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Biomedical subjects

E Fosslien

Publications and source records attributed to E Fosslien.

At least 19 recordsLinked to original sources
PubMed2002

Establishment, maintenance, and remodeling of curvature in biology.

A new hypothesis is presented, which explains how exponential tissue concentration gradients of biphasic morphogens that inhibit and stimulate basic growth rates of cells at high and low concentration respectively, determine curvatures of folds and invaginations, tubular, dome-shaped, lenticular, and spherical biological structures. For example, TGF-beta induces endothelial cells and smooth muscle cells to form tubular, vessel-like structures in vitro and blood vessels in vivo. The morphogen modulates cell growth rates via inhibitory and stimulatory receptor pathways respectively, forming a concave curvature as seen from the source concentration end of a radial, vessel-wall diffusion/perfusion driven exponential morphogen concentration gradient. From the source, inhibition declines along the radial gradient, switching to increasing stimulation beyond a neutral point, at which growth inhibition equals growth stimulation. The source concentration, shape of the gradient, and nature of the inhibitory and stimulatory pathways determine mural curvature, independent of mural-cell basic growth rate.

Animals↗
PubMed2001

Mitochondrial medicine--molecular pathology of defective oxidative phosphorylation.

Different tissues display distinct sensitivities to defective mitochondrial oxidative phosphorylation (OXPHOS). Tissues highly dependent on oxygen such as the cardiac muscle, skeletal and smooth muscle, the central and peripheral nervous system, the kidney, and the insulin-producing pancreatic beta-cell are especially susceptible to defective OXPHOS. There is evidence that defective OXPHOS plays an important role in atherogenesis, in the pathogenesis of Alzheimer's disease, Parkinson's disease, diabetes, and aging. Defective OXPHOS may be caused by abnormal mitochondrial biosynthesis due to inherited or acquired mutations in the nuclear (n) or mitochondrial (mt) deoxyribonucleic acid (DNA). For instance, the presence of a mutation of the mtDNA in the pancreatic beta-cell impairs adenosine triphosphate (ATP) generation and insulin synthesis. The nuclear genome controls mitochondrial biosynthesis, but mtDNA has a much higher mutation rate than nDNA because it lacks histones and is exposed to the radical oxygen species (ROS) generated by the electron transport chain, and the mtDNA repair system is limited. Defective OXPHOS may be caused by insufficient fuel supply, by defective electron transport chain enzymes (Complexes I - IV), lack of the electron carrier coenzyme Q10, lack of oxygen due to ischemia or anemia, or excessive membrane leakage, resulting in insufficient mitochondrial inner membrane potential for ATP synthesis by the F0F1-ATPase. Human tissues can counteract OXPHOS defects by stimulating mitochondrial biosynthesis; however, above a certain threshold the lack of ATP causes cell death. Many agents affect OXPHOS. Several nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit or uncouple OXPHOS and induce the 'topical' phase of gastrointestinal ulcer formation. Uncoupled mitochondria reduce cell viability. The Helicobacter pylori induces uncoupling. The uncoupling that opens the membrane pores can activate apoptosis. Cholic acid in experimental atherogenic diets inhibits Complex IV, cocaine inhibits Complex I, the poliovirus inhibits Complex II, ceramide inhibits Complex III, azide, cyanide, chloroform, and methamphetamine inhibit Complex IV. Ethanol abuse and antiviral nucleoside analogue therapy inhibit mtDNA replication. By contrast, melatonin stimulates Complexes I and IV and Gingko biloba stimulates Complexes I and III. Oral Q10 supplementation is effective in treating cardiomyopathies and in restoring plasma levels reduced by the statin type of cholesterol-lowering drugs.

Adenosine Triphosphate↗
PubMed2001

Review: molecular pathology of cyclooxygenase-2 in cancer-induced angiogenesis.

Cancer-induced angiogenesis is the result of increased expression of angiogenic factors, or decreased expression of anti-angiogenic factors, or a combination of both events. For instance, in colon cancer, the malignant cells, the stromal fibroblasts, and the endothelial cells all exhibit strong staining for cyclooxygenase-2 (COX-2), the rate-controlling enzyme in prostaglandin (PG) synthesis. In various cancer tissues, vascular endothelial growth factor (VEGF) and transforming growth factor beta (TGF-beta) co-localize with COX-2. Strong COX-2 and VEGF expression is highly correlated with increased tumor microvascular density (MCD); new vessels proliferate in areas of the tumor that express COX-2. Moreover, high MVD is a predictor of poor prognosis in breast and cervical cancers. COX-2 and VEGF expression are elevated in breast and prostate cancer tissues and their cell-lines. In vitro, PGE2 induces VEGE Supernatants of cultured cells from breast, prostate, and squamous cell cancers contain angiogenic proteins such as COX-2 and VEGF that induce in vitro angiogenesis. A selective COX-2 inhibitor, NS-398, restores tumor cell apoptosis, reduces microvascular density, and reduces tumor growth of PC-3 prostate carcinoma cells xenografted into nude mice. The COX-2 produced by a malignant tumor and COX-2 produced by the surrounding host tissue both contribute to new vessel formation, which explains how selective COX-2 inhibition reduces tumor growth where the tumor COX-2 gene has been silenced by methylation.

Animals↗
PubMed2000

Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of COX-2 in neoplasia.

Several types of human tumors overexpress cyclooxygenase (COX) -2 but not COX-1, and gene knockout transfection experiments demonstrate a central role of COX-2 in experimental tumorigenesis. COX-2 produces prostaglandins that inhibit apoptosis and stimulate angiogenesis and invasiveness. Selective COX-2 inhibitors reduce prostaglandin synthesis, restore apoptosis, and inhibit cancer cell proliferation. In animal studies they limit carcinogen-induced tumorigenesis. In contrast, aspirin-like nonselective NSAIDs such as sulindac and indomethacin inhibit not only the enzymatic action of the highly inducible, proinflammatory COX-2 but the constitutively expressed, cytoprotective COX-1 as well. Consequently, nonselective NSAIDs can cause platelet dysfunction, gastrointestinal ulceration, and kidney damage. For that reason, selective inhibition of COX-2 to treat neoplastic proliferation is preferable to nonselective inhibition. Selective COX-2 inhibitors, such as meloxicam, celecoxib (SC-58635), and rofecoxib (MK-0966), are NSAIDs that have been modified chemically to preferentially inhibit COX-2 but not COX-1. For instance, meloxicam inhibits the growth of cultured colon cancer cells (HCA-7 and Moser-S) that express COX-2 but has no effect on HCT-116 tumor cells that do not express COX-2. NS-398 induces apoptosis in COX-2 expressing LNCaP prostate cancer cells and, surprisingly, in colon cancer S/KS cells that does not express COX-2. This effect may due to induction of apoptosis through uncoupling of oxidative phosphorylation and down-regulation of Bcl-2, as has been demonstrated for some nonselective NSAIDs, for instance, flurbiprofen. COX-2 mRNA and COX-2 protein is constitutively expressed in the kidney, brain, spinal cord, and ductus deferens, and in the uterus during implantation. In addition, COX-2 is constitutively and dominantly expressed in the pancreatic islet cells. These findings might somewhat limit the use of presently available selective COX-2 inhibitors in cancer prevention but will probably not deter their successful application for the treatment of human cancers.

Animals↗
PubMed2000

Molecular pathology of cyclooxygenase-2 in neoplasia.

Cyclooxygenase (COX)-2 levels are elevated in several types of human cancer tissues. Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both the COX-1 and COX-2 protein, the two enzymes that convert arachidonic acids to prostaglandins. Regular use of such NSAIDs significantly reduces the risk and spread of some cancers. The objective of this study was to elucidate the molecular pathology of neoplasms that overexpress COX-2. Epidemiological data and clinical studies were analyzed and compared with results of studies of human tumor tissues, animal models, and cultured tumor cells. COX-2, but not COX-1, is highly expressed in human colon carcinoma, squamous cell carcinoma of the esophagus, and skin cancer. COX-2 is inducible by oncogenes ras and scr, interleukin-1, hypoxia, benzo[a]pyrene, ultraviolet light, epidermal growth factor, transforming growth factor beta, and tumor necrosis factor alpha. Dexamethasone, antioxidants, and tumor-suppressor protein p53 suppress COX-2 expression. COX-2 synthesizes prostaglandin E2 (PGE2) which stimulates bcl-2 and inhibits apoptosis, and induces interleukin-6 (IL-6) which enhances haptoglobin synthesis. PGE2 is associated with tumor metastases, IL-6 with cancer cell invasion, and haptoglobin with implantation and angiogenesis. Drastic reduction in polyp number results from COX-2 gene knockout as well as from selective COX-2 inhibition in a mouse model of human familial adenomatous polyposis. Nonselective NSAIDs, for instance aspirin, and selective COX-2 inhibitors such as celecoxib (SC-58635) and NS-398 suppress azoxymethane-induced colon carcinogenesis in rats. Aspirin, indomethacin, and ibuprofen decrease cultured lung cancer cell proliferation. Selective inhibition of COX-2 is preferable to nonselective inhibition. It reduces cancer cell proliferation, induces cancer cell apoptosis, and spares COX-1-induced cytoprotection of the gastrointestinal tract.

Animals↗
PubMed1992

Quantitative alteration of some aortic intima proteins in fatty streaks and fibro-fatty lesions.

Proteins from grossly and histologically normal human aortic intimas and human aortic intima with fatty streaks or fibro-fatty lesions were extracted with 9 M urea mixture. Protein extracts were mixed with an internal absorbance calibrator (carbonic anhydrase) and subsequently separated by two-dimensional gel electrophoresis, silver stained, and quantitated by a laser beam densitometer. The vascular-origin proteins actin, tropomyosin-like proteins, tubulin, glycoprotein G35, and two myosin light chains were present in the highest amounts in normal aortic intima (27-year-old male). Quantitation of vascular-origin proteins in aortic intima with a fibro-fatty lesion from the same subject showed a slight decrease in relative amount of these proteins as compared to the normal intima. Several polypeptides (P15, P18, P60, P110b) and plasma-derived proteins not observed in the normal intima were found in fibro-fatty lesion (albumin, haptoglobin beta-chain, fibrinogen beta-chain, alpha 1-HS-glycoprotein). Other proteins which were present in very low amounts in the normal intima (transferrin, alpha 1-antitrypsin, apolipoprotein A-1, P56, P190) were found to be major proteins of intima with fibro-fatty lesion. Differences in relative amount of plasma-derived and vascular-origin proteins between normal intima and intima with fatty streaks, studied in a large number of specimens from 38 thoracic intimas and 18 paired abdominal intimas (16-34 years old) were less prominent. Statistically significant increases of the albumin/actin ratio were found in fatty streaks as compared to paired normal intimas as well as in the mean value of albumin/actin ratio in the group of fibro-fatty lesions (mean = 6.1) as compared to the group of fatty streaks (mean = 1.7) or normal intima (mean = 0.7). Several lesion unique proteins were observed; however, the frequency of the occurrence of these proteins in 41 specimens with lesion was low. No significant differences were observed in intima protein pattern and quantities of selected intima proteins between paired thoracic and abdominal aortas.

Actins↗
PubMed1988

Long-term oral ciprofloxacin: experience in the treatment of incurable infective endocarditis.

Acute septic infective endocarditis caused by Pseudomonas aeruginosa, in two patients with conditions that made it incurable, was treated with long-term orally administered ciprofloxacin. Bacteremia and symptoms cleared, resulting in subjective well-being without cure for three and one half and 22 months, respectively. Large amounts of ciprofloxacin, 150 and 1,440 g, respectively, were given continuously without apparent adverse reactions. Blood isolates of P. aeruginosa after treatment had limited progression of resistance to ciprofloxacin. Use of orally administered ciprofloxacin provides new opportunities for the long-term treatment of serious infections with restricted risk of bacterial drug resistance and no appreciable side effects.

Administration, Oral↗
PubMed1987

Effect of menstrual cycle on protein expression in human uterine leiomyomas.

Tissue proteins in paired samples of uterine leiomyomas and normal myometria from 26 patients were compared after extraction with 9 M urea, separation by two-dimensional polyacrylamide gel electrophoresis (2-D PAGE), and visualization by silver staining. A creatine kinase carbamylation train and a rat heart extract were used as internal standards for the relative charge and the relative molecular weight (Mr) scales, respectively. Two groups of four proteins each, a first group of Mr = 34,500 (34K) and relative charge of creatine kinase of -14 to -21(P34a-d) and a second group of Mr = 56,000 (56K) and relative charge of creatine kinase less than -23(P56a-d), were more frequently expressed in uterine leiomyoma tissue than in normal myometrial tissue: P34, 14 of 26 (53.8%) in tumors and zero of 26 (0%) in normal myometria; P56a&d, 17 of 26 (65.3%); P56b&c, 20 of 26 (76.9%) in tumors and P56a&d, zero of 26 (0%); and P56b&c, 12 of 26 (46.1%) in normal myometria. Both P34 and P56 were expressed more frequently in the uterine leiomyoma during the proliferative phase than during the nonproliferative phase (P34 in proliferative phase: 12 of 13, 92.3%; and in nonproliferative phase: two of 13, 15.3%; P56a-d in proliferative phase: 13 of 13, 100%; and in nonproliferative phase: P56a&d, four of 13, 30.7%, and P56b&c, seven of 13, 53.8%). The cyclic expression of P34 and P56 suggests that their synthesis is related to the intrinsic hormonal environment of the tumors.

Adult↗
PubMed1986

Basic proteins in the human aortic intima: nonequilibrium two-dimensional electrophoretic analysis of tissue extracts.

The protein composition of atheroma-free human thoracic intima was compared with that containing fatty streaks or fibro-fatty lesions utilizing two-dimensional gel electrophoresis (2-DE) and silver staining. Intimal proteins extracted with 9 M urea were separated by nonequilibrium pH gradient electrophoresis (NEPHGE) followed by polyacrylamide gel electrophoresis (PAGE) in the second dimension. NEPHGE-PAGE of proteins extracted from atheroma-free intima revealed several major proteins: actin, tropomyosin-like proteins, proteins with relative molecular weight (Mr) of 250,000 (P250), two proteins with Mr about 15,000 (P15a, P15b), and many medium proteins such as a myosin heavy chain, two myosin light chains, and proteins P47, P44, P32, P27, P20a, P20b, P19a, P19b. Several additional proteins were observed in intimas with fatty streaks and fibro-fatty lesions. Most of them, such as albumin, transferrin, Apo A-I, alpha 1-antitrypsin, fibrinogen beta-chain, IgG, appear to originate from plasma. Differences in protein composition of intima with fibro-fatty streaks compared with adjacent lesion-free intima varied from case to case and need further study. NEPHGE-PAGE in combination with isoelectric focusing (ISO)-PAGE revealed more intimal proteins in atheroma-free and diseased aortas than either method alone, proteins which might be quantitated, isolated for binding studies, and further evaluated for their potential role in atherogenesis.

Actins↗
PubMed1986

Human aortic intima protein composition during initial stages of atherogenesis.

Protein extracted from 24 human aortic intimas (6-33 years old) with 9 M urea mixture, were studied after separation by two-dimensional gel electrophoresis (2-DE) and silver staining. The protein composition of normal intima in 4 cases, each without any gross changes in the thoracic aorta, displayed similarity. In each 2-DE protein pattern of these intimas about 150 polypeptide spots were detectable/mg of wet tissue. Major and medium polypeptides were described by relative molecular weight Mr in kilodaltons (kDa) and relative charge Cr. Major proteins found were actin (P44-18; Mr = 44 kDa; Cr = -18), tropomyosin-like proteins (P34-29, P35-28.5, P36-31) and two glycoproteins (G35-21, G35-23.5). Several new major and medium extracellular proteins were demonstrated in fibro-fatty lesions as well as in the lesion-free intimas adjacent to lesion in 3 cases. Many of these proteins appeared to originate from plasma: albumin, IgG, alpha 1-antitrypsin, transferrin, haptoglobin beta-chain, apo A-I, apo A-II, fibrinogen beta-chain, alpha 2-HS glycoprotein and alpha 1-antichymotrypsin. Visual comparison of intimal protein patterns from 17 different cases with varying degree of fatty streaks in the thoracic aorta, showed variability in 2 polypeptides P32-17.8 and P32-19.8 as well as 4 plasma proteins albumin, alpha 1-antitrypsin, transferrin and apo A-I. This study suggests that changes in protein composition may occur in the human aortic intima during the initial histological stages of atherogenesis providing potentially useful markers for their identification and pathophysiological evaluation.

Adolescent↗
PubMed1985

Effect of aging on human aortic protein composition. I. One-dimensional polyacrylamide gel electrophoretic analysis of tissue extracts.

Proteins extracted from matching areas of homogenized intimas of 17 human aortas, from two age groups (15-34 and 35-82), were studied after separation by polyacrylamide gel electrophoresis, silver staining, and densitometric scanning. Several definite protein bands including 6 major and 16 minor bands were identified in 17 aortic intima samples grossly and microscopically lesion free. However, such electrophoretic patterns were found to differ in the two age groups studied. For instance, (1) the integrated densities (amounts) of protein bands 1, 6, 13, 16, and 19 which we interpreted as of mural vascular origin were significantly higher in the younger age group, whereas the amounts of bands 2, 7, 9, 11, and 21 suspected to be of plasma origin were found to be significantly higher in the older age group; (2) protein band No. 8 was found to be double in the younger age group vs a single line in the older age group, whereas band No. 12 was the opposite. These changes in protein composition appear to correlate closely with diffuse intimal thickening found histologically in older age group, and will be further studied to relate to those in atherosclerotic lesions.

Adolescent↗
PubMed1985

Effect of aging on human aortic protein composition. II. Two-dimensional polyacrylamide gel electrophoretic analysis.

Arterial intima proteins were extracted by 9 M urea from matching histologically atheroma-free areas of 27 human thoracic aortas of both sexes from younger (15-34) and older (35-82) age groups and studied after separation by high-resolution two-dimensional polyacrylamide gel electrophoresis. Seventeen specific protein groups on each gel were identified according to their relative charges and molecular weights and their distribution in the two age groups compared. Some plasma-derived proteins occurred rarely in young aortas while they were consistently found in those from older cases, i.e., protein group 4 (alpha 1-antichymotrypsin) 1/13 (8%) vs 12/14 (86%), group 7 (haptoglobin beta-chain) 1/13 (8%) vs 13/14 (93%) and groups 6 and 9 (IgG chains) 3/13 (23%) vs 9/14 (64%), respectively. Other plasma-derived proteins such as group 3 (albumin) and 5 (alpha 1-antitrypsin) were identified in all samples of both age groups but their expression in the aortic intima increased with age. Proteins which are typically found intracellularly such as those from groups 11 (actin), 12 (cytoskeleton proteins), and 13 (tropomyosin-like proteins) appeared in samples of intima of both age groups but were less apparent in older specimens. These studies suggest that the changes in aortic intima protein distribution in the absence of atherosclerosis closely correlate with histological changes such as intimal thickening often found with aging, providing new sensitive markers of vascular senescence.

Adolescent↗
PubMed1984

Tissue proteins in breast cancer, as studied by use of two-dimensional electrophoresis.

Proteins from 25 specimens of malignant breast tissue were separated by "high-resolution" two-dimensional gel electrophoresis. The number of polypeptide spots detectable in individual gels varied from 259 to 471 (mean 347; SD 68) per milligram of wet tissue. Many polypeptide spots were not consistently present in all malignant tissues. Ten different in vivo polypeptides, observed neither in five non-malignant breast tissues nor in human milk, were present in more than 22 of the 25 cases of breast tumor tissues examined. Five of these polypeptides appeared to be identical to five in vitro polypeptides found in separations from cultured human ductal carcinoma cells. Further studies are required to verify the specificity of these tumor-associated proteins before they can be considered for breast tumor-specific in vitro diagnostic testing or targeting in selective in vivo anti-cancer therapy.

Adult↗
PubMed1980

Continuous-flow zone electrophoresis: experimental demonstration and discussion of potential clinical and research applications.

We report continuous-flow sample application and continuous electrophoretic separation on a moving cellulose acetate tape. This very simple automated electrophoretic system requires minimum electronic control circuitry. Samples and calibrators are pumped by a peristaltic pump from sample containers onto a continuously moving cellulose acetate tape. Applied samples are interspaced with rinse solution (buffer) and small air segments for sample integrity. Electrophoretic separation, staining, and destaining are all continuous functions performed on the continuously moving tape. The system appears suitable for separation of proteins. Continuous-flow application could be combined with discrete sample application onto the same tape for continuous counter-immunoelectrophoresis; moreover, counter-electrophoresis of two continuously applied proteins, with one applied in a gradient, could potentially produce a system for automated gradient counter-immunoelectrophoresis. It should also be possible to design a simple system for automated immunofixation electrophoresis.

Autoanalysis↗
PubMed1977

Automated zone electrophoresis--experiments and new concepts.

I have investigated various modalities of automation of zone electrophoresis. One system has already been previously described (U.S. Pat. No. 3,896,021). Other systems investigated can be divided into batch systems and one random-access system; the former involve separation on cellulose acetate that is supported on 0.127 mm thick polyester (Mylar) film in the form of tape, cards, or discs. Systems in which the separation is in a direction transverse to the long axis of the tape use a typical tape width of 7.5 cm; systems in which separation is longitudinal make use of supports of various widths, depending upon the assay rate desired. Concepts were also developed for a random-access systems for automated electrophoresis, which requires no start-up time. Small Lucite cassettes are used, one for each sample. Each cassette has one surface of either cellulose acetate or any of several gels used for electrophoretic separation. There are further small wells for sample and calibrator. The loaded cassette is inserted into an input queue that allows serial processing. The cassettes move sequentially through prewetting (if needed), sample application, electrophoretic separation, staining, and scanning. This system should also be suitable for automated isoelectric focusing.

Automation↗