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Biomedical subjects

P S Lin

Publications and source records attributed to P S Lin.

At least 37 records · Page 2Linked to original sources
PubMed1998

The sit-to-stand movement in stroke patients and its correlation with falling.

OBJECTIVE: To use kinetic assessment of the sit-to-stand movement as a means of sorting out those stroke patients at risk for falling. DESIGN: A retrospective study, using a force platform to assess sit-to-stand performance and to determine its correlation with falls in stroke patients. SETTING: Hospital-based rehabilitation units. METHODS: Thirty-three stroke patients (18 fallers, 15 nonfallers) and 25 age-matched healthy subjects were included in this study. Subjects sat in an adjustable chair with their feet on two force plates and performed the standing up/sitting down movement at a self-paced, comfortable speed. RESULTS: The rate of rise in force (dF/dT) was significantly lower in stroke fallers than in stroke nonfallers and healthy subjects (23.78+/-17.38, 55.23+/-31.24, and 85.96+/-42.4 percent body weight per second, respectively [p < .005]). The center of pressure sway in mediolateral direction during rising/ sitting down was much greater in stroke fallers than in stroke nonfallers or healthy subjects (p < .05). Body weight distribution was asymmetric on the feet of stroke patients, with much more body weight on their sound side. CONCLUSIONS: The significantly lower rate of rise in force and greater postural sway while rising/sitting down may be useful in identifying stroke patients who are at risk for falling.

Accidental Falls↗
PubMed1998

Interaction of diabetes and hypertension on determinants of endothelial adhesiveness.

Epidemiological studies have established that diabetes mellitus and hypertension are independent risk factors for atherosclerosis. One of the earliest abnormalities seen in atherogenesis is enhanced monocyte adherence to the endothelium. The mechanisms by which diabetes mellitus or hypertension enhances monocyte-endothelial cell interactions are incompletely characterized. It is not known whether there are additive interactions between these risk factors on endothelial adhesiveness for monocytes. Male Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats were fed a normal or fructose-enriched diet. In some cases, animals were injected with streptozotocin (35 mg/kg body weight) to induce diabetes. After 2 weeks, plasma was drawn for biochemical measurements, and thoracic aortas were harvested, opened longitudinally, and exposed to fluorescently labeled mouse monocytoid cells (WEHI 78/24, 2 x 10(6)/mL) for 30 minutes on a rocking platform. Adherent cells were counted by epifluorescence microscopy. WEHI 78/24 binding to aortic segments from SHR animals was elevated compared with segments from WKYs. Fructose feeding alone had no effect on endothelial adhesiveness. When WKYs were made hyperglycemic by STZ injection, monocyte binding was 160% of the control value. Elevated monocyte binding was also observed in aortas derived from SHR animals injected with STZ, indicating an additive effect of hypertension and hyperglycemia. To determine whether alterations in oxidative state played a role in the endothelial adhesiveness, aortic segments were exposed to lucigenin (250 micromol/L) for measurement of superoxide anion. Aortic segments from SHR elaborated 120% more superoxide anion than did controls. Elevated free-radical production was also observed in aortas from diabetic WKYs. Furthermore, thoracic aortas derived from diabetic SHR animals elaborated more superoxide anion than did any of the other groups (374%, P<0.05). Immunohistochemical staining for monocyte chemotactic protein-1 demonstrated increased expression in aortas isolated from diabetic WKY and SHR compared with control vessels. These studies demonstrate that both diabetes and hypertension lead to increased monocyte adherence to the endothelium. This abnormality is associated with increased vascular superoxide production and monocyte chemotactic protein-1 expression. Furthermore, there appears to be an additive interaction between hyperglycemia and hypertension in their effects on endothelial adhesiveness and its determinants.

Animals↗
PubMed1998

The inhibition of the estrogenic effects of pesticides and environmental chemicals by curcumin and isoflavonoids.

Many environmental chemicals and pesticides have been found to be estrogenic and have been shown to stimulate the growth of estrogen receptor-positive (ER-positive) human breast cancer cells. Since it is difficult to avoid human exposure to environmental estrogens, a potentially important area of research is the development of dietary strategies to prevent the stimulated growth of breast tumors by environmental estrogens. In this context, the inhibitory action of curcumin and a combination of curcumin and isoflavonoids were studied in ER-positive human breast cancer cells (MCF-7 and T47D) and ER-negative MDA-MB-231 cells induced by the pesticide o,p'-DDT and the environmental pollutants 4-nonylphenol and 4-octylphenol. The median inhibitory concentration (IC50) for curcumin in T47D cells was 10 microM when measured at either a 48-hr or a 6-day incubation time. The IC50 value for curcumin was within the 8-10 microM range for inhibiting the growth of T47D cells induced by a 10- microM concentration each of 4-nonylphenol, 4-octylphenol, and o, p'-DDT. The IC50 for curcumin in MCF-7 cells induced by 10 microM of either o,p'-DDT, 4-octylphenol, or 4-nonylphenol were 9, 39, and >50 microM, respectively. A combination of curcumin and isoflavonoids was able to inhibit the induced growth of ER-positive cells up to 95%. For MDA-MB-231 cells, the IC50 for curcumin was 17 microM, which was reduced to 11 microM in the presence of 25 microM genistein. Curcumin and genistein induce drastic changes in the morphological shape of both ER-positive and ER-negative cells. Data presented here indicate that a mixture of curcumin and isoflavonoids is the most potent inhibitor against the growth of human breast tumor cells. These data suggest that combinations of natural plant compounds may have preventive and therapeutic applications against the growth of breast tumors induced by environmental estrogens.

Antineoplastic Agents↗
PubMed1998

CuTira brachytherapy: a new combination of radioactive copper isotopes and the hypoxic cytotoxin, tirapazamine, for targeted tumor therapy.

We previously showed a significant enhancement of tirapazamine-induced cytotoxicity and DNA damage after binding with copper. This result suggests that conjugates of tirapazamine with radioactive copper, i.e., 64Cu and 67Cu, may offer potential for targeted therapy of a wide range of advanced stage tumors including a possible treatment for patients with solitary hepatocellular carcinoma by intrahepatic arterial infusion. Major supporting considerations include: (a) tirapazamine having a high selective toxicity against hypoxic cells; (b) the nature of radioactive decay of these copper isotopes and obtainable high specific activity; and (c) simple procedure for the production of copper-tirapazamine complex.

Brachytherapy↗
PubMed1997

The biological effectiveness of intermittent irradiation as a function of overall treatment time: development of correction factors for linac-based stereotactic radiotherapy.

PURPOSE: Continuous irradiation of relatively short duration as administered in gamma-ray stereotactic radiosurgery (SRS) is biologically not equivalent to the more protracted intermittent exposures during accelerator-based radiosurgery with multiple arcs. Accelerator-based SRS and fractionated stereotactic radiotherapy (SRT) is currently performed with a high degree of variability in equipment and techniques resulting in highly variable treatment delivery times. The present work is designed to quantify the effects of radiation delivery times on biological effectiveness. For this, the intermittent radiation delivery schemes, typical for linac-based SRS/SRT, have been simulated in vitro to derive biological correction factors. METHODS AND MATERIALS: The experiments were carried out using U-87MG human glioma cells in suspension at 37 degrees C irradiated with 6 MV X-rays to clinically relevant doses ranging from 6 to 18 Gy, delivered over total irradiation times from 16 min to 3 h. The resulting cell survival data was used to calculate dose correction factors to compensate for wide variations in dose delivery times. RESULTS: At each total dose level, cell survival increased with increasing total irradiation time. The increase in survival was more pronounced at higher dose levels. At a total dose of 12 Gy, cell survival increased by a factor of 4.7 when irradiation time was increased from 16 to 112 min. Dose correction factors were calculated to allow biologically equivalent irradiations over the range of exposure times. Cells irradiated with corrected total doses of 11.5 Gy delivered incrementally in 16 min up to 13.3 Gy in 112 min were found to exhibit the same survival within the experimental limits of accuracy. CONCLUSIONS: For a given total dose, variations in dose delivery time typical of SRS/SRT techniques will result in significant changes in cell survival. In the dose range studied, an isoeffect dose correction factor of 2 to 3 cGy/min was shown to compensate for the change in delivery time for U-87 MG human gloma cells in vitro.

Brain Neoplasms↗
PubMed1996

Tirapazamine (SR 4233) interrupts cell cycle progression and induces apoptosis.

Tirapazamine (Tira), a bioreductive agent, is highly toxic to cells under low oxygen conditions. Since active investigations of this agent are focusing on its potential as an adjunct of radiotherapy to improve overall effects on radioresistant hypoxic tumor cells, understanding its toxic mechanisms under aerobic conditions is important to the clinical application of this agent. Tira-treated V79 Chinese hamster cells were tested for cytotoxicity by colony assay and growth inhibition by the MTT assay. The survival of V79 cells after being exposed to 100 microM of Tira for 2 h was about 78% of untreated controls. The mitotic cell counts of V79 cells approached zero after 4 h treatment of Tira at 100 microM or 3 h at 300 microM. The fragmentation pattern of DNA isolated from cells 2 h after 300 microM Tira treatment showed characteristics of apoptotic cells. The induction of apoptosis by Tira was also detected by flow cytometric analysis and microscopic observation. These effects of Tira may be part of underlying toxic mechanisms to cells (including normal cells) under aerobic conditions.

Animals↗
PubMed1996

Tumor necrosis factor-alpha suppresses the regrowth of fractionated irradiated endothelial cells in vitro.

Cytokines from two sources may affect endothelial cells (ECs) in tumor therapy: endogenously from cells in tumors and exogenously from therapeutic applications. These cytokines could modulate the influence of other therapy on tumor ECs. We use the colorimetric MTT method to assess the growth of irradiated ECs isolated from bovine pulmonary artery (CPAEC) and human umbilical cord vein (HUVEC) treated by cytokines. CPAECs given a single radiation dose of 2.5 to 15 Gy showed a small reduction in viable cells 2 to 3 days post-treatment. Neither tumor necrosis factor-alpha (TNF), interleukin-1 alpha (IL-1), nor interferon-gamma (INF) altered the growth of CPAECs treated by single radiation doses. HUVECs irradiated by a single dose of 12 Gy showed continuous reduction in viable cell numbers while those treated by 3 fractions of 4 Gy in 3 days or 6 fractions of 2 Gy in 3 days began to regrow 7 to 8 days after irradiation. Addition of TNF during the fractionated irradiation period limits the regrowth of HUVECs. Addition of IL-1 does not have the same effect. We have also tested the combined effect of another EC active agent flavone acetic acid (FAA), which has also been shown to stimulate the expression of TNF, with radiation, FAA (200 micrograms/ml) has a greater inhibitory effect on the growth and regrowth of fractionatedly irradiated HUVECs than TNF. These data suggest that TNF or FAA should be explored along with radiotherapy for their anti-tumor effect.

Animals↗
PubMed1995

Radiation-induced enhanced proliferation of human squamous cancer cells in vitro: a release from inhibition by epidermal growth factor.

Ionizing radiation is believed to stimulate the repopulation of squamous carcinoma cells that survive the early portion of a fractionated course of radiotherapy. To characterize any intrinsic radiation-induced adaptive response and to examine whether epidermal growth factor (EGF) influences this response, A431 and 183A cells were irradiated with repeated daily exposures of 0.5-0.75 Gy and then grown in monolayer culture for 7 days with or without EGF at a 1 ng/ml concentration. Cell numbers were quantified using a microtiter dye-reduction assay. EGF alone caused approximately 70% and 30% growth inhibition of human SC A431 and 183A cells, respectively. Although radiation alone did not affect proliferative rates in these conditions, radiation eliminated the EGF-related growth inhibition in both cell lines. This effect was dose dependent in single radiation exposure experiments. Cell cycle analyses indicated that EGF initially promoted entry into S-phase 3 days after treatment but caused a G1-S block after 7 days. Treatment with radiation recruited cells into S-phase and G2-M, an effect which was sustained 7 days after treatment, overriding the influence of EGF. Radiation-induced modulation of the response of human squamous carcinoma cells to EGF in vitro after single and repeated radiation exposures suggests a proliferation response that may underlie enhanced repopulation of tumor clonogens in vivo.

Carcinoma, Squamous Cell↗
PubMed1994

The macrocyclic lactone protein kinase C activator, bryostatin 1, either alone, or in conjunction with recombinant murine granulocyte-macrophage colony-stimulating factor, protects Balb/c and C3H/HeN mice from the lethal in vivo effects of ionizing radiation.

We have examined the in vivo radioprotective effects of the macrocyclic lactone protein kinase C (PK-C) activator, bryostatin 1, administered either alone or in conjunction with recombinant murine granulocyte-macrophage colony-stimulating factor (rmGM-CSF), in Balb/c and C3H/HeN mice subjected to lethal total body irradiation (TBI). When administered alone on a divided dose schedule (24 hours and 30 minutes before TBI), rmGM-CSF (20 micrograms/kg) was ineffective in increasing survival in either strain. However, in Balb/c mice, bryostatin 1 alone (1 microgram) permitted the long-term survival (60 days) of 70% of the animals following TBI, and 80% when administered in conjunction with rmGM-CSF. Bryostatin 1 administered alone according to this schedule exerted minimal radioprotective effects in C3H/HeN mice, but, when combined with a subeffective dose of rmGM-CSF, allowed 50% of the animals to survive. Treatment of Balb/c mice with bryostatin 1 administered as a single dose 4 hours before TBI resulted in a 20% survival rate, and 45% when administered with rmGM-CSF; corresponding values for the C3H/HeN strain were 60% and 40%, respectively. Lastly, the survival rates of Balb/c mice treated with bryostatin 1 administered as a single dose 4 hours following TBI was 20%, and 25% with rmGM-CSF; corresponding values were 50% and 25% for C3H/HeN mice. These findings indicate that the PK-C activator bryostatin 1 exhibits intrinsic in vivo radioprotective effects in lethally irradiated Balb/c and C3H/HeN mice, and may, under some circumstances, augment the radioprotective capacity of rmGM-CSF. They also underscore the critical role that strain differences and scheduling considerations play in determining the in vivo radioprotective capacity of bryostatin 1, as well as its interactions with rmGM-CSF.

Animals↗
PubMed1994

Effects of the protein kinase C stimulant bryostatin 1 on the proliferation and colony formation of irradiated human T-lymphocytes.

The protein kinase C stimulant bryostatin 1 (Bryo) was used in examining human peripheral blood T-lymphocyte radiosensitivities in proliferation assays. Bryo was similar to PMA in inducing T-cell proliferation by the CD3, CD28 and CD69 pathways. No difference in radiosensitivities was observed in T-cells stimulated by the three independent surface antigen-mediated activation pathways. CD3 was chosen as the second signal for comparing the potencies of the three different first signals Bryo, phorbol 12-myristate, 13-acetate (PMA), and interleukin 2 (IL-2) in stimulating T-cell proliferation and in maintaining this response after radiation. Though there were radioresponse differences among various individuals, the irradiated lymphocytes consistently showed significantly greater proliferation when treated with Bryo or PMA than with IL-2 (p < 0.05- < 0.005). No difference in proliferative responses was observed in T-cells irradiated between 4 h before and 15 h after the addition of stimulants. Colony forming assays showed higher colony survival for irradiated T-cells stimulated with Bryo than with PMA. These results support the important role of protein kinase C in T-cell radiation responses, and suggest a potential role for Bryo in enhancing T-lymphocyte survival during radiation therapy.

Adjuvants, Immunologic↗
PubMed1993

Modulation by bryostatin 1 of the in vitro radioprotective effects of the GM-CSF/IL-3 fusion protein, PIXY 321, on normal human myeloid progenitors.

We have examined the effect of the macrocyclic lactone PK-C activator, bryostatin 1, on the in vitro radioprotective capacity of the GM-CSF/IL-3 fusion protein, PIXY 321, toward normal committed myeloid progenitors (day 14 CFU-GM). Preincubation of CD 34+ cells for 24 h with 10 ng/ml PIXY 321 exerted significant radioprotective effects on these progenitors, (D = 1.403 vs 0.715 for controls), which were at least as great as those previously reported for higher concentrations (e.g., 50 ng/ml) or rGM-CSF. In contrast to the results of earlier studies involving rGM-CSF, preincubation of cells with both PIXY 321 and 10 nM bryostatin 1 did not lead to an increase in radioprotective effect when the total number of day 14 colonies was assessed. However, combinations of PIXY 321 and bryostatin 1 (or the tumour-promoting PK-C activator, PDBu) significantly increased the relative percentage and absolute number of surviving non-eosinophilic colonies (e.g., pure neutrophil, pure monocyte-macrophage, or mixed neutrophil-macrophage) at each radiation dose level. A similar pattern of response was noted in cells irradiated without a preconditioning interval, and in cells exposed to divided radiation doses. These results indicate that the GM-CSF/IL-3 fusion protein PIXY 321 exhibits significant in vitro radioprotective effects toward normal human bone marrow myeloid progenitors, and that co-administration of PK-C activators such as bryostatin 1 of PDBu selectively augments the radioprotective capacity of this hybrid cytokine toward non-eosinophilic elements.

Bryostatins↗
PubMed1993

Enhanced oxygenation in vivo by allosteric inhibitors of hemoglobin saturation.

The in vivo effects on hemoglobin (Hb)-O2 affinity and tissue PO2 were investigated after intraperitoneal administration of 2-[4-(((dichloroanilino)-carbonyl)methyl)phenoxyl]-2-methyl propionic acid (RSR4; 150 mg/kg) or its 3,5-dimethyl derivative (RSR13; 300 mg/kg) in C3Hf/Sed mice. The Hb-O2 dissociation curve was plotted from tail vein blood samples using an O2 dissociation analyzer before and up to 160 min after compound administration. Twenty to 40 min after injection, the PO2 at 50% saturation of hemoglobin (Hb P50) increased by a mean of 25% (range 18-31%) after RSR4 and 53% (range 36-76%) after RSR13. Tissue PO2 was continuously measured using an O2 microelectrode in thigh muscle before and up to 40 min after RSR4 or RSR13 injection. Twenty to 40 min after administration, tissue PO2 increased by a mean of 78% (range 30-127%) after RSR4 and 66% (range 39-97%) after RSR13 administration in anesthetized mice. No change in tissue PO2 was seen in anesthetized controls.

Aniline Compounds↗
PubMed1993

Cytotoxicity and manganese superoxide dismutase induction by tumor necrosis factor-alpha and ionizing radiation in MCF-7 human breast carcinoma cells.

Both tumor necrosis factor-alpha (TNF) and ionizing radiation cause active-oxygen radical-mediated cell injuries and cell death. Thus cells treated by both TNF and radiation may suffer greater injuries than cells treated by either agent alone. On the other hand, TNF or radiation treatment can stimulate the expression of a mitochondrial superoxide scavenging enzyme, manganese superoxide dismutase (MnSOD), which can lower the cytotoxic effects of both agents. Thus, the induction of MnSOD by radiation may interfere with the cytotoxic action of TNF and vice versa. We used a human breast tumor cell line, MCF-7, to determine the interaction of TNF and radiation on cytotoxicity and MnSOD expression. TNF was found to be more effective as a cytotoxic agent when used before than after radiation treatment. These observations suggest that radiation induced-MnSOD was more effective in reducing the cytotoxic effect of TNF whereas TNF induction of MnSOD was less effective in counteracting the radiation action. Our results not only underscore the different effects of the treatment order of TNF and radiation, but also point to potential implication in the radiotherapy of breast tumors.

Breast Neoplasms↗
PubMed1992

Potentiation of the activity of 1-beta-D-arabinofuranosylcytosine by the protein kinase C activator bryostatin 1 in HL-60 cells: association with enhanced fragmentation of mature DNA.

We have examined the interaction between 1-beta-D-arabinofuranosylcytosine (ara-C) and the macrocyclic lactone protein kinase C activator bryostatin 1 in the human promyelocytic leukemia cell line HL-60. Preexposure of cells to 10 nM bryostatin 1 for 24 h, followed by an additional 24-h incubation with 10 microM ara-C, resulted in greater than additive inhibitory effects toward clonogenic HL-60 cells. In a series of alkaline elution assays, cells preincubated with bryostatin 1 and prelabeled with [3H]thymidine exhibited a significant increase in DNA fragmentation following exposure to ara-C in comparison to cells exposed to ara-C alone. This increase in DNA damage was apparent at both neutral and alkaline pH and was not protein associated. In contrast, studies using cells pulse-labeled with [3H]thymidine immediately before analysis suggested that bryostatin 1 pretreatment did not increase the ability of ara-C to interfere with DNA replicative intermediates. Additional studies demonstrated that the increase in DNA fragmentation induced by bryostatin 1 and ara-C preceded both loss of cell membrane integrity (as determined by trypan blue exclusion) as well as depletion of intracellular ATP and NAD pools. Furthermore, the enhanced inhibitory effects of bryostatin 1 and ara-C toward clonogenic HL-60 cells did not appear to result from the induction of cellular differentiation. Finally, agarose gel electrophoresis of DNA obtained from cells exposed to both bryostatin 1 and ara-C revealed a pattern of integer multiples of 180- to 200-base pair fragments commonly associated with endonucleolytic cleavage; the extent of this fragmentation was considerably greater than that observed in cells exposed to ara-C alone. Taken together, these findings suggest that exposure of HL-60 cells to bryostatin 1 renders them more susceptible to ara-C-related DNA damage and that this phenomenon contributes to the cytotoxic effects of this drug combination. They also raise the possibility that bryostatin 1, perhaps through modulation of intracellular signaling events in leukemic cells, has the capacity to potentiate ara-C-related apoptosis or programmed cell death.

Adenosine Triphosphate↗
PubMed1992

Hexachlorocyclohexane pesticides reduce survival and alter plasma membrane structure of Chinese hamster V79 cells.

We studied the cytotoxic effects of alpha-, beta-, gamma-, and delta-hexachlorocyclohexanes (HCCH) on the survival of Chinese hamster V79 cells using clonogenic assays. Lethal dose yielding 50% cell survival (LD50) suggests the following order of cytotoxicity: delta-(+)gamma-HCCH (LD50 4 micrograms/ml) (1:1, w/w, mixture) > delta-HCCH (LD50 6 micrograms/ml) > gamma-HCCH (LD50 13 micrograms/ml) > alpha-HCCH (LD50 approx. 35 micrograms/ml) >> beta-HCCH. Structural changes in plasma membranes prepared from HCCH-treated V79 cells at dose yielding 10% cell survival (LD10) were analyzed using Raman spectroscopy. Raman spectra of plasma membranes show bands at 2850, 2880-2890, and 2935 cm-1 in the C-H stretching region. The plot of the ratio (I2880-2890/I2850) vs temperature for control plasma membranes shows two transitions between -5 and 5 degrees C and between 12 and 20 degrees C. Plasma membranes prepared from gamma- and delta-HCCH-treated Chinese hamster V79 cells show single transitions between -4 and 11 degrees C and between -2 and 11 degrees C, respectively. These changes in the thermal transition properties suggest that both gamma- and delta-HCCH alter lipid and lipid-protein phases of the plasma membrane of V79 cells. Raman analysis of the amide I and amide III region spectra further suggest that delta-HCCH also alters the secondary structure and the environment of highly amidated segments of plasma membrane proteins. We suggest that the primary action of biologically active HCCH isomers is to disrupt the organization of the plasma membrane and that may affect cell viability.

Animals↗