RESUMO
Reports of terminal and interstitial deletions of the long arm of chromosome 2 are rare in the literature. Here, we present a case report concerning a Chinese boy with a 47,XYY karyotype and a de novo deletion comprising approximately 5 Mb between 2q35 and q36.1, along with syndactyly, type III Waardenburg syndrome, and congenital heart disease. High-resolution chromosome analysis to detect copy number variations was carried out using an Affymetrix microarray platform, and the genes affected by the patient's deletion, including IHH, were determined. However, no copy number changes were observed in his healthy parents. The present case exhibited novel syndactyly features, broadening the spectrum of clinical findings observed in individuals with 2q interstitial deletions. Our data, together with previous observations, suggest that IHH haploinsufficiency is the principal pathogenic factor in the syndactyly phenotype in this study, and that different types of variations at the IHH locus may cause divergent disease phenotypes. This is the first report of the involvement of IHH haploinsufficiency in syndactyly phenotype.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 2/genética , Dedos/anormalidades , Cardiopatias Congênitas/genética , Sindactilia/genética , Síndrome de Waardenburg/genética , Povo Asiático/genética , Criança , Proteínas Hedgehog/genética , Humanos , Cariótipo , MasculinoRESUMO
We aimed to investigate the effects of an anti-tumor necrosis factor-α antibody (ATNF) on cartilage and subchondral bone in a rat model of osteoarthritis. Twenty-four rats were randomly divided into three groups: sham-operated group (n=8); anterior cruciate ligament transection (ACLT)+normal saline (NS) group (n=8); and ACLT+ATNF group (n=8). The rats in the ACLT+ATNF group received subcutaneous injections of ATNF (20 µg/kg) for 12 weeks, while those in the ACLT+NS group received NS at the same dose for 12 weeks. All rats were euthanized at 12 weeks after surgery and specimens from the affected knees were harvested. Hematoxylin and eosin staining, Masson's trichrome staining, and Mankin score assessment were carried out to evaluate the cartilage status and cartilage matrix degradation. Matrix metalloproteinase (MMP)-13 immunohistochemistry was performed to assess the cartilage molecular metabolism. Bone histomorphometry was used to observe the subchondral trabecular microstructure. Compared with the rats in the ACLT+NS group, histological and Mankin score analyses showed that ATNF treatment reduced the severity of the cartilage lesions and led to a lower Mankin score. Immunohistochemical and histomorphometric analyses revealed that ATNF treatment reduced the ACLT-induced destruction of the subchondral trabecular microstructure, and decreased MMP-13 expression. ATNF treatment may delay degradation of the extracellular matrix via a decrease in MMP-13 expression. ATNF treatment probably protects articular cartilage by improving the structure of the subchondral bone and reducing the degradation of the cartilage matrix.
Assuntos
Adalimumab/farmacologia , Antirreumáticos/farmacologia , Osso e Ossos/efeitos dos fármacos , Cartilagem Articular/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Ligamento Cruzado Anterior/cirurgia , Artrite Experimental/tratamento farmacológico , Artroplastia Subcondral , Osso e Ossos/metabolismo , Cartilagem Articular/metabolismo , Matriz Extracelular/efeitos dos fármacos , Feminino , Membro Posterior/patologia , Membro Posterior/cirurgia , Imuno-Histoquímica , Escala de Gravidade do Ferimento , Metaloproteinase 13 da Matriz/efeitos dos fármacos , Metaloproteinase 13 da Matriz/metabolismo , Osteoartrite/cirurgia , Fatores de Proteção , Distribuição Aleatória , Ratos Sprague-DawleyRESUMO
The aim of this study was to explore the correlation between the expression levels of Gli1 and p53 in pancreatic ductal adenocarcinoma (PDAC) and its pathological significance. Immunohistochemistry (IHC) was employed to measure the expression level of Gli1 and p53 in 85 sets of paraffin-embedded PDAC and corresponding para-carcinoma tissue specimens. The relationship between these results and the respective patients' clinicopathologic parameters was analyzed. IHC staining revealed that the expression levels of Gli1 and p53 in cancer tissues were evidently higher than that of para-carcinoma tissues (P < 0.05); while Gli1 expression levels correlated with the corresponding TNM stage and tumor infiltration depth, p53 expression level correlated with the respective TNM stage (P < 0.05). Taken together, this study demonstrates increased expression of Gli1 and p53 in PDAC, and proves that Gli1 could be apotential biomarker for prognostic judgment.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fatores de Transcrição/genética , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/genética , Feminino , Humanos , Imuno-Histoquímica , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Pâncreas/metabolismo , Pâncreas/patologia , Neoplasias Pancreáticas/genética , Prognóstico , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína GLI1 em Dedos de Zinco , Neoplasias PancreáticasRESUMO
We aimed to investigate the effects of an anti-tumor necrosis factor-α antibody (ATNF) on cartilage and subchondral bone in a rat model of osteoarthritis. Twenty-four rats were randomly divided into three groups: sham-operated group (n=8); anterior cruciate ligament transection (ACLT)+normal saline (NS) group (n=8); and ACLT+ATNF group (n=8). The rats in the ACLT+ATNF group received subcutaneous injections of ATNF (20 μg/kg) for 12 weeks, while those in the ACLT+NS group received NS at the same dose for 12 weeks. All rats were euthanized at 12 weeks after surgery and specimens from the affected knees were harvested. Hematoxylin and eosin staining, Masson's trichrome staining, and Mankin score assessment were carried out to evaluate the cartilage status and cartilage matrix degradation. Matrix metalloproteinase (MMP)-13 immunohistochemistry was performed to assess the cartilage molecular metabolism. Bone histomorphometry was used to observe the subchondral trabecular microstructure. Compared with the rats in the ACLT+NS group, histological and Mankin score analyses showed that ATNF treatment reduced the severity of the cartilage lesions and led to a lower Mankin score. Immunohistochemical and histomorphometric analyses revealed that ATNF treatment reduced the ACLT-induced destruction of the subchondral trabecular microstructure, and decreased MMP-13 expression. ATNF treatment may delay degradation of the extracellular matrix via a decrease in MMP-13 expression. ATNF treatment probably protects articular cartilage by improving the structure of the subchondral bone and reducing the degradation of the cartilage matrix.
Assuntos
Animais , Feminino , Adalimumab/farmacologia , Antirreumáticos/farmacologia , Osso e Ossos/efeitos dos fármacos , Cartilagem Articular/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Artroplastia Subcondral , Ligamento Cruzado Anterior/cirurgia , Artrite Experimental/tratamento farmacológico , Osso e Ossos/metabolismo , Cartilagem Articular/metabolismo , Matriz Extracelular/efeitos dos fármacos , Membro Posterior/patologia , Membro Posterior/cirurgia , Imuno-Histoquímica , Escala de Gravidade do Ferimento , /efeitos dos fármacos , /metabolismo , Osteoartrite/cirurgia , Fatores de Proteção , Distribuição Aleatória , Ratos Sprague-DawleyRESUMO
Tuberous sclerosis complex (TSC) is an autosomal dominant neurogenetic disorder characterized by hamartomas in multiple organs and is caused by a wide spectrum of mutations in 1 of 2 causative genes (TSC1 or TSC2). Here, we present mutational analyses of the TSC1 and TSC2 genes in 4 cases of TSC in Chinese Han children, including 2 familial and 2 sporadic cases, using PCR and DNA sequencing of the entire coding region as well as exon-intron boundaries of these genes. Three mutations were identified in the TSC2 gene. Of these mutations, 2 mutations (c.3312-3313delGA and c.45delT) were novel, and the 3rd mutation (c.5238-5255del) was previously reported in Chinese Han and other populations. These mutations were not present in healthy family members or in 100 unrelated normal controls. The identification of these mutations in this study further expands the spectrum of known TSC2 gene mutations and contributes to prenatal molecular diagnosis and preimplantation genetic testing of TSC.
Assuntos
Povo Asiático/genética , Mutação , Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Angiofibroma/patologia , Sequência de Bases , Encéfalo/patologia , Pré-Escolar , China , Éxons , Feminino , Humanos , Lactente , Masculino , Linhagem , Análise de Sequência de DNA , Tomografia Computadorizada por Raios X , Esclerose Tuberosa/diagnóstico , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose TuberosaRESUMO
Both rheumatoid arthritis (RA) and osteoarthritis (OA) are complex diseases. Studies and treatment of RA and OA have mainly focused on individual factors. However, there is still no clear understanding of their causes and adequate treatment alternatives are still being sought. We applied gene set-enrichment analysis to microarray datasets of RA and OA to look for regulatory mechanisms. We found 32 highly significant pathways, including 18 downregulated and 14 upregulated pathways associated with RA. We also identified 18 highly significant pathways, including 7 downregulated and 11 up-regulated pathways associated with OA. Several such pathways were found in both RA and OA, including an upregulated PPAR signaling pathway and downregulated leukocyte transendothelial migration. Regulatory mechanisms in RA seem to be more complex than in OA. This information could be useful for diagnosis and treatment of these two diseases.
Assuntos
Artrite Reumatoide/genética , Regulação da Expressão Gênica/genética , Osteoartrite/genética , Receptores Ativados por Proliferador de Peroxissomo/genética , Artrite Reumatoide/patologia , Regulação para Baixo , Fibroblastos/citologia , Fibroblastos/metabolismo , Genoma Humano , Humanos , Redes e Vias Metabólicas/genética , Análise de Sequência com Séries de Oligonucleotídeos , Osteoartrite/patologia , Transdução de Sinais/genética , Regulação para CimaRESUMO
The aim of the present study was to determine the effect of the combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and adriamycin (ADM) on the human breast cancer cell line MCF-7 and to identify potential mechanisms of apoptosis. Cell viability was analyzed by the MTT assay and the synergistic effect was assessed by the Webb coefficient. Apoptosis was quantified using the annexin V-FITC and propidium iodide staining flow cytometry. The mRNA expression of TRAIL receptors was measured by RT-PCR. Changes in the quantities of Bax and caspase-9 proteins were determined by Western blot. MCF-7 cells were relatively resistant to TRAIL (IC50 >10 microg/mL), while MCF-7 cells were sensitive to ADM (IC50 <10 microg/mL). A subtoxic concentration of ADM (0.5 microg/mL) combined with 0.1, 1, or 10 microg/mL TRAIL had a synergistic cytotoxic effect on MCF-7 cells, which was more marked with the combination of TRAIL (0.1 microg/mL) and ADM (0.5 microg/mL). In addition, the combined treatment with TRAIL and ADM significantly increased cell apoptosis from 9.8% (TRAIL) or 17% (ADM) to 38.7%, resulting in a synergistic apoptotic effect, which is proposed to be mediated by up-regulation of DR4 and DR5 mRNA expression and increased expression of Bax and caspase-9 proteins. These results suggest that the combination of TRAIL and ADM might be a promising therapy for breast cancer.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Doxorrubicina/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Western Blotting , Caspase 9/análise , Linhagem Celular Tumoral , Sinergismo Farmacológico , Citometria de Fluxo , Humanos , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína X Associada a bcl-2/análiseRESUMO
The aim of the present study was to determine the effect of the combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and adriamycin (ADM) on the human breast cancer cell line MCF-7 and to identify potential mechanisms of apoptosis. Cell viability was analyzed by the MTT assay and the synergistic effect was assessed by the Webb coefficient. Apoptosis was quantified using the annexin V-FITC and propidium iodide staining flow cytometry. The mRNA expression of TRAIL receptors was measured by RT-PCR. Changes in the quantities of Bax and caspase-9 proteins were determined by Western blot. MCF-7 cells were relatively resistant to TRAIL (IC50 >10 µg/mL), while MCF-7 cells were sensitive to ADM (IC50 <10 µg/mL). A subtoxic concentration of ADM (0.5 µg/mL) combined with 0.1, 1, or 10 µg/mL TRAIL had a synergistic cytotoxic effect on MCF-7 cells, which was more marked with the combination of TRAIL (0.1 µg/mL) and ADM (0.5 µg/mL). In addition, the combined treatment with TRAIL and ADM significantly increased cell apoptosis from 9.8 percent (TRAIL) or 17 percent (ADM) to 38.7 percent, resulting in a synergistic apoptotic effect, which is proposed to be mediated by up-regulation of DR4 and DR5 mRNA expression and increased expression of Bax and caspase-9 proteins. These results suggest that the combination of TRAIL and ADM might be a promising therapy for breast cancer.
Assuntos
Humanos , Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Doxorrubicina/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Western Blotting , Linhagem Celular Tumoral , Caspase 9/análise , Sinergismo Farmacológico , Citometria de Fluxo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , RNA Mensageiro/análise , /análiseRESUMO
The objective of the present study was to investigate the effects of recombinant human growth hormone (rhGH) on the intestinal mucosa barrier of septic rats and explore its possible mechanism. Female Sprague-Dawley rats were randomized into three groups: control, Escherichia coli-induced sepsis (S) and treatment (T) groups. Groups S and T were subdivided into subgroups 1d and 3d, respectively. Expression of liver insulin-like growth factor-1 (IGF-1) mRNA, Bcl-2 and Bax protein levels and the intestinal Bax/Bcl-2 ratio, and plasma GH and IGF-1 levels were determined. Histological examination of the intestine was performed and bacterial translocation was determined. rhGH significantly attenuated intestinal mucosal injuries and bacterial translocation in septic rats, markedly decreased Bax protein levels, inhibited the decrease of Bcl-2 protein expression and maintained the Bax/Bcl-2 ratio in the intestine. rhGH given after sepsis significantly improved levels of plasma GH (T1d: 1.28 +/- 0.24; T3d: 2.14 +/- 0.48 microg/L vs S1d: 0.74 +/- 0.12; S3d: 0.60 +/- 0.18 microg/L; P < 0.05) and IGF-1 (T1d: 168.94 +/- 65.67; T3d: 201.56 +/- 64.98 microg/L vs S1d: 116.72 +/- 13.96; S3d: 107.50 +/- 23.53 microg/L; P < 0.05) and expression of liver IGF-1 mRNA (T1d: 0.98 +/- 0.20; T3d: 1.76 +/- 0.17 vs S1d: 0.38 +/- 0.09; S3d: 0.46 +/- 0.10; P < 0.05). These findings indicate that treatment with rhGH had beneficial effects on the maintenance of the integrity of the intestinal mucosa barrier in septic rats.
Assuntos
Translocação Bacteriana , Infecções por Escherichia coli/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Mucosa Intestinal/efeitos dos fármacos , Choque Séptico/tratamento farmacológico , Abdome , Animais , Translocação Bacteriana/efeitos dos fármacos , Biomarcadores/análise , Infecções por Escherichia coli/fisiopatologia , Feminino , Humanos , Fator de Crescimento Insulin-Like I/análise , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/uso terapêutico , Choque Séptico/fisiopatologia , Proteína X Associada a bcl-2/análiseRESUMO
The objective of the present study was to investigate the effects of recombinant human growth hormone (rhGH) on the intestinal mucosa barrier of septic rats and explore its possible mechanism. Female Sprague-Dawley rats were randomized into three groups: control, Escherichia coli-induced sepsis (S) and treatment (T) groups. Groups S and T were subdivided into subgroups 1d and 3d, respectively. Expression of liver insulin-like growth factor-1 (IGF-1) mRNA, Bcl-2 and Bax protein levels and the intestinal Bax/Bcl-2 ratio, and plasma GH and IGF-1 levels were determined. Histological examination of the intestine was performed and bacterial translocation was determined. rhGH significantly attenuated intestinal mucosal injuries and bacterial translocation in septic rats, markedly decreased Bax protein levels, inhibited the decrease of Bcl-2 protein expression and maintained the Bax/Bcl-2 ratio in the intestine. rhGH given after sepsis significantly improved levels of plasma GH (T1d: 1.28 ± 0.24; T3d: 2.14 ± 0.48 æg/L vs S1d: 0.74 ± 0.12; S3d: 0.60 ± 0.18 æg/L; P < 0.05) and IGF-1 (T1d: 168.94 ± 65.67; T3d: 201.56 ± 64.98 æg/L vs S1d: 116.72 ± 13.96; S3d: 107.50 ± 23.53 æg/L; P < 0.05) and expression of liver IGF-1 mRNA (T1d: 0.98 ± 0.20; T3d: 1.76 ± 0.17 vs S1d: 0.38 ± 0.09; S3d: 0.46 ± 0.10; P < 0.05). These findings indicate that treatment with rhGH had beneficial effects on the maintenance of the integrity of the intestinal mucosa barrier in septic rats.