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91.
Adrenocortical adenoma and carcinoma: histopathological and molecular comparative analysis. 总被引:8,自引:0,他引:8
Alexander Stojadinovic Murray F Brennan Axel Hoos Atilla Omeroglu Denis H Y Leung Maria E Dudas Aviram Nissan Carlos Cordon-Cardo Ronald A Ghossein 《Modern pathology》2003,16(8):742-751
We compared histomorphological features and molecular expression profiles of adrenocortical adenomas (ACAd) and carcinomas (ACCa). A critical histopathological review (mean, 11 slides per patient) was conducted of 37 ACAd and 67 ACCa. Paraffin-embedded tissue cores of ACAd (n = 33) and ACCa (n = 38) were arrayed in triplicate on tissue microarrays. Expression profiles of p53, mdm-2, p21, Bcl-2, cyclin D1, p27, and Ki-67 were investigated by immunohistochemistry and correlated with histopathology and patient outcome using standard statistical methodology. Median follow-up period was 5 years. Tumor necrosis, atypical mitoses, and >1 mitosis per 50 high-power fields were factors that were highly specific for ACCa (P <.001). Number (0 to 4) of unfavorable markers [Ki-67 (+), p21 (+), p27 (+), mdm-2(-)] expressed was significantly associated with mitotic activity and morphologic index (i.e., number of adverse morphologic features) and highly predictive of malignancy (P <.001). Ki-67 overexpression occurred in 0 ACAd and 36% ACCa (P <.001) and was significantly associated with mitotic rate and unfavorable morphologic index (P <.001). Tumor necrosis, atypical mitoses, >5 mitoses per 50 high-power fields, sinusoidal invasion, histologic index of >5, and presence of more than two unfavorable molecular markers were associated significantly with metastasis in ACCa. Well-established histopathologic criteria and Ki-67 can specifically distinguish ACCAd from ACCa. Tumor cell proliferation (Ki-67) correlates with mitotic activity and morphologic index. Tumor morphology is a better predictor of metastatic risk in ACCa than current immunohistochemistry-detected cell cycle regulatory and proliferation-associated proteins. 相似文献
92.
Over-expression of fibroblast growth factor 8 (FGF8) in human prostate cancer is associated with clinically aggressive disease. Among different members of the FGF family, FGF17 and FGF8 share high sequence homology and have similar patterns of expression during embryogenesis. In this study, the clinical significance of FGF17 expression and its in vitro function in prostate cancer cells were tested. Forty resected prostate specimens from patients with benign prostatic hyperplasia (BPH, n = 12) and prostate cancer (CaP, n = 28; Gleason sum scores 3-10) were studied using semi-quantitative RT-PCR. In addition, 85 cases of CaP (Gleason sum scores 5-9) and 20 cases of BPH were examined using immunohistochemistry and findings were correlated with clinical parameters. In vitro experiments using prostate cancer cell lines examined the functional significance of FGF17 in prostate cancer. These studies revealed a significant linear correlation between increasing Gleason sum scores and FGF17 expression using both immunohistochemistry (p < 0.0001, rho = 0.99) and RT-PCR (p = 0.008, rho = 0.99). Immunohistochemistry demonstrated upregulation of FGF17 in CaP compared with BPH (p < 0.0001) and, when comparing high-grade CaP (Gleason sum score 7-10) with BPH, RT-PCR showed a fourfold upregulation of FGF17 mRNA expression (p < 0.0001). Men with tumours displaying high levels of FGF17 expression had a worse outcome on survival analysis (p = 0.044) and a higher risk of progression with metastases (p < 0.0001). Proliferation assays showed low-dose recombinant (r) FGF17 (1 ng/ml) to be a more potent mitogen than rFGF1 and rFGF8 in prostate cancer cell lines (LNCaP, DU145, and PC3M) (p < 0.001). Furthermore, FGF8 was shown to induce expression of FGF17 in these cell lines. These data support a role for FGF17, and a model of co-expression of multiple FGFs, with FGF17 as a potential mediator of FGF8 function, in human prostate carcinogenesis. 相似文献
93.
94.
The GAP-related domain of tuberin, the product of the TSC2 gene, is a target for missense mutations in tuberous sclerosis 总被引:5,自引:0,他引:5
Maheshwar MM; Cheadle JP; Jones AC; Myring J; Fryer AE; Harris PC; Sampson JR 《Human molecular genetics》1997,6(11):1991-1996
Tuberous sclerosis is an autosomal dominant trait in which the
dysregulation of cellular proliferation and differentiation results in the
development of hamartomatous growths in many organs. The TSC2 gene is one
of two genes determining tuberous sclerosis. Inactivating germline
mutations of TSC2 in patients with tuberous sclerosis and somatic loss of
heterozygosity at the TSC2 locus in the associated hamartomas indicate that
TSC2 functions as a tumour suppressor gene and that loss of function is
critical to expression of the tuberous sclerosis phenotype. The TSC2
product, tuberin, has a region of homology with the GTPase activating
protein rap1GAP and stimulates the GTPase activity of rap1a and rab5a in
vitro. Here we show that the region of homology between tuberin and human
rap1GAP and the murine GAP mSpa1 is more extensive than previously reported
and spans approximately 160 amino acid residues encoded within exons 34-38
of the TSC2 gene. Single strand conformation polymorphism analysis of these
exons in 173 unrelated patients with tuberous sclerosis and direct
sequencing of variant conformers together with study of additional family
members enabled characterisation of disease associated mutations in 14
cases. Missense mutations, which occurred in exons 36, 37 and 38 were
identified in eight cases, four of whom shared the same recurrent change
P1675L. Each of the five different missense mutations identified was shown
to occur de novo in at least one sporadic case of tuberous sclerosis. The
high proportion of missense mutations detected in the region of the TSC2
gene encoding the GAP-related domain supports its key role in the
regulation of cellular growth.
相似文献
95.
Berry V; Ionides AC; Moore AT; Plant C; Bhattacharya SS; Shiels A 《Human molecular genetics》1996,5(3):415-419
Inherited cataract is a clinically and genetically heterogeneous disease.
Here we report the identification of a new locus for an autosomal dominant
anterior polar cataract on the short arm of chromosome 17. To map this new
locus we performed genetic linkage analysis with microsatellite markers in
a four-generation pedigree. After exclusion of seven candidate loci for
cataract, we obtained significant positive LOD scores for markers D17S849
(Z = 4.01 / theta = 0.05) and D17S796 (Z = 4.17 / theta = 0.05). Multipoint
analysis gave a maximum LOD score of 5.2 (theta max = 0.06) between these
two markers. From haplotype analysis, the cataract locus lies in the 13 cM
interval between markers D17S849 and D17S796. This study provides the first
genetic mapping of an autosomal dominant anterior polar cataract.
相似文献
96.
Y. Cheng R. Wong Y. O. Y. Soo W. S. Wong C. K. Lee M. H. L. Ng P. Chan K. C. Wong C. B. Leung G. Cheng 《European journal of clinical microbiology & infectious diseases》2005,24(1):44-46
In order to evaluate the efficacy of convalescent plasma therapy in the treatment of patients with severe acute respiratory syndrome (SARS), 80 SARS patients were given convalescent plasma at Prince of Wales Hospital, Hong Kong, between 20 March and 26 May 2003. Good outcome was defined as discharge by day 22 following the onset of SARS symptoms. Poor outcome was defined as death or hospitalization beyond 22 days. A higher day-22 discharge rate was observed among patients who were given convalescent plasma before day 14 of illness (58.3% vs 15.6%; P<0.001) and among those who were PCR positive and seronegative for coronavirus at the time of plasma infusion (66.7% vs 20%; P=0.001). 相似文献
97.
Staphylococcus aureus is an important human pathogen which is implicated in a wide variety of diseases. Major determinants of the virulence of this organism include extracellular virulence factors. Staphylococcal enterotoxins (SEs) are important causative agents in staphylococcal toxic shock syndrome and food poisoning. Our study identified a novel enterotoxin, SEK, and examined its biochemical and biological properties. SEK had a molecular weight of 26,000 and an experimentally determined pI of between 7.0 and 7.5. SEK was secreted by clinical isolates of S. aureus. We demonstrated that SEK had many of the biological activities associated with the SEs, including superantigenicity, pyrogenicity, the ability to enhance the lethal effect of endotoxin, and lethality in a rabbit model when administered by subcutaneous miniosmotic pump. Recombinant SEK was shown to stimulate human CD4(+) and CD8(+) T cells in a Vbeta-specific manner; T-cells bearing Vbeta 5.1, 5.2, and 6.7 were significantly stimulated to proliferate. 相似文献
98.
Sequence and comparative analysis of the mouse 1-megabase region orthologous to the human 11p15 imprinted domain 总被引:8,自引:4,他引:8
Onyango P Miller W Lehoczky J Leung CT Birren B Wheelan S Dewar K Feinberg AP 《Genome research》2000,10(11):1697-1710
A major barrier to conceptual advances in understanding the mechanisms and regulation of imprinting of a genomic region is our relatively poor understanding of the overall organization of genes and of the potentially important cis-acting regulatory sequences that lie in the nonexonic segments that make up 97% of the genome. Interspecies sequence comparison offers an effective approach to identify sequence from conserved functional elements. In this article we describe the successful use of this approach in comparing a approximately 1-Mb imprinted genomic domain on mouse chromosome 7 to its orthologous region on human 11p15.5. Within the region, we identified 112 exons of known genes as well as a novel gene identified uniquely in the mouse region, termed Msuit, that was found to be imprinted. In addition to these coding elements, we identified 33 CpG islands and 49 orthologous nonexonic, nonisland sequences that met our criteria as being conserved, and making up 4.1% of the total sequence. These conserved noncoding sequence elements were generally clustered near imprinted genes and the majority were between Igf2 and H19 or within Kvlqt1. Finally, the location of CpG islands provided evidence that suggested a two-island rule for imprinted genes. This study provides the first global view of the architecture of an entire imprinted domain and provides candidate sequence elements for subsequent functional analyses. 相似文献
99.
100.
Chloe Miu Mak Ching-Wan Lam Sidney Tam Ching-Lung Lai Lik-Yuen Chan Sheung-Tat Fan Yu-Lung Lau Sik-To Lai Patrick Yuen Joannie Hui Chun-Cheung Fu Ka-Sing Wong Wing-Lai Mak Kong Tze Sui-Fan Tong Abby Lau Nancy Leung Aric Hui Ka-Ming Cheung Chun-Hung Ko Yiu-Ki Chan Oliver Ma Tai-Nin Chau Alexander Chiu Yan-Wo Chan 《Journal of human genetics》2008,53(4):375-375