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Biomedical subjects

D R Olsen

Publications and source records attributed to D R Olsen.

At least 19 recordsLinked to original sources
PubMed1995

31P NMR spectroscopy studies of phospholipid metabolism in human melanoma xenograft lines differing in rate of tumour cell proliferation.

The concentration of phospholipid metabolites in tumours has been hypothesized to be related to rate of cell membrane turnover and may reflect rate of cell proliferation. The purpose of the study reported here was to investigate whether 31P NMR resonance ratios involving the phosphomonoester (PME) or phosphodiester (PDE) resonance are correlated to fraction of cells in S-phase or volume-doubling time in experimental tumours. Four human melanoma xenograft lines (BEX-t, HUX-t, SAX-t, WIX-t) were included in the study. The tumours were grown subcutaneously in male BALB/c-nu/nu mice. 31P NMR spectroscopy was performed at a magnetic field strength of 4.7 T. Fraction of cells in S-phase was measured by flow cytometry. Tumour volume-doubling time was determined by Gompertzian analysis of volumetric growth data. BEX-t and SAX-t tumours differed in fraction of cells in S-phase and volume-doubling time, but showed similar 31P NMR resonance ratios. BEX-t and WIX-t tumours showed significantly different 31P NMR resonance ratios but similar fractions of cells in S-phase. The 31P NMR resonance ratios were significantly different for small and large HUX-t tumours even though fraction of cells in S-phase and volume-doubling time did not differ with tumour volume. None of the 31P NMR resonance ratios showed significant increase with increasing fraction of cells in S-phase or significant decrease with increasing tumour volume-doubling time across the four xenograft lines.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Effect of melanin on phosphorus T1S in human melanoma xenografts studied by 31P MRS.

31P MRS resonance ratios of tumors depend on the T1S of the phosphorus compounds. The objective of the 31P MRS study reported here was to investigate whether the phosphorus T1S of melanomas are influenced by the presence of melanin. One amelanotic (COX-t) and one melanotic (ROX-t) human melanoma xenograft line were studied at two different tumor volumes: 200 and 1000 mm3. 31P MRS was performed in nonanaesthetized mice at 4.7 T. The T1S were measured by using the superfast inversion recovery technique. Fraction of necrotic tissue in the tumors was determined by histological examination. The ROX-t tumors showed shorter T1S than the COX-t tumors at a volume of 200 mm3, where the fraction of necrotic tissue in the tumors was insignificant. The difference was similar in magnitude for all resonances. The T1S were not significantly different for COX-t and ROX-t at a volume of 1000 mm3, where the tumors of both lines had developed significant necrosis. The phosphorus T1S of melanomas without necrosis can be shortened significantly by the presence of melanin. The magnitude of the T1 shortening is similar for all major compounds. 31P MRS resonance ratios of melanomas are not altered significantly by correcting for effects of partial saturation.

Animals↗
PubMed1995

Field homogeneity of bevelled intraoperative electron beam cones: the influence of virtual focus surface distance.

Field flatness of bevelled intraoperative electron therapy cones were evaluated from dose profiles, taken at dmax, both in the longitudinal plane (long axis direction) and the transversal plane (short axis direction), and were found to depend strongly on the setting of the x-ray collimators. Dose gradients in the longitudinal plane of 10-12% were found for collimator settings of 5 mm larger than the cone diameter for low energies, while the dose gradient were smaller for higher energies, both decreasing with larger collimator setting. The dose increase, relative to the central dose, of the hot spots observed in the profile of the transversal plane were in the range of 5-10% for high energies and large collimator settings, decreasing to less than 3% for low electron beam energies and smaller collimator setting. A decrease in virtual focus to surface distance (VFSD) was found to accompany the increasing dose gradient in the longitudinal plane with decreasing collimator setting, this due to increased scatter of electrons at collimator level. Increasing scatter with smaller collimator setting is also indicated by the increase in photon contamination ranging from 1-2.5% for low energies and 3.5-5% for high energies.

Humans↗
PubMed1995

Calculation of the biological effect of fractionated radiotherapy: the importance of radiation-induced apoptosis.

The total effect (TE) has been calculated for two different fractionation formalisms: the consecutive and repetitive fractionation mechanism, using a modified linear quadratic (LQ) model which includes the effect of apoptosis. For a given total dose, an increase in TE is seen when increasing the dose per fraction as well as the apoptotic fraction (Fa). Also, the TE increases with increasing alpha/beta ratio (of the modified LQ model). The ratio of TE for tumour tissue and TE for late reacting tissue is calculated assuming the absence of apoptosis in late reacting tissue and a common value of alpha/beta (of the modified LQ model). The biological effect ratio (BR) is higher for a large Fa and low doses per fraction, than for large doses per fraction and a small Fa. Assuming a consecutive fractionation mechanism, the TE formalism is unable to predict a log cell kill of more than 3 for beta values of 0.010-0.028. It is less dependent on dose per fraction and Fa than the repetitive fractionation mechanism. The biological effect ratio is only slightly higher than 1, and is less influenced by Fa, dose per fraction and alpha/beta ratio. A repetitive fractionation mechanism is also consistent with the preliminary results of published fractionation experiments. The calculations indicate that designing fractionation regimes for optimization of biological effect is a process where the role of apoptotic cell inactivation must be maximized, and where the influence of mitotic cell inactivation may be of less importance.

Apoptosis↗
PubMed1995

Spin-lattice relaxation time of inorganic phosphate in human tumor xenografts measured in vivo by 31P-magnetic resonance spectroscopy. Influence of oxygen tension.

Previous 31P-magnetic resonance spectroscopy (31P-MRS) studies have suggested that the spin-lattice relaxation time (T1) of the inorganic phosphate (Pi) resonance is shorter in well-oxygenated than in poorly oxygenated tumors. Amelanotic human melanoma xenografts were therefore subjected to 31P-MRS to investigate whether the T1 of the Pi resonance might be a useful parameter for assessment of tumor oxygenation status. It was searched for possible correlations between the T1 of the Pi resonance and oxygen tension or parameters closely related to oxygen tension, including 31P-MRS tumor energy status and blood supply per viable tumor cell. Oxygen tension, tumor energy status, and blood supply per viable tumor cell decreased with increasing tumor volume. In contrast to previous suggestions, the T1 of the Pi resonance decreased with increasing tumor volume and decreasing oxygen tension, tumor energy status, and blood supply per viable tumor cell, possibly because the tumors developed necrotic regions concomitantly with the decrease in oxygenation status, resulting in increased concentrations of freely dissolved para-magnetic ions in the tissue. Consequently, the T1 of the Pi resonance can probably not be utilized to estimate the oxygenation status of tumors, at least not in tumors with necrotic regions.

Animals↗
PubMed1994

31P-nuclear magnetic resonance spectroscopy in vivo of four human melanoma xenograft lines: spin-lattice relaxation times.

Phosphorus spin-lattice relaxation times (T1s) were measured in vivo by 31P-nuclear magnetic resonance spectroscopy in tumors from four amelanotic human melanoma xenograft lines grown subcutaneously in BALB/c-nu/nu mice. The T1s were analyzed in relation to tumor volume, fractional tumor water content, and fraction of necrotic tumor tissue. The following resonances were studied: phosphomonoesters (PME), inorganic phosphate (Pi), phosphodiesters (PDE), phosphocreatine (PCr), and nucleoside triphosphates gamma, alpha, and beta (NTP gamma, alpha, and beta). Two different techniques were used to measure the T1s: superfast inversion recovery (SUFIR) and conventional inversion recovery (IR). The SUFIR and IR methods gave similar results. Tumors in the volume range 100-3000 mm3 were studied. The PME, Pi, PDE, and PCr resonances showed significantly longer T1s than the NTP gamma, alpha, and beta resonances at small tumor volumes. The T1s at small tumor volumes also differed significantly between the tumor lines. The T1s either decreased or remained unchanged with increasing tumor volume; the volume-dependence of the T1s differed significantly between the tumor lines but not between the resonances. Calculations based on the T1s measured here indicated that the errors in PCr/Pi and NTP beta/Pi resonance ratios due to partial saturation can vary with tumor volume but are usually < 20% at a repetition time of 2.0 s and < 15% at a repetition time of 3.0 s. There was no correlation between the T1s and fractional tumor water content.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Absorbed dose distribution measurements in brachytherapy using ferrous sulphate gel and magnetic resonance imaging.

Measurements of spatial dose distribution by means of Fricke gel dosimetry and magnetic resonance imaging (MRI) are reported for two different brachytherapy applications: a configuration of three parallel linear high dose-rate (HDR) microSelectron 192Ir source trains and a low dose-rate (LDR) 106Ru eye applicator. The presented results verify that sufficient radiation induced change in spin-lattice relaxation time (T1) is obtained within the gel dosimeter to achieve satisfactory resolution for both the HDR 192Ir source train and the LDR 106Ru applicator. Satisfactory spatial resolution is also obtained, so that the large dose gradients of the brachytherapy sources can be visualized by MRI of irradiated dosimetry gels. A reliable representation of the relative dose level is achieved by calculated T1 images. The presented study supports the use of dose distribution measurements by means of gel dosimetry and MRI in complex brachytherapy applications.

Brachytherapy↗
PubMed1994

Calculation of radiation induced complication probabilities for brain, liver and kidney, and the use of a reliability model to estimate critical volume fractions.

Radiation induced normal tissue complication probability is calculated for three different organs: brain, liver and kidney. The model applied is a reliability model where the volume effect of the tissue is described by the structural parameter, k, which reflects the architecture of the functional subunits (p) and the irradiated volume fraction (n). For partial, homogeneous irradiation of the brain, a k-value close to unity was found, and the respective values for liver and kidney were 0.92 and 0.77. An extension of the reliability model to account for individual inactivation probability of the subunits allows calculation of complication probability for inhomogeneous dose distributions. For the brain, intercomparison of a three-field and a two-field technique demonstrated a small reduction in complication probability for the former at low total doses. At high total doses a minimum complication probability was achieved applying a three-field technique, being three times less than that associated with the two-field technique.

Brain↗
PubMed1993

Bladder cancer definitive radiation therapy of muscle-invasive bladder cancer. A retrospective analysis of 317 patients.

BACKGROUND: The role of radiation therapy as curative treatment of muscle-invasive bladder cancer was to be analyzed. METHODS: From 1980-1990, 308 patients with transitional cell carcinoma of the urinary bladder received definitive pelvic radiation therapy (nominal standardized dose greater than or equal to 1700 ret). T categorization was based on clinical examination assessing the palpability of the bladder tumor and its extent (TNM 1978/1982). RESULTS: The cancer-specific 5-year survival rate for all patients was 24% (crude survival, 20%). The 135 patients with T2/T3a tumors lived significantly longer (5-year survival, 38%) than those with greater than or equal to T3b tumors (5-year survival, 14%). In the former group of patients, age (75 years and younger versus older than 75 years) was significantly correlated with a favorable outcome. The cancer-specific 2-year survival was significantly correlated to clinical response assessed 3-4 months after radiation therapy was 72%, 38%, and 10% in cases of complete response, partial response, and no response/inevaluability, respectively. In a multivariate analysis, the T categorization, patient age, serum creatinine level (less than or equal to 150 mumol/l versus greater than 150 mumol/l), and radiation therapy schedule predicted the 5-year survival rate. CONCLUSIONS: The clinical T category (< or = T3a versus > or = T3b), based on bimanual palpation, represents an important prognostic parameter, if done by clinicians experienced in onco-urology. High-dose radiation therapy offers a reasonable chance for long-term survival in patients with T2/T3 tumors confined to the bladder wall, especially in patients younger than 76 years. Greater than or equal to 80% of patients with more extended tumors (greater than or equal to T3b) and those older than 75 years of age are not curable by radiation therapy alone. In these patients palliative treatment modalities should be considered, in particular if cisplatin-based chemotherapy is not feasible.

Adult↗
PubMed1993

31P-nuclear magnetic resonance spectroscopy in vivo of six human melanoma xenograft lines: tumour bioenergetic status and blood supply.

Six human melanoma xenograft lines grown s.c. in BALB/c-nu/nu mice were subjected to 31P-nuclear magnetic resonance (31P-NMR) spectroscopy in vivo. The following resonances were detected: phosphomonoesters (PME), inorganic phosphate (Pi), phosphodiesters (PDE), phosphocreatine (PCr) and nucleoside triphosphate gamma, alpha and beta (NTP gamma, alpha and beta). The main purpose of the work was to search for possible relationships between 31P-NMR resonance ratios and tumour pH on the one hand and blood supply per viable tumour cell on the other. The latter parameter was measured by using the 86Rb uptake method. Tumour bioenergetic status [the (PCr + NTP beta)/Pi resonance ratio], tumour pH and blood supply per viable tumour cell decreased with increasing tumour volume for five of the six xenograft lines. The decrease in tumour bioenergetic status was due to a decrease in the (PCr + NTP beta)/total resonance ratio as well as an increase in the Pi/total resonance ratio. The decrease in the (PCr + NTP beta)/total resonance ratio was mainly a consequence of a decrease in the PCr/total resonance ratio for two lines and mainly a consequence of a decrease in the NTP beta/total resonance ratio for three lines. The magnitude of the decrease in the (PCr + NTP beta)/total resonance ratio and the magnitude of the decrease in tumour pH were correlated to the magnitude of the decrease in blood supply per viable tumour cell. Tumour pH decreased with decreasing tumour bioenergetic status, and the magnitude of this decrease was larger for the tumour lines showing a high than for those showing a low blood supply per viable tumour cell. No correlations across the tumour lines were found between tumour pH and tumour bioenergetic status or any other resonance ratio on the one hand and blood supply per viable tumour cell on the other. The differences in the 31P-NMR spectrum between the tumour lines were probably caused by differences in the intrinsic biochemical properties of the tumour cells rather than by the differences in blood supply per viable tumour cell. Biochemical properties of particular importance included rate of respiration, glycolytic capacity and tolerance to hypoxic stress. On the other hand, tumour bioenergetic status and tumour pH were correlated to blood supply per viable tumour cell within individual tumour lines. These observations suggest that 31P-NMR spectroscopy may be developed to be a clinically useful method for monitoring tumour blood supply and parameters related to tumour blood supply during and after physiological intervention and tumour treatment. However, clinically useful parameters for prediction of tumour treatment resistance caused by insufficient blood supply can probably not be derived from a single 31P-NMR spectrum since correlations across tumour lines were not detected; additional information is needed.

Analysis of Variance↗
PubMed1992

De Barsy syndrome: report of a case, literature review, and elastin gene expression studies of the skin.

Several "progeroid" syndromes have now been identified. The De Barsy syndrome is an autosomal recessive syndrome of dwarfism, mental deficiency, an "aged" appearance at birth, abnormal elastic fibers on skin biopsy, and lax skin, large helices, eye abnormalities, lax joints, hypotonia, and athetoid posturing. We report one case and review 11 cases from the literature. To understand the abnormal appearance of the elastic fibers on biopsy, we performed elastin gene expression studies on fibroblasts cultured from our patient's skin. Molecular hybridization studies revealed reduced elastin mRNA steady-state levels as compared with age matched control individuals. Assuming normal rates of mRNA translation, reduced elastin synthesis would occur. Diminished dermal elastin content could explain the altered cutaneous elasticity, decreased elastic fibers in the skin, and many clinical manifestations of individuals with this condition.

Child, Preschool↗
PubMed1992

Differential extracellular matrix gene expression by fibroblasts during their proliferative life span in vitro and at senescence.

Increasing evidence supports the idea that the finite proliferative life span of normal fibroblasts is a differentiation-like phenomenon. If this were correct, an ordered sequence of differential gene expression should be associated with the in vitro progression of cells from low passage to high passage (senescence). To define the pattern of expression of fibroblast differentiation-associated genes during this in vitro progression, we have determined the temporal pattern of expression of extracellular matrix (ECM) genes in Syrian hamster dermal fibroblasts as a function of passage level and percentage of proliferative life span in vitro. Steady-state mRNA levels were determined by Northern and dot blot analyses of total cellular RNA hybridized with cDNA probes specific for fibronectin, procollagen alpha 1III, and procollagen alpha 1I. Cells were analyzed at 24 hr postconfluence to minimize the presence of actively proliferating cells, and because maximal levels of fibronectin, alpha 1III, and alpha 1I mRNAs were observed 24 hr postconfluence. Unique, multiphasic patterns of expression of each of these ECM components were observed as the cells progressed from low passage to high passage. As the cells reached midhigh passage, fibronectin mRNA levels increased. This midpassage increase in fibronectin was followed by an increase in the level of alpha 1III mRNA as the cells reached the end of their in vitro proliferative life span, and then alpha 1I when the cells entered the postmitotic senescent phase, at which time the level of fibronectin mRNA also declined. A similar overlapping cascade pattern of up-regulation of these genes is seen during development and wound repair. This suggests that as cultured fibroblasts reach the end of their proliferative life span, they reinitiate a gene expression program used in tissue development and repair.

Aging↗
PubMed1992

Transforming growth factor-beta up-regulates the expression of the genes for beta 4 integrin and bullous pemphigoid antigens (BPAG1 and BPAG2) in normal and transformed human keratinocytes.

Three distinct proteins, namely, beta 4 integrins, and the 230-kDa (BPAG1) and 180-kDa (BPAG2) bullous and pemphigoid antigens, have been shown to co-localize with hemidesmosomes at the dermal-epidermal basement membrane zone. In this study, we examined the expression of the corresponding genes in cultures of normal and transformed human epidermal keratinocytes. The expression of these genes was detected by Northern and in situ hybridizations, and the expression of beta 4 integrins was also demonstrated by indirect immunofluorescence. The results indicated clearly detectable expression of all three genes in normal keratinocytes, whereas extremely low or undetectable levels of expression were noted in two transformed cell lines. Addition of TGF-beta 1 or TGF-beta 2 (10 ng/ml) up-regulated mRNA levels for all three proteins (up to 4.6 times). The increase by TGF-beta 1 was particularly striking in keratinocyte cultures incubated in the presence of low (0.15 mM) Ca++, and somewhat less pronounced in the presence of high (1.2 mM) Ca++. The increase in beta 4 integrin synthesis was also documented by enhanced immunosignal of the corresponding epitopes. These results indicate that the three hemidesmosomal genes studied here are all responsive to TGF-beta. These observations, together with previous data on the effects of TGF-beta on other components of the skin, suggest that this cytokine may play a role in the development and repair of the cutaneous basement membrane zone.

Adult↗
PubMed1992

Transforming growth factor-beta up-regulates elastin gene expression in human skin fibroblasts. Evidence for post-transcriptional modulation.

Transforming growth factor-beta s (TGF-beta) are potent enhancers of the expression of several connective tissue genes. In this study we examined the effects of TGF-beta 1 and TGF-beta 2 on human elastin mRNA abundance, promoter activity, and mRNA stability in cultured human skin fibroblasts. Treatment of cell cultures with varying concentrations of TGF-beta 1 or TGF-beta 2 for 24 hours resulted in a dose-dependent increase in the elastin mRNA steady-state levels, with a maximum enhancement of approximately 30-fold being noted with 1 ng/ml. Addition of cycloheximide (10 micrograms/ml) failed to block up-regulation of elastin gene expression by TGF-beta, indicating that this effect can occur in the absence of active protein synthesis. Furthermore, TGF-beta elicited enhancement of elastin mRNA levels could be abrogated by tumor necrosis factor-alpha and partially counteracted by interferon-gamma. Transient transfections of human skin fibroblasts with elastin promoter/chloramphenicol acetyl-transferase reporter gene constructs, which contained up to approximately 5 kb of the 5' flanking DNA, revealed no change in the promoter activity in the presence of TGF-beta. However, TGF-beta appeared to stabilize the elastin mRNA transcripts as determined by Northern hybridizations after inhibition of initiation of the transcription. As a result of this stabilization, the elastin mRNA levels were clearly detectable in TGF-beta 1-treated cultures even up to 48 hours after inhibition of transcription while they were undetectable in the control cells after 24 hours of incubation. These results demonstrate that TGF-beta 1 and TGF-beta 2 are potent enhancers of elastin gene expression and that this effect is mediated, at least in part, post-transcriptionally. These results suggest that TGF-beta s are involved in regulation of elastin deposition during fetal development and tissue repair, as well as in pathological conditions.

Dinoprostone↗
PubMed1991

Transforming growth factor-beta up-regulates type VII collagen gene expression in normal and transformed epidermal keratinocytes in culture.

Transforming growth factor-betas (TGF-betas) have been shown to enhance the expression of extracellular matrix genes, including several collagens. In this study, the effects of TGF-beta 1 and TGF-beta 2 on the expression of the gene for type VII collagen, the major component of anchoring fibrils, in human epidermal cell cultures were examined. Incubation of human epidermal keratinocytes or oral epidermoid carcinoma KB cells with TGF-beta 1 or TGF-beta 2 markedly (up to 6.3-fold) elevated the alpha 1(VII) collagen mRNA levels. This elevation was accompanied by enhanced synthesis of type VII collagen, as demonstrated by indirect immunofluorescence with a monoclonal antibody. The results indicate that TGF-beta 1 and TGF-beta 2 have similar biological activities with respect to enhanced type VII collagen gene expression.

Adult↗
PubMed1991

Extracellular matrix gene expression by human endothelial and smooth muscle cells.

In this study, the expression of extracellular matrix genes by vascular cells from human iliac blood vessels was characterized on the mRNA steady-state level by slot blot and Northern transfer analyses, as well as by in situ hybridization. Endothelial cells were isolated from adult human iliac arteries and veins, as well as from umbilical veins; smooth muscle cells were isolated from adult human iliac arteries and inferior vena cava. The results show that confluent umbilical vein endothelial cells expressed the genes that encode types I, III, IV and VI collagens, as well as fibronectin and laminin. In contrast, the iliac endothelial cells expressed the genes for types IV and V collagens, fibronectin and laminin; mRNA transcripts for types I, III and VI collagens were not detectable. The smooth muscle cells from iliac arteries or inferior vena cava displayed gene expression for types I, III, IV, V and VI collagens, fibronectin and laminin. The results indicate major differences in gene expression for the various types of collagens by human iliac endothelial and smooth muscle cells. Furthermore, the fetal-derived umbilical endothelial cells displayed differential collagen gene expression from that of adult iliac endothelial cells.

Adolescent↗
PubMed1991

Magnetic resonance imaging (MRI) and model-free estimates of brain volume determined using the Cavalieri principle.

A complete set of parallel (coronal) slices through a fixed human forebrain was generated by magnetic resonance imaging (MRI) and the Cavalieri principle, combined with point counting, was used to estimate brain volume. Alternative sampling schemes for estimating volume were then assessed by taking systematic and simple random selections of slices. Later, the brain was weighed and its fixed volume determined by fluid displacement. For the complete set of n = 28 MRI slices, the volume (1025 ml) was estimated with a coefficient of error (CE) of less than 1%. Decreasing the number of slices by systematic sampling increased the CE but this was still only 5% when just 5-6 slices were analysed. Estimated volumes varied from 947 ml to 1098 ml. Simple random sampling was less efficient (estimated volumes for 5-6 slices were 644-1187 ml). The forebrain actually weighed 1090 g and displaced 1060 ml of fluid. A set of 14 other brains was physically sliced in order to assess sampling errors in the context of observed brain-to-brain variation. It was found that 5-6 slices per brain is enough to yield efficient estimates of mean brain volume. The findings demonstrate the practicability of using MRI to estimate brain volumes unbiasedly and efficiently. The methods have great potential for noninvasive, longitudinal studies on in vivo brains and other organs.

Brain↗