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1.
Adv Ther ; 37(1): 288-299, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31721113

RESUMO

INTRODUCTION: The corticotropin-releasing hormone (CRH) system, its receptors corticotropin-releasing hormone receptor 1 (CRHR1) and 2 (CRHR2), and its corresponding binding protein corticotropin-releasing hormone-binding protein (CRHBP) as well as the urocortin proteins-structural homologues to CRH, which are included in this peptide family-have become interesting oncological targets recently. Carcinogenesis of various human tumors has been reported with an altered presence of members of this system. The aim of the present study was to examine the role of urocortin 3 (UCN3) in renal cell carcinoma (RCC). METHODS: Therefore, tumoral tissues of 106 patients with RCC and available corresponding normal tissues were analyzed using qPCR for quantitative mRNA expression analysis. Tissue localization and protein signals of UCN3 in normal and tumoral renal specimens were evaluated using western blot and immunohistochemistry. In addition, correlation studies of UCN3 mRNA expression with clinicopathological parameters of patients with RCC and different histological subtypes were evaluated. RESULTS: UCN3 mRNA was significantly downregulated in nearly all tumoral tissues (p = 7.92 × 10-13). The same effect was observed at protein level using immunohistochemistry. Level of UCN3 mRNA expression was not directly correlated with clinicopathological parameters. CONCLUSION: We report for the first time the significant downregulation of UCN3 in RCC. These results demonstrate a possible involvement of the CRH system and its significance in carcinogenesis of RCC.

2.
Clin Immunol ; 210: 108269, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31683054

RESUMO

Genetic studies have led to identification of an increasing number of monogenic primary immunodeficiency disorders. Monoallelic pathogenic gain-of-function (GOF) variants in NFKBIA, the gene encoding IκBα, result in an immunodeficiency disorder, typically accompanied by anhidrotic ectodermal dysplasia (EDA). So far, 14 patients with immunodeficiency due to NFKBIA GOF mutations have been reported. In this study we report three patients from the same family with immunodeficiency, presenting with recurrent respiratory tract infections, bronchiectasis and viral skin conditions due to a novel pathogenic NFKBIA variant (c.106 T > G, p.Ser36Ala), which results in reduced IκBα degradation. Immunological investigations revealed inadequate antibody responses against vaccine antigens, despite hypergammaglobulinemia. Interestingly, none of the studied patients displayed features of EDA. Therefore, missense NFKBIA variants substituting serine 36 of IκBα, differ from the rest of pathogenic GOF NFKBIA variants in that they cause combined immunodeficiency, even in the absence of EDA.

3.
Front Immunol ; 10: 2618, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31803180

RESUMO

Adult-onset primary immunodeficiency is characterized by recurrent infections, hypogammaglobulinemia, and poor antibody response to vaccines. In this study, we have analyzed targeted gene panel sequencing results of 270 patients diagnosed with antibody deficiency and identified five disease-associated variants in NFKB1 in five unrelated families. We detected two single base pair deletions and two single base pair insertions, causing severe protein truncations, and one missense mutation. Immunoblotting, lymphocyte stimulation, immunophenotyping, and ectopic expression assays demonstrated the functional relevance of NFKB1 mutations. Besides antibody deficiency, clinical manifestations included infections, autoimmune features, lymphoproliferation, lymphoma, Addison's disease, type 2 diabetes and asthma. Although partial clinical penetrance was observed in almost all pedigrees, all carriers presented a deficiency in certain serum immunoglobulins and the majority showed a lack of memory B cells (CD19+CD27+). Among all tested genes, NFKB1 alterations were the most common monoallelic cause of antibody deficiency in our cohort.

4.
Front Immunol ; 10: 1272, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379802

RESUMO

Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1-25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0-88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%-subcutaneous; 29%-intravenous; 1%-unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.

5.
Diseases ; 7(2)2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30987377

RESUMO

Immunodeficiency, centromeric instability and facial anomalies syndrome 2 (ICF2) is a rare autosomal recessive primary immunodeficiency disorder. So far, 27 patients have been reported. Here, we present three siblings with ICF2 due to a homozygous ZBTB24 gene mutation (c.1222 T>G, p. (Cys408Gly)). Immune deficiency in these patients ranged from late-onset combined immunodeficiency (CID) with severe respiratory tract infections and recurrent shingles to asymptomatic selective antibody deficiency. Evident clinical heterogeneity manifested despite a common genetic background, suggesting the pathogenic relevance of epigenetic modification. Immunological follow-up reveals a previously unidentified gradual depletion of B and CD4⁺ T cells in all three presented patients with transition of a common variable immunodeficiency (CVID)-like disease to late-onset-CID in one of them. Considering all previously published cases with ICF2, we identify inadequate antibody responses to vaccines and reduction in CD27⁺ memory B cells as prevalent immunological traits. High mortality among ICF2 patients (20%) together with the progressive course of immunodeficiency suggest that hematopoietic stem cell transplantation (HSCT) should be considered as a treatment option in due time.

7.
Infect Dis Ther ; 7(4): 485-494, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30377976

RESUMO

INTRODUCTION: The way syphilis affects the immunologic and virologic parameters of a human immunodeficiency virus (HIV) infection remains controversial. The aim of this study was to investigate the impact of syphilis infection on lymphocyte and lymphocyte subset counts as well as viral load in HIV-infected patients. METHODS: All HIV-infected patients attending the outpatient clinic for infectious diseases of Hannover Medical University Hospital diagnosed with syphilis between 2009 and 2016 were retrospectively evaluated for changes in total lymphocyte, B cell, CD3+ T cell, CD4+ and CD8+ T cell counts as well as in HIV viral load. These parameters were assessed at three different time points, i.e., 3-6 months before, at diagnosis and 3-6 months after treatment of syphilis. RESULTS: Eighty-four HIV-infected patients, all with early syphilis, were identified. The vast majority were men who have sex with men (MSM), and 80% were receiving antiretroviral therapy (ART). Syphilis was associated with a significant reduction in the total lymphocyte count and counts of all studied lymphocyte subsets, including CD4+ T cells, whose percentage among lymphocytes did not change. No significant changes in HIV viral load were observed at any of the studied time points. Further, antibiotic treatment of syphilis restored lymphocyte counts back to pretreatment levels. CONCLUSION: Syphilis induces a relative non-CD4+ T cell-specific lymphopenia in HIV-infected patients. Our data suggest that serologic testing for syphilis should be considered in HIV-infected MSM in case of an otherwise unexplained drop in total lymphocyte count.

9.
Artigo em Inglês | MEDLINE | ID: mdl-29904012

RESUMO

BACKGROUND: In 2015, a high number of refugees with largely unknown health statuses immigrated to Western Europe. To improve caretaking strategies, we assessed the prevalence of latent tuberculosis infection (LTBI) in a refugee cohort. METHODS: Interferon-Gamma release assays (IGRA, Quantiferon) were performed in n = 232 inhabitants of four German refugee centers in the summer of 2015. RESULTS: Most refugees were young, male adults. Overall, IGRA testing was positive in 17.9% (95% CI = 13.2⁻23.5%) of subjects. Positivity rates increased with age (0% <18 years versus 46.2% >50 years). Age was the only factor significantly associated with a positive IGRA in multiple regression analysis including gender, C reactive protein, hemoglobin, leukocyte, and thrombocyte count and lymphocyte, monocyte, neutrophil, basophil, and eosinophil fraction. For one year change in age, the odds are expected to be 1.06 times larger, holding all other variables constant (p = 0.015). CONCLUSION: Observed LTBI frequencies are lower than previously reported in similar refugee cohorts. However, as elderly people are at higher risk for developing active tuberculosis, the observed high rate of LTBI in senior refugees emphasizes the need for new policies on the detection and treatment regimens in this group.


Assuntos
Tuberculose Latente/diagnóstico , Tuberculose Latente/epidemiologia , Refugiados/estatística & dados numéricos , Adolescente , Adulto , Fatores Etários , Idoso , Criança , Estudos de Coortes , Feminino , Alemanha/epidemiologia , Humanos , Testes de Liberação de Interferon-gama , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores Sexuais , Teste Tuberculínico , Adulto Jovem
11.
Inflammation ; 41(1): 42-49, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28852968

RESUMO

Store-operated calcium entry (SOCE) is the most common mode of calcium influx in non-excitable cells, including immune cells. The two STIM isoforms mediate SOCE as well as Fc receptor (FcR)-downstream activation of macrophages and mast cells-which appears to be relevant in vivo, in models of antibody-dependent tissue injury and allergy. Hence, the pathway of SOCE may be a therapeutic target for treatment of immune complex (IC)-mediated autoimmunity and allergic asthma. The pyrazole derivative, BTP2 is an efficient inhibitor of SOCE, which has already been shown to attenuate allergic inflammation. However, its effect on Fc gamma receptor (FcγR) signaling and IC-induced tissue injury had not yet been studied. Here, we show that BTP2 is a potent inhibitor of SOCE in primary macrophages, blocking FcγR-mediated responses. To investigate the effect of inhibition of SOCE in IC-mediated tissue injury, we induced reverse passive Arthus reaction to IgG immune complexes in the skin and lungs of BTP2- or control-treated mice. Treatment with BTP2 resulted in markedly attenuated inflammation in both the skin and the lungs. Our findings indicate the involvement of SOCE in FcγR-mediated responses in vitro and in vivo and suggest that BTP2-mediated inhibition of SOCE may have a therapeutic potential on IC-mediated autoimmunity.


Assuntos
Anilidas/farmacologia , Anti-Inflamatórios/farmacologia , Complexo Antígeno-Anticorpo/imunologia , Reação de Arthus/prevenção & controle , Imunoglobulina G/imunologia , Macrófagos Peritoneais/efeitos dos fármacos , Pneumonia/prevenção & controle , Tiadiazóis/farmacologia , Animais , Complexo Antígeno-Anticorpo/metabolismo , Reação de Arthus/imunologia , Reação de Arthus/metabolismo , Autoimunidade/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Imunoglobulina G/metabolismo , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Camundongos Endogâmicos C57BL , Fagocitose/efeitos dos fármacos , Pneumonia/imunologia , Pneumonia/metabolismo , Receptores de IgG/imunologia , Receptores de IgG/metabolismo , Molécula 1 de Interação Estromal/metabolismo , Fatores de Tempo
12.
Front Immunol ; 8: 885, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28804486

RESUMO

INTRODUCTION: Interleukin 12 receptor beta 1 (IL12Rß1) deficiency is a primary immunodeficiency resulting mainly in susceptibility to opportunistic infection by non-tuberculous, environmental mycobacteria and severe infection caused by Salmonella spp. Till now, less than 300 patients with IL12Rß1 deficiency have been reported. Among them, only three have been described to develop autoimmunity. CASE PRESENTATION: We present the case of a 50-year-old male with IL12Rß1 deficiency due to compound heterozygosity [c. 1623_1624delGCinsTT (pGln542Stop) and c.1791 + 2T > C (donor splice site)], who-18 months after diagnosis of disseminated BCGitis-presented with recurrent fever and sicca syndrome. No indication of an infectious origin of these symptoms could be found at that point. The diagnosis of a Sjögren's syndrome (SS) was made on the basis of fulfilled American-European consensus classification criteria, including a positive minor salivary gland biopsy. CONCLUSION: Apart from persistent antigenic stimulation, which may drive autoimmune inflammation in primary immunodeficiency, evidence on the involvement of interleukin 12 in pathogenesis of SS suggests that the same immunological mechanism may underlie both defense against infection and the maintenance of tolerance. To our knowledge, this is the first report of a case of autoimmunity in the form of SS in a patient with a primary immunodeficiency and one of the rare cases of IL12Rß1 deficiency with manifested autoimmunity.

13.
Cytokine ; 96: 71-74, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28324805

RESUMO

We used whole exome sequencing to determine the genetic background of CVID in two non-consanguineous German families. We identified IFNK (interferon-kappa) as the only candidate gene that harbored truncating mutations in affected members from both families. One family segregated c.30_31insTGTT, a known frameshift variant, while the other family segregated the novel IFNK mutation p.K199X that creates a premature stop codon. We sequenced the whole coding region of IFNK in a further series of 167 CVID patients and 192 healthy controls. Frameshift mutation c.30_31insTGTT was identified in 12 cases and 17 controls (OR 0.79, 95% CI 0.33-1.81, p=0.79), whereas the p.K199X mutation remained restricted to the original family. No additional truncating variants were found. We conclude that, given their frequent occurrence in non-diseased family members and controls, it is unlikely that truncating variants in IFNK constitute a major factor in the development of CVID.


Assuntos
Imunodeficiência de Variável Comum/genética , Imunodeficiência de Variável Comum/imunologia , Mutação da Fase de Leitura , Interferon Tipo I/genética , Adulto , Idoso , Imunodeficiência de Variável Comum/congênito , Feminino , Genoma Humano , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Análise de Sequência de DNA , Sequenciamento Completo do Exoma
14.
Clin Immunol ; 179: 1-7, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28216420

RESUMO

Here we describe novel mutations in recombination activation gene 1 (RAG1) in a compound heterozygous male patient with combined T and B cell immunodeficiency (CID). Clinical manifestations besides antibody deficiency included airway infections, granulomatosis and autoimmune features. He died at the age of 37 due to PML caused by JC virus infection. By targeted next-generation sequencing we detected post mortem in this patient three mutations in RAG1. One allele harbored two novel mutations (c.1123C>G, p.H375D and c.1430delC, p.F478Sfs*14), namely a missense variant and a frameshift deletion, of which the latter leads to a truncated RAG1 protein. The other allele revealed a previously described missense mutation (c.1420C>T, p.R474C, rs199474678). Functional analysis of the p.R474C variant in an in vitro V(D)J recombination assay exhibited reduced recombination activity compared to a wild-type control. Our findings suggest that mutations in RAG1, specifically the p.R474C variant, can be associated with relatively mild clinical symptoms or delayed occurrence of T cell and B cell deficiencies but may predispose to PML.


Assuntos
Proteínas de Homeodomínio/genética , Síndromes de Imunodeficiência/genética , Leucoencefalopatia Multifocal Progressiva/genética , Adulto , Linfócitos B/imunologia , Biópsia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Proliferação de Células , Humanos , Imunoglobulinas/sangue , Síndromes de Imunodeficiência/sangue , Síndromes de Imunodeficiência/diagnóstico por imagem , Síndromes de Imunodeficiência/imunologia , Leucoencefalopatia Multifocal Progressiva/sangue , Leucoencefalopatia Multifocal Progressiva/diagnóstico por imagem , Leucoencefalopatia Multifocal Progressiva/imunologia , Contagem de Linfócitos , Imagem por Ressonância Magnética , Masculino , Mutação , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Recombinação V(D)J
15.
Int Arch Allergy Immunol ; 171(2): 136-140, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27902982

RESUMO

AIM OF STUDY: We used a triplex real-time polymerase chain reaction (PCR) to classify our common variable immunodeficiency (CVID) patients into distinct groups according to the amount of their T-cell receptor excision circles (TRECs) and κ-deleting recombination excision circles (KRECs). MATERIALS AND METHODS: TREC and KREC analysis was performed using a multiplex real-time PCR assay. The T- and B-lymphocyte subsets were measured by flow cytometry. RESULTS: The copy number of TRECs and KRECs was significantly reduced in CVID patients compared to healthy controls. The TREC copy number was inversely correlated with age in both healthy subjects and patients; however, the KREC copy number was inversely correlated with age only in CVID patients. Moreover, no association was seen between TREC/KREC copy number and clinical manifestations such as bronchiectasis, splenomegaly, granulomata, autoimmune cytopenias, organ-specific autoimmunity, enteropathy and lymphoid hyperplasia. CONCLUSION: TREC and KREC quantification might be a useful tool to differentiate between CVID and combined immunodeficiency, but considering the results of this study a classification of CVID patients in certain groups is hardly possible.


Assuntos
Imunodeficiência de Variável Comum/genética , Reação em Cadeia da Polimerase Multiplex , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Antígenos de Linfócitos T/genética , Recombinação Genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Imunodeficiência de Variável Comum/imunologia , Variações do Número de Cópias de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
16.
PLoS One ; 11(10): e0163873, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27695045

RESUMO

The relevance of Corticotropin Releasing Hormone (CRH)-system in human malignancies is a question of growing interest. Here we investigated hypermethylation and epigenetic silencing of the CRH-Binding Protein (CRHBP) gene in clear cell renal cell cancer (ccRCC). Relative methylation of the CRHBP CpG island (CGI) was determined in 17 tumor cell lines as well as 86 ccRCC samples and 66 paired normal tissues using pyrosequencing and quantitative methylation specific PCR of bisulfite converted DNA. Results were statistically compared with relative mRNA expression levels of CRHBP and clinicopathological parameters of patients. Re-expression of CRHBP following 5-aza-2´-deoxycytidine treatment was investigated by quantitative mRNA expression analysis. Real-time impedance analysis was applied for analysis of invasiveness of renal tumor cells following si-RNA knockdown of CRHBP expression or ectopic expression of CRHBP. We found the CRHBP CGI to be frequently methylated in tumor cell lines of renal, prostatic, and bladder cancer. Comparison of methylation in normal and paired renal cancer tissue specimens revealed hypermethylation of the CRHBP CGI in tumors (p<1*10-12). DNA methylation and decreased mRNA expression were correlated (R = 0.83, p<1*10-12). Tumor cell lines showed 5-aza-2´-deoxycytidine dependent reduction of methylation and re-expression of CRHBP was associated with altered cellular invasiveness of renal cancer cells in real-time impedance invasion assays. Hypermethylation and inverse relationship with mRNA expression were validated in silico using the TCGA network data. We describe for the first time tumor specific epigenetic silencing of CRHBP and statistical association with aggressive tumors thus suggesting the CRH system to contribute to the development of kidney cancer.


Assuntos
Carcinoma de Células Renais/genética , Proteínas de Transporte/genética , Metilação de DNA/genética , Inativação Gênica , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , RNA Mensageiro/genética
17.
Nat Commun ; 6: 6804, 2015 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-25891430

RESUMO

Common variable immunodeficiency disorder (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by B-cell abnormalities and inadequate antibody response. CVID patients have considerable autoimmune comorbidity and we therefore hypothesized that genetic susceptibility to CVID may overlap with autoimmune disorders. Here, in the largest genetic study performed in CVID to date, we compare 778 CVID cases with 10,999 controls across 123,127 single-nucleotide polymorphisms (SNPs) on the Immunochip. We identify the first non-HLA genome-wide significant risk locus at CLEC16A (rs17806056, P=2.0 × 10(-9)) and confirm the previously reported human leukocyte antigen (HLA) associations on chromosome 6p21 (rs1049225, P=4.8 × 10(-16)). Clec16a knockdown (KD) mice showed reduced number of B cells and elevated IgM levels compared with controls, suggesting that CLEC16A may be involved in immune regulatory pathways of relevance to CVID. In conclusion, the CLEC16A associations in CVID represent the first robust evidence of non-HLA associations in this immunodeficiency condition.


Assuntos
Linfócitos B/metabolismo , Imunodeficiência de Variável Comum/genética , Lectinas Tipo C/metabolismo , Proteínas de Transporte de Monossacarídeos/metabolismo , Animais , Estudos de Casos e Controles , Células Cultivadas , Imunodeficiência de Variável Comum/epidemiologia , Europa (Continente)/epidemiologia , Regulação da Expressão Gênica/fisiologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Lectinas Tipo C/genética , Modelos Logísticos , Camundongos , Proteínas de Transporte de Monossacarídeos/genética , Razão de Chances , Polimorfismo de Nucleotídeo Único , Baço/citologia , Estados Unidos/epidemiologia
18.
Oncol Rep ; 31(4): 1523-30, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24549248

RESUMO

Transcriptional inactivation and CpG island (CGI) methylation of GATA transcription factor family members GATA3 and GATA5 have been reported for a few types of human cancer. Whether high-density CGI methylation of GATA3 or GATA5 is associated with the clinical course of patients with renal cell cancer (RCC) has not been clarified. Quantitative methylation-specific PCR assays were carried out to analyze 25 tumor cell lines including 6 RCC lines and 119 RCC and 87 adjacent normal tissues for the presence of densely methylated sequences. Methylation values were statistically compared with clinicopathological and recurrence-free survival (RFS) data for patients. Comparison of GATA3 and GATA5 methylation in different tumor cell lines revealed a marker-specific methylation characteristic with high and frequent signals for both methylation marks in RCC lines. GATA3 and GATA5 CGI relative methylation levels were found to be strongly associated with the state of metastasis (P=0.003 and P<0.001, respectively) and advanced disease (P=0.024 and P<0.001, respectively). Moreover, an independent decrease in RFS in Cox proportional hazard analysis was found for tumors exhibiting high GATA5 methylation (P<0.001, hazard ratio, 19.3; 95% confidence interval, 4.58-81.6). Epigenetic alterations in GATA family members may be associated with aggressive tumor phenotypes in RCC, and in the case of GATA5, may serve as a new independent molecular marker for aggressiveness and disease progression.


Assuntos
Carcinoma de Células Renais/genética , Ilhas de CpG/genética , Metilação de DNA/genética , Fator de Transcrição GATA5/genética , Neoplasias Renais/genética , Idoso , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/mortalidade , Intervalo Livre de Doença , Feminino , Fator de Transcrição GATA3/genética , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Reação em Cadeia da Polimerase em Tempo Real
19.
BMC Cancer ; 13: 199, 2013 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-23607589

RESUMO

BACKGROUND: Significance of Urocortin (Ucn or UcnI), Ucn2, Ucn3 and their receptors, Corticotropin Releasing Factor Receptor 1 and 2 (CRFR1 and CRFR2), and the binding protein, Corticotropin-Releasing Hormone-Binding Protein (CRHBP) in oncology is growing rapidly. The objective of our study was to assess the expression of the CRHBP mRNA and protein in renal cancer. METHODS: Tumoral tissues of 78 patients with clear cell renal cell cancer and their corresponding normal tissues were analyzed using quantitative mRNA expression analysis for detection of mRNA expression level. Protein expression and tissue localization of CRHBP protein in renal specimens was evaluated using western blotting, immunohistochemistry and double immunofluorescence, respectively. RESULTS: We found an approx. 33 fold decrease of average CRHBP mRNA level in tumoral tissues compared to paired normal tissues (p<0.001). Diminished CRHBP mRNA expression was positively correlated with advanced, metastasized and higher stage of disease (p<0.001, p=0.026, p=0.028 respectively). CRHBP protein was detected in glomeruli and proximal tubules of normal kidney while none or weak immunopositivity was found in cc-RCC (p<0.001). CONCLUSIONS: The expression analysis of CRHBP shows that cc-RCC is characterized by a significant loss of CRHBP mRNA expression that furthermore is associated with a more aggressive state of tumors. Depletion of CRHBP proteins also indicate that the protein as part of the UCN system may be involved in renal carcinogenesis.


Assuntos
Carcinoma de Células Renais/genética , Carcinoma de Células Renais/secundário , Proteínas de Transporte/genética , Neoplasias Renais/genética , Neoplasias Renais/patologia , RNA Mensageiro/metabolismo , Idoso , Carcinoma de Células Renais/metabolismo , Proteínas de Transporte/metabolismo , Feminino , Humanos , Glomérulos Renais/metabolismo , Neoplasias Renais/metabolismo , Túbulos Renais Proximais/metabolismo , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias
20.
Epigenetics ; 7(5): 447-57, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22419128

RESUMO

Loss of the secreted Fzd-related protein 1 (SFRP1) and concurrent alteration of the SFRP1/WNT pathway are frequently observed in human cancers such as in renal cell cancer (RCC). Whether methylation of a SFRP1 CpG island locus in normal human solid tissues is associated with increased tissue specific cancer risk has not been determined to date. Here we measure the cancer risk attributable to SFRP1 DNA methylation in renal tissue. Pyrosequencing of bisulfite treated DNA was used for a case-control study including 120 normal-appearing renal tissues of autopsy specimens and 72 normal-appearing tissues obtained from tumor adjacent areas, and a cross sectional study of 96 RCCs. Association of methylation with demographic risk factor age, clinicopathological parameters and course of patients was investigated. We show significant hypermethylation of a SFRP1 CpG island locus in normal-appearing renal tissues from RCC patients compared with normal-appearing autopsy kidney tissues. Inter quartile analysis revealed a 6-, 13- and 11-fold increased cancer risk for the second, third and fourth quartiles of methylation in the age matched subgroup of tissues (p = 0.001, p = 1.3E-6, p = 6.9E-6). Methylation in autopsy tissues increased with age and methylation in tumors was an independent predictor of recurrence free survival. SFRP1 DNA methylation, accumulates with age in normal-appearing kidney tissues and is associated with increased renal cancer risk, suggesting this CGI sub region as an epigenetic susceptibility locus for RCC. Our data underline the need to further analyze the tissue specific risks conferred by methylated loci for the development of human cancers.


Assuntos
Carcinoma de Células Renais/genética , Ilhas de CpG , Metilação de DNA , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Membrana/metabolismo , Recidiva Local de Neoplasia/patologia , Autopsia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Índice de Massa Corporal , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Estudos de Casos e Controles , Estudos Transversais , Epigênese Genética , Feminino , Perfilação da Expressão Gênica/métodos , Loci Gênicos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Rim/metabolismo , Rim/patologia , Modelos Logísticos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Estadiamento de Neoplasias , Fatores de Risco , Sensibilidade e Especificidade , Análise de Sequência de DNA/métodos
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