and 75% (71/94) of the cases, respectively. There was no significant association between p27 staining and tumour stage, nodal status or overall survival. We observed that negative p21 immunoreactivity was significantly associated with poorly differentiated anal carcinomas. Furthermore, a shorter overall survival for patients with no p21 protein expression was seen. CONCLUSIONS: Our data indicate that p21 levels, but not p27 expression, may be a useful predictor of survival in patients with anal carcinomas.

Adult↗
PubMed2001

p53, p21 and mdm2 expression vs the response to radiotherapy in transitional cell carcinoma of the bladder.

OBJECTIVE: To identify, in a retrospective study, possible molecular markers predictive of radioresponsiveness in patients with transitional cell carcinoma (TCC) of the bladder. PATIENTS AND METHODS: Patients with T2-T4a TCC treated with preoperative radiotherapy and cystectomy were included in the study if their cystectomy specimen was pT3b (in 42) or pT0 (in 17). Because treatment schedules changed over time, radiotherapy was given either as 2 Gy x 23 over 4-5 weeks with cystectomy 4-5 weeks later (in 23), or as 4 Gy x 5 during 1 week with cystectomy in the following week (in 36 patients). Protein expression of p53, mdm2 and p21 (CDKN1 A/WAF1/CIP1/SDI1) was assessed immunohistochemically in biopsies taken before radiotherapy. RESULTS: There was no difference in protein expression when comparing all patients with pT0 and pT3b. However, for patients receiving 46 Gy, increased p53 expression (but not p21 or mdm2) predicted the absence of residual tumour (P = 0.005): six of seven patients with > 50% p53 expression had pT0 in the cystectomy specimen, whereas 10 of 12 patients with < or = 5% expression had pT3b. Over-expression of p53 correlated with longer overall (P = 0.045) and cancer-specific survival (P = 0.020). CONCLUSION: The expression of mdm2 or p21 did not predict radioresponsiveness in patients with TCC of the bladder. The role of p53 remains unclear; the view that p53 over-expression confers radioresistance in bladder cancer is not supported.

Adult↗
PubMed2001

Fibroblast growth factor receptor 3 (FGFR3) - analyses of the S249C mutation and protein expression in primary cervical carcinomas.

Fibroblast growth factor receptor 3 (FGFR3) seems to play an inhibitory role in bone development, as activating mutations in the gene underlie disorders such as achondroplasia and thanatophoric dysplasia. Findings from multiple myeloma (MM) indicate that FGFR3 also can act as an oncogene, and mutation of codon 249 in the fibroblast growth factor receptor 3 (FGFR3) gene was recently detected in 3/12 primary cervical carcinomas. We have analysed 91 cervical carcinomas for this specific S249C mutation using amplification created restriction site methodology (ACRS), and detected no mutations. Immunohistochemistry was performed on 73 of the tumours. Reduced protein staining was seen in 43 (58.8%) samples. Six of the tumours (8.2%) revealed increased protein staining compared with normal cervical tissue. These patients had a better prognosis than those with reduced or normal levels, although not statistically significant. This report weakens the hypothesis of FGFR3 as an oncogene of importance in cervical carcinomas.

Adult↗
PubMed2000

Expression of apoptosis-related proteins is an independent determinant of patient prognosis in advanced ovarian cancer.

PURPOSE: The present study was undertaken to investigate the prognostic and predictive relevance of the expression of apoptosis-related proteins Bax, Bcl-X(L), and Mcl-1 in advanced ovarian cancer. PATIENTS AND METHODS: Tumor biopsies from 185 consecutive and homogeneously treated patients with stage III ovarian cancer were examined immunohistochemically for the expression of Bax, Bcl-X(L) and Mcl-1 proteins. Their prognostic relevance was examined in a uni- and multivariate survival analysis. RESULTS: Sixty-six percent of cancer cases expressed Bax, 62% Bcl-X(L), and 53% Mcl-1. The expression of Bax correlated with tumor differentiation (P: =.016) and less residual disease after surgery (P <.0001). In univariate analysis, Bax expression was associated with improved (P =.0004) prognosis and Mcl-1 expression with poorer (P =.011) prognosis. None of the factors studied was of independent prognostic significance by itself, but when Bax and Bcl-2 expression data were considered together, this combined variable was of independent prognostic significance (P =.0115), together with residual disease status (P =.0016), differentiation grade (P =.0014), and the presence of ascites (P =.0122). Patients with a long median survival (104 months) could be discriminated from those with a short one (16 months) by combining the individual patients' expression data for p53, Bax, and Bcl-2 with their residual disease status (P <.00001). None of the factors studied was able to predict response to chemotherapy. CONCLUSION: The expression of selected apoptosis-related proteins is of independent prognostic significance and may be helpful in a molecular substaging of patients with stage III ovarian cancer.

Adult↗
PubMed2000

Primary cervical carcinomas show 2 common regions of deletion at 3P, 1 within the FHIT gene: evaluation of allelic imbalance at FHIT, RB1 and TP53 in relation to survival.

Chromosome arm 3p is re-arranged in many tumor types, including cervical carcinomas. Putative tumor-suppressor genes on 3p have been proposed, including the FHIT gene, which maps to chromosome band 3p14.2. We have analyzed 79 primary cervical carcinomas for allelic imbalance (AI) at 17 chromosome 3 loci, including 3 within the FHIT gene. Expression of the FHIT gene was evaluated after immunohistochemistry with an antibody against the pFHIT protein. Previously determined human papillomavirus status, defined after in situ hybridization, showed type 16 or 18 in 56/77 tumors. Tumors were also analyzed for AI at loci within the RB1 (chromosome band 13q14.2) and the TP53 (17p13) genes for AI. AI was found at 1 or more 3p loci in 50/79 tumors, at frequencies ranging from 30% to 52% at the individual loci. Two smallest regions of overlapping deletion (SROs) were found, 1 including parts of the FHIT gene (SRO flanked by D3S1481 and D3S1313) and another more distal SRO between D3S32 and D3S1286. FHIT protein expression was reduced in 57/69 (83%) tumors but not associated with AI at FHIT loci (p = 0.56). AI was found in TP53 and RB1 in 18% and 29% of the samples, respectively. Relapse-free survival was associated with AI in the TP53 gene in both a univariate (p = 0.0003) and a multivariate (p = 0.004) analysis. This study confirms a high frequency of AI at chromosome arm 3p in primary cervical carcinomas. The AI results and the reduced FHIT protein staining indicate that FHIT alterations are important in cervical carcinogenesis.

Acid Anhydride Hydrolases↗
PubMed2000

[Prolonged neck pain following automobile accidents. Gender and age related risk calculated on basis of data from an emergency department].

Whiplash injuries following road traffic accidents seem to be an increasing problem in many countries. Many studies are based on biased material from specialized departments or data from insurance companies. The aim of this study was to calculate the risk of longer lasting neck pain for persons involved in road traffic accidents and treated in the emergency room. We found that 49% of the patients treated following road traffic accidents in motor vehicles reported problems with neck pain. Thirteen percent had neck pain with more than six months of duration. The highest risk of neck pain was recorded in women aged 20-59 years. Accidents with front to back collisions presented the highest risk. The conclusion was that whiplash associated disorders following road traffic accidents in motor vehicles apparently is a large problem. The treatment and rehabilitation must be centralized at the level of the general practitioners.

Accidents, Traffic↗
PubMed2000

A highly sensitive nonisotopic detection method for in situ hybridization.

In situ hybridization is a technique that allows detection of specific DNA and RNA sequences in tissue sections. Nonisotopic techniques are fast and give a precise localization of the hybridization product, but a drawback is the low sensitivity. However, the sensitivity is dependent on the detection system used. To evaluate a sensitive in situ hybridization method with nonradioactive probes we compared three different detection systems, using biotin-labeled human papillomavirus (HPV) 16 probes. The three detection systems included (i) STAV-FITC method (streptavidin-fluorescein isothiocyanate/alkaline phosphatase anti-FITC), (ii) APAAP method (mouse anti-biotin/anti-mouse IgG/alkaline phosphatase mouse anti-alkaline phosphatase), and (iii) tyramide signal amplification (TSA) method (STAV-horseradish peroxidase (HRP)/biotinyl tyramide/STAV-HRP). The in situ hybridization methods were tested on CaSki and SiHa cells and two cervical carcinomas known to be HPV16 positive. The cells and tissues and been fixed in 4% buffered formalin and paraffin embedded. The three different detection systems gave satisfactory nuclear staining in CaSki cells (CaSki cells contain > 500 copies of HPV16 DNA) and the two cervical carcinomas. However, demonstration of HPV16 DNA in SiHa cells (SiHa cells contain one to two HPV16 genome copies) was possible only by use of the APAAP method. It was concluded that the APAAP method provides the best sensitivity among the nonisotopic detection systems and can detect single viral copies in formalin-fixed and paraffin-embedded material.

Animals↗