Clinical characteristics and prognostic analysis of pediatric pro-B cell acute lymphoblastic leukemia / 中国当代儿科杂志

OBJECTIVE@#To explore the clinical-biological characteristics and prognosis of pediatric pro-B cell acute lymphoblastic leukemia (pro-B-ALL).@*METHODS@#A total of 64 patients aged less than 18 years old with pro-BALL were enrolled. Clinical characteristics, therapeutic effect and prognostic factors were retrospectively analyzed.@*RESULTS@#Pro-B-ALL occurred in 6.23% (64/1 028) of pediatric ALL. Among the 64 patients, 35 were male and 29 were female. The median age was 7.0 years (range 0.4-16.0 years) at diagnosis, of which 39% and 6% were ≥ 10 years old and < 1 year old respectively. The median WBC count was 25.5×10@*CONCLUSIONS@#Pediatric pro-B ALL is a heterogeneous disease with clinical and biological diversity. Biological characteristics, such as immunological markers, genetic alterations, and MRD at 3 months after chemotherapy may be important factors for the long-term prognosis.

Social network of family caregivers of disabled and dependent patients / Red social de cuidadores familiares de pacientes con discapacidad y dependencia / Rede social de cuidadores familiares de pacientes com incapacidades e dependência

Cross-sectional study that used the Social Network Index and the genogram to assess the social network of 110 family caregivers of dependent patients attended by a Home Care Service in São Paulo, Brazil. Data were analyzed using the test U of Mann-Whitney, Kruskal-Wallis and Spearman correlation. Results were considered statistically significant when p<0,05. Few caregivers participated in activities outside the home and the average number of people they had a bond was 4,4 relatives and 3,6 friends. Caregivers who reported pain and those who had a partner had higher average number of relatives who to trust. The average number of friends was higher in the group that reported use of medication for depression. Total and per capita incomes correlated with the social network. It was found that family members are the primary caregiver’s social network.



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Estudio transversal que utiliza el Índice de la Red Social y el genograma para evaluar la red social de los 110 cuidadores familiares de enfermos dependientes atendidos por un servicio de cuidados en el hogar, en São Paulo. Los datos fueron analizados por las pruebas de Mann-Whitney, Kruskal-Wallis y la correlación de Spearman. Los resultados se consideraron estadísticamente significativos cuando p<0,05. Pocos cuidadores participaban en actividades fuera del hogar y el número promedio de personas con las cuales tenían vínculo fueran 4,4 personas de la familia y 3,6 amigos. Los que informaron dolor en el cuerpo y los que tenían una pareja tenían mayor número medio de familiares en que confiar. El número medio de amigos fue mayor en el grupo que informó el uso de medicación para la depresión. Los ingresos totales y per cápita se correlacionaron con la red social. Se encontró que los miembros de la familia son la principal red social del cuidador.

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Objetivo Avaliar a rede social de 110 cuidadores familiares de pacientes dependentes atendidos por um Serviço de Assistência Domiciliária no município de São Paulo. Método Estudo transversal, que utilizou o Social Network Index e o genograma. Os dados foram analisados pelos testes U de Mann-Whitney, Kruskal-Wallis e correlação de Spearman. Foram considerados estatisticamente significantes quando p <0,05. Resultados Poucos cuidadores participavam de atividades extradomiciliares e o número médio de pessoas com quem mantinham vínculo era de 4,4 familiares e 3,6 amigos. Cuidadores que referiram dor no corpo e aqueles que possuíam companheiro apresentaram maior número médio de parentes em quem confiar. A média de amigos foi superior no grupo que referiu uso de medicamentos para depressão. As rendas total e per capita mostraram correlação com a rede social. Conclusão Verificou-se que os familiares são a principal rede social do cuidador. .

Genetic characterisation of Langerin gene in human immunodeficiency virus-1-infected women from Bahia, Brazil

Studies on human genetic variations are a useful source of knowledge about human immunodeficiency virus (HIV)-1 infection. The Langerin protein, found at the surface of Langerhans cells, has an important protective role in HIV-1 infection. Differences in Langerin function due to host genetic factors could influence susceptibility to HIV-1 infection. To verify the frequency of mutations in the Langerin gene, 118 samples from HIV-1-infected women and 99 samples from HIV-1-uninfected individuals were selected for sequencing of the promoter and carbohydrate recognition domain (CRD)-encoding regions of the Langerin gene. Langerin promoter analysis revealed two single nucleotide polymorphisms (SNPs) and one mutation in both studied groups, which created new binding sites for certain transcription factors, such as NFAT5, HOXB9.01 and STAT6.01, according to MatInspector software analysis. Three SNPs were observed in the CRD-encoding region in HIV-1-infected and uninfected individuals: p.K313I, c.941C>T and c.983C>T. This study shows that mutations in the Langerin gene are present in the analysed populations at different genotypic and allelic frequencies. Further studies should be conducted to verify the role of these mutations in HIV-1 susceptibility.

Knockdown of 14-3-3zeta enhances radiosensitivity and radio-induced apoptosis in CD133+ liver cancer stem cells

14-3-3zeta is related to many cancer survival cellular processes. In a previous study, we showed that silencing 14-3-3zeta decreases the resistance of hepatocellular carcinoma (HCC) to chemotherapy. In this study, we investigated whether silencing 14-3-3zeta affects the radioresistance of cancer stem-like cells (CSCs) in HCC. Knockdown of 14-3-3zeta decreased cell viability and the number of spheres by reducing radioresistance in CSCs after gamma-irradiation (IR). Furthermore, the levels of pro-apoptotic proteins were upregulated in CSCs via silencing 14-3-3zeta after IR. These results suggest that 14-3-3zeta knockdown enhances radio-induced apoptosis by reducing radioresistance in liver CSCs.

Whole-Genome Analysis in Korean Patients with Autoimmune Myasthenia Gravis

PURPOSE: The underlying cause of myasthenia gravis (MG) is unknown, although it likely involves a genetic component. However, no common genetic variants have been unequivocally linked to autoimmune MG. We sought to identify the genetic variants associated with an increased or decreased risk of developing MG in samples from a Korean Multicenter MG Cohort. MATERIALS AND METHODS: To determine new genetic targets related to autoimmune MG, a whole genome-based single nucleotide polymorphisms (SNP) analysis was conducted using an Axiom(TM) Genome-Wide ASI 1 Array, comprising 598375 SNPs and samples from 109 MG patients and 150 neurologically normal controls. RESULTS: In total, 641 SNPs from five case-control associations showed p-values of less than 10(-5). From regional analysis, we selected seven candidate genes (RYR3, CACNA1S, SLAMF1, SOX5, FHOD3, GABRB1, and SACS) for further analysis. CONCLUSION: The present study suggests that a few genetic polymorphisms, such as in RYR3, CACNA1S, and SLAMF1, might be related to autoimmune MG. Our findings also encourage further studies, particularly confirmatory studies with larger samples, to validate and analyze the association between these SNPs and autoimmune MG.

Human salivary gland stem cells ameliorate hyposalivation of radiation-damaged rat salivary glands

Salivary function in mammals may be defective for various reasons, such as aging, Sjogren's syndrome or radiation therapy in head and neck cancer patients. Recently, tissue-specific stem cell therapy has attracted public attention as a next-generation therapeutic reagent. In the present study, we isolated tissue-specific stem cells from the human submandibular salivary gland (hSGSCs). To efficiently isolate and amplify hSGSCs in large amounts, we developed a culture system (lasting 4-5 weeks) without any selection. After five passages, we obtained adherent cells that expressed mesenchymal stem cell surface antigen markers, such as CD44, CD49f, CD90 and CD105, but not the hematopoietic stem cell markers, CD34 and CD45, and that were able to undergo adipogenic, osteogenic and chondrogenic differentiation. In addition, hSGSCs were differentiated into amylase-expressing cells by using a two-step differentiation method. Transplantation of hSGSCs to radiation-damaged rat salivary glands rescued hyposalivation and body weight loss, restored acinar and duct cell structure, and decreased the amount of apoptotic cells. These data suggest that the isolated hSGSCs, which may have characteristics of mesenchymal-like stem cells, could be used as a cell therapy agent for the damaged salivary gland.

Significance of Preoperative Tissue Levels of Vascular-endothelial Cadherin, Liver-intestine Cadherin and Vascular Endothelial Growth Factor in Gastric Cancer / 대한소화기학회지

BACKGROUND/AIMS: The aims of this study were to examine the expressions of endothelium specific VE-cadherin, intestine specific LI-cadherin, and vascular endothelial growth factor (VEGF), and to determine their relationships with the clinicopathological parameters of gastric cancer. METHODS: A total 47 patients with gastric cancer who underwent surgery were enrolled. Endoscopic biopsies were obtained from the cancer and normal mucosa, respectively. Using semiquantitative RT-PCR, the mRNA expression levels of VE-cadherin, LI-cadherin and VEGF were measured by tumor/normal (T/N) ratios. The protein expressions of VE-cadherin, LI-cadherin and VEGF were examined by Western blot and immunohistochemical stain in surgically resected tissues. The clinicopathological variables were reviewed and analyzed, retrospectively. RESULTS: Twenty two cases (46.8%) of VE-cadherin, 25 cases (53.2%) of LI-cadherin and 27 cases (51.1%) of VEGF mRNA expressions were overexpressed in gastric cancer compared to normal tissue. There was a tendency for T/N ratio of VE-cadherin mRNA to correlate with the lymphatic invasion (p=0.07) and the lymph node metastasis (p=0.099) in advanced gastric cancer. The T/N ratio of LI-cadherin mRNA showed significant association with distant metastasis (p=0.031) and lymphatic invasion especially in advanced gastric cancer (p=0.023). There was a tendency for the T/N ratio of VEGF mRNA to correlate with the distant metastasis (p=0.073) in advanced gastric cancer. CONCLUSIONS: As increased mRNA expression of LI-cadherin was associated with distant metastasis and lymphatic invasion especially in the biopsy specimen of advanced gastric cancer before surgery, it may provide useful preoperative information on tumor aggressiveness.

Isolation and Characterization of Chorionic Mesenchymal Stromal Cells from Human Full Term Placenta

This study focused on the characterization of mesenchymal stromal cells (MSCs) from the chorion of human full term placenta from 15 donors. Chorionic MSCs revealed homologous fibroblast-like morphology and expressed CD73, CD29, CD105, and CD90. The hematopoietic stem cell markers including HLA DR, CD11b, CD34, CD79a, and CD45 were not expressed. The growth kinetics of their serial passage was steady at the later passages (passage 10). The multilineage capability of chorionic MSCs was demonstrated by successful adipogenic, osteogenic and chondrogenic differentiation and associated gene expression. Chorionic MSCs expressed genes associated with undifferentiated cells (NANOG, OCT4, REX1) and cardiogenic or neurogenic markers such as SOX2, FGF4, NES, MAP2, and NF. TERT was negative in all the samples. These findings suggest that chorionic MSCs undifferentiated stem cells and less likely to be transformed into cancer cells. A low HLA DR expression suggests that chorionic MSCs may serve as a great source of stem cells for transplantation because of their immune-privileged status and their immunosuppressive effect. Based on these unique properties, it is concluded that chorionic MSCs are pluripotent stem cells that are probably less differentiated than BM-MSCs, and they have considerable potential for use in cell-based therapies.

Investigation of CTLA-4 and CD28 gene polymorphisms in patients with diabetes mellitus Type 2 using PCR-RFLP in a Turkish population / Investigación de polimorfismos en los genes CTLA-4 y CD28 en pacientes con diabetes mellitus tipo 2 usando PCR-RFLP en una población turca

OBJECTIVE: The aim of this study is to investigate whether specific polymorphisms in the CTLA-4 and CD28 gene are associated with Type 2 diabetes mellitus (T2DM). METHODS: Blood samples were collected from 241 individuals (72 patients with T2DM and 169 healthy individuals) and DNA was isolated. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to detect the frequencies of CTLA-4 NM_005214.3:c.49A > G and c.-319C > T, and CD28 NM_006139.1:c.534+17T> C polymorphisms in T2DM patients in the Sanliurfa Population. RESULTS: The data suggested that body mass index (BMI), total cholesterol (TC), triglyceride (TG), lowdensity lipoprotein cholesterol (LDL-c) and haemoglobin A1c (HbA1c) were significantly higher in T2DM patients than in the control individuals (p < 0.05). No significant differences were observed for the frequencies of c.49A > G, c.-319C > T genotype and allele of CTLA-4 gene and c.534+17T> C of the CD28 gene in T2DMpatients compared to healthy individuals (p > 0.05). CONCLUSION: The CTLA-4 gene c.49A >G and c.-319C >T and CD28 gene c.534+17T> C polymorphisms did not represent an important risk factor for this disease in a group of the Turkish population.

OBJETIVO: El objetivo de este estudio es investigar si los polimorfismos específicos en los genes CTLA- 4 y CD28 se hallan asociados con la diabetes mellitus tipo 2 (DMT2). MÉTODOS: Se recogieron muestras de sangre de 241 individuos (72 pacientes con DMT2 y 169 individuos sanos) y se aisló el ADN. Se usó un método de polimorfismo de la longitud de los fragmentos de restricción-reacción en cadena por la polimerasa (PCR-RFLP), con el fin de detectar las frecuencias de CTLA-4 NM_005214.3:c.49A > G y c. -319C > T, y los polimorfismos CD28 NM_006139.1:c.534 + 17T > C en pacientes con DMT2 en la población de Sanliurfa. RESULTADOS: Los datos sugirieron que el índice de masa corporal (IMC), el colesterol total (CT), el triglicérido (TG), el colesterol de lipoproteína de baja densidad (CLBD) y la hemoglobina A1c (HbA1c) eran significativamente más altas en los pacientes con DMT2 que en los individuos del grupo control (p < 0.05). No se observó diferencia significativa alguna en relación con las frecuencias de c.49A > G, c. -319C > el genotipo de T y el alelo del gene CTLA-4 y c.534+17T > C del gene de CD28 en pacientes con DMT2 comparados a los individuos sanos (p > 0.05). CONCLUSIÓN: Los polimorfismos del gene CTLA-4 c.49A > G y el gene de c. -319C > T, y los polimorfismos del gene CD28 c.534 + 17T > C no representaron un factor de riesgo importante para esta enfermedad en un grupo de la población turca.

Polimorfismos del gen del receptor de muerte celular programada 1 (PDCD1) y diabetes tipo 1 en población Chilena / Programmed cell death 1 (PDCD1) gene polymorphisms and type 1 diabetes in Chilean children

Background: Programmed cell death 1 (PDCD-1) immune-receptor is a key element in the negative regulation of peripheral tolerance in T cells. Several polymorphisms of this gene have been described and it is linked with susceptibility to autoimmune diseases like Lupus and Multiple Sclerosis. Aim: To analyze four gene polymorphisms of PDCD-1 gene and explore its possible contribution as a susceptibility gene for type 1 diabetes (T1D). Patients and Methods: We analyzed 160 cases with T1D of recent diagnosis aged 9.5 ± 3.3 years and 160 control children aged 10.7 ± 3.1 years. Four genetic variants of PDCD-1 gene were studied (PD1.2; PD1.5; PD1.6 and PD1.9) by polymerase chain reaction and restriction enzymes. Autoantibodies GAD65 and anti-IA-2 were also measured in all studied children. The comparison of allelic and genotypic frequency and consistency with respect to Hardy-Weinberg equilibrium test were analyzed using Chi-square and Fisher exact test. Results: No differences between cases and controls were observed for PDCD1.2; PDCD1.5 and PDCD1.9 polymorphisms. PDCD1.6 polymorphism (carriers of allele A) had a higher frequency in the control group (0.794 versus 0.644, p < 0.017). There was no particular association of these polymorphisms with anti- GAD65 and anti-IA-2 antibodies among patients with T1D. Conclusions: Only PDCD1.6 polymorphism showed differences between T1D cases and controls. Possibly, none of these genetic variants of PDCD1 has a relevant role as a marker for T1D in the Chilean population.

[Cytotoxic T lymphocyte associated molecule -4 [CTLA-4] gene polymorphisms in ovarian cancer patients]

Ovarian cancer is a relatively common cancer among postmenopausal women. Nowadays, there is controversy about immunotherapy of ovarian cancer patients with interleukins such as interferon to reach better out come in prognosis of patients under chemotherapy. CTLA-4 is a gene, which has an important role in homeostasis and regulation of immune response. Inhibitory nature of CTLA-4 is proved to be of significance in autoimmune diseases as well as in cancer. In this study we intend to find out the relationship between polymorphisms of this gene at the sites of +49 A/G and -318 C/T and ovarian cancer. The polymorphisms of the CTLA-4 gene at the sites of +49 A/G exon and -318 C/T promoter were investigated. Blood samples of 73 patients with ovarian cancer and 115 healthy subjects used for DNA extraction. Two groups genotypes and alleles were determined using PCR method and compared by statistical t-student test. There was no statistically significant difference in genotypes and alleles prevalence of +49 A/G and -317 C/T between two groups [p>0.05]. Further researches with larger sample size while paying attention to the relation between the gene polymorphism and stage and type of tumor is recommended

Type 1 diabetes susceptibility determined by HLA alleles and CTLA-4 and insulin genes polymorphisms in Brazilians / Suscetibilidade ao diabetes tipo 1 determinada por alelos de HLA e polimorfismos nos genes CTLA-4 e insulina em brasileiros

INTRODUCTION:Type 1A diabetes mellitus (T1ADM) is a multifactorial disease in which genetic and environmental aspects are important to its development. The association of genetic variations with disease has been demonstrated in several studies; however, the role of some gene loci has not yet been fully elucidated. OBJECTIVE:To compare the frequency of HLA alleles and polymorphism in CTLA-4 and insulin genes in Brazilians with T1ADM and individuals without the disease, as well as to identify genetic markers that are able to discriminate between diabetic and non-diabetic individuals. METHODS: The presence of HLA DQB1, DQA1 and DRB1 alleles, as well as the -2221 MspI polymorphism in the insulin gene and 49 A/G in the CTLA-4 gene were identified by the "Time-resolved fluorometer" technique after hybridization with probes labeled with Eu (III) / Sm (III) and Tb (III). RESULTS: The DQB1 *0302 and DQA1 *03 alleles were identified as predisposed to T1ADM, and the DQB1 *0301 allele presented a protective effect against the disease.The DQA1 label proved to be able to differentiate between 71.13 percent of the diabetic and non-diabetic individuals.This value increased to 82.47 percent when the DQB1 label was added. No significant difference in the frequency of polymorphisms in the insulin and CTLA-4 genes was observed between the two groups. CONCLUSIONS: The genetic markers that best characterized and discriminated diabetic and non-diabetic individuals were the HLA DQA1 and DQB1.alleles.

INTRODUÇÃO: O diabetes melito tipo 1 (T1ADM) é uma doença multifatorial em que os aspectos genéticos e ambientais são importantes para o seu desenvolvimento. A associação das variações genéticas com a doença tem sido demonstrada em vários trabalhos, no entanto, o papel de alguns locos gênicos não foi ainda completamente elucidado. OBJETIVOS: Comparar a frequência de alelos do HLA e polimorfismos nos genes CTLA-4 e insulina em brasileiros com T1ADM e indivíduos sem a doença, além de identificar marcadores gênicos que sejam capazes de discriminar indivíduos diabéticos e não diabéticos. MÉTODOS: A presença dos alelos de HLA DQB1, DQA1 e DRB1, bem como dos polimorfismos -2221 MspI no gene da insulina e 49 A/G no gene CTLA-4, foram identificados por meio da técnica Time-resolved fluorometer, após hibridização com sondas marcadas com Eu (III)/Sm (III) e Tb (III). RESULTADOS: Os alelos DQB1*0302 e DQA1*03 foram identificados como sendo de predisposição ao T1ADM, e o alelo DQB1*0301 mostrou um efeito protetor à doença. Analisando somente o marcador DQA1, este mostrou ser capaz de diferenciar 71,13 por cento dos indivíduos entre diabéticos e não diabéticos, cujo valor aumentou para 82,47 por cento quando adicionado o marcador DQB1. A frequência dos polimorfismos nos genes da insulina e CTLA-4 não mostrou diferença significativa entre os dois grupos estudados. CONCLUSÕES: Os marcadores genéticos que melhor caracterizaram e discriminaram diabéticos e não diabéticos foram os alelos de HLA DQA1 e DQB1.

Polimorfismo +49 A/G del gen del antígeno 4 del linfocito T citotóxico (CTLA-4) en la diabetes tipo 1: Asociación con el perfil de anticuerpos y citoquinas / +49 A/G genetic polymorphism of cytotoxic T lymphocyte associated antigen 4 (CTLA-4) in type 7 diabetes: Association with autoantibodies and cytokines

Background: Cytotoxic T lymphocyte associated antigen 4 (CTLA-4) has been one ofthe non HLA genes more commonly studied in type 1 diabetes mellitus (TID). CTLA-4 is a co-stimulation protein that has a key role in the negative regulation ofT cells and is related with a functional cytokine imbalance, generating a T helper (Th) 1 over Th2 dominance. Aim: To analyze the association of +49 A/G polymorphism of CTLA-4 and its relationship with autoantibodies and cytokine expression in recently diagnosed TID patients. Patients and Methods: CTLA-4 genetic variants and auto-antibody levéis were studied in 260 chiídren with TID and 255 healthy chiídren matched by age and gender +49 A/G polymorphism of CTLA-4 was studied by polymerase chain reaction and restriction fragmentpolymorphism (PCR-RFLP). Autoantibody levéis were measured by conventional ELISA. A panel of60 cytokines was studied simultaneously by serum array analysis in 15 TID and 15 healthy controls stratified according CTLA-4 genotype. Results: The +49 A/G genetic frequency was similar in TID cases and healthy chiídren. A positive anti-GAD65 and anti-IA-2 level was observed in 673 percent of TID group. This percentage was increased among GG carriers (79.4 percent to GAD65 and 70.6 percent to IA-2). Finally, TID patients carrying this genotype showed a high expression of interleukin 2, 10, tumor necrosis factor alpha and interferon gamma. Conclusions: The +49 A/G polymorphism of CTLA-4 was similar in diabetic and control chiídren. Among patients with TID and carriers of GG genotype, a higher frequency of anti-GAD65 and a preferential Thl cytokine expression profile was observed.

Placental histomorphology in unexplained foetal loss with thrombophilia.

BACKGROUND & OBJECTIVES: Acquired and genetic thrombotic conditions, both organ and non organ specific, are associated with increased foetal wastage. This study was carried out to examine the placenta from women with abnormal pregnancies and a history of unexplained foetal loss, and to associate with maternal thrombophilia status. METHODS: Placentas from eight women with history of unexplained foetal loss were analyzed for histopathological characteristics. All the women were simultaneously screened for the common acquired and genetic thrombophilia markers i.e., lupus anticoagulants ( LA), IgG / IgM antibodies for anticardiolipin (ACA), beta2 glycoprotein 1 (beta2GPI) and annexin V, protein C (PC), protein S (PS), antithrombin III (AT III), factor V Leiden ( FVL) mutation, prothrombin (PT) gene G20210A, methylene tetrahydrofolate reductase (MTHFR) C 677T, endothelial protein C receptor (EPCR) 23 bp insertion and plasminogen activator inhibitor ( PAI-1 4G/5G) polymorphisms RESULTS: Six of eight women were positive for one or more thrombophilia markers. The placenta in all the cases except one, showed the characteristic features of infarct fibrin deposition and calcification. Among two women who were negative for thrombophilia, one showed clear evidence of thrombus in the placental sections while the other did not show any characteristic infarcts in the placental sections. INTERPRETATION & CONCLUSION: Our findings showed that the histopathological examination of the placentas confirmed thrombophilia as the aetiological cause of thrombosis in 6 of the 8 women. The presence of thrombus in a negative thrombophilia woman suggests yet unidentified thrombophilia markers or probably non-haemostatic factors causing thrombosis.

Costimulatory molecule B7-H1 on the immune escape of bladder cancer and its clinical significance / 华中科技大学学报（医学）（英德文版）

B7-H1, a recently described member of the B7 family of costimulatory molecules, is thought to be involved in tumor immune escape by inducing T-cell apoptosis. In order to investigate the relationship between B7-H1 and immune escape of bladder cancer, B7-H1 expression in 50 cases of bladder cancer was detected by using immunohistochemical method. Survival curves were constructed using the Kaplan-Meier method and independent prognostic factors were evaluated using the Cox regression model. Our results showed that the positive rate of B7-H1 immunostaining in normal bladder tissue and bladder cancer was 0 and 72% respectively. The expression of B7-H1 was strongly associated with the pathological grade, clinical stage and recurrence (P<0.05). The survival rate was significantly lower in patients with B7-H1 positive group than in those with B7-H1 negative group and multi-variable analysis revealed that B7-H1 could be regarded as an independent factor in evaluating the prognosis of bladder cancer. It is concluded that the expression of B7-H1 is strongly associated with neoplastic progression and prognosis of bladder cancer. The manipulation of B7-H1 may become a beneficial target for immunotherapy in human bladder cancer.

Clinical Features and Mutations in the ENG, ACVRL1, and SMAD4 genes in Korean Patients with Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder that is characterized by abnormal communication between the arteries and veins in the skin, mucosa, and various organs. HHT has been reported to show significant phenotypic variability and genetic heterogeneity with wide ethnic and geographic variations. Although mutations in the endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes have been known to cause HHT for more than 10 yr, little is known about the clinical features or genetic background of Korean patients with HHT. In addition, mutations in mothers against decapentaplegic homolog 4 (SMAD4) are also seen in patients with the combined syndrome of juvenile polyposis and HHT. This study examined five Korean patients with the typical manifestations of HHT such as frequent epistaxis and pulmonary arteriovenous malformations. Direct sequencing of the ENG and ACVRL1 genes revealed one known mutation, ENG c.277C>T, in one patient and two novel mutations, ENG c.992-1G>C and ACVRL1 c.81dupT in two patients, respectively. The remaining two patients with negative results were screened for SMAD4 mutations as well as gross deletions of ENG and ACVRL1 using multiple ligation-dependent probe amplification, but none was detected. Despite the small number of patients investigated, we firstly report Korean patients with genetically confirmed HHT, and show the genetic and allelic heterogeneity underlying HHT.

Association of Cytotoxic T Lymphocyte Antigen-4 Gene Polymorphisms and HLA Class II Alleles with the Development of Type 1 Diabetes in Korean Children and Adolescents

We studied the association of cytotoxic T lymphocyte antigen-4 gene (CTLA4) polymorphisms with the development of type 1 diabetes (T1D) in Korean children and adolescents. A total of 176 Korean subjects (92 females and 84 males) with childhood-onset T1D were studied. The A/G polymorphism at position 49 in CTLA4 exon 1 and the C/T polymorphism at position -318 in the CTLA4 promoter were analyzed by PCR-RFLP methods. The genotype and allele frequencies of the CTLA4 polymorphisms in the T1D patients were not different from those in the controls. These polymorphisms were not associated with the clinical characteristics or the development of autoimmune thyroid disease in the T1D patients. The frequency of the A allele was significantly higher in the patients that did not have two out of the three susceptible HLA-DRB1 alleles, which were DRB1*0301, *0405 and *09012, compared to the controls (P<0.05). These results suggest that CTLA4 polymorphisms do not directly confer any susceptibility to T1D. However, a CTLA4-mediated susceptibility effect on the development of T1D might be significant in children and adolescents that do not have susceptible HLA class II alleles.

Biomarkers of susceptibility to type 1 diabetes with special reference to the Indian population.

Type 1 diabetes (T1D) is a polygenic autoimmune disease. Susceptibility to T1D is strongly linked to a major genetic locus that is the major histocompatibility complex (MHC) and several other minor loci including insulin, CTLA4 that contribute to diabetes risk in an epistatic way. MHC harbours genes whose primary function is to govern immune responsiveness. Being the most polymorphic genomic region known in humans, MHC serves as a very exciting minigenome model for studying susceptibility to T1D. We have observed enormous diversity in HLA class I and class II genes in the north Indian population and identified several 'novel alleles' and 'unique haplotypes'. For example, multiple DR3+ve autoimmunity favouring haplotypes have been identified, some of which are unique to the Asian north Indian T1D patients. Our molecular studies have revealed that (i) the classical Caucasian autoimmunity favouring AH8.1 (HLA-A1 B8 DR3) is rare in the Indian population and has been replaced by a variant AH8.1v that differs from the Caucasian AH8.1 at several gene loci, (ii) AH8.2 (HLA-A26 B8 DR3) is the most common DR3 positive haplotype in this population and resembles the Indian AH8.1v rather than Caucasian AH8.1, and (iii) there are additional HLA-DR3 haplotypes HLA-A24 B8 DR3 (AH8.3), A3 B8 DR3 (AH8.4) and A31 B8 DR 3 (AH 8.5) that occur in the Indian population. The studies have led to a hypothesis that AH8.1 and AH8.1v might have co-evolved from a common ancestor but preferential divergence of AH8.2 over AH8.1 leading to survival advantage might have been driven by vigorous pathogenic challenges encountered by the Indian population. These studies have important implications in our understanding of disease pathogenesis, identification of high risk individuals, disease diagnosis, disease management and immunological therapeutic approaches.

Polymorphism of the promoter region and exon 1 of the CTLA4 gene in endemic pemphigus foliaceus (fogo selvagem)

Endemic pemphigus foliaceus (EPF) is an autoimmune bullous skin disease characterized by acantholysis and antibodies against a desmosomal protein, desmoglein 1. Genetic and environmental factors contribute to development of this multifactorial disease. HLA class II and some cytokine gene polymorphisms are the only genetic markers thus far known to be associated with susceptibility to or protection from EPF. The cytotoxic T-lymphocyte antigen-4 gene (CTLA4) encodes a key immunoreceptor molecule that regulates and inhibits T-cell proliferation. It participates in the regulatory process controlling autoreactivity and therefore has been considered a strong candidate gene in autoimmune diseases. In the search for genes that might influence EPF pathogenesis, we analyzed variants of the CTLA4 gene in a sample of 118 patients and 291 controls from a Brazilian population. This is the first study investigating the possible role of polymorphisms of the 2q33 chromosomal region in differential susceptibility to pemphigus foliaceus. Promoter region and exon 1 single nucleotide polymorphisms -318 (C,T) and 49 (A,G) were genotyped using sequence-specific oligonucleotide probes after amplification by the polymerase chain reaction. The allelic and genotypic frequencies did not differ significantly between the patient and the control groups (-318T: 9.8 and 10.9 percent, 49G: 33.0 and 35.2 percent were the allelic frequencies in patients and controls, respectively). In addition, no significant difference was found when the patient and control population samples were stratified by the presence of HLA-DRB1 alleles. We conclude that the CTLA4 -318 (C,T) and 49 (A,G) polymorphisms do not play a major role in EPF development.