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1.
Nat Immunol ; 15(6): 562-70, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24777531

RESUMO

Deubiquitinases (DUBs) are a new class of drug targets, although the physiological function of only few DUBs has been characterized. Here we identified the DUB USP15 as a crucial negative regulator of T cell activation. USP15 stabilized the E3 ubiquitin ligase MDM2, which in turn negatively regulated T cell activation by targeting the degradation of the transcription factor NFATc2. USP15 deficiency promoted T cell activation in vitro and enhanced T cell responses to bacterial infection and tumor challenge in vivo. USP15 also stabilized MDM2 in cancer cells and regulated p53 function and cancer-cell survival. Our results suggest that inhibition of USP15 may both induce tumor cell apoptosis and boost antitumor T cell responses.


Assuntos
Fatores de Transcrição NFATC/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/imunologia , Células Th1/imunologia , Proteases Específicas de Ubiquitina/imunologia , Transferência Adotiva , Animais , Apoptose/imunologia , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Sobrevivência Celular , Células HCT116 , Humanos , Leupeptinas/farmacologia , Listeria monocytogenes/imunologia , Listeriose/imunologia , Ativação Linfocitária/imunologia , Melanoma Experimental/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Proto-Oncogênicas c-mdm2/genética , Evasão Tumoral , Proteína Supressora de Tumor p53/imunologia , Proteases Específicas de Ubiquitina/genética , Ubiquitinação/genética , Ubiquitinação/imunologia
2.
Proc Natl Acad Sci U S A ; 115(9): 2198-2203, 2018 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-29440484

RESUMO

TP53 mutations occur in ∼50% of all human tumors, with increased frequency in aggressive cancers that are notoriously difficult to treat. Additionally, p53 missense mutations are remarkably predictive of refractoriness to chemo/radiotherapy in various malignancies. These observations have led to the development of mutant p53-targeting agents that restore p53 function. An important unknown is which p53-mutant tumors will respond to p53 reactivation-based therapies. Here, we found a heterogeneous impact on therapeutic response to p53 restoration, suggesting that it will unlikely be effective as a monotherapy. Through gene expression profiling of p53R172H -mutant lymphomas, we identified retinoic acid receptor gamma (RARγ) as an actionable target and demonstrated that pharmacological activation of RARγ with a synthetic retinoid sensitizes resistant p53-mutant lymphomas to p53 restoration, while additively improving outcome and survival in inherently sensitive tumors.


Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Experimentais/tratamento farmacológico , Retinoides/farmacologia , Tamoxifeno/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/farmacocinética , Antineoplásicos Hormonais/farmacologia , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Camundongos , Camundongos Endogâmicos , Mutação de Sentido Incorreto , Retinoides/administração & dosagem , Retinoides/farmacocinética , Tamoxifeno/administração & dosagem , Tamoxifeno/farmacocinética , Transcriptoma , Fator de Necrose Tumoral alfa/metabolismo , Proteína Supressora de Tumor p53/genética
3.
Qual Life Res ; 27(7): 1921-1931, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29730851

RESUMO

PURPOSE: The Child Health Utility 9D (CHU9D), a new generic preference-based health-related quality of life (HRQoL) instrument, was developed specifically for the application in cost-effectiveness analyses of treatments and interventions for children and adolescents. The main objective of this study was to examine the psychometric property of the Chinese version of CHU9D (CHU9D-CHN) in a large school-based sample in China. METHODS: Data were collected using a multi-stage sampling method from third-to-ninth-grade students in Shaanxi Province, China. Participants self-completed a hard-copy questionnaire including the CHU9D-CHN instrument, the Pediatric Quality of Life Inventory™ 4.0 Generic Core Scales (PedsQL), information on socio-demographic characteristics and self-reported health status. The psychometric properties of the CHU9D-CHN, including the internal consistency, 2-week test-retest reliability, convergent and known-groups validity were studied. RESULTS: A total of 1912 students participated in the survey. The CHU9D-CHN internal consistency and test-retest reliability were good to excellent with a Cronbach's alpha of 0.77 and an intra-class correlation coefficient of 0.65, respectively. The CHU9D utility scores moderately correlated with the PedsQL total scores (r = .57, P < .001), demonstrating good convergent validity. Difference of the CHU9D utility scores among the different participants with levels of self-reported general health, health services utilisation and left-behind status demonstrated good construct validity. CONCLUSION: The findings demonstrated adequate psychometric performance for the CHU9D-CHN. The CHU9D-CHN was a satisfactory, reliable and valid instrument to measure and value HRQoL for children and adolescents in China.


Assuntos
Saúde da Criança/normas , Nível de Saúde , Psicometria/métodos , Qualidade de Vida/psicologia , Adolescente , Povo Asiático , Criança , China , Feminino , Humanos , Masculino , Instituições Acadêmicas , Inquéritos e Questionários
4.
Proc Natl Acad Sci U S A ; 111(30): 11145-50, 2014 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-25024203

RESUMO

p53(R172H/+) mice inherit a p53 mutation found in Li-Fraumeni syndrome and develop metastatic tumors at much higher frequency than p53(+/-) mice. To explore the mutant p53 metastatic phenotype, we used expression arrays to compare primary osteosarcomas from p53(R172H/+) mice with metastasis to osteosarcomas from p53(+/-) mice lacking metastasis. For this study, 213 genes were differentially expressed with a P value <0.05. Of particular interest, Pla2g16, which encodes a phospholipase that catalyzes phosphatidic acid into lysophosphatidic acid and free fatty acid (both implicated in metastasis), was increased in p53(R172H/+) osteosarcomas. Functional analyses showed that Pla2g16 knockdown decreased migration and invasion in mutant p53-expressing cells, and vice versa: overexpression of Pla2g16 increased the invasion of p53-null cells. Furthermore, Pla2g16 levels were increased upon expression of mutant p53 in both mouse and human osteosarcoma cell lines, indicating that Pla2g16 is a downstream target of the mutant p53 protein. ChIP analysis revealed that several mutant p53 proteins bind the Pla2g16 promoter at E26 transformation-specific (ETS) binding motifs and knockdown of ETS2 suppressed mutant p53 induction of Pla2g16. Thus, our study identifies a phospholipase as a transcriptional target of mutant p53 that is required for metastasis.


Assuntos
Neoplasias Ósseas/metabolismo , Síndrome de Li-Fraumeni/metabolismo , Mutação , Osteossarcoma/metabolismo , Fosfolipases A2 Independentes de Cálcio/biossíntese , Proteínas Supressoras de Tumor/biossíntese , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Humanos , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/patologia , Camundongos , Camundongos Mutantes , Invasividade Neoplásica , Osteossarcoma/genética , Osteossarcoma/patologia , Fosfolipases A2 Independentes de Cálcio/genética , Elementos de Resposta , Proteínas Supressoras de Tumor/genética
5.
J Hepatol ; 62(2): 371-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25281858

RESUMO

BACKGROUND & AIMS: Aberrantly high expression of TRIM24 occurs in human cancers, including hepatocellular carcinoma. In contrast, TRIM24 in the mouse is reportedly a liver-specific tumour suppressor. To address this dichotomy and to uncover direct regulatory functions of TRIM24 in vivo, we developed a new mouse model that lacks expression of all Trim24 isoforms, as the previous model expressed normal levels of Trim24 lacking only exon 4. METHODS: To produce germline-deleted Trim24(dlE1) mice, deletion of the promoter and exon 1 of Trim24 was induced in Trim24(LoxP) mice by crossing with a zona pellucida 3-Cre line for global deletion. Liver-specific deletion (Trim24(hep)) was achieved by crossing with an albumin-Cre line. Phenotypic analyses were complemented by protein, gene-specific and global RNA expression analyses and quantitative chromatin immunoprecipitation. RESULTS: Global loss of Trim24 disrupted hepatic homeostasis in 100% of mice with highly significant, decreased expression of oxidation/reduction, steroid, fatty acid, and lipid metabolism genes, as well as increased expression of genes involved in unfolded protein response, endoplasmic reticulum stress and cell cycle pathways. Trim24(dlE1/dlE1) mice have markedly depleted visceral fat and, like Trim24(hep/hep) mice, spontaneously develop hepatic lipid-filled lesions, steatosis, hepatic injury, fibrosis and hepatocellular carcinoma. CONCLUSIONS: TRIM24, an epigenetic co-regulator of transcription, directly and indirectly represses hepatic lipid accumulation, inflammation, fibrosis and damage in the murine liver. Complete loss of Trim24 offers a model of human non-alcoholic fatty liver disease, steatosis, fibrosis and development of hepatocellular carcinoma in the absence of high-fat diet or obesity.


Assuntos
Carcinoma Hepatocelular/genética , Fígado Gorduroso/genética , Regulação Neoplásica da Expressão Gênica , Lipídeos/análise , Neoplasias Hepáticas Experimentais/genética , Proteínas Nucleares/genética , RNA Neoplásico/genética , Fatores de Transcrição/genética , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Progressão da Doença , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Humanos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Camundongos Knockout , Proteínas Nucleares/biossíntese , Reação em Cadeia da Polimerase , Fatores de Transcrição/biossíntese
6.
J Pathol ; 234(1): 108-19, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24890125

RESUMO

Deregulation of cell polarity proteins has been linked to the processes of invasion and metastasis. TRIM62 is a regulator of cell polarity and a tumour suppressor in breast cancer. Here, we demonstrate that human non-small cell lung cancer lesions show a step-wise loss of TRIM62 levels during disease progression, which was associated with poor clinical outcomes. To directly examine the role of Trim62 in development of lung cancer, we deleted Trim62 in a mutant K-Ras mouse model of lung cancer. In this context, haploinsufficiency of Trim62 synergized with a K-RasG12D mutation to promote invasiveness and disrupt three-dimensional morphogenesis, both of which are associated with epithelial-mesenchymal transitions. Re-expression of Trim62 reverted these phenotypes in tumour cell lines. Thus, Trim62 loss cooperates with K-Ras mutation in tumourigenesis and metastasis in vivo, indicating that decreased levels of TRIM62 may play an important role in the evolution of lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Regulação Neoplásica da Expressão Gênica , Genes ras/genética , Neoplasias Pulmonares/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética , Animais , Carcinoma Pulmonar de Células não Pequenas/patologia , Transformação Celular Neoplásica , Transição Epitelial-Mesenquimal , Feminino , Humanos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mutação , Receptores de Angiotensina/genética , Receptores de Angiotensina/metabolismo , Receptores de Endotelina/genética , Receptores de Endotelina/metabolismo , Proteínas com Motivo Tripartido , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
7.
Cancer Res ; 82(10): 1926-1936, 2022 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-35320355

RESUMO

The majority of TP53 missense mutations identified in cancer patients are in the DNA-binding domain and are characterized as either structural or contact mutations. These missense mutations exhibit inhibitory effects on wild-type p53 activity. More importantly, these mutations also demonstrate gain-of-function (GOF) activities characterized by increased metastasis, poor prognosis, and drug resistance. To better understand the activities by which TP53 mutations, identified in Li-Fraumeni syndrome, contribute to tumorigenesis, we generated mice harboring a novel germline Trp53R245W allele (contact mutation) and compared them with existing models with Trp53R172H (structural mutation) and Trp53R270H (contact mutation) alleles. Thymocytes from heterozygous mice showed that all three hotspot mutations exhibited similar inhibitory effects on wild-type p53 transcription in vivo, and tumors from these mice had similar levels of loss of heterozygosity. However, the overall survival of Trp53R245W/+ and Trp53R270H/+ mice, but not Trp53R172H/+ mice, was significantly shorter than that of Trp53+/- mice, providing strong evidence for p53-mutant-specific GOF contributions to tumor development. Furthermore, Trp53R245W/+ and Trp53R270H/+ mice had more osteosarcoma metastases than Trp53R172H/+ mice, suggesting that these two contact mutants have stronger GOF in driving osteosarcoma metastasis. Transcriptomic analyses using RNA sequencing data from Trp53R172H/+, Trp53R245W/+, and Trp53R270H/+ primary osteosarcomas in comparison with Trp53+/- indicated that GOF of the three mutants was mediated by distinct pathways. Thus, both the inhibitory effect of mutant over wild-type p53 and GOF activities of mutant p53 contributed to tumorigenesis in vivo. Targeting p53 mutant-specific pathways may be important for therapeutic outcomes in osteosarcoma. SIGNIFICANCE: p53 hotspot mutants inhibit wild-type p53 similarly but differ in their GOF activities, with stronger tumor-promoting activity in contact mutants and distinct protein partners of each mutant driving tumorigenesis and metastasis.


Assuntos
Mutação com Ganho de Função , Osteossarcoma , Proteína Supressora de Tumor p53 , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Carcinogênese/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Camundongos , Osteossarcoma/genética , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
8.
Int J Chronic Dis ; 2021: 9919443, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34692822

RESUMO

BACKGROUND: Overweight and obesity have become a serious health problem. There are a few data on the prevalence of overweight and obesity in Baoji city of western China, this study was conducted to investigate the epidemiologic features of overweight and obesity and explored influencing factors among Baoji adult residents. METHODS: A cross-sectional study, including 36,600 participants aged above 15 years, was carried out in Baoji city in 2018. Each participant's weight and height were measured, and demographic and behavioral characteristics were collected using questionnaires. Data were analyzed by means of logistic regression considering 95% level of significance. RESULTS: Overall, the prevalence of overweight and obesity was 30.73% and 3.11%, respectively. Male had a significantly higher prevalence of overweight (31.45% vs. 29.98%, P < 0.05) while female had a higher prevalence of obesity (3.50 vs. 2.74, P < 0.001). In the logistic regression analysis, being married or living with a partner (OR = 1.266, P < 0.001), unemployed or retired (OR = 1.183, P < 0.001), former smokers (OR = 1.116, P < 0.05), drinking alcohol (OR = 1.410, P < 0.001), sleeping more than 10 hours (OR = 1.274, P < 0.001), and increasing age were all significantly associated with a higher prevalence of overweight/obesity, whereas people who lived in rural areas (R = 0.904, P < 0.001) or had a sufficient leisure time physical activity per week (R = 0.945, P < 0.05) were associated with a lower prevalence. CONCLUSION: Our results demonstrate that demographic and behavioral factors play an important role in prevalence of overweight/obesity, which can support the implementation of interventions aimed at weight control and consequently prevention of related diseases in this population.

9.
Zhonghua Yu Fang Yi Xue Za Zhi ; 43(11): 960-4, 2009 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-20137516

RESUMO

OBJECTIVE: To research the co-infections of HIV and human herpesvirus 8 (HHV8) in Uygur high-risk groups of HIV infection in a city Xinjiang. METHODS: All 468 Uygurs at high HIV risk registered in the sentinel monitoring system in 2006 were enrolled in this study. The antibodies to HHV8 latency-associated nuclear antigens 1 (LANA1), lytic antigens open reading frame 65 (ORF65) and K8.1 were measured by enzyme linked immunosorbent assay (ELISA). Chi-square test and non-condition Logistic regression model were used for data analysis. RESULTS: Of 468 sera samples, 67 (14.3%) were HIV and HHV8 co-infection positive.Male's HIV and HHV8 co-infection rate (22.6%, 54/239) was higher than the female's (5.7%, 13/229) (chi(2) = 27.285, P < 0.001). For those above 24 year old, HIV and HHV8 co-infection rate (15.8%, 65/412) was higher than the < 24 year old group's (3.6%, 2/56) (chi(2) = 5.987, P = 0.014). The group of Elementary school and illiterate people's HIV and HHV8 co-infection rate (20.7%, 40/193) was higher than the junior middle school and the above culture (9.8%, 27/275) (chi(2) = 10.999, P = 0.001). For the unmarried people, the co-infecting rate of HIV and HHV8 for the married, the cohabitants, the divorced or the widowers were 16.9% (14/83), 12.2% (42/345), 27.5% (11/40) respectively. There was significantly statistical difference among three marital status (chi(2) = 7.399, P = 0.025). Injecting drug users' HIV and HHV8 co-infection rate (26.5%, 50/189) was higher than non-injecting drug users' (6.1%, 17/279) (chi(2) = 38.083, P < 0.001), and stratified by gender, OR(M-H) was 4.207 (95%CI: 1.529 - 11.578). Via non-condition logistic stepwise regression analysis, only injecting drug use entered model, compared with non-injecting drug users, injecting drug users were more dangerous for HIV and HHV8 co-infecting (OR = 5.544; 95%CI: 3.081 - 9.975). CONCLUSION: The HIV and HHV8 co-infection rate was higher in the Uygurs at high HIV risk in Xinjiang. Injecting drug use is a risk factor of the HIV and HHV8 co-infection, which might be one of routes of HIV and HHV8 co-infection among this group.


Assuntos
Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Infecções por Herpesviridae/epidemiologia , Vigilância da População , Adolescente , Adulto , Idoso , Criança , China/epidemiologia , Feminino , Infecções por HIV/etnologia , Herpesvirus Humano 8/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
J Pediatr Endocrinol Metab ; 31(3): 323-329, 2018 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-29466239

RESUMO

BACKGROUND: This study aimed to identify the predictive value of basal sex hormone levels for activation of the hypothalamic-pituitary-gonadal (HPG) axis in girls. METHODS: Gonadotropin-releasing hormone (GnRH) stimulation tests were performed and evaluated in a total of 1750 girls with development of secondary sex characteristics. Correlation analyses were conducted between basal sex hormones and peak luteinizing hormone (LH) levels ≥5 IU/L during the GnRH stimulation test. Receiver operating characteristic (ROC) curves for basal levels of LH, follicle-stimulating hormone (FSH), LH/FSH, and estradiol (E2) before the GnRH stimulation test were plotted. The area under the curve (AUC) and 95% confidence intervals (CIs) were measured for each curve. RESULTS: The maximum AUC value was observed for basal LH levels (0.77, 95% CI: 0.74-0.79), followed by basal FSH levels (0.73, 95% CI: 0.70-0.75), the basal LH/FSH ratio (0.68, 95% CI: 0.65-0.71), and basal E2 levels (0.61, 95% CI: 0.59-0.64). The appropriate cutoff value of basal LH levels associated with a positive response of the GnRH stimulation test was 0.35 IU/L, with a sensitivity of 63.96% and specificity of 76.3% from the ROC curves when Youden's index showed the maximum value. When 100% of patients had peak LH levels ≥5 IU/L, basal LH values were >2.72 IU/L, but the specificity was only 5.45%. CONCLUSIONS: Increased basal LH levels are a significant predictor of a positive response during the GnRH stimulation test for assessing activation of the HPG axis in most girls with early pubertal signs.


Assuntos
Estradiol/sangue , Hormônio Foliculoestimulante/sangue , Hormônio Liberador de Gonadotropina/administração & dosagem , Sistema Hipotálamo-Hipofisário/fisiologia , Hormônio Luteinizante/sangue , Ovário/fisiologia , Criança , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Modelos Logísticos , Ovário/efeitos dos fármacos , Puberdade Precoce/diagnóstico , Curva ROC
11.
Nat Commun ; 9(1): 3953, 2018 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-30262850

RESUMO

TP53 mutations are the most frequent genetic alterations in breast cancer and are associated with more aggressive disease and worse overall survival. We have created two conditional mutant Trp53 alleles in the mouse that allow expression of Trp53R172H or Trp53R245W missense mutations in single cells surrounded by a normal stroma and immune system. Mice with Trp53 mutations in a few breast epithelial cells develop breast cancers with high similarity to human breast cancer including triple negative. p53R245W tumors are the most aggressive and exhibit metastases to lung and liver. Development of p53R172H breast tumors with some metastases requires additional hits. Sequencing of primary tumors and metastases shows p53R245W drives a parallel evolutionary pattern of metastases. These in vivo models most closely simulate the genesis of human breast cancer and will thus be invaluable in testing novel therapeutic options.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias Mamárias Animais/genética , Neoplasias Mamárias Animais/patologia , Mutação/genética , Proteína Supressora de Tumor p53/genética , Alelos , Animais , Carcinogênese/genética , Carcinogênese/patologia , Feminino , Heterogeneidade Genética , Humanos , Camundongos Endogâmicos C57BL , Metástase Neoplásica
12.
Zhongguo Dang Dai Er Ke Za Zhi ; 8(4): 279-82, 2006 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-16923356

RESUMO

The occurrence of eating disorders in Chinese adolescents is increasing. However the cause, diagnosis, treatment and prognosis of this disorder are rarely reported by pediatricians. This paper investigated the cause and treatment of six cases of eating disorders in adolescent patients. The medical data of six cases of eating disorders in the Shanghai Children's Medical Center from January 2003 to September 2005 were retrospectively reviewed. The patients were 5 girls and 1 boy, whose onset ages ranged from 12.4 to 15.8 years. They were initially referred to the clinic between 12.9 to 16.7 years, with a course of disease varying from three to twelve months. The patients' body mass index (BMI) varied from 9.07 to 17.0. Four out of the six patients were hospitalized because of low temperature, low blood pressure, bradycardia, dehydration and multiple systems damages. The other two were treated in the out-patient clinic. Based on the medical history and physical examination as well as laboratory findings, five of them were diagnosed with anorexia nervosa and the other one were bulimia nervosa. All of the patients were under the care of a team consisting of pediatricians, dietitians, psychiatrists and nurses. When the patients whose vital signs were unstable, medical treatment focused on life sustention and they were kept on beds compulsively and given nutrition transfusion. Meanwhile cognition and behavior therapy was administered to help the patients find out the internal and environmental factors related to the development of this disorder, establish a new conception of healthy weight, and correct their abnormal eating behaviors. The patients who had a severe distortion of body image and a big resistance to the treatment were additionally administered with psychiatry drugs. After treatment, three patients set up a healthy eating behavior, their body weights gradually recovered and they had no relapse during a 1-year follow-up. The other three patients retained some abnormal eating behaviors and their body weights were always below normal. It was found that eating disorders in adolescents may be triggered by some environmental factors, such as comments on body shape from their peers, fashion influence, academic pressures, and problems in communication. Since the patients' abnormal eating behaviors were masked or neglected by parents at the early stage of the disease and the clinical presentations were related to multiple systems, it is difficult to make an early diagnosis and treatment. It is important to improve the pediatricians' knowledge of eating disorders of adolescents and perform cooperation between a multidisciplinary team for the early diagnosis and treatment of this disorder.


Assuntos
Transtornos da Alimentação e da Ingestão de Alimentos/etiologia , Adolescente , Criança , Transtornos da Alimentação e da Ingestão de Alimentos/psicologia , Transtornos da Alimentação e da Ingestão de Alimentos/terapia , Feminino , Humanos , Masculino
13.
Nutr Res Pract ; 9(3): 313-8, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26060544

RESUMO

BACKGROUND/OBJECTIVES: Dietary pattern and its association with cardio-cerebrovascular disease have not been studied in Baoji city by now. This study was aimed to identify the dietary patterns among Chinese adults in Baoji, and explore the association between these dietary patterns and cardio-cerebrovascular disease. SUBJECTS/METHODS: A total of 4,968 participants were included in this study at 12 counties. With multistage stratified random sampling and semi quantitative food frequency questionnaire, the prevalence of cardio-cerebrovascular disease and dietary intake were investigated in 2013. We used factor analysis to establish dietary patterns. RESULTS: A total of 4,968 participants over 15 years old were included in this study. Five dietary patterns were identified in Baoji: protein, balanced, beans, prudent, and traditional patterns. The protein dietary pattern mainly included animal and plant proteins and was negatively associated with hypertension as well as stroke. The balanced pattern included carbohydrates, protein, and fat and was negatively associated with hypertension as well as stroke. The beans pattern was mainly beans and beans products and was negatively associated with hypertension. The prudent pattern only included staple foods and pickled vegetables and was positively associated with hypertension as well as coronary heart disease. The traditional pattern was representative of local Baoji traditional recipes and was positively associated with hypertension. CONCLUSIONS: The protein, balanced, and beans dietary patterns showed many protective effects on cardio-cerebrovascular disease. Based on these results, Baoji city residents should be encouraged to choose protein, balanced, and beans dietary patterns and abandon prudent and traditional patterns to prevent incidence of hypertension, coronary heart disease, and stroke.

14.
Int J Chronic Dis ; 2014: 548269, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-26464858

RESUMO

Objective. This study was aimed to identify the dietary patterns among Chinese adults in Baoji and explore the association between these dietary patterns and chronic diseases. Methods. With multistage stratified random sampling and semiquantitative food frequency questionnaire, the prevalence of chronic disease and dietary intake was investigated in 2013. We used factor analysis to establish dietary patterns. Results. A total of 5020 participants over 15 years old were included in this study. Five dietary patterns were identified in Baoji named as protein, balanced, beans, prudent, and traditional patterns. There are many protective effects with protein, balanced, and beans dietary patterns on chronic diseases. Conclusions. We should encourage Baoji city residents to choose protein, balanced, and beans dietary patterns and abandon prudent and traditional patterns.

15.
Mol Cancer Res ; 12(6): 901-11, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24598047

RESUMO

UNLABELLED: The p53 (TP53) tumor suppressor is the most frequently mutated gene in human cancers. Restoring expression of wild-type p53 has led to tumor growth suppression in a variety of tumor models that are p53 deficient. Other mechanisms, for example, upregulation of Mdm2, exist in tumors to inactivate the p53 pathway. Mdm2, an E3 ubiquitin ligase that targets p53 for proteasomal degradation, is present at high levels in many tumors with wild-type p53. In this study, the effects of restoring p53 activity were probed in Mdm2-overexpressing tumors genetically using animal models. Here, it was demonstrated that elevated levels of Mdm2 and decreased levels of p53 act additively to dampen p53 activity in DNA damage response and tumor development. Our data further indicate that restoration of wild-type p53 expression in Mdm2-overexpressing angiosarcomas results in tumor stasis and regression in some cases. Finally, it was determined that restored p53 suppressed cell proliferation but did not elicit apoptosis in the Mdm2-overexpressing angiosarcomas. IMPLICATIONS: Restoration of wild-type p53 expression in Mdm2-overexpressing tumors suppresses tumor growth, which represents a potential clinical strategy to treat tumors with high levels of Mdm2.


Assuntos
Genes p53 , Hemangiossarcoma/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/biossíntese , Proteína Supressora de Tumor p53/biossíntese , Animais , Apoptose/fisiologia , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Hemangiossarcoma/genética , Hemangiossarcoma/patologia , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-mdm2/genética , Ativação Transcricional , Proteína Supressora de Tumor p53/genética
16.
PLoS One ; 8(8): e71553, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23940767

RESUMO

Phenylketonuria (PKU), an autosomal recessive disorder of amino acid metabolism caused by mutations in the phenylalanine hydroxylase (PAH) gene, leads to childhood mental retardation by exposing neurons to cytotoxic levels of phenylalanine (Phe). A recent study showed that the mitochondria-mediated (intrinsic) apoptotic pathway is involved in Phe-induced apoptosis in cultured cortical neurons, but it is not known if the death receptor (extrinsic) apoptotic pathway and endoplasmic reticulum (ER) stress-associated apoptosis also contribute to neurodegeneration in PKU. To answer this question, we used specific inhibitors to block each apoptotic pathway in cortical neurons under neurotoxic levels of Phe. The caspase-8 inhibitor Z-IETD-FMK strongly attenuated apoptosis in Phe-treated neurons (0.9 mM, 18 h), suggesting involvement of the Fas receptor (FasR)-mediated cell death receptor pathway in Phe toxicity. In addition, Phe significantly increased cell surface Fas expression and formation of the Fas/FasL complex. Blocking Fas/FasL signaling using an anti-Fas antibody markedly inhibited apoptosis caused by Phe. In contrast, blocking the ER stress-induced cell death pathway with salubrinal had no effect on apoptosis in Phe-treated cortical neurons. These experiments demonstrate that the Fas death receptor pathway contributes to Phe-induced apoptosis and suggest that inhibition of the death receptor pathway may be a novel target for neuroprotection in PKU patients.


Assuntos
Apoptose , Proteína Ligante Fas/fisiologia , Neurônios/fisiologia , Fenilalanina/fisiologia , Receptor fas/metabolismo , Animais , Células Cultivadas , Córtex Cerebral/patologia , Estresse do Retículo Endoplasmático , Fenilcetonúrias/metabolismo , Fenilcetonúrias/patologia , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
17.
PLoS One ; 8(6): e67039, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23825611

RESUMO

OBJECTIVE: To investigate potential functional variants in FTO and SH2B1 genes among Chinese children with obesity. METHODS: Sanger sequencing of PCR products of all FTO and SH2B1 exons and their flanking regions were performed in 338 Chinese Han children with obesity and 221 age- and sex-matched lean controls. RESULTS: A total of seven and five rare non-synonymous variants were identified in FTO and SH2B1, respectively. The overall frequencies of FTO and SH2B1 rare non-synonymous variants were similar in obese and lean children (2.37% and 0.90% vs. 1.81% and 1.36%, P>0.05). However, four out of the seven variants in FTO were novel and all were unique to obese children (p>0.05). None of the novel variants was consistently being predicted to be deleterious. Four out of five variants in SH2B1 were novel and one was unique to obese children (p>0.05). One variant (L293R) that was consistently being predicted as deleterious in SH2B1 gene was unique to lean control. While rare missense mutations were more frequently detected in girls from obesity as well as lean control than boys, the difference was not statistically significant. In addition, it's shown that the prevalence of rare missense mutations of FTO as well as SH2B1 was similar across different ethnic groups. CONCLUSION: The rare missense mutations of FTO and SH2B1 did not confer risks of obesity in Chinese Han children in our cohort.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Povo Asiático/genética , Mutação de Sentido Incorreto , Obesidade/genética , Proteínas/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Povo Asiático/etnologia , Criança , Estudos de Coortes , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Obesidade/etnologia
18.
Cancer Cell ; 21(6): 793-806, 2012 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-22698404

RESUMO

Studies on the role of TP53 mutation in breast cancer response to chemotherapy are conflicting. Here, we show that, contrary to dogma, MMTV-Wnt1 mammary tumors with mutant p53 exhibited a superior clinical response compared to tumors with wild-type p53. Doxorubicin-treated p53 mutant tumors failed to arrest proliferation, leading to abnormal mitoses and cell death, whereas p53 wild-type tumors arrested, avoiding mitotic catastrophe. Senescent tumor cells persisted, secreting senescence-associated cytokines exhibiting autocrine/paracrine activity and mitogenic potential. Wild-type p53 still mediated arrest and inhibited drug response even in the context of heterozygous p53 point mutations or absence of p21. Thus, we show that wild-type p53 activity hinders chemotherapy response and demonstrate the need to reassess the paradigm for p53 in cancer therapy.


Assuntos
Doxorrubicina/farmacologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Carga Tumoral/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Animais , Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Western Blotting , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Citocinas/genética , Citocinas/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/patologia , Vírus do Tumor Mamário do Camundongo/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mutação , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Resultado do Tratamento , Carga Tumoral/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína Wnt1/genética
20.
Genet Test Mol Biomarkers ; 15(3): 137-42, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21198393

RESUMO

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders mainly caused by a defect in the steroid 21-hydroxylase gene (CYP21A2). In this study, we investigated the molecular defects of 25 Chinese pedigrees with 21-hydroxylase deficiency (21-OHD). Diagnosis of the probands in the families was based on their typical clinical presentations, such as inborn ambiguous genitalia, or early onset of salt wasting and biochemical metabolite abnormalities. All 10 exons and exon-intron boundaries of the CYP21A2 gene were amplified from the genomic DNA of the probands and then analyzed by direct sequencing. The phenotypes of the 26 patients from 25 pedigrees were classified as the classical form of 21-OHD. One novel mutation (c.1223 G>T) and 13 recurrent mutations of CYP21A2 were identified in the 25 pedigrees by genetic analysis. The novel c.1223 G>T mutation results in the substitution of arginine by leucine at amino acid position 408 (p.Arg408Leu). The most frequent mutation alleles were IVS2-13A/C>G (14/52) and I172N (11/52), followed by chimeric mutations (10/52). Forty six of 52 mutated alleles resulted from pseudogene conversion and 6 of 52 from random mutations. The spectrum of CYP21A2 mutation in our study was slightly different from those previously reported in Chinese and in other ethnic groups of the world. Although microconversion events were the main cause of mutations in the CYP21 gene, random mutations with a common origin can also be the reason for 21-OHD.


Assuntos
Povo Asiático/genética , Mutação , Linhagem , Esteroide 21-Hidroxilase/genética , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/genética , Alelos , Criança , Pré-Escolar , Feminino , Frequência do Gene , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Modelos Moleculares , Reação em Cadeia da Polimerase , Esteroide 21-Hidroxilase/química
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