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Query: UNIPROT:P06889 (Mol)
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cDNA microarray-based CGH (Microarray-CGH) is a useful technique for detecting genomic aberrations with a high resolution. However, the criteria for determining a genomic alteration have not been determined. We evaluated the genome-wide measurement of copy number of each gene in normal gastric and placenta tissues with both sex-matched, direct and sex-mismatched, indirect designs using 17K cDNA microarray. The results revealed the range of genomic copy number of normal tissues to be +/-0.3 of the log(2) ratio (gain >0.3, loss <-0.3) in the autosomal genes with direct and indirect designs. The copy number at a gene level from the X chromosomal genes using the direct and indirect sex-mismatched designs was +/-0.68 of the log(2) ratio (amplification >0.68, deletion <-0.68). In summary, the suggested method can be used as a guideline for analysis of genomic aberration using a Microarray-CGH in both direct and indirect designs.
Int J Mol Med 2006 Feb
PMID:Systematic analysis of cDNA microarray-based CGH. 1639 24

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. KIT and PDGFRA activating mutations are the oncogenic mechanisms in most sporadic GISTs. In addition to sporadic occurrences, GISTs are increasingly being recognized in association with neurofibromatosis type 1 (NF1), yet the underlying pathogenic mechanism remains elusive. To gain an insight into the mechanisms underlying GIST formation in NF1 patients, we studied seven GISTs from three NF1 patients with a combination of different techniques: mutation analysis (KIT, PDGFRA and NF1), western blotting, array CGH and ex vivo imatinib response experiments. We demonstrate that (i) the NF1-related GISTs do not have KIT or PDGFRA mutations, (ii) the molecular event underlying GIST development in this patient group is a somatic inactivation of the wild-type NF1 allele in the tumor and (iii) inactivation of neurofibromin is an alternate mechanism to (hyper) activate the MAP-kinase pathway, while the JAK-STAT3 and PI3K-AKT pathways are less activated in NF1-related GIST compared with sporadic GISTs. In conclusion, we report for the first time the molecular pathogenesis of GISTs in NF1 individuals and demonstrate that this type of tumor clearly belongs to the spectrum of clinical symptoms in NF1.
Hum Mol Genet 2006 Mar 15
PMID:Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients. 1646 35

A 10-year-old African-American male has been followed since 2 years of age due to his mental retardation, severe behavioral problems, and dysmorphism. Conventional cytogenetic analysis, chromosome painting, high-resolution comparative genomic hybridization (HR-CGH), and bacterial artificial chromosome fluorescent in situ hybridization (BAC FISH) revealed an apparent duplication in the short arm of a chromosome 11, dup(11)(p14.3p15.1), seen also in his mentally retarded mother. The proband had moderate to severe mental retardation, a history of IUGR, infantile hypotonia, FTT, exotropia, inguinal hernia repair, and several dysmorphic features. His mother had mild mental retardation, a history of impulsivity, assaultive outbursts, and similar dysmorphism. Although G-banding and FISH indicated a duplication, HR-CGH confined the localization of material to bands 11p14-11p15 and aided the selection of locus-specific BAC clones to more precisely characterize the duplicated region. To our knowledge, the results represent the first example of a familial, cytogenetically visible duplication of euchromatin in 11p that excludes the Beckwith-Wiedemann syndrome critical region. It is possible that one or more genes had been disrupted at the breakpoints of the above structural chromosomal rearrangement giving rise to the present phenotype.
Exp Mol Pathol 2006 Jun
PMID:Duplication of 11p14.3-p15.1 in a mentally retarded proband and his mother detected by G-banding and confirmed by high-resolution CGH and BAC FISH. 1651 86

In vitro germinal vesicle breakdown (GVBD) in Cyprinus carpio oocytes was induced by recombinant human insulin-like growth factor-I and -II (IGF-I and IGF-II) and bovine insulin (b-insulin). Treatment of postvitellogenic ovarian follicles with IGF-I and b-insulin increased concentration of maturation-inducing hormone (MIH), 17alpha,20beta-dihydroxy-4-pregnane-3-one (DHP) in the medium. IGF-I and IGF-II both and b-insulin induced GVBD in denuded oocytes. IGF-I analogue R3 IGF-I was more potent than IGF-I in inducing GVBD of postvitellogenic follicles suggesting that ovarian IGF binding proteins may inhibit IGF-I action. Vitellogenic follicles, which were immature for oocytes to complete GVBD in response to DHP or HCG, underwent GVBD by IGF-I, not by b-insulin. IGF-I was also able to stimulate DHP production in such follicles. Addition of DHP and HCG to the culture of vitellogenic follicles containing IGF-I or b-insulin did neither potentiate the stimulation of GVBD induced by IGF-I nor initiate the same in response to b-insulin. Incubation of postvitellogenic follicles with trilostane (3beta-HSD inhibitor) had no inhibitory effects on IGF-I- and b-insulin-induced GVBD but attenuated the same under HCG stimulation. Trilostane, however, strongly inhibited DHP production induced by all these effectors. Induction of GVBD by IGF-I and b-insulin was not altered in the presence of actinomycin D. However, it significantly blocked the HCG-induced GVBD. Cycloheximide was shown to inhibit the induction of GVBD and DHP production by IGF-I, b-insulin and HCG. Both actinomycin D and cycloheximide were found to inhibit DHP production stimulated by all the three effectors. Collectively, these observations indicate that IGF-I and b-insulin can induce GVBD via MIH- and transcription-independent pathway. Incubation of the follicles with gap junction uncouplers, 1-heptanol or 1-octanol, had no effect on IGF-I- and b-insulin-induced GVBD, but attenuated the same induced by HCG. These uncouplers, however, inhibited DHP production induced by IGF-I, b-insulin and HCG. This result suggests that both IGF-I and b-insulin can induce oocyte maturation without coupled gap junction between oocytes and granulosa cells, while homologous gap junctions are required for DHP production. Inhibitors of phosphatidylinositol-3 kinase (PI-3 kinase), wortmannin and LY294002 inhibited GVBD by IGF-I and b-insulin. These two inhibitors also attenuated HCG-induced GVBD. These data suggest that PI-3 kinase activity is required for IGF-I, b-insulin and HCG induction of GVBD in C. carpio.
Comp Biochem Physiol A Mol Integr Physiol 2006 May
PMID:In vitro effects of insulin-like growth factors and insulin on oocyte maturation and maturation-inducing steroid production in ovarian follicles of common carp, Cyprinus carpio. 1653 Oct 89

An autopsy case of a 19-year-old male Japanese student with a primary mixed choriocarcinoma and mature teratoma in the thymic region is reported. The patient died 7 days after he first noticed fever and dyspnea. On autopsy, an anterior mediastinal mass was found to be in contact with the thymic gland. The mass weighed 270 g and measured 12.5 cm x 10 cm x 5 cm. The left thoracic cavity contained 2200 ml bloody pleural effusion and 200 g coagula due to hemorrhage from the tumor. Metastasized choriocarcinoma was seen in both lungs and the liver. High serum levels of human chorionic gonadotropin (HCG, 1 634 000 mIU/ml) and a decreased weight of the testes (2.0 g each) with Leydig cell hyperplasia/hypertrophy and the seminiferous tubules with hyaline ghost tubules or Sertoli cell only tubules were seen; other male reproductive organs were histologically normal. Although the serum testosterone level was within the normal range (5.75 ng/ml), luteinizing hormone (LH, 0.1 mIU/ml) and follicle-stimulating hormone (FSH, 0.3 mIU/ml) levels were decreased. High serum levels of HCG and characteristic testicular changes are drscribed.
Med Mol Morphol 2006 Mar
PMID:An autopsy case of primary mixed choriocarcinoma and mature teratoma located in the thymic region associated with elevated human chorionic gonadotropin levels and characteristic testicular changes. 1657 15

Ovarian follicles from vitellogenic greenback flounder (Rhombosolea tapirina) were incubated in L15 medium alone, or containing human chorionic gonadotropin (hCG), dibutyryl cyclic AMP (dbcAMP) or the steroid precursors testosterone (T), 17-hydroxyprogesterone (17P) and androstenedione (A) in the presence of vitellogenin (Vtg) at 0.1-5.0mg mL(-)(1). Medium concentrations of 17beta-estradiol (E(2)) and T were measured by radioimmunoassay. HCG generally stimulated follicular E(2) but not T production, whereas 17P, A and T stimulated production of E(2), T, and E(2) respectively. Treatment of follicles with dbcAMP inhibited follicular E(2) production, but increased follicular T production at high doses. The effect of low concentrations of Vtg on follicular steroid production was variable; however, higher doses of Vtg significantly suppressed basal, hCG-, dbcAMP- and steroid precursor-stimulated follicular E(2) and T production. The results of this study show that high concentrations of Vtg may suppress follicular steroid production by interfering in the steroidogenic pathway. This suggests that Vtg may regulate its own production by limiting the ovarian production of E(2).
Comp Biochem Physiol A Mol Integr Physiol 2006 May
PMID:In vitro effect of vitellogenin on steroid production by ovarian follicles of greenback flounder Rhombosolea tapirina. 1658 Aug 56

This paper develops a Bayes regression model having change points for the analysis of array-CGH data by utilizing not only the underlying spatial structure of the genomic alterations but also the observation that the noise associated with the ratio of the fluorescence intensities is bigger when the intensities get smaller. We show that this Bayes regression approach is particularly suitable for the analysis of cDNA microarray-CGH data, which are generally noisier than those using genomic clones. A simulation study and a real data analysis are included to illustrate this approach.
Stat Appl Genet Mol Biol 2006
PMID:A Bayes regression approach to array-CGH data. 1664 67

The near completeness of human chromosome sequences is facilitating accurate characterization and assessment of all classes of genomic variation. Particularly, using the DNA reference sequence as a guide, genome scanning technologies, such as microarray-based comparative genomic hybridization (array CGH) and genome-wide single nucleotide polymorphism (SNP) platforms, have now enabled the detection of a previously unrecognized degree of larger-sized (non-SNP) variability in all genomes. This heterogeneity can include copy number variations (CNVs), inversions, insertions, deletions and other complex rearrangements, most of which are not detected by standard cytogenetics or DNA sequencing. Although these genomic alterations (collectively termed structural variants or polymorphisms) have been described previously, mainly through locus-specific studies, they are now known to be more global in occurrence. Moreover, as just one example, CNVs can contain entire genes and their number can correlate with the level of gene expression. It is also plausible that structural variants may commonly influence nearby genes through chromosomal positional or domain effects. Here, we discuss what is known of the prevalence of structural variants in the human genome and how they might influence phenotype, including the continuum of etiologic events underlying monogenic to complex diseases. Particularly, we highlight the newest studies and some classic examples of how structural variants might have adverse genetic consequences. We also discuss why analysis of structural variants should become a vital step in any genetic study going forward. All these progresses have set the stage for a golden era of combined microscopic and sub-microscopic (cytogenomic)-based research of chromosomes leading to a more complete understanding of the human genome.
Hum Mol Genet 2006 Apr 15
PMID:Structural variants: changing the landscape of chromosomes and design of disease studies. 1665 70

Oral squamous cell carcinoma (OSCC) is a common worldwide malignancy. However, it is unclear what, if any, genomic alterations occur as the disease progresses to invasive and metastatic OSCC. This study used genomewide array-CGH in microdissected specimens to map genetic alterations found in primary OSCC and neck lymph node metastases. We used array-based comparative genomic hybridization (array-CGH) to screen genomewide alterations in eight pairs of microdissected tissue samples from primary and metastatic OSCC. In addition, 25 primary and metastatic OSCC tissue pairs were examined with immunohistochemistry for protein expression of the most frequently altered genes. The highest frequencies of gains were detected in LMYC, REL, TERC, PIK3CA, MYB, MDR1, HRAS, GARP, CCND2, FES, HER2, SIS, and SRY. The highest frequencies of losses were detected in p44S10, TIF1, LPL, MTAP, BMI1, EGR2, and MAP2K5. Genomic alterations in TGFbeta2, cellular retinoid-binding protein 1 gene (CRBP1), PIK3CA, HTR1B, HRAS, ERBB3, and STK6 differed significantly between primary OSCC and their metastatic counterparts. Genomic alterations in PRKCZ, ABL1, and FGF4 were significantly different in patients who died compared with those who survived. Immunohistochemistry confirmed high PIK3CA immunoreactivity in primary and metastatic OSCC. Higher FGF4 immunoreactivity in primary OSCC is associated with a worse prognosis. Loss of CRBP1 immunoreactivity is evident in primary and metastatic OSCC. Our study suggests that precise genomic profiling can be useful in determining gene number changes in OSCC. As our understanding of these changes grow, this profiling may become a practical tool for clinical evaluation.
Mol Carcinog 2006 Oct
PMID:Array-comparative genomic hybridization to detect genomewide changes in microdissected primary and metastatic oral squamous cell carcinomas. 1667 65

Microarray-based comparative genomic hybridization (array CGH) is a revolutionary platform that was recently adopted in the clinical laboratory. This technology was first developed as a research tool for the investigation of genomic alterations in cancer. It allows for a high-resolution evaluation of DNA copy number alterations associated with chromosome abnormalities. Array CGH is based on the use of differentially labeled test and reference genomic DNA samples that are simultaneously hybridized to DNA targets arrayed on a glass slide or other solid platform. In this review, we examine the technology and its transformation from a research tool into a maturing diagnostic instrument. We also evaluate the various approaches that have shaped the current platforms that are used for clinical applications. Finally, we discuss the advantages and shortcomings of "whole-genome" arrays and compare their diagnostic use to "targeted" arrays. Depending on their design, microarrays provide distinct advantages over conventional cytogenetic analysis because they have the potential to detect the majority of microscopic and submicroscopic chromosomal abnormalities. This new platform is poised to revolutionize modern cytogenetic diagnostics and to provide clinicians with a powerful tool to use in their increasingly sophisticated diagnostic capabilities.
J Mol Diagn 2006 Nov
PMID:Application of array-based comparative genomic hybridization to clinical diagnostics. 1738 22


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