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At least 55 records · Page 3Linked to original sources
PubMed1999

Activity of the multitargeted antifolate LY231514 in the human tumor cloning assay.

PURPOSE: This study was performed to evaluate the activity of the multitargeted antifolate (MTA or LY231514) against a broad range of human tumors taken directly from patients. MATERIALS AND METHODS: Human tumor colony-forming units were treated with MTA at concentrations of 0.1, 1.0, and 10 microg/ml in 1-h exposure studies. The responses of a limited number of specimens were also evaluated concurrently in 1-h exposures to cisplatin, fluorouracil, irinotecan, and/or paclitaxel. RESULTS: Of 358 specimens plated in the 1-h exposure studies, 148 (41%) were evaluable. Overall, responses were observed in 3% of specimens (4/144) at 0.1 microg/ml, 11% (17/148) at 1.0 microg/ml, and 23% (33/141) at 10 microg/ml. In this range of concentrations achievable clinically, there was a significant concentration-response relationship. At 10 microg/ml in the 1-h exposure studies, the response rate in colorectal cancer specimens was 32% (9/28), and the response rate in non-small-cell lung cancer was 25% (6/24). Responses were also observed in several chemoresistant tumors, including renal cell carcinoma, hepatocellular carcinoma, mesothelioma, and pancreatic carcinoma. The activity of MTA was not completely cross-resistant with that of cisplatin, fluorouracil, irinotecan, and paclitaxel. CONCLUSIONS: MTA demonstrated in vitro activity against a spectrum of tumors, including several tumors generally considered chemoresistant.

Antineoplastic Agents↗
PubMed2006

Genotoxic effect of Goeckerman regimen of psoriasis.

Goeckerman regimen (GR) of psoriasis includes daily dermal application of crude coal tar (CCT) and dermal exposure to UV-A and UV-B radiation. Observed group consisted of 23 patients with psoriasis treated by GR. Therapeutic ointment contained 5% of CCT. The level of psoriasis area and severity index was significantly decreased after GR (P < 0.001) and confirms high efficiency of GR. High levels of selected metabolites of pyrene and phenanthrene indicated high level of dermal penetration. We found significantly increased urinary mutagenicity in samples collected in the middle and in the end of GR (TA98+S9, P < 0.01; YG1041-S9, P < 0.001; YG1041+S9, P < 0.001). Significant increasing of chromosomal aberrations in peripheral lymphocytes (CA) in blood samples collected in the end of GR (P < 0.001) and consecutive decreasing of CA in 78th day after the end of GR has been observed. Almost all results indicated that the patients could be endangered by a peak genotoxic exposure. Nevertheless, the genotoxic effect does not seem to be long lasting. Despite conflicting results from cancer epidemiological studies, it is evident that single GR can contribute to the total load of environmental mutagens in a group of treated patients.

Adolescent↗
PubMed1990

Sub-site preferences of the aspartic proteinase from the human immunodeficiency virus, HIV-1.

A series of synthetic, chromogenic substrates for HIV-1 proteinase with the general structure Ala-Thr-His-Xaa-Yaa-Zaa*Nph-Val-Arg-Lys-Ala was synthesised with a variety of residues introduced into the Xaa, Yaa and Zaa positions. Kinetics parameters for hydrolysis of each peptide by HIV-1 proteinase at pH 4.7, 37 degrees C and u = 1.0 M were measured spectrophotometrically and/or by reverse phase FPLC. A variety of residues was found to be acceptable in the P3 position whilst hydrophobic/aromatic residues were preferable in P1. The nature of the residue occupying the P2 position had a strong influence on kcat (with little effect on Km); beta-branched residues Val or Ile in this position resulted in considerably faster peptide hydrolysis than when e.g. the Leu-containing analogue was present in P2.

Amino Acid Sequence↗
PubMed1993

Differences in HLA class II alleles of isolated South American Indian populations from Brazil and Argentina.

We have studied the HLA class II alleles in 277 South American Indians, which included Argentinian tribes from the Gran Chaco: Toba (n = 135), Toba-Pilaga (n = 19), Mataco-Wichi (n = 49), and Xavantes, a tribe from Central Brazil (n = 74). In the Brazilian tribe, only four DR groups were found: DRB1*1602 (gf = 0.303), DRB1*04 including DRB1*0404 (gf = 0.070) and DRB1*0407 (gf = 0.077), DRB1*0802 (gf = 0.265), and DRB1*1402 (gf = 0.303). The HLA class II allele frequencies were similar among the different Argentinian tribes, and 90% of DRB1 alleles belonged to three families: DRB1*04 (including DRB1*0403, DRB1*0404, DRB1*0407, DRB1*0411, and DRB1*0417), DRB1*0802, and DRB1*14 (including DRB1*1402 and DRB1*1406). At the DPB1 locus, we found only seven alleles, the most frequent being DPB1*0402. Comparison of HLA class II alleles with those of North American Indians that we have previously studied shows that the frequency of some HLA class II alleles in Brazilian Xavantes resembles that of North American Indians more than that of the Argentinian Indian tribes. The allele DRB1*0417 was found exclusively in this population.

Adult↗
PubMed1994

DQA1*03 subtypes have different associations with DRB1 and DQB1 alleles.

Polymorphisms outside the hypervariable regions of HLA class II alleles that do not affect the peptide-binding site are probably not under selective pressure and could therefore be useful as markers of the evolutionary pathways of the HLA class II haplotypes. We have analyzed such a polymorphism in the variants of DQA1*03, which differ at residue 160 encoded in exon 3. Our study included homozygous BCLs of the 10th IHWS and samples of a multiracial panel of 723 unrelated subjects which were also typed for allelic variations in exon 2 by hybridization with SSOP. BCLs having DQA1*03 and 131 selected DQA1*03-positive samples were typed for the dimorphism in exon 3 that distinguishes DQA1*0301 and DQA1*0302. DQA1*0301 was found to be exclusively associated with DQB1*0302, while samples carrying DQB1*0201, 0301, 0303, and 0401 always had DQA1*0302. A few haplotypes carrying DQB1*0302 had DQA1*0302. The fact that DQA1*0301 is completely included in DQB1*0302, and not vice versa, suggests that DQA1*0301 may have arisen from a mutation in a haplotype containing DQA1*0302-DQB1*0302. DQB1*0302 was found to be associated with all DR4 subtypes, suggesting possibly that the current variants of DRB1-DR4 may be of more recent origin. DRB1*0405 was the only subtype of DR4 which was not associated with DQA1*0301 and had multiple associations with the DQB1 alleles, therefore, perhaps representing the oldest allele of this group.

Alleles↗
PubMed2006

Identification of a new in-frame deletion of six amino acids in ribosomal protein S19 in a patient with Diamond-Blackfan anemia.

Ribosomal protein S19 (RPS19) is currently the only gene associated with Diamond-Blackfan anemia (DBA), a rare congenital pure red cell aplasia characterized by normochromic macrocytic anemia, reticulocytopenia, and normocellular bone marrow with a selective deficiency of erythroid precursors. RPS19 is mutated in 25% of DBA patients, but its role in DBA pathogenesis remains elusive. We have identified a novel heterozygous microdeletion in RPS19 in a DBA patient presenting with profound anemia after birth. The deletion of 18 nucleotides (233-250; A in start codon is +1) in exon 4 leads to the elimination of 6 amino acids 78IYGGRQ83, affecting the most conserved stretch of three amino acids (YGG) in RPS19. The mutated allele was not detected in the patient's family members, indicating de novo mutation. Both alleles were expressed at the same level. Using an immunofluorescence technique, the mutated RPS19 protein localized to nucleoli, and its intracellular distribution did not differ from the wild-type RPS19. The deletion of only a few amino acids of this protein with a preserved reading frame is rare, and this type of a mutation could be very helpful in further experiments to define the role of the RPS19 protein in DBA pathogenesis.

Anemia, Diamond-Blackfan↗
PubMed2003

Effect of nitric oxide on cytotoxicity of Taxol: enhanced Taxol transcellular permeability.

The present studies were aimed at testing the hypothesis that nitric oxide (NO) may enhance Taxol-induced cytotoxicity in carcinoma cells by increasing influx of Taxol into intracellular compartments. Prostate carcinoma cells (PC-3, LNCaP) and neuroblastoma cells (SKNDZ, CHP212) were used to investigate both transmembrane permeability and cytotoxicity of Taxol in the presence and absence of S-nitrosocaptopril (CapNO), a nitric oxide donating compound. The order of permeability rate of Taxol across the four cell lines was SKNDZ>LNCaP>PC-3>CHP212. Pretreatment of the cell lines with CapNO (100 microM) enhanced permeability of Taxol across prostate PC-3 and LNCaP cells, but not neuroblastoma SKNDZ and CHP212 cells. Taxol inhibited cell growth at nanomolar levels with IC(50)s of 0.21, 17.4, 96.4 and 842.9 nM corresponding to SKNDZ, PC-3, LNCaP and CHP212 cells, respectively. However, CapNO inhibited proliferation of the four cell lines at millimolar levels with IC(50)s ranging from 0.3 to 1.1 mM. Enhancing effect of CapNO (100 microM) on Taxol cytotoxicity were found in PC-3 and LNCaP cells, but not in SKNDZ and CHP212. The findings suggest that the cytotoxic potency of Taxol is mainly dependent upon the cell membrane permeabilization to Taxol, and the enhancing effect of CapNO on Taxol-induced cytotoxicity is primarily mediated via the increased influx of Taxol by NO into intracellular compartments, while NO-induced cytotoxicity cannot be excluded.

Biological Transport↗
PubMed2005

Multinucleate cells (MNC) as sensitive semiquantitative biomarkers of the toxic effect after experimental fibrous dust and cigarette smoke inhalation by rats.

Changes in the counts of binucleate (BNC) and multinucleate cells (MNC) in cell mixtures from lung tissue and bronchoalveolar lavage fluid (BALF) as well as in proportions of four types of BALF cells: Alveolar macrophages (AM), lymphocytes, polymorphonuclears (PMN), BNC and in total BALF protein were followed in a study comparing the toxicity of wollastonite with that of amosite asbestos in Fischer 344 rats. Both of the fibrous dusts were inhaled every second day at 30 or 60 mg/m3 air combined with daily exposure to cigarette smoke at 30 mg of total particulate matter (TPM)/m3 air for 1 h. The exposures lasted 175 days. Both, proportions of BNC as well as of MNC in lung cell mixtures rose significantly after exposure to cigarette smoke only. After inhalation of wollastonite the BNC proportions in all except the lower dust exposure group compared to controls showed a significant rise with the maximal factor value of 2.1 in the higher dust plus smoke exposure group. Wollastonite caused only marginal changes in MNC and other inflammation parameters. After inhalation of amosite at comparing to controls the proportion of BNC rose 8 times in the 30 mg/m3 and 11 times in the 60 mg/m3 exposure group, respectively. The effect of smoking was additive. The proportions of MNC were 39 times higher in the 30 mg/m3 and 41 times higher in the 60 mg/m3 amosite exposure group than in controls. In the higher exposure group the effect of smoking was synergic in that the MNC proportion rose about 58 times over control values from 0.05% up to about 3.0% (99% confidence interval--CI = 2.7-3.3%). The other followed inflammation parameters showed the presence of inflammation in the lung. It could be concluded that wollastonite at the same inhalation exposure concentration caused in rats less toxic effects than amosite, and, that the number of MNC, as well as BNC in lung cell mixtures and in BALF may serve as an important semiquantitative biomarker of inflammation.

Animals↗
PubMed2006

NFkappaB and its inhibitor IkappaB in relation to type 2 diabetes and its microvascular and atherosclerotic complications.

Nuclear factor kappa B (NFkappaB) is an important transcription factor that together with its inhibitor (IkappaB) participates in the activation of genes involved in immune responses. We examined the CA repeat polymorphism of the NFKB1 gene (encoding for NFkappaB) and A/G point variation in the 3'UTR region of the nuclear factor kappa B inhibitor alpha (NFKBIA) gene (encoding for IkappaB) in Czech and German patients with type 2 diabetes. The sample consisted of 211 patients, both with and without kidney complications, and 159 controls. Additionally, 152 patients with systemic lupus erythematosus (SLE) were genotyped for NFKBIA polymorphism. We observed a significant increase in the homozygous AA genotype of the NFKBIA gene when compared with the control group (the highest value was in diabetics without diabetic nephropathy [p(c)* = 0.0015, odds ratio = 3.59]). No differences were seen between the SLE and control groups. With regard to the polymorphism of the NFKB1 gene, we did not observe any significant differences between the groups. Since the AA genotype of the NFKBIA gene presents a risk for type 2 diabetes development but not for diabetic nephropathy alone, we believe that the NFkappaB gene polymorphism can influence the pathogenesis of diabetes mellitus and affect its complications. Negative findings relative to other inflammatory autoimmune diseases, such as SLE, suggest a specific relationship between NFkappaB and type 2 diabetes mellitus.

Aged↗
PubMed2004

Diabetes mellitus in adults: association of HLA DRB1 and DQB1 diabetes risk alleles with GADab presence and C-peptide secretion.

In our study, we investigated the relationship of HLA class II alleles to antibody production against glutamic acid decarboxylase (GADab) and to C-peptide secretion (CP) in diabetic patients. A group of 334 patients (190 women) diagnosed after 35 years of age and 99 control subjects were studied. Patients were divided into four groups according to concentrations of CP and GADab, respectively (CP high/low, GADab positive/negative). HLA DQB1 and DRB1 alleles were genotyped by SSP-PCR. The significance of DQB1 and DRB1 risk alleles was evaluated by examination of their odds ratios computed by testing 2x2 tables considering Bonferonis' corrected P<0.05 as significant. We found strong association between the HLA DRB1*03 risk allele and presence of GADab, and close relationship of the HLA DRB1*04 and HLA DQB1*0302 risk alleles with decreased CP level. Taken together we conclude that the DRB1*04 and DQB1*0302 alleles are associated with progressive decrease of CP level, while DRB1*03 is a significant genetic marker of autoantibody (GADab) development.

Adult↗
PubMed2005

Interleukin IL-18 gene promoter polymorphisms in adult patients with type 1 diabetes mellitus and latent autoimmune diabetes in adults.

Interleukin-18 (IL-18) gene promoter polymorphism is known as a genetic risk factor for child type 1 diabetes mellitus development. To test the role of IL-18 gene polymorphism in predisposition to adult type 1 diabetes (T1DM) and latent autoimmune diabetes in adults (LADA), we analysed SNPs at position -607 (C/A) and -137 (G/C) in the promoter region of IL-18 gene by sequence-specific PCR in 49 T1DM, 66 LADA patients and 139 healthy controls. We found differences in allele, genotype or haplotype distribution in tested patients when compared to frequencies found in control group but these differences did not reach statistical significance. However, there was a difference in -607 (C/A) allele and genotype distribution found in LADA and T1DM patients that reached statistical significance. These results suggest that the IL-18 gene promoter polymorphisms are not associated with adult type 1 diabetes or LADA susceptibility, and according to our findings genes involved in onset and progression of LADA and T1DM are probably different.

Adult↗
PubMed2005

The structure of Sif2p, a WD repeat protein functioning in the SET3 corepressor complex.

In Saccharomyces cerevisiae, the SIF2 gene product is an integral component of the Set3 complex (SET3C), an assembly of proteins with some homology to the human SMRT and N-CoR corepressor complexes. SET3C has histone deacetylase activity that is responsible for repressing a set of meiotic genes. We have determined the X-ray crystal structure of a 46 kDa C-terminal domain of a SET3C core protein, Sif2p to 1.55 A resolution and a crystallographic R-factor of 19.0%. This domain contains an unusual eight-bladed beta-propeller structure, which differs from other transcriptional corepressor structures such as yeast Tup1p and human groucho (Gro)/TLE1, which have only seven. We have demonstrated intact Sif2p is a tetramer and the N-terminal LisH (Lis-homology)-containing domain mediates tetramerization and interaction with another component of SET3C, Snt1p. Multiple sequence alignments indicate that a surface on the "top" of the protein is conserved among species, suggesting that it may play a common role in binding partner proteins. Since Sif2p appears to be the yeast homolog of human TBL1 and TBLR1, which function in the N-CoR/SMRT complexes, its structural and oligomeric properties are likely to be very similar.

Amino Acid Sequence↗
PubMed2006

Dystrophin Dp71f associates with the beta1-integrin adhesion complex to modulate PC12 cell adhesion.

Dystrophin Dp71 is the main product of the Duchenne muscular dystrophy gene in the brain; however, its function is unknown. To study the role of Dp71 in neuronal cells, we previously generated by antisense treatment PC12 neuronal cell clones with decreased Dp71 expression (antisense-Dp71 cells). PC12 cells express two different splicing isoforms of Dp71, a cytoplasmic variant called Dp71f and a nuclear isoform called Dp71d. We previously reported that antisense-Dp71 cells display deficient adhesion to substrate and reduced immunostaining of beta1-integrin in the cell area contacting the substrate. In this study, we isolated additional antisense-Dp71 clones to analyze in detail the potential involvement of Dp71f isoform with the beta1-integrin adhesion system of PC12 cells. Immunofluorescence analyses as well as immunoprecipitation assays demonstrated that the PC12 cell beta1-integrin adhesion complex is composed of beta1-integrin, talin, paxillin, alpha-actinin, FAK and actin. In addition, our results showed that Dp71f associates with most of the beta1-integrin complex components (beta1-integrin, FAK, alpha-actinin, talin and actin). In the antisense-Dp71 cells, the deficiency of Dp71 provokes a significant reduction of the beta1-integrin adhesion complex and, consequently, the deficient adhesion of these cells to laminin. In vitro binding experiments confirmed the interaction of Dp71f with FAK and beta1-integrin. Our data indicate that Dp71f is a structural component of the beta1-integrin adhesion complex of PC12 cells that modulates PC12 cell adhesion by conferring proper complex assembly and/or maintenance.

Actinin↗
PubMed2006

Impact of water quality on setting of irreversible hydrocolloid impression materials.

STATEMENT OF PROBLEM: Setting of irreversible hydrocolloid impression materials is based on the ionic reaction between carboxylic groups and calcium ions and may, therefore, be affected by ionic species present in the mixing water. The impact of this phenomenon on the clinical performance of these materials has not been well documented. PURPOSE: The purpose of this study was to compare the setting behavior of irreversible hydrocolloid impression materials when mixed with tap and distilled water, and to determine the impact of typical cations present in tap water and their concentrations on the setting process. MATERIAL AND METHODS: Six brands of irreversible hydrocolloid impression materials (Kromopan 100, Xantalgin Select FS, Alginoplast, Elastic Plus, Ypeen, and Ypeen Premium) were mixed with tap and distilled water (control) according to manufacturers' recommendations. Elastic Plus was also mixed with aqueous solutions containing various concentrations of NaCl, CaCl(2), and AlCl(3) to determine the role of typical cations on setting. Using a controlled shear stress oscillatory rheometer, time changes of storage (G') and loss (G'') moduli during setting were measured at 23 degrees C and used to determine the working and setting times and rigidity of set impression materials. The sample size (n=3) for each material/mixing system was increased to 8 to increase reliability of measurements in systems where the effect of mixing water was low or variance of results was high. The data were analyzed (alpha=.05) using a t test (tap water), a 1-way ANOVA, a Tukey post hoc test (shear stress), and a nested ANOVA and Fisher Least Significant Difference post hoc analysis (cation and cation concentration). RESULTS: Statistical analysis showed significant (P<.001) acceleration in the setting rate for Kromopan 100, the working time of which was shorter with tap water by 23.4 seconds and the setting time, by 32.8 seconds. Similar significant reductions (in seconds) in both working and setting times, respectively, were found with Xantalgin Select FS (12.0, P<.001 and 23.6, P<.002), Alginoplast (24.3, P<.001 and 44.7, P<.005), and Elastic Plus (23.0, P<.001 and 22.0, P<.002), when compared with the same materials mixed with distilled water. At the same time, the rigidity of the set impression materials mixed with tap water increased by approximately 10%. With Ypeen Premium, the setting time decreased significantly by 20.0 seconds (P<.001) with tap water, while the working time and rigidity did not change. The setting behavior of Ypeen was not significantly affected by water quality. Acceleration of the setting reactions and increase in impression rigidity depended (P<.001) primarily on concentration and valency of cations present in mixing water. CONCLUSION: Setting of irreversible hydrocolloid impression materials can be significantly accelerated when tap water with high water hardness is used for mixing or when the mixing water contains higher concentrations of cations such as Na(+), Ca(2+), and Al(3+).

Aluminum↗