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Biomedical subjects

H Lee

Publications and source records attributed to H Lee.

At least 289 records · Page 16Linked to original sources
PubMed2000

A double-blind, placebo-controlled, multicenter study of Cerebrolysin for Alzheimer's disease.

OBJECTIVE: To assess the efficacy and safety of Cerebrolysin over 4 weeks in patients with probable Alzheimer's disease (AD). DESIGN: A 4-week randomized, double-blind, placebo-controlled, multicenter clinical trial. An unequal (Cerebrolysin:placebo = 2:1) randomization was used to assign more patients to the treatment group. SETTINGS: University medical centers and community geriatric hospitals in Korea. PARTICIPANTS: Fifty-three men and women at least 50 years of age admitted to hospitals with mild to moderate AD and otherwise in good health. INTERVENTION: The treatment group (n = 34) received Cerebrolysin (30 mL Cerebrolysin in 100 mL physiologic saline IV) once a day from Monday to Friday for 4 weeks. The control group (n = 19) received placebo. MEASUREMENTS: Primary outcome measures were the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Clinical Global Impression of Severity/ Change (CGIS/C). Secondary outcome measures included Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS), Katz Index of Activities of Daily Living (ADL), and Lawton Instrumental Activities of Daily Living (IADL) Scale. RESULTS: After 4 weeks of treatment, Cerebrolysin-treated patients demonstrated significant improvements in the ADAS-Cog (P = .02), CGIS/C (P = .01), and MMSE (P = .04) compared with placebo-treated patients. Among Cerebrolysin-treated patients, 82%, 62%, and 44% were rated improved on ADAS-Cog, CGIS/C, and MMSE, respectively, compared with 31.6%, 22%, and 17% of placebo-treated patients, respectively. However, there were no significant improvements in the Cerebrolysin group compared with the placebo group on the GDS, ADL, and IADL. There were no dropouts in either groups, with 100% compliance to Cerebrolysin and placebo. Only one patient reported a febrile sensation, which was transient and mild in severity. CONCLUSIONS: This study indicates that Cerebrolysin is a safe drug that improves the cognitive deficits and global function in patients with mild to moderate AD. Long-term efficacy and safety of Cerebrolysin in Alzheimer's patients should be evaluated in the future.

Activities of Daily Living↗
PubMed2000

Mechanisms of lysolipid phosphate effects on cellular survival and proliferation.

The specificity of cellular effects of lysolipid phosphate (LLP) growth factors is determined by binding to endothelial differentiation gene-encoded G protein-coupled receptors (EDG Rs), which transduce diverse proliferative and effector signals. The primary determinants of cellular responses to LLPs are the generative and biodegradative events, which establish steady-state concentrations of each LLP at cell surfaces, and the relative frequency of expression of each EDG R. There are major differences among types of cells in the net effective generation of the LLPs, lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), and in their profile of expression of EDG Rs. The less well characterized secondary determinants of cellular specificity of LLPs are high-affinity binding proteins with carrier and cell-presentation functions, cell-selective regulators of expression of EDG Rs, and cellular factors that govern coupling of EDG Rs to G protein transductional pathways. The roles of components of the LLP-EDG R system in normal physiology and disease processes will be definitively elucidated only after development of animal models with biologically meaningful alterations in genes encoding EDG Rs and the discovery of potent and selective pharmacological probes.

Breast Neoplasms↗
PubMed2000

TraG from RP4 and TraG and VirD4 from Ti plasmids confer relaxosome specificity to the conjugal transfer system of pTiC58.

Plasmid conjugation systems are composed of two components, the DNA transfer and replication system, or Dtr, and the mating pair formation system, or Mpf. During conjugal transfer an essential factor, called the coupling protein, is thought to interface the Dtr, in the form of the relaxosome, with the Mpf, in the form of the mating bridge. These proteins, such as TraG from the IncP1 plasmid RP4 (TraG(RP4)) and TraG and VirD4 from the conjugal transfer and T-DNA transfer systems of Ti plasmids, are believed to dictate specificity of the interactions that can occur between different Dtr and Mpf components. The Ti plasmids of Agrobacterium tumefaciens do not mobilize vectors containing the oriT of RP4, but these IncP1 plasmid derivatives lack the trans-acting Dtr functions and TraG(RP4). A. tumefaciens donors transferred a chimeric plasmid that contains the oriT and Dtr genes of RP4 and the Mpf genes of pTiC58, indicating that the Ti plasmid mating bridge can interact with the RP4 relaxosome. However, the Ti plasmid did not mobilize transfer from an IncQ relaxosome. The Ti plasmid did mobilize such plasmids if TraG(RP4) was expressed in the donors. Mutations in traG(RP4) with defined effects on the RP4 transfer system exhibited similar phenotypes for Ti plasmid-mediated mobilization of the IncQ vector. When provided with VirD4, the tra system of pTiC58 mobilized plasmids from the IncQ relaxosome. However, neither TraG(RP4) nor VirD4 restored transfer to a traG mutant of the Ti plasmid. VirD4 also failed to complement a traG(RP4) mutant for transfer from the RP4 relaxosome or for RP4-mediated mobilization from the IncQ relaxosome. TraG(RP4)-mediated mobilization of the IncQ plasmid by pTiC58 did not inhibit Ti plasmid transfer, suggesting that the relaxosomes of the two plasmids do not compete for the same mating bridge. We conclude that TraG(RP4) and VirD4 couples the IncQ but not the Ti plasmid relaxosome to the Ti plasmid mating bridge. However, VirD4 cannot couple the IncP1 or the IncQ relaxosome to the RP4 mating bridge. These results support a model in which the coupling proteins specify the interactions between Dtr and Mpf components of mating systems.

Agrobacterium tumefaciens↗
PubMed2000

Variable numbers of TTC repeats in Mycobacterium leprae DNA from leprosy patients and use in strain differentiation.

Strain differentiation of Mycobacterium leprae would be of great value for epidemiological investigation to identify the infectious sources of leprosy, to understand transmission patterns, and to distinguish between relapse and reinfection. From the M. leprae genome sequence database, TTC DNA repeats were identified. Primer sets designed to amplify the region flanking TTC repeats revealed PCR products of different sizes, indicating that the number of repeats at each locus may be variable among M. leprae strains. The TTC repeats were not found in Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium marinum, or human tissues, which indicated their specificity to M. leprae. Sequence analysis of the TTC repeat region in each of the M. leprae strains showed a variation of 10 to 37 repeats. In the M. leprae strains of 34 multibacillary patients at Cebu, Philippines, M. leprae with 24 and 25 TTC repeats was most common, and this was followed by strains with 14, 15, 20, 21, and 28 repeats. This study thus indicates that there are variable numbers of TTC repeats in a noncoding region of M. leprae strains and that the TTC region may be useful for strain differentiation for epidemiological investigations of leprosy.

Autoradiography↗
PubMed2000

Molecular characterization of multidrug-resistant Streptococcus pneumoniae isolates in Korea. The Asian Network for Surveillance of Resistant Pathogens (ANSORP) Study Group.

Pulsed-field gel electrophoresis, ribotyping, and fingerprinting analysis of 22 invasive isolates of multidrug-resistant (MDR) pneumococci from Korea showed that 59 to 82% were genetically related. DNA sequencing of the PBP 2B gene showed relatively uniform alterations in nucleotides (5.4 to 7.8%) and amino acids (3.0 to 4. 3%), while Asn-276-->Lys, Arg-285-->Cys and Ser-305-->Phe substitutions were unique to Korean MDR strains, suggesting the spread of a few epidemic clones of resistant pneumococci within Korea.

Anti-Bacterial Agents↗
PubMed2000

Species identification of mycobacteria by PCR-restriction fragment length polymorphism of the rpoB gene.

PCR-restriction fragment length polymorphism analysis (PRA) using the novel region of the rpoB gene was developed for rapid and precise identification of mycobacteria to the species level. A total of 50 mycobacterial reference strains and 3 related bacterial strains were used to amplify the 360-bp region of rpoB, and the amplified DNAs were subsequently digested with restriction enzymes such as MspI and HaeIII. The results from this study clearly show that most of the mycobacterial species were easily differentiated at the species level by this PRA method. In addition, species with several subtypes, such as Mycobacterium gordonae, M. kansasii, M. celatum, and M. fortuitum, were also differentiated by this PRA method. Subsequently, an algorithm was constructed based on the results, and a blinded test was carried out with more than 260 clinical isolates that had been identified on the basis of conventional tests. Comparison of these two sets of results clearly indicates that this new PRA method based on the rpoB gene is more simple, more rapid, and more accurate than conventional procedures for differentiating mycobacterial species.

DNA-Directed RNA Polymerases↗
PubMed2000

A single deletion in the membrane-proximal region of the Sindbis virus glycoprotein E2 endodomain blocks virus assembly.

The envelopment of the Sindbis virus nucleocapsid in the modified cell plasma membrane involves a highly specific interaction between the capsid (C) protein and the endodomain of the E2 glycoprotein. We have previously identified a domain of the Sindbis virus C protein involved in binding to the E2 endodomain (H. Lee and D. T. Brown, Virology 202:390-400, 1994). The C-E2 binding domain resides in a hydrophobic cleft with C Y180 and W247 on opposing sides of the cleft. Structural modeling studies indicate that the E2 domain, which is proposed to bind the C protein (E2 398T, 399P, and 400Y), is located at a sufficient distance from the membrane to occupy the C protein binding cleft (S. Lee, K. E. Owen, H. K. Choi, H. Lee, G. Lu, G. Wengler, D. T. Brown, M. G. Rossmann, and R. J. Kuhn, Structure 4:531-541, 1996). To measure the critical spanning length of the E2 endodomain which positions the TPY domain into the putative C binding cleft, we have constructed a deletion mutant, DeltaK391, in which a nonconserved lysine (E2 K391) at the membrane-cytoplasm junction of the E2 tail has been deleted. This mutant was found to produce very low levels of virus from BHK-21 cells due to a defect in an unidentified step in nucleocapsid binding to the E2 endodomain. In contrast, DeltaK391 produced wild-type levels of virus from tissue-cultured mosquito cells. We propose that the phenotypic differences displayed by this mutant in the two diverse host cells arise from fundamental differences in the lipid composition of the insect cell membranes which affect the physical and structural properties of membranes and thereby virus assembly. The data suggest that these viruses have evolved properties adapted specifically for assembly in the diverse hosts in which they grow.

Amino Acid Sequence↗
PubMed2000

Tyrosine phosphorylation mediates both activation and downmodulation of the biological activity of Vav.

Vav works as a GDP/GTP exchange factor for Rac GTPases, thereby facilitating the transition of these proteins from the inactive (GDP-bound) into the active (GTP-bound) state. The stimulation of Vav exchange activity during cell signaling is mediated by tyrosine phosphorylation. To understand the roles of phosphorylation in the regulation of Vav activity, we have initiated the characterization of the residues of Vav that are phosphorylated during signal transduction. Here we show that a Y-to-F mutation in one of these residues, Y174, leads to the oncogenic activation of Vav and to the enhancement of other Vav-mediated signals such as those for cytoskeletal reorganization, JNK activation, and stimulation of the nuclear factor of activated T cells. The effect induced by the Y174F mutation is further accentuated by mutations in residue Y142 or Y160. The Y174F mutation has no effect on the exchange activity of Vav in vitro but results in higher levels of phosphorylation in vivo. Using a phosphospecific antibody, we found that Y174 is phosphorylated following stimulation of mitogenic and antigenic receptors. This phosphorylation event is conserved in Vav-2 and Vav-3, the other two members of the Vav family. These results identify a previously unknown mechanism for the oncogenic activation of Vav and suggest that the activity of this exchange factor is modulated by two antagonistic phosphorylation events, one involved in Vav activation and a second one implicated in Vav inactivation.

3T3 Cells↗
PubMed2000

No strong association between alleles of tumour necrosis factor alpha and interleukin-1 receptor antagonist and corneal melting associated with systemic vasculitis.

AIMS: To investigate polymorphism within the tumour necrosis factor alpha (TNF-alpha) promoter region and within the interleukin-1 receptor antagonist (IL-1Ra) gene in a group of patients with vasculitis associated corneal melting. METHODS: The polymorphic regions at position -308 on the TNF-alpha promoter region and in intron 2 of the IL-1Ra gene were amplified by the polymerase chain reaction (PCR). The resultant products were separated by electrophoresis on agarose gels and visualised by ethidium bromide staining. Genotype and allele frequencies for the 20 patients were compared with healthy controls from the same geographical area. RESULTS: The allele frequencies in the patient and control groups respectively for the TNF-alpha and IL-1Ra sites studied were as follows: TNF1, 82.5% and 80.2%; TNF2, 17.5% and 19.8%; IL-1Ra*1, 82. 5% and 78.3%; IL-1Ra*2, 15% and 20%; IL-1Ra*3 2.5% and 1.5%. Although there was a trend for the IL1Ra*2 allele to be more common in the control group, no allele was found to have a statistically significantly association with the patient group: TNF1 p = 0.89; TNF2 p = 0.89; IL-1Ra*1 p = 0.65; IL-1Ra*2 p = 0.68; IL-1Ra*3 p= 0. 50. CONCLUSIONS: The results suggest that the polymorphic alleles of TNF-alpha and IL-1Ra studied play little or no part in the susceptibility to corneal melting among these patients with systemic vasculitis.

Alleles↗
PubMed2000

Lysophosphatidic acid and sphingosine 1-phosphate stimulate endothelial cell wound healing.

Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are potent lipid growth factors with similar abilities to stimulate cytoskeleton-based cellular functions. Their effects are mediated by a subfamily of G protein-coupled receptors (GPCRs) encoded by endothelial differentiation genes (edgs). We hypothesize that large quantities of LPA and S1P generated by activated platelets may influence endothelial cell functions. Using an in vitro wound healing assay, we observed that LPA and S1P stimulated closure of wounded monolayers of human umbilical vein endothelial cells and adult bovine aortic endothelial cells, which express LPA receptor Edg2, and S1P receptors Edg1 and Edg3. The two major components of wound healing, cell migration and proliferation, were stimulated individually by both lipids. LPA and S1P also stimulated intracellular Ca(2+) mobilization and mitogen-activated protein kinase (MAPK) phosphorylation. Pertussis toxin partially blocked the effects of both lipids on endothelial cell migration, MAPK phosphorylation, and Ca(2+) mobilization, implicating G(i)/(o)-coupled Edg receptor signaling in endothelial cells. LPA and S1P did not cross-desensitize each other in Ca(2+) responses, suggesting involvement of distinct receptors. Thus LPA and S1P affect endothelial cell functions through signaling pathways activated by distinct GPCRs and may contribute to the healing of wounded vasculatures.

Animals↗
PubMed2000

The ACAT inhibitor avasimibe reduces macrophages and matrix metalloproteinase expression in atherosclerotic lesions of hypercholesterolemic rabbits.

Given the significance of cholesteryl ester (CE) accumulation in macrophage foam cell formation, we hypothesized that inhibitors of acyl-CoA:cholesterol O-acyltransferase (ACAT) would produce a histologically stable lesion by limiting macrophage enrichment and thereby a source of matrix metalloproteinases (MMPs). Male New Zealand White rabbits were sequentially fed a cholesterol/fat diet for 9 weeks, a fat-only diet for 6 weeks, and 25 mg/kg avasimibe for 7 to 8 weeks. Avasimibe had no effect on plasma total cholesterol exposure. Plasma avasimibe maximal concentration and 24-hour area-under-the-curve levels were 178 ng/mL and 2525 ng. h/mL, respectively, after 7 weeks of treatment with 25 mg/kg avasimibe. The median inhibitory concentration against human monocyte-macrophage ACAT was 12 ng/mL when determined in the absence of albumin, and aortic arch avasimibe levels were 25 ng/g of tissue wet weight. Avasimibe reduced thoracic aortic and iliac-femoral CE content by 39%, the extent of thoracic aortic lesions by 41%, aortic arch cross-sectional lesions area by 35%, and monocyte-macrophage area by 27%. The reduction in monocyte-macrophage area reflected a change in cell number and not cell size. In the iliac-femoral artery, avasimibe decreased monocyte-macrophage content by 77% and reduced the macrophage-to-lesion ratio from 0.16 to 0.05. Within the aortic arch, the catalytic activity of latent and active MMP-9 was reduced by 65% and 33%, respectively; latent and active MMP-1 and MMP-3 activity measured collectively was decreased by 52% and 60%, respectively, and MMP-2 was unchanged. Aortic arch MMP-9, tissue inhibitor of matrix metalloproteinase (TIMP)-1, and TIMP-2 mRNA levels were reduced 29% to 39%, and MMP-2 mRNA levels increased. We conclude that the bioavailable ACAT inhibitor avasimibe can directly limit macrophage accumulation, resulting in the histological appearance of mainly fibromuscular lesions, and can potentially stabilize preestablished atherosclerotic lesions by reducing MMP expression within the lesion.

Acetamides↗
PubMed2000

Determinants of bioactivity of oxidized phospholipids. Specific oxidized fatty acyl groups at the sn-2 position.

We previously described 3 bioactive oxidation products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (PAPC) containing oxovaleroyl (POVPC), glutaroyl (PGPC), and epoxyisoprostane (PEIPC) groups at the sn-2 position that were increased in minimally modified/oxidized low density lipoprotein (MM-LDL) and rabbit atherosclerotic lesions. We demonstrated specific and contrasting effects of POVPC and PGPC on leukocyte-endothelial interactions and described an effect of PEIPC on monocyte binding. The major purpose of the present study was to determine the effects of structural changes on the bioactivities of these 3 lipids. We demonstrate herein that the group at the sn-2 position determines the specific bioactivity and that the substitution of stearoyl for palmitoyl at the sn-1 position or ethanolamine for choline at the sn-3 position of the phospholipid did not alter bioactivity. Oxidized PAPC, oxidized 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine, and oxidized 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphorylethanolamine stimulated monocyte binding and inhibited lipopolysaccharide-induced expression of the neutrophil-binding molecule E-selectin. Furthermore, all oxovaleroyl phospholipids but not the glutaroyl phospholipids induced monocyte binding without an increase in vascular cell adhesion molecule-1 (VCAM-1) expression and inhibited lipopolysaccharide-induced E-selectin expression. In contrast, glutaroyl phospholipids but not oxovaleroyl phospholipids stimulated E-selectin and VCAM-1 expression. We further demonstrate that all parts of the phospholipid molecules are required for these bioactivities. Hydrolysis with phospholipase (PL) A(1), PLA(2), and PLC strongly reduced the bioactivities of POVPC, PGPC, and mixed isomers of PEIPC. PLD had a smaller but still significant effect. The effects of POVPC and PEIPC could be abolished by sodium borohydride treatment, indicating the importance of the reducible groups (carbonyl and epoxide) in these molecules. In summary, these studies identify 6 new bioactive, oxidized phospholipids that are increased in MM-LDL and, where measured, in atherosclerotic lesions. They thus suggest that a family of phospholipid oxidation products containing oxovaleroyl, glutaroyl, and epoxyisoprostane at the sn-2 position play an important role in the regulation of leukocyte-endothelial interactions, bioactivity being in part controlled by several types of phospholipid hydrolases.

Animals↗
PubMed2000

Cognitive deficits after focal cerebral ischemia in mice.

BACKGROUND AND PURPOSE: The interpretation of cognitive data in many experimental stroke studies is problematic because middle cerebral artery occlusion (MCAO) is associated with sensorimotor alterations that may become confounding factors in cognitive testing. The purpose of the current study was to determine if it is possible to measure MCAO-induced cognitive deficits by using short durations of ischemia that do not result in alterations in sensorimotor behavior in mice. METHODS: Male C57/Bl6 mice were subjected to 60 or 90 minutes of intraluminal MCAO or sham surgery. In the first cohort of animals (n=12/group), locomotor activity, balance, and coordination were evaluated 2 weeks after surgery. In a second cohort of animals (n=10/group), the effects of 60 minutes of MCAO on subsequent learning and memory were assessed with a step-down passive avoidance task beginning 1 week after surgery. In a third cohort of animals (n=8 to 10/group), training in a passive avoidance task was completed before 60 minutes of MCAO, then retention of the task was assessed 1 week after surgery. In all animals, infarction size was determined after 14 days of reperfusion with use of cresyl violet staining and quantitative image analysis. RESULTS: There was no significant difference in infarction volume in the cerebral cortex or caudoputamen after 60 versus 90 minutes of MCAO. However, there was a significant increase in latency to move 1 body length in the 90-minute MCAO group compared with the 60-minute MCAO and sham groups. In 2 additional cohorts of animals, 60-minute MCAO was associated with a deficit in the acquisition and retention of a passive avoidance task regardless of whether the task training occurred before or after MCAO. CONCLUSIONS: Long-term cognitive deficits can be induced in mice by using a short duration of MCAO (60 minutes) that does not result in concomitant sensorimotor deficits.

Animals↗
PubMed2000

Surface pitting of heart valve disks tested in an accelerated fatigue tester.

There are various reports on the fracture of mechanical heart valves implanted in humans or animals and it has been pointed out that fractures are induced by erosion of the disk surface due to cavitation bubbles. Cavitation erosion on mechanical heart valves was studied using our originally designed accelerated fatigue tester. Several valve housings with different compliance values were used. The number and position of pits on the valve disk were measured using an optical microscope. Disk-closing velocity was measured and cavitation bubbles were monitored by a high-speed video camera. It was found that disk-closing velocity increased and cavitation erosion was enhanced with an increase in compliance of the valve holder. Therefore, careful attention should be paid to the compliance of an accelerated fatigue tester.

Animals↗
PubMed2000

Clozapine in the treatment of refractory psychotic mania.

OBJECTIVE: The efficacy of clozapine was examined in a group of patients with treatment-refractory bipolar disorder, manic type with psychotic features. METHOD: Twenty-two subjects with treatment-refractory bipolar disorder with active manic and psychotic symptoms participated in a 12-week open-label trial of clozapine. After a 2-10-day drug washout period, patients began treatment with clozapine at 25 mg/day; the dose was increased 25 mg/day (as tolerated) to a maximum level of 550 mg/day. Patients were evaluated longitudinally over the course of the study with the Brief Psychiatric Rating Scale (BPRS), the Young Mania Rating Scale, and the Clinical Global Impressions (CGI) scale. RESULTS: Fourteen of the 22 subjects in the study continued taking clozapine for at least 10 of the 12 weeks. Among the entire group, mean improvements of 56. 7%, 56.6%, and 39.1% were seen on the BPRS, Young Mania Rating Scale, and CGI, respectively. Seventeen of the 22 subjects (77.3%) experienced at least a 20% improvement in scores on all three scales. CONCLUSIONS: The findings from this open-label study, which are consistent with previous retrospective studies, case reports, and one other open-label prospective study, suggest that clozapine is an effective agent for patients with treatment-refractory psychotic mania.

Adult↗
PubMed2000

Results of a phase II study using estramustine phosphate and vinblastine in combination with high-dose three-dimensional conformal radiotherapy for patients with locally advanced prostate cancer.

PURPOSE: To assess the feasibility and tolerance of neoadjuvant and concomitant estramustine phosphate and vinblastine (EV) with high-dose three-dimensional conformal radiotherapy (3D-CRT) for patients with unfavorable-risk prostate cancer. PATIENTS AND METHODS: Twenty-seven patients with unfavorable-risk prostate cancer were enrolled onto a prospective study to determine the feasibility of combining EV with 3D-CRT. Patients were eligible if any of the following requirements were satisfied: (1) Gleason score > or =8 and prostate-specific antigen (PSA) > 10 ng/mL; (2) Gleason score of 7 and PSA > 20 ng/mL; (3) clinical stage T3N0M0 disease with PSA > 20 ng/mL; (4) any patient with T4N0M0 disease; or (5) patients with TXN1MO disease. Therapy consisted of three 8-week cycles of EV and 8 weeks of 3D-CRT. Estramustine phosphate was given orally beginning on week 1 and continued until the completion of 3D-CRT. Each 8-week cycle of vinblastine consisted of 6 weekly intravenous injections followed by a 2-week rest period. Radiation therapy was administered using a three-dimensional conformal approach to a prescription dose of 75.6 Gy. The median follow-up was 26 months (range, 6 to 40 months). RESULTS: Twenty-three (85%) of 27 patients completed the entire course of therapy and were assessable for toxicities and biochemical outcome. Two patients (7%) developed grade 3 hematologic toxicity that resolved, and two patients (7%) developed grade 3 hepatoxicity, manifesting as persistent elevation of serum transaminase levels, necessitating discontinuation of the chemotherapy and withdrawal from the treatment program. The most prominent adverse effects from this regimen were mild to moderate (grade 1 to 2) nausea and fatigue related to estramustine. Mild peripheral edema was seen in 15% of patients and was treated with diuresis. 3D-CRT was tolerated well in these patients. Medications were required for relief of acute grade 2 rectal (gastrointestinal [GI]) and urinary (genitourinary [GU]) symptoms in 35% and 48% of patients, respectively. Three patients developed acute grade 3 GU toxicities. The 2-year actuarial likelihood of late grade 2 GI toxicity was 20%. No late grade 3 or 4 GI toxicities were observed. The 2-year actuarial likelihoods of late grade 2 and 3 GU toxicities were 25% and 12%, respectively. No grade 4 GU toxicity was observed. CONCLUSION: Neoadjuvant and concomitant EV with high-dose 3D-CRT is well tolerated in patients with unfavorable-risk prostate cancer. Although the incidence of modest (grade 2) late GI and GU toxicities seem to be increased compared with 3D-CRT alone or in combination with androgen ablation therapy, no severe toxicities were encountered with this regimen.

Administration, Oral↗
PubMed2000

Studies on human pregnancy-induced insulin-like growth factor (IGF)-binding protein-4 proteases in serum: determination of IGF-II dependency and localization of cleavage site.

Insulin-like growth factor (IGF)-binding protein-4 (IGFBP-4), a consistent inhibitor of IGF action, is subject to proteolytic cleavage by the IGF-II-dependent IGFBP-4 protease. However, regulation of the IGF-II-dependent IGFBP-4 protease in vivo is not known. As IGFBP proteases are known to be triggered during pregnancy, we systematically evaluated the changes in IGFBP-4 proteolysis by serum collected throughout human pregnancy. Results from in vitro protease assays using recombinant IGFBP-4 revealed that IGFBP-4 proteolysis determined in both the presence and absence of exogenous IGF-II significantly increased during the first and second trimesters and reached a plateau by the third trimester. However, in the absence of IGF-II, IGFBP-4 proteolysis by pregnancy serum was only observed after prolonged incubation. IGF-II dose dependently increased IGFBP-4 proteolysis by pregnancy serum, with maximal stimulation observed at a concentration of 0.7 mol/L relative to IGFBP-4. In contrast, IGF-II at an equimolar dose had little effect on proteolysis of recombinant human IGFBP-3, whereas excess IGF-II reproducibly inhibited recombinant human IGFBP-3 proteolysis by pregnancy serum. Although IGF-II enhanced IGFBP-4 proteolysis, results from N-terminal sequence and mass spectrometric analyses of IGFBP-4 proteolytic fragments demonstrate that the cleavage site (Met135-Lys136) in human IGFBP-4 was not altered by IGF-II. Deletion of the residues 121-141 containing this cleavage site blocked IGFBP-4 proteolysis. These findings demonstrate that the increase in IGFBP-4 proteolysis during pregnancy was accounted for mainly by the IGF-II-dependent IGFBP-4 proteolysis. Because IGFBP-4 is a potent inhibitor of IGF actions, it can be speculated that the pregnancy-induced IGFBP-4 proteases may play an important role in regulating fetal growth.

Adult↗