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1.
HLA ; 90(4): 228-233, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28695657

RESUMO

Primary sclerosing cholangitis (PSC) is strongly associated with several human leukocyte antigen (HLA) haplotypes. Due to extensive linkage disequilibrium and multiple polymorphic candidate genes in the HLA complex, identifying the alleles responsible for these associations has proven difficult. We aimed to evaluate whether studying populations of admixed or non-European descent could help in defining the causative HLA alleles. When assessing haplotypes carrying HLA-DRB1*13:01 (hypothesized to specifically increase the susceptibility to chronic cholangitis), we observed that every haplotype in the Scandinavian PSC population carried HLA-DQB1*06:03. In contrast, only 65% of HLA-DRB1*13:01 haplotypes in an admixed/non-European PSC population carried this allele, suggesting that further assessments of the PSC-associated haplotype HLA-DRB1*13:01-DQA1*01:03-DQB1*06:03 in admixed or multi-ethnic populations could aid in identifying the causative allele.


Assuntos
Colangite Esclerosante/genética , Predisposição Genética para Doença , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Haplótipos , Alelos , Colangite Esclerosante/etnologia , Colangite Esclerosante/imunologia , Etnicidade , Expressão Gênica , Frequência do Gene , Cadeias beta de HLA-DQ/classificação , Cadeias beta de HLA-DQ/imunologia , Cadeias HLA-DRB1/classificação , Cadeias HLA-DRB1/imunologia , Humanos , Desequilíbrio de Ligação , Países Escandinavos e Nórdicos , População Branca
3.
Neuropathol Appl Neurobiol ; 31(5): 455-66, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16150117

RESUMO

An immunohistochemical method for assessing cell cycle phase distribution in neurosurgical biopsies would enable such data to be incorporated into diagnostic algorithms for the estimation of prognosis and response to adjuvant chemotherapy in glial neoplasms, without the requirement for flow cytometric analysis. Paraffin-embedded sections of intracerebral gliomas (n = 48), consisting of diffuse astrocytoma (n = 9), anaplastic astrocytoma (n = 8) and glioblastoma (n = 31), were analysed by immunohistochemistry using markers of cell cycle entry, Mcm-2 and Ki67, and putative markers of cell cycle phase, cyclins D1 (G1-phase), cyclin A (S-phase), cyclin B1 (G2-phase) and phosphohistone H3 (Mitosis). Double labelling confocal microscopy confirmed that the phase markers were infrequently coexpressed. Cell cycle estimations by immunohistochemistry were corroborated by flow cytometric analysis. There was a significant increase in Mcm-2 (P < 0.0001), Ki67 (P < 0.0001), cyclin A (P < 0.0001) and cyclin B1 (P = 0.002) expression with increasing grade from diffuse astrocytoma through anaplastic astrocytoma to glioblastoma, suggesting that any of these four markers has potential as a marker of tumour grade. In a subset of glioblastomas (n = 16) for which accurate clinical follow-up data were available, there was a suggestion that the cyclin A:Mcm-2 labelling fraction might predict a relatively favourable response to radical radiotherapy. These provisional findings, however, require confirmation by a larger study. We conclude that it is feasible to obtain detailed cell cycle data by immunohistochemical analysis of tissue biopsies. Such information may facilitate tumour grading and may enable information of prognostic value to be obtained in the routine diagnostic laboratory.


Assuntos
Astrocitoma/patologia , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Ciclo Celular/fisiologia , Imuno-Histoquímica/métodos , Adulto , Astrocitoma/metabolismo , Proteínas de Ciclo Celular/biossíntese , Ciclina A/biossíntese , Ciclina B/biossíntese , Ciclina B1 , Ciclina D1/biossíntese , Citometria de Fluxo , Histonas/biossíntese , Humanos , Microscopia Confocal , Prognóstico , Reprodutibilidade dos Testes
4.
Br J Cancer ; 90(8): 1583-90, 2004 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-15083189

RESUMO

We have investigated whether immunohistochemical markers can identify differences in cell cycle phase distribution in ovarian serous neoplasms, including borderline tumours of different grades. Sections of normal ovary (n=18), serous cystadenoma (n=21), borderline serous tumours (n=21) and serous cystadenocarcinoma (n=15) were analysed by immunohistochemistry using markers of cell cycle entry (Mcm-2) and cell cycle phase, including cyclin D1 (mid-to-late G1), cyclin A (S phase), cyclin B1 (G2 phase) and phosphohistone H3 (mitosis). Double-labelling confocal microscopy confirmed marker phase specificity and phase estimations were corroborated by flow cytometry. On progression from normal ovary through serous cystadenoma and borderline tumours to cystadenocarcinomas, expression of Mcm-2 (P<0.0001), cyclin D1 (P=0.002), cyclin A (P<0.0001), cyclin B1 (P<0.0001) and phosphohistone H3 (P<0.0001) increased, paralleled by an increase in the S-phase fraction (cyclin A : Mcm-2 ratio; P=0.002). Borderline tumours of increasing grade also showed increased Mcm-2 and cyclin A expression, together with an increase in the S-phase fraction. Immunohistochemistry can be used to estimate cell cycle phase distribution in ovarian serous neoplasms, giving results similar to flow cytometric analysis and enabling direct assessment of tumour heterogeneity. Immunohistochemical estimates of the S-phase fraction may identify serous borderline tumours likely to exhibit malignant progression and/or select serous cystadenocarcinomas likely to respond to adjuvant therapy.


Assuntos
Biomarcadores Tumorais/análise , Proteínas de Ciclo Celular/análise , Ciclo Celular , Cistadenocarcinoma Seroso/patologia , Neoplasias Ovarianas/patologia , Proteínas de Ciclo Celular/biossíntese , Transformação Celular Neoplásica , Progressão da Doença , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica/métodos , Microscopia Confocal , Lesões Pré-Cancerosas , Manejo de Espécimes
5.
Colorectal Dis ; 6(2): 103-10, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15008907

RESUMO

OBJECTIVE: Minichromosome maintenance protein 2 (Mcm2) is an accurate indicator of cell cycle entry in tissue samples, but its expression in inflammatory bowel disease (IBD) has not previously been investigated. We have used immunohistochemistry to assess the expression of Mcm2, in comparison to the existing proliferation marker Ki-67, in active IBD and IBD without inflammatory activity. MATERIALS AND METHODS: For this experimental study, sections from colonic biopsy and resection specimens of 48 patients with IBD (5 inactive/quiescent Crohn's disease (CD), 13 active CD, 19 inactive/quiescent ulcerative colitis (UC) and 11 active UC) and 15 normal controls were immunostained with antibodies to Mcm2 and Ki-67. The percentage of immunopositive epithelial nuclei was determined by calculating a labelling index (LI) for entire glands and for gland thirds (superficial, middle and basal). RESULTS: The Mcm2 LI was significantly increased in the superficial third of glands in active vs. inactive/quiescent UC (P < 0.0001) and active vs. inactive/quiescent CD (P = 0.001). The Mcm2 LI was significantly greater than the Ki-67 LI in active IBD, both in entire glands (P < 0.0001) and in the superficial third of glands (UC, P = 0.001; CD, P = 0.0002). Mcm2 LIs for entire glands were significantly higher in UC (all cases) compared to CD (all cases) (P = 0.032). CONCLUSIONS: There is increased cell cycle entry, as indicated by expression of Mcm2 and to a lesser extent Ki-67, in the superficial third of colonic glands in active IBD compared to inactive/quiescent IBD. Detection of Mcm2 may contribute to improved histological assessment of small tissue biopsies and may enable the development of a direct stool-based test for detection of active IBD and potentially for assessment of disease activity.


Assuntos
Proteínas de Ciclo Celular/biossíntese , Colo/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/metabolismo , Colite Ulcerativa/metabolismo , Doença de Crohn/metabolismo , Humanos , Antígeno Ki-67/biossíntese
6.
Br J Cancer ; 89(6): 1048-54, 2003 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-12966424

RESUMO

Histological classification of laryngeal epithelial lesions is highly subjective, and methods of cytological detection are not well developed. Improved determination of aberrant cell cycle entry may allow increased objectivity in histological assessment and enable the development of less invasive diagnostic cytology tests. Sections of normal larynx (n=10), laryngeal dysplasia (n=20) and laryngeal squamous cell carcinoma (SCC) (n=10) were classified according to the Ljubljana classification and stained for markers of cell cycle entry, minichromosome maintenance protein-2 (Mcm-2) and Ki67. Expression patterns were compared using double labelling confocal microscopy. There was a correlation between Mcm-2 and Ki67 labelling indices (rho=0.93; 95% CI [0.84, 0.97]) and both markers showed increased expression from normal epithelium to SCC (Mcm-2, P=0.001; Ki67, P=0.0002). Importantly, there was minimal expression of Mcm-2 or Ki67 in the most superficial layers of normal larynx and abnormal or atypical hyperplasia, in contrast to carcinoma in situ and SCC. Clusters of Mcm-2/5-positive cells were present in cytological preparations from SCC, but not from those showing atypical hyperplasia or inflammation in non-neoplastic tissue. Minichromosome maintenance protein-2 staining may increase the objectivity and reliability of histological grading of laryngeal epithelial lesions. Laryngeal brushings, combined with immuno-enhanced liquid-based cytology, could be useful, as a less invasive approach, to the detection of laryngeal malignant and premalignant lesions.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Antígeno Ki-67/metabolismo , Neoplasias Laríngeas/metabolismo , Proteínas Nucleares/metabolismo , Antígenos de Neoplasias/metabolismo , Biópsia , Carcinoma in Situ/metabolismo , Carcinoma in Situ/patologia , Carcinoma de Células Escamosas/patologia , Ciclo Celular , Replicação do DNA , Humanos , Hiperplasia/metabolismo , Hiperplasia/patologia , Técnicas Imunoenzimáticas , Neoplasias Laríngeas/patologia , Componente 2 do Complexo de Manutenção de Minicromossomo , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia
7.
Br J Cancer ; 88(2): 257-62, 2003 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-12610511

RESUMO

Vulval intraepithelial neoplasia (VIN) is defined histopathologically by distinctive abnormalities of cellular maturation and differentiation. To investigate the functional properties of VIN, the expression of several proteins involved in the regulation of the cell cycle as well as in situ DNA replication competence was analysed by immunohistochemistry. Snap-frozen vulval biopsies were graded as normal squamous epithelium (n=6), undifferentiated HPV positive VIN 1 (n=3), VIN 2 (n=8) and VIN 3 (n=20). Immunohistochemistry was performed using the following markers: cyclin D1 (expressed in middle/late G1), cyclin B1 (expressed in G2/early M), phosphorylated histone H3 (expressed during mitosis) and minichromosome maintenance (Mcm) proteins 2 and 5 (expressed during the cell cycle, but not in differentiated or quiescent cells). In situ DNA replication competence was used to identify S-phase cells. The percentage of positively stained nuclei in three representative microscopic fields was calculated per biopsy. In normal vulva, the expression of all markers was restricted to the proliferative compartment of the basal layer of the epithelium. In contrast in high-grade VIN, the majority of epithelial cells expressed the Mcm proteins from basal to superficial layer. The detection of cyclins B1 and D1, phospho-histone H3 and in situ DNA replication was also found through the full thickness of these lesions but by a lower proportion of the cells. This is consistent with these markers providing a series of 'snapshots' of the cell cycle status of individual cells. The low-grade VIN showed reduced expression of the cell cycle markers in relation to the level of dysplasia. The combination of these analyses establishes that the majority of VIN cells remain in a functional replicative or prereplicative state of the cell cycle. Clinical application of these analyses may provide a basis for improved diagnosis of VIN.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma in Situ/genética , Carcinoma in Situ/metabolismo , Replicação do DNA , DNA de Neoplasias/metabolismo , Neoplasias Vulvares/genética , Neoplasias Vulvares/metabolismo , Biópsia , Carcinoma in Situ/patologia , Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Ciclina B/metabolismo , Ciclina B1 , Ciclina D1/genética , Ciclina D1/metabolismo , Proteínas de Ligação a DNA , Feminino , Histonas/genética , Humanos , Técnicas Imunoenzimáticas , Componente 2 do Complexo de Manutenção de Minicromossomo , Proteínas Nucleares/metabolismo , Proteínas de Schizosaccharomyces pombe , Neoplasias Vulvares/patologia
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