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At least 703 records · Page 39Linked to original sources
PubMed2002

IFN-gammaupregulates apoptosis-related molecules and enhances Fas-mediated apoptosis in human cholangiocarcinoma.

Human cholangiocarcinoma is a malignancy with no effective therapy and a poor prognosis. Previously, we demonstrated that cultured human cholangiocarcinoma cell lines heterogeneously express Fas on their surface, resulting in 2 subpopulations, Fas-high and Fas-low cells. Fas-low cells are resistant to apoptosis induced by Fas antibody and the calmodulin antagonists tamoxifen and trifluoperazine and are tumorigenic in nude mice (Pan et al., Am J Pathol 1999;155:193-203). Here, we show that IFN-gamma enhances apoptosis in both Fas-high and Fas-low cells. IFN-gamma upregulates many apoptosis-related molecules, including Fas, caspase-3, caspase-4, caspase-7, caspase-8 and Bak, in both cell lines. Pretreatment with IFN-gamma facilitated Fas-mediated caspase cleavage, cytochrome c release and Bax translocation. The ability of IFN-gamma to inhibit tumorigenesis of Fas-low cells was demonstrated in nude mice. Intratumoral injection of IFN-gamma decreased tumor volumes by 78%. These findings indicate that IFN-gamma modulates the apoptotic pathway by upregulating apoptosis-related genes. This renders tumorigenic Fas-low cholangiocarcinoma cells nontumorigenic and sensitive to Fas apoptosis, thus representing a possible therapeutic modality.

Apoptosis↗
PubMed1988

Epitopic diversity of African swine fever virus.

African swine fever (ASF) is caused by an icosahedral cytoplasmic, double stranded DNA virus. In the acute form of the disease, pigs die from disseminated intravascular coagulation (DIC) with extensive damage of the free and fixed macrophage systems and the reticular epithelial cells of the thymus; mortality is virtually 100%. In recent years, subacute and chronic forms of ASF have become more prevalent in the field, especially in outbreaks occurring outside the continent of Africa, and virus isolated from these outbreaks have often been of lesser virulence. In pigs experimentally infected with such isolates, a number of immunopathological manifestations have been encountered, e.g. hypergammaglobulinemia associated with necrotizing pneumonia, persistent infection in the presence of ASF-specific antibodies, and lack of demonstrable virus neutralizing antibodies. Nevertheless, the immune systems of pigs that have clinically recovered have not been impaired by the infection. We suggest that the heterogeneous composition of the virus population in a given isolate may be one of the causes of the anomalous immune responses. When a number of biological markers, i.e., hemadsorption characteristics, plaque size, infectivity, virulence, antigenic determinants, and genomic structure, were used to characterize the virus clones derived from various ASF virus (ASFV) isolates, considerable heterogeneity was apparent. In the present investigation, 20 monoclonal antibodies (MAb), which specifically identified the 14 kDa viral protein within the cytoplasmic membrane of the infected cells, were used to determine epitopic differences among a number of virus clones derived from various isolates. All of the non-African isolates examined contained two epitopically different groups of virus clones, and the reaction profiles obtained were distinctly different from those obtained with the clones of an African isolate (Tengani). It was concluded that an ASFV isolate is composed of a biologically diverse virus population with distinctly different members which are only identified after cloning.

African Swine Fever↗
PubMed2005

Genetic analysis of parkin co-regulated gene (PACRG) in patients with early-onset parkinsonism.

Parkin co-regulated gene (PACRG) is a recently identified gene which is transcriptionally co-regulated with parkin gene (PRKN) by a shared bidirectional promoter. To determine whether early-onset parkinsonism (EOP) is associated with PACRG mutation, we screened 112 patients with EOP and found three nucleotide variants: (1) T>C transition in intron 2 (nt 87004; NT_007422), (2) C>T transition (L214L) in exon 6 (nt 585706; NT_007422), and (3) T>A substitution in intron 5 (nt 585630; NT_007422), located 18 bp upstream from exon 6. Since none of these variations appear to be pathogenically relevant, our results suggest that mutation of PACRG plays little or no role in the development of EOP.

Adult↗
PubMed2003

Quantitation of cytochrome P450 mRNA levels in human skin.

There is considerable interindividual variation in man's ability to metabolize drugs and foreign compounds. These differences can partly be attributed to genetic polymorphisms that result in the generation of multiple phenotypes with different drug-metabolizing capabilities. Genetically derived differences can easily be assessed by genotyping assays in cases where the polymorphism has been identified. However, many of the polymorphisms that result in these are not known, secondly not all the differences can be attributed to genetic polymorphisms, hence genotyping methods cannot be employed. We have therefore, developed real-time (Taqman) PCR assays to quantitate levels of P450 mRNAs in human tissues. These assays are highly sensitive, reproducible, and specific and will allow quantitation of P450 mRNA levels in various human tissues. We have applied these assays to quantitate cytochrome P450 mRNA levels in human skin samples from 27 healthy volunteers. The expression of 13 P450s was assessed. The major enzymes detected were CYP1B1, CYP2B6, CYP2D6, and CYP3A4 with mean values of 2.5, 2.6, 2.7, and 1.1 fg/18S rRNA in 50ng total RNA, respectively. Lower levels of CYP2C18, CYP2C19, and CYP3A5 were also detected while CYP1A2, 2A6, and 2C8 were below limits of detection. There was interindividual variation in the levels of mRNA among the 27 subjects studied although Poisson analysis showed data to be normally distributed, except for CYP2B6, as some individuals completely lacked CYP2B6 mRNA.

Cytochrome P-450 Enzyme System↗
PubMed2005

Single-nucleotide polymorphisms in NAGNAG acceptors are highly predictive for variations of alternative splicing.

Aberrant or modified splicing patterns of genes are causative for many human diseases. Therefore, the identification of genetic variations that cause changes in the splicing pattern of a gene is important. Elsewhere, we described the widespread occurrence of alternative splicing at NAGNAG acceptors. Here, we report a genomewide screen for single-nucleotide polymorphisms (SNPs) that affect such tandem acceptors. From 121 SNPs identified, we extracted 64 SNPs that most likely affect alternative NAGNAG splicing. We demonstrate that the NAGNAG motif is necessary and sufficient for this type of alternative splicing. The evolutionarily young NAGNAG alleles, as determined by the comparison with the chimpanzee genome, exhibit the same biases toward intron phase 1 and single-amino acid insertion/deletions that were already observed for all human NAGNAG acceptors. Since 28% of the NAGNAG SNPs occur in known disease genes, they represent preferable candidates for a more-detailed functional analysis, especially since the splice relevance for some of the coding SNPs is overlooked. Against the background of a general lack of methods for identifying splice-relevant SNPs, the presented approach is highly effective in the prediction of polymorphisms that are causal for variations in alternative splicing.

Alleles↗
PubMed1997

Ethambutol resistance in Mycobacterium tuberculosis: critical role of embB mutations.

Ethambutol [(S,S')-2,2'-(ethylenediimino)di-1-butanol; EMB], is a first-line drug used to treat tuberculosis. To gain insight into the molecular basis of EMB resistance, we characterized the 10-kb embCAB locus in 16 EMB-resistant and 3 EMB-susceptible genetically distinct Mycobacterium tuberculosis strains from diverse localities by automated DNA sequencing and single-stranded conformation polymorphism analysis. All 19 organisms had virtually identical sequences for the entire 10-kb region. Eight EMB-resistant organisms had mutations located in codon 306 of embB that resulted in the replacement of the wild-type Met residue with Ile or Val. Automated sequence analysis of the 5' region (1,892 bp) of embB in an additional 69 EMB-resistant and 30 EMB-susceptible M. tuberculosis isolates from diverse geographic localities and representing 70 distinct IS6110 fingerprints confirmed the unique association of substitutions in amino acid residue 306 of EmbB with EMB resistance. Six other embB nucleotide substitutions resulting in four amino acid replacements were uniquely found in resistant strains. Sixty-nine percent of epidemiologically unassociated EMB-resistant organisms had an amino acid substitution not found in susceptible strains, and most (89%) replacements occurred at amino acid residue 306 of EmbB. For strains with the Met306Leu or Met306Val replacements EMB MICs were generally higher (40 microg/ml) than those for organisms with Met306Ile substitutions (20 microg/ml). The data are consistent with the idea that amino acid substitutions in EmbB alter the drug-protein interaction and thereby cause EMB resistance.

Antitubercular Agents↗
PubMed1984

Hominoid dental microwear: complications in the use of microwear analysis to detect diet.

Analysis of dental microwear on chimpanzee molars reveals much variation that reflects jaw mechanics and occlusal function rather than diet. Observed microwear pattern differences relate to variations in molar position, facet type, and overall age of the tooth. Gradients in the amounts of shear and compression generated at different points in the molar series relative to the condyle probably account for pattern variations associated with molar position, while differences in facet inclination may affect the vectors of compression and shear, resulting in facet differences. Age-related pattern differences may be a result of surface and subsurface variations in enamel hardness. These results demonstrate that intraspecific and intra-individual differences in microwear may be extreme, and care must be taken to distinguish normal variation due to occlusal mechanics from variations due to dietary difference. The finding that microwear variations are reflective of subtle changes in occlusal forces and vectors along the tooth row might in itself be a clinically useful phenomenon.

Age Factors↗
PubMed1978

Microvascular architecture of anthropoid primate intestine.

Microvascular architecture of the small intestine of New World monkey, ape, and man was examined with the silicone rubber injection technique and the results compared to previous observations in dogs and Old World monkeys. In man, chimpanzee, and New World monkey the small intestine villus contains a single centrally located vein draining a subepithelial capillary plexus converging at the apex of the villus. These villi also contain a single eccentrically located artery rising to the midlevel of the villus, where it branches into subepithelial capillaries over the rest of its length. This vascular architecture most closely resembles that observed in the gut of Old World monkeys in which the villus artery is absent altogether. This observation contrasts the microvascular architecture of canine intestinal villi in which marginal arteries surround a centrally located vein. These patterns of microvascular anatomy are analyzed in terms of the role of the gut in the pathogenesis of experimental shock. The differences observed may account for the known species variations in canine and primate experimental shock.

Adult↗
PubMed1991

[Detection of steroid 21-hydroxylase gene variation among normal Chinese and patients with congenital adrenal hyperplasia].

Genomic DNA from 40 unrelated healthy individuals and 16 families affected with 21-hydroxylase deficiency were digested with restriction enzyme Taq I followed by Southern blot and hybridization using a 21-hydroxylase (21-OH) gene cDNA probe. In healthy individuals the number of copies of 21-OHB gene was constant while that of 21-OHA gene was variable including deletion and duplication. In addition, we found an extra 5.6 kb band in one normal person and in one CAH family. Among the 16 affected families, 19% of 21-OHB gene were deleted. No homologous deletion was found. The frequency of deletion is lower than that reported in the literature. There was variation in the copy-number of 21-OHA gene among patients with CAH, yet no difference was found between the patients and normal persons. The information on prenatal diagnosis of CAH is briefly discussed.

Adrenal Hyperplasia, Congenital↗
PubMed1993

Seasonal variation in the onset of Wegener's granulomatosis, polyarteritis nodosa and giant cell arteritis.

OBJECTIVE: The hypothesis of a seasonal pattern in the onset of symptoms for some vasculitides has been raised in previous small studies. METHODS: Using the data collected by the American College of Rheumatology (ACR) Subcommittee on Classification of Vasculitis, we specifically tested for a higher proportion of onset of symptoms in winter, lower in summer, and intermediate for the other seasons for polyarteritis nodosa (PAN) and Wegener's granulomatosis. We also tested for a higher proportion of onset of symptoms in the spring-summer months for giant cell arteritis (GCA). RESULTS AND CONCLUSIONS: The results of our study support the hypothesis of a seasonal trend for the onset of symptoms of Wegener's granulomatosis (p = 0.04) as described previously. No seasonal pattern was found for the other vasculitides studied (PAN and GCA).

Giant Cell Arteritis↗
PubMed2005

Sequence analysis of the MHC class II DPB1 gene in chimpanzees (Pan troglodytes).

The diversity of the MHC class II region in non-human primates is a focus of biomedical research because this region plays a crucial role in the recognition of antigens in the immune system. In particular, the chimpanzee [Pan troglodytes (Patr)], which belongs to the superfamily Hominoidea, has been used as a human model for the study of diseases such as human hepatitis C virus (HCV), human hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infections, to which only humans and chimpanzees are susceptible. In the present study, polymorphisms of the MHC-DPB1 gene (Patr-DPB1) in a chimpanzee colony in Japan were examined using a stepwise polymerase chain reaction (PCR) technique. In order to design a suitable primer pair which would amplify exon 2 of the Patr-DPB1 gene, a fragment of approximately 8 kb from exon 1 to exon 3 was amplified from chimpanzee genomic DNA. After designing a 500-bp primer pair at the 3' region of intron 1 and the 5' region of intron 2, analysis of DPB1 exon 2 alleles of each chimpanzee was carried out. Twenty-two chimpanzees were used in our study, and we identified seven alleles by sequence analysis on the Patr-DPB1 gene, including one new allele. The obtained nucleotide sequence patterns suggest that Patr-DPB1 alleles emerge by genetic variations such as the exchange of sequence motifs and the accumulation of point mutations.

Alleles↗
PubMed2000

Variation of the ganglioside compositions of human milk, cow's milk and infant formulas.

The ganglioside compositions of human milk, cow's milk and infant formulas were compared. The results showed that there was a drastic change in the ganglioside composition from the colostrum to later human milk, and that both the patterns and contents of gangliosides in human milk, cow's milk and infant formulas differed markedly. In human milk, the total lipid-bound sialic acid level was two times higher than those in cow's milk and infant formulas. The major ganglioside in the later human milk, GM3 (27.7%), was only a minor component in the colostrum, cow's milk and infant formulas (3.3, 2.8 and 0.4-2.6%, respectively). GD3 represented 49.0, 61.0 and 72.4-86.6%, respectively, of the colostrum, cow's milk and infant formulas, compared to 31.8% of the later human milk gangliosides. Another four gangliosides, which were assumed to be c-series gangliosides, were detected in the colostrum and the later human milk. They represented 33-38% of total lipid-bound sialic acid, and were tentatively designated as GX1, GX2, GX3 and GX4, respectively. However, only GX1 and GX2 were observed in cow's milk and infant formulas. The variation of the gangliosides in human and cow's milk, and infant formulas might have some biological significance regarding neonatal brain development, allergies, infant growth and non-immunoglobulin prophylactic activities against some bacterial toxins.

Animals↗
PubMed1994

Ventral medullary surface activity during sleep, waking, and anesthetic states in the goat.

We examined activity, measured as changes in reflected light, from the surface of a rostral ventral medullary area that is involved in cardiorespiratory control. We collected images during sleep and waking states and during halothane anesthesia in five adult unrestrained goats. During quiet sleep, overall activity increased and overall variability decreased compared with waking levels, whereas rapid eye movement sleep increased variability, and average activity decreased to near-waking levels. Distinct regions of activation and suppression appeared during sleep states. Deep anesthesia decreased activity and minimized variation. We speculate that alterations in rostral ventral medullary surface activity may play a role in state-dependent changes in cardiorespiratory control mechanisms.

Activity Cycles↗
PubMed2002

Comparative mapping of CDY and DAZ in higher primates.

The human male specific expressed gene families CDY and DAZ are known to be repetitively clustered in the Y-specific region of the human Y chromosome. Comparative FISH-mapping of DNA clones specific for CDY and DAZ resulted in a Y-specific but diverse signal pattern within the non-recombining region of the Y-chromosomes of human and great apes. It can be concluded that the non-recombining part of the Y-chromosomes including CDY and DAZ, was exposed to species-specific amplifications, diversifications and rearrangements. Evolutionary fast fixation of any of these variations was possible as long as they did not interfere with male fertility.

Animals↗
PubMed2004

Cytoplasmic immunoreactivity for thyroid transcription factor-1 in hepatocellular carcinoma: a comparative immunohistochemical analysis of four commercial antibodies using a tissue array technique.

To evaluate the consistency of cytoplasmic immunoreactivity in hepatocellular carcinoma (HCC), we performed immunohistochemical stains for 4 commercial anti-thyroid transcription factor (TTF)-1 antibodies (DAKO, Zymed, Novocastra, Santa Cruz Biotechnology [see text]) on 77 HCCs and 334 nonhepatic epithelial tumors. The HCC cases were submitted for hepatocvte antigen immunohistochemical stain. Heat-induced epitope retrieval (HIER) methods were used: with DAKO Target Retrieval Solution, the positive rates of cytoplasmic TTF-1 in HCC for DAKO, Zymed, Santa Cruz, and Novocastra antibodies were 58% (45), 14% (11), 6% (5), and 0% (0), respectively; with EDTA buffer, the positive rates increased to 70% (54), 40% (31), 69% (53), and 0% (0), respectively. Immunoreactivity for the DAKO anti-TTF-1 antibody generally correlated with that for hepatocyte antigen. Among nonhepatic tumors, 2 of 6 ovarian mucinous carcinomas and 2 of 11 pancreatic adenocarcinomas showed cytoplasmic reactivity for the DAKO antibody; 28 cases showed nonspecific cytoplasmic staining for the Santa Cruz antibody with EDTA HIER. Zymed and Novocastra antibodies did not produce cytoplasmic staining in nonhepatic tumors. Owing to the staining variation, we do not consider TTF-1 a reliable marker to distinguish HCC. In general, the Novocastra antibody with EDTA HIER is superior for its consistent nuclear positivity and absence of erratic cytoplasmic staining.

Biomarkers, Tumor↗
PubMed2002

The angular distribution of vertebral trabeculae in modern humans, chimpanzees and the Kebara 2 Neanderthal.

Bone is known to remodel to optimize its structure according to its mechanical environment. In particular trabecular arcades are thought to align with the orientations of components of principal strain. This paper presents the application of a novel method for quantifying trabecular orientation to test the hypothesis that hominoid posture and locomotion are reflected in trabecular architecture. Lateral radiographs were taken of vertebrae from the entire thoracolumbar spines of eight modern humans, seven Pan troglodytes and one Neanderthal. The radiographs were digitized and a square region of interest located at the centre of each vertebral body selected. Fourier transforms of the regions of interest were performed and the relative magnitude of the transform in each of 16 angular segments calculated. The simple indices of external vertebral body morphology, wedge angle and aspect ratio, were also calculated from the radiographs. All three species exhibit the same pattern, with the majority of trabeculae oriented either axially or dorsoventrally. This suggests that vertebral mechanical loading is similar in chimpanzees and humans, despite their apparent postural and locomotor differences. Significant differences between the magnitudes of the Fourier transform in the 78.75 degrees and 135 degrees orientations of chimpanzee and human vertebrae were observed in all but the upper thoracic spine. As the magnitudes at these orientations in the Neanderthal correspond more closely to that in the human and the orientational features were unrelated to the external vertebral morphology, the difference between the two magnitudes may well prove to be a useful parameter in future phylogenetic analysis. Modern human spines were found to show a greater variation in the proportions of axial and dorsoventral trabeculae with spinal level than chimpanzees, with the greatest differences observed in the upper thoracic spine and thoracolumbar junction, suggesting an association with postural spinal curves.

Animals↗