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Biomedical subjects

C Lin

Publications and source records attributed to C Lin.

At least 199 records · Page 11Linked to original sources
PubMed1996

Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide.

An estimated 1% of the global human population is infected by hepatitis C viruses (HCVs), and there are no broadly effective treatments for the debilitating progression of chronic hepatitis C. A serine protease located within the HCV NS3 protein processes the viral polyprotein at four specific sites and is considered essential for replication. Thus, it emerges as an attractive target for drug design. We report here the 2.5 angstrom resolution X-ray crystal structure of the NS3 protease domain complexed with a synthetic NS4A activator peptide. The protease has a chymotrypsin-like fold and features a tetrahedrally coordinated metal ion distal to the active site. The NS4A peptide intercalates within a beta sheet of the enzyme core.

Amino Acid Sequence↗
PubMed1996

Immunohistochemical demonstration of 3,2'-dimethyl-4-aminobiphenyl DNA adduct formation in various organs of Syrian golden hamsters.

3,2'-Dimethyl-4-aminobiphenyl (DMAB), known to be a wide-spectrum genotoxic carcinogen in rats, is also tumorigenic to hamster organs such as the forestomach, small and large intestines, gallbladder and urinary bladder. Using a specific antibody against DMAB-DNA adducts, adduct formation in various organs of Syrian golden hamsters after single s.c., i.g. or i.p. injections of DMAB was immunohistochemically examined in relation to its carcinogenic specificity. The nuclei of basal cells of forestomach, epithelia of small intestine, large intestine, gallbladder and urinary bladder of hamsters were stained to various degrees. However, no differences in the formation of DMAB-DNA adducts were observed between these and non-target organs regarding carcinogenicity. The staining intensity after i.g. or i.p. injections was slightly stronger than after s.c. injection. In line with previous findings for rats, the present results indicate that adduct formation is necessary but not itself sufficient for tumor induction in the Syrian golden hamster.

Aminobiphenyl Compounds↗
PubMed1996

An automated sample preparation and high performance liquid chromatographic method for the determination of MK-591, a novel leukotriene biosynthesis inhibitor, in human plasma.

A high performance liquid chromatography assay utilizing an automated sample preparation procedure for the determination of a novel leukotriene biosynthesis inhibitor, (MK-591), in human plasma has been developed. After aliquoting plasma samples and adding internal standard manually, the BenchMate Workstation executed protein precipitation and solid-phase extraction. Following evaporation to dryness, the residue was reconstituted and chromatographed isocratically on a cyano-phase analytical column. MK-591 and the internal standard were separated from each other and from endogenous plasma substances and detected with an absorbance detector. The assay has been validated in the concentration range 10-1000 ng ml-1 and has the sensitivity and specificity necessary to quantify plasma concentrations from several clinical studies.

Chromatography, High Pressure Liquid↗
PubMed1996

Renin inhibition: a novel therapy for cardiovascular disease.

The renin-angiotensin system (RAS) is a major contributor in the regulation of blood pressure, and pharmacologic manipulation of this system has resulted in a beneficial class of therapeutic agents, which include angiotensin-converting enzyme (ACE) inhibitors. However, ACE inhibitors are not specific for RAS, and in addition, they can affect bradykinin and prostaglandin, which can also cause changes in vascular tone. Under development are renin inhibitors that are specific for angiotensinogen and act at the initial, rate-determining step of the RAS cascade. The various pharmacologic approaches to renin inhibition include specific renin antibodies, synthetic derivatives of the prosegment of renin precursor, pepstatin analogs, and angiotensinogen analogs. The last approach is the most promising for patient therapy. Multiple studies have shown the effectiveness of the renin inhibitors in both primates and human beings. Further research is now directed toward the development of an agent with good oral bioavailability for patient treatment and as a biologic probe for helping to understand the role of the RAS in control of blood pressure and blood volume.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Arabidopsis cryptochrome 1 is a soluble protein mediating blue light-dependent regulation of plant growth and development.

Cryptochrome 1 (CRY1) is a flavin-type blue type receptor of Arabidopsis thaliana which mediates inhibition of hypocotyl elongation. In the work described in this report it is demonstrated that CRY1 is a soluble protein expressed in both young seedlings grown either in the dark or under light, and in different organs of adult plants. The functional role of CRY1 was further investigated using transgenic Arabidopsis plants overexpressing CRY1. It is demonstrated that overexpression of CRY1 resulted in hypersensitivity to blue, UV-A, and green light for the inhibition of hypocotyl elongation response. Transgenic plants overexpressing CRY1 also exhibited a dwarf phenotype with reduced size in almost every organ. This was in keeping with the previous observation of reciprocal alterations found in hy4 mutant plants and is consistent with a hypothesis that CRY1 mediates a light-dependent process resulting in a general inhibitory effect on plant growth. In addition, transgenic plants overexpressing CRY1 showed increased anthocyanin accumulation in response to blue, UV-A, and green light in a fluence rate-dependent manner. This increase in anthocyanin accumulation in transgenic plants was shown to be concomitant with increased blue light-induction of CHS gene expression. It is concluded that CRY1 is a photoreceptor mediating blue light-dependent regulation of gene expression in addition to its affect on plant growth.

Anthocyanins↗
PubMed1996

Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant.

Missense mutations in the presenilin 2 (PS-2) gene on chromosome 1 were sought by direct nucleotide sequence analysis of the open reading frame of 60 pedigrees with familial Alzheimer's disease (FAD). In the majority of these pedigrees, PS-1 and beta-amyloid precursor protein (beta APP) gene mutations had been excluded. While no additional PS-2 pathogenic mutations were detected, four silent nucleotide substitutions and alternative splicing of nucleotides 1338-1340 (Glu325) were observed. Analysis of additional members of a pedigree known to segregate a Met239Val mutation in PS-2 revealed that the age of onset of symptoms is highly variable (range 45-88 years). This variability is not attributable to differences in ApoE genotypes. These results suggest (i) that, in contrast to mutations in PS-1, mutations in PS-2 are a relatively rare cause of FAD; (ii) that other genetic or environmental factor modify the AD phenotype associated with PS-2 mutations; and (iii) that still other FAD susceptibility genes remain to be identified.

Age of Onset↗
PubMed1996

Purification and properties of Arabidopsis thaliana COR (cold-regulated) gene polypeptides COR15am and COR6.6 expressed in Escherichia coli.

Arabidopsis thaliana cold-regulated genes COR15a and COR6.6 encode 15- and 6.6-kD polypeptides, respectively. The COR15a polypeptide is known to be targeted to chloroplasts and, during import, to be processed to a 9.4-kD polypeptide designated COR15am. The COR6.6 polypeptide is thought to be located in the cytosol. The coding sequences for COR15am and COR6.6 were fused to the bacteriophage T7 promoter and expressed in Escherichia coli. The recombinant polypeptides COR15amr and COR6.6r were purified to near homogeneity using a combination of ammonium sulfate fractionation, ion-exchange chromatography, and adsorption chromatography on hydroxyapatite. COR15amr and the major species of COR15am in chloroplasts co-migrated on both two-dimensional O'Farrell gels and nondenaturing polyacrylamide gels. These data corroborate the site of COR15a processing and indicate no difference in charge or quaternary structure between COR15amr and the major species of COR15am in plants. In contrast, the migration patterns of COR6.6r and COR6.6 on two-dimensional gels suggest that a considerable portion of the COR6.6 population in plants is modified. In the accompanying papers (M.S. Webb, S.J. Gilmour, M.F. Thomashow, P.L. Steponkus [1996] Plant Physiology 111: 301-312; M. Uemura, S.J. Gilmour, M.F. Thomashow, P.L. Steponkus [1996] Plant Physiology 111: 313-327), the effects of COR15amr and COR6.6r on the cryostability and lyotropic phase behavior of liposomes are examined.

Arabidopsis↗
PubMed1996

Pharmacokinetics and metabolism of genaconazole, a potent antifungal drug, in men.

The pharmacokinetics of genaconazole, a racemic triazole antifungal agent comprising 50% RR and 50% SS enantiomers, were studied in 12 healthy male volunteers after a single oral dose of 200 mg. The serum samples were analyzed for the two enantiomers by using a chiral high-pressure liquid chromatography assay. The concentrations of the RR and SS enantiomers in serum were virtually identical. The mean values for the maximum concentrations in serum (Cmax) (1.7 micrograms/ml), times to Cmax (4.0 to 4.2 h), half-lives (83 h), and areas under the concentration-time curve from 0 h to infinity (195 to 199 micrograms.h/ml) were similar for the two enantiomers. The results showed that the pharmacokinetic profiles of the two enantiomers were similar after a single oral dosing of the racemate. The pharmacokinetics of the RR enantiomer were also evaluated in 12 healthy male volunteers after a single oral dose of 100 or 200 mg. The ratios of the Cmaxs and of the areas under the concentration-time curves from 0 h to infinity for the two doses were about 2, indicating a dose proportionality. In a separate study, six healthy male volunteers received a single oral dose of 50 mg of 14C-labeled genaconazole. The Cmax values for total radioactivity (14C) and intact genaconazole were virtually identical (0.6 micrograms/ml). The mean half-lives in serum were about 73 h for both total radioactivity and genaconazole. The amounts of total radioactivity excreted in the 0 to 240-h interval (representing approximately three half-lives) in urine and feces were 66.6 and 9.3% of the dose, respectively; 64.4% of the dose was excreted in urine as parent drug. There were no detectable metabolites in either serum or urine. The data demonstrate that genaconazole (racemate) is well absorbed, undergoes negligible biotransformation, and is slowly excreted, primarily in the urine.

Administration, Oral↗
PubMed1996

Penetration of ceftibuten into middle ear fluid.

The penetration of ceftibuten, an extended-spectrum oral cephalosporin, into middle ear fluid (MEF) was evaluated in pediatric patients during a course of daily oral doses of 9 mg/kg of body weight for 10 days. Plasma and MEF collected at 2, 4, 6, or 12 h after at least 3 days of dosing were analyzed for ceftibuten by a high-pressure liquid chromatography method, and the data were used to calculate pharmacokinetic parameters. Plasma and MEF had almost identical maximum concentrations (Cmax) of ceftibuten (14 micrograms/ml). These Cmax values in MEF during acute otitis media were well in excess of the MIC for 90% of the isolates of each of four major pathogens in this disease. The time to Cmax was longer in MEF (4 h) than in plasma (2 h). Excellent penetration (71%) of ceftibuten into MEF was observed on the basis of the area under the curve ratio (MEF/plasma). These data clearly indicate that ceftibuten penetrated well into the MEF to yield clinically effective concentrations.

Acute Disease↗
PubMed1996

The ability of bile to scavenge superoxide radicals and pigment gallstone formation in guinea pigs.

After partial ligation of the common bile duct (CBD) of guinea pigs, 14 of 16 animals developed pigment gallstones within one week (S group). Intraperitoneal injection of Vit. E and C, each 10 mg/kg daily from 3 days before CBD ligation to one week after the operation (S+V group), decreased the gallstone incidence to 5/14 (exact probability < 0.01). The gallstone incidence in the control group, that only received laparotomy without ligation of the CBD, was 0/15. Biochemical analysis of the gallbladder bile showed that stricture of the CBD was associated with a significant increase in levels of unconjugated bilirubin (UCB) and Ca2+ (p < 0.05 and < 0.01). Simultaneously the scavenging rate (SR) of superoxide radical in bile significantly decreased (p < 0.05). Comparing S+V group with S group, the effect of Vit. E and C on the concentrations of UCB and Ca2+ in bile was not significant (both p > 0.05), but Vit. E and C normalized the SR, and the difference between S group and S+V group was significant (p < 0.05). These results suggested that Vit. E and C, known as antioxidants, enhanced the ability to scavenge oxygen radical in S+V group; and that in addition to the increases of UCB and Ca2+ concentrations, the participation of oxygen radicals might be of importance for pigment gallstone formation induced by bile duct obstruction.

Animals↗
PubMed1996

Effect of framing on adolescents' decision making.

92 young adolescents were tested using Tversky and Kahneman's (1981) decision problems for framing effects. A notable number of young adolescents tested were not influenced by the context of the decision problems, thus they selected the same response option for positively and negatively framed problems. Parallel information was not available in Tversky and Kahneman's study for adults because they used a between-subjects design. However, for present adolescents who selected different response options for different framing problems, the response pattern exhibited by them resembled the general pattern exhibited by the adults tested in Tversky and Kahneman's study-negative frames led them to accept risk to avoid certain loss; positive frames prevented them from risking what they were certain to gain. Boys and girls were similar in their susceptibility to framing effects as were honors students in mathematics as compared to nonhonors students. Although the positive vs negative framing only influenced some of the young adolescents tested in this study, because the influence was consistent, researchers and educators interested in adolescents' decisions involving risky choices might use framing principles to design and assess cognitive interventions for high-risk behaviors among young adolescents.

Adolescent↗
PubMed1996

Transcriptional control of cell phenotypes in the neuroendocrine system.

A fundamental aspect of the development of complex organ systems is a requirement for precise temporal and spatial coordination in the genesis of tissues of distinct embryonic origins, in order to form functional units required for physiological homeostasis and survival. Such a requirement is particularly well exemplified in mammalian development in the formation of the hypothalamic-pituitary axis. Neuronally expressed POU domain factors might exert effects on terminal differentiation events similar to those of Pit-1 in the maturation of anterior pituitary gland cell phenotypes. Neurons comprising the endocrine hypothalamus develop in tandem with their ultimate target, the pituitary gland, and arise from a primordium in which three related class III POU domain factors-Brn-2, Brn-4, and Brn-1-are initially co-expressed. These factors subsequently exhibit stratified patterns of ontogenic expression, correlating with the appearance of distinct neuropeptides that define three major endocrine hypothalamic cell types. Deletion of the Brn-2 genomic locus affects terminal differentiation and/or maintenance of hypothalamic neurosecretory neurons and development of the posterior pituitary gland. Thus, both neuronal and endocrine components of the hypothalamic-pituitary axis are critically dependent upon the action of specific POU domain factors at a penultimate step in the sequential events that underlie the appearance of mature cellular phenotypes.

Amino Acid Sequence↗
PubMed1996

Rectal carcinoma: are we making a difference?

Evaluation of preliminary results at our institution revealed an improvement in survival of patients treated for rectal cancer from 1950-1988. A study was conducted to analyze responsible factors. A total of 335 patients with accurate staging and follow up for at least 5 years or until death were reviewed retrospectively. Of the 335 patients, 295 (88%) were treated by surgical resection, abdominal perineal resection (APR) (n=179), and anterior resections (n=105), the most common procedures. Operative mortality for patients with curable disease (n=188) was 18 per cent (n=34), which has significantly decreased from 24 per cent (n=28) (1950-1969) to 8 per cent (n=6) (1970-1988), (P < 0.01). Operative mortality for APR and anterior resection was 22 per cent (n=29) and 8 per cent (n=5), respectively. Mortality for APR decreased from 28 per cent (1950-1969) to 10 per cent (1970-1988) (P < 0.02) accounting for most of the improvement. Of the 335 patients, 142 (42%) presented with stage IV disease, which decreased from 54 per cent (n=47) (1950s) to 22 per cent (n=10) (1980s), P < 0.01. The overall 5-year survival was 19 per cent (n=64), with a corresponding increase per decade from 13 per cent (1950s) to 43 per cent (1980s), (P < 0.001). Of the remaining 188 patients, 41 had involved surgical margins and decreased 5-year survival of 8 per cent when compared to patients with clear surgical margins (37%) P < 0.01). Multifactor analysis revealed that stage of disease at presentation, involved surgical margins, and operative mortality were significant independent variables. Earlier stage at presentation and improved operative management increased the survival of patients with rectal cancer at our institution.

Cause of Death↗
PubMed1996

Presence of free radicals in pigment gallstone in vivo.

OBJECTIVE: To clarify whether free radical, which may play a role in pigment gallstone formation, is present in pigment gallstones in vivo. MATERIALS AND METHODS: Free radical signal of gallstones from 18 patients was detected by electron paramagnetic resonance spectroscopy at 77K under anaerobic condition and in air (control). As soon as the anaerobic determination was finished, the fresh anaerobic sample was exposed to air and stored in a freezer at -20 degrees C. RESULTS: Free radical signal (g = 2.0038) was detected in fresh anaerobic samples containing more than 2% bilirubin compound, and the signal intensity correlated linearly with the content of calcium bilirubinate (r = +0.95, P < 0.0005). During the storage at -20 degrees C and exposure to air, the signal intensity of each anaerobic sample and its control increased gradually, eventually reaching the same stable level. Fe(III) signal intensity was enhanced synchronously and related linearly with free radical signal (r = +0.99, P < 0.0005). CONCLUSIONS: Free radical exists originally in pigment gallstones in vivo, and it may play an important role in pigment gallstone formation. The free radical signal carried by gallstones may be strengthened by the action of oxygen in air on bilirubin. The transition metal ions probably take part in the formation of bilirubin free radical.

Bilirubin↗
PubMed1996

The amplification and expression of MDR1 gene in adriamycine resistant cell line of colon cancer cell HR8348.

P-glycoprotein plays an important role in highly drug resistant cells. But its high expression cannot be achieved by chemotherapy. In order to study the effect of P-glycoprotein on clinical tumors, we established a low ADM resistant colon cancer cell line HR/ADM and determined the amplification and expression of mdr-1 gene. The GLC/ADM showed a resistant pattern similar to classical MDR and the transcription of mdr-1 gene determined by RT-PCR increased. The immunocytochemical analysis showed strong positive staining with monoclonal antibody. The gene amplification of mdr-1 was clearly demonstrated by southern blot. Our results suggested that moderate expression of P-glycoprotein might be enough for a high resistant pattern.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

An observation on combined use of chemotherapy and traditional Chinese medicine to relieve cancer pain.

We have treated 50 patients with stage III, VI malignant tumors confirmed by pathology. The patients were divided into two groups. One group was treated by combination of chemotherapy and traditional Chinese medicine (treatment group); the other only by chemotherapy (control group). The effect of cancer treatment was evaluated according to the criteria of WHO. The results showed that the effective rate was 80% in treatment group and 52% in control group. The pain relieving rate was 68% in treatment group and 40% in control group (P < 0.01). This fact demonstrates that the application of traditional Chinese medicine can invigorate blood circulation, eliminate blood stasis, soften hardness and dissolve the mass, nourish blood and increase vigor. This kind of application can not only enhance the effect of cancer treatment but also increase the cancer pain relieving rate.

Adult↗