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1.
Front Oncol ; 9: 630, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31428571

RESUMO

Castration Resistant Prostate Cancer (CRPC) is thought to be driven by a collaborative mechanism between TNFα/NFκB and TGFß signaling, leading to inflammation, Epithelial-to-Mesenchymal-Transition (EMT), and metastasis. Initially, TGFß is a tumor suppressor, but in advanced metastatic disease it switches to being a tumor promoter. TGFBR2 may play a critical role in this collaboration, as its expression is driven by NFκB and it is the primary receptor for TGFß. We have previously reported that the cardenolide drug digitoxin blocks TNFα/NFκB-driven proinflammatory signaling. We therefore hypothesized that digitoxin might break the collaborative process between NFκB and TGFß by also inhibiting expression of TGFBR2. We therefore tested whether TGFß-driven EMT and resulting metastases would be suppressed. Here we show, in vitro, that digitoxin inhibits NFκB-driven TGFBR2 expression, as well as Vimentin, while elevating E-cadherin expression. Digitoxin also significantly reduces HSPB1 mRNA and the HSPB1/RBFOX2 mRNA ratio in PC3 cells. In vivo, in a syngeneic, immune competent rat model of metastatic CRPC, we show that digitoxin also suppresses Tgfbr2 expression, as well as expression of other genes classically driven by NFκB, and of multiple EMT genes associated with metastasis. Concurrently, digitoxin suppresses tumor growth and metastasis in these animals, and prolongs survival. Gross tumor recurrence following tumor resection also appears prevented in ca 30% of cases. While the existence of a collaboration between NFκB and TGFß to drive EMT and metastasis has previously been appreciated, we show here, for the first time, that chronic, low concentrations of digitoxin are able to block CRPC tumor progression, EMT and the ensuing metastatic disease.

2.
Exp Mol Pathol ; 110: 104281, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31288012

RESUMO

BACKGROUND: Pressure ulcers (PUs) prevalence has been considered as an index for patient safety and cure quality of hospital and community. Skin cellular oxidative response damage is existed in the development of PUs. Angelica polysaccharide (AP) has the anti-oxidation function. Therefore, our goal was to investigate the mechanism of AP in relieving cellular oxidative damage. METHODS: Transfected HaCaT cells with miR-126 inhibitor, pre-treated by AP, and then treated by H2O2. CCK-8 assay and flow cytometry detection were set to test viability and apoptosis of cells respectively. qRT-PCR and western blot tested levels of miR-126 and oxidative damage relative factors. ROS assay tested the production of ROS in cells. RESULTS: Cellular oxidative response damage was induced by H2O2 at concentration of 300 µM. We found that AP could attenuate cellular oxidative response damage caused by H2O2 that it elevated cell viability, attenuated cell apoptosis and production of ROS and promoted activation of PI3K/AKT and mTOR signal pathways. Further, miR-126 was up-regulated by AP. The up-regulation of miR-126 could activate the PI3K/AKT and mTOR signal pathways. CONCLUSION: Our study demonstrated that AP attenuated cellular oxidative response damage in HaCaT cells by positively regulated miR-126.


Assuntos
Angelica/química , Queratinócitos/efeitos dos fármacos , MicroRNAs/genética , Estresse Oxidativo/efeitos dos fármacos , Polissacarídeos/farmacologia , Regulação para Cima/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Humanos , Peróxido de Hidrogênio/farmacologia , Queratinócitos/citologia , Queratinócitos/metabolismo , Oxidantes/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Regulação para Cima/genética
3.
Mol Brain ; 12(1): 47, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31072367

RESUMO

Following publication of the original article [1], the authors reported that one of the authors' names was spelled incorrectly.

4.
Mol Brain ; 12(1): 25, 2019 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-30922409

RESUMO

Posttraumatic stress disorder is developed by exposure to a threatening and/or a horrifying event and characterized by the presence of anxiety, hyperarousal, avoidance, and sleep abnormality for a prolonged period of time. To elucidate the potential molecular mechanisms, we constructed a mouse model by electric foot shock followed by situational reminders and performed transcriptome analysis in brain tissues. The stressed mice acquired anxiety-like behavior after 2 weeks and exaggerated startle response after 4 weeks. Avoidance latency and freezing behavior were sustained up to 5 weeks post stress and abnormal static behavior was observed during the sleep period. RNA sequencing was performed in two of the emotional regulatory regions, anterior cingulate cortex and amygdala, at 2 and 5 weeks post stress. More than 1000 differentially expressed genes were identified at 2 weeks in both regions. The number of the regulated genes remained constant in amygdala at 5 weeks post stress, whereas those in anterior cingulate cortex were plummeted. Although synaptic remodeling and endocrine system were the most enriched signaling pathways in both anterior cingulate cortex and amygdala, the individual gene expression profile was regulated in a region- and time-dependent manner. In addition, several genes associated with PTSD involved in Hypothalamic-Pituitary-Adrenal axis were differentially regulated. These findings suggested that global gene expression profile was dynamically regulated in accordance with the disease development stage, and therefore targeting the distinct signaling molecules in different region and development stage might be critical for effective treatment to PTSD.


Assuntos
Tonsila do Cerebelo/metabolismo , Regulação da Expressão Gênica , Giro do Cíngulo/metabolismo , Transtornos de Estresse Pós-Traumáticos/genética , Tonsila do Cerebelo/fisiopatologia , Animais , Ansiedade/complicações , Ansiedade/genética , Ansiedade/fisiopatologia , Nível de Alerta/genética , Aprendizagem da Esquiva , Comportamento Animal , Modelos Animais de Doenças , Reação de Congelamento Cataléptica , Perfilação da Expressão Gênica , Ontologia Genética , Giro do Cíngulo/fisiopatologia , Imobilização , Masculino , Aprendizagem em Labirinto , Memória , Camundongos Endogâmicos C57BL , Tempo de Reação/genética , Reflexo de Sobressalto , Sono , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Fatores de Tempo
5.
Exp Ther Med ; 17(3): 2279-2283, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30783486

RESUMO

Expression levels of interleukin-17 (IL-17) and IL-34 was investigated to analyze the influencing factors for prognosis in patients with lupus nephritis (LN). Clinical data of 45 patients (LN group) treated and diagnosed with LN via renal biopsy in Yanan University Affiliated Hospital from October 2010 to October 2012 and 50 healthy subjects (control group) were analyzed retrospectively. Levels of serum IL-17 and IL-34 were detected via enzyme-linked immunosorbent assay. Correlations of serum IL-17 and IL-34 with urinary protein in LN patients were analyzed via Pearson correlation analysis. Univariate survival analysis was performed using the Kaplan-Meier method, and multivariate analysis was performed for LN prognosis using the Cox proportional hazards model. Levels of serum IL-34 and IL-17 in patients in LN group were significantly higher than those in control group (P<0.001). Serum IL-17 and IL-34 in LN patients were positively correlated with urinary protein (r= 0.436 and 0.714, P<0.05). Adverse factors affecting the prognosis of 45 LN patients including age, hemoglobin, platelet, blood uric acid, urinary protein, IL-17 and IL-34, showing statistically significant differences (P<0.05). Age, hemoglobin, blood uric acid, urinary protein, IL-17 and IL-34 were independent risk factors for poor prognosis of LN (P<0.05). The inflammatory factors IL-17 and IL-34 are highly expressed in the serum of LN patients. Levels of serum IL-17 and IL-34 in LN patients have positive correlations with urinary protein. Results of univariate and multivariate Cox regression analyses reveal that age, hemoglobin, blood uric acid, urinary protein, IL-17 and IL-34 are independent risk factors for poor prognosis of LN. IL-17 and IL-34 can therefore serve as effective indexes for clinical diagnosis, treatment and prognosis of LN.

6.
Echocardiography ; 35(11): 1841-1846, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30255620

RESUMO

OBJECTIVE: This in vitro study calculated longitudinal strain (LS) from different ultrasound systems (GE Vivid E9 and Philips IE 33) before and after myocardial infarct (MI) using a vendor-independent analysis software package (TomTec's 4D LV Analysis) to validate the variation of two ultrasound systems. METHODS: Ten freshly harvested porcine hearts were passively driven by a pulsatile pump apparatus at stroke volumes (SV) 30-70 mL. Full-volume three-dimensional echocardiography (3DE) data were acquired before and after MI using two different ultrasound systems. LS was derived from TomTec and validated against sonomicrometry data. RESULTS: Linear regression analyses showed excellent correlations between TomTec-calculated LS values and sonomicrometry data for both normal and simulated MI groups (GE: R2  = 0.72/0.68, Philip: R2  = 0.71/0.66). Bland-Altman analyses demonstrated overestimation of echo-derived strain values for all groups. Both ultrasound system-derived strain values demonstrated decreased LS after MI, and the average change in strain after infarct was roughly 30% in GE images and 25% in Philips images. CONCLUSIONS: Both GE and Philips echocardiographic systems can be analyzed with TomTec's program, and these images correlated well with sonomicrometry with acceptable variations.


Assuntos
Ecocardiografia Tridimensional/métodos , Processamento de Imagem Assistida por Computador/métodos , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/fisiopatologia , Animais , Modelos Animais de Doenças , Coração/diagnóstico por imagem , Coração/fisiopatologia , Técnicas In Vitro , Reprodutibilidade dos Testes , Suínos
7.
Gut ; 67(3): 521-533, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28634199

RESUMO

OBJECTIVE: To elucidate the genetic architecture of gene expression in pancreatic tissues. DESIGN: We performed expression quantitative trait locus (eQTL) analysis in histologically normal pancreatic tissue samples (n=95) using RNA sequencing and the corresponding 1000 genomes imputed germline genotypes. Data from pancreatic tumour-derived tissue samples (n=115) from The Cancer Genome Atlas were included for comparison. RESULTS: We identified 38 615 cis-eQTLs (in 484 genes) in histologically normal tissues and 39 713 cis-eQTL (in 237 genes) in tumour-derived tissues (false discovery rate <0.1), with the strongest effects seen near transcriptional start sites. Approximately 23% and 42% of genes with significant cis-eQTLs appeared to be specific for tumour-derived and normal-derived tissues, respectively. Significant enrichment of cis-eQTL variants was noted in non-coding regulatory regions, in particular for pancreatic tissues (1.53-fold to 3.12-fold, p≤0.0001), indicating tissue-specific functional relevance. A common pancreatic cancer risk locus on 9q34.2 (rs687289) was associated with ABO expression in histologically normal (p=5.8×10-8) and tumour-derived (p=8.3×10-5) tissues. The high linkage disequilibrium between this variant and the O blood group generating deletion variant in ABO (exon 6) suggested that nonsense-mediated decay (NMD) of the 'O' mRNA might explain this finding. However, knockdown of crucial NMD regulators did not influence decay of the ABO 'O' mRNA, indicating that a gene regulatory element influenced by pancreatic cancer risk alleles may underlie the eQTL. CONCLUSIONS: We have identified cis-eQTLs representing potential functional regulatory variants in the pancreas and generated a rich data set for further studies on gene expression and its regulation in pancreatic tissues.


Assuntos
Sistema do Grupo Sanguíneo ABO/genética , Expressão Gênica , Pâncreas , Neoplasias Pancreáticas/genética , Locos de Características Quantitativas , RNA Neoplásico/análise , Transcriptoma , Alelos , Cromossomos Humanos Par 9 , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Degradação do RNAm Mediada por Códon sem Sentido , Polimorfismo de Nucleotídeo Único , Sequências Reguladoras de Ácido Nucleico , Análise de Sequência de RNA
8.
Biomed Pharmacother ; 83: 1164-1174, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27551764

RESUMO

Targeting cancer cells is crucial for improving the efficiency of laryngeal cancer treatment. However, the signaling pathway and therapeutic strategy, related to the tumor, still need further research. Dietary flavonoid fisetin (3,3',4',7-tetrahydroxyflavone) found in many fruits and vegetables has been shown in preclinical studies to inhibit cancer growth through regulating cell cycle, apoptosis, angiogenesis, invasion and metastasis without causing any toxicity to normal cells. PI3K/AKT and ERK1/2 have been known as essential signaling pathways to modulate cell proliferation, apoptosis as well as autophagy via mTOR, Caspase-3 and NF-κB signals. In our study, flow cytometry and western blot assays suggested that apoptosis was induced by fisetin administration, promoting Caspase-3 expressions by regulating PI3K/AKT/NF-κB. Additionally, fisetin suppressed TU212 cells proliferation, which was linked with ERK1/2 inactivation. Further, the activation of PI3K/AKT-regulated mTOR was inhibited by fisetin, leading to transcription suppression and proliferation inhibition of TU212 cells. In vivo studies also showed that the tumor volume and weight of nude mice were reduced for fisetin use with KI-67 decrease and LC3II increase in tumor tissue samples. Together, our data indicated that fisetin had a potential role in controlling human laryngeal cancer through inhibiting tumor cell proliferation, inducing apoptosis and autophagy regulated by ERK1/2 and AKT/NF-κB/mTOR signaling pathways, which might provide a therapeutic strategy for laryngeal cancer inhibition in future.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Flavonoides/uso terapêutico , Neoplasias Laríngeas/tratamento farmacológico , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Forma Celular , Sobrevivência Celular/efeitos dos fármacos , Flavonoides/química , Flavonoides/farmacologia , Humanos , Neoplasias Laríngeas/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Associadas aos Microtúbulos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Invest Dermatol ; 136(12): 2436-2443, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27476724

RESUMO

Mounting evidence suggests that copy number variations (CNVs) can contribute to cancer susceptibility. The main goal of this study was to evaluate the role of germline CNVs in melanoma predisposition in high-risk melanoma families. We used genome-wide tiling comparative genomic hybridization and single nucleotide polymorphism arrays to characterize CNVs in 335 individuals (240 melanoma cases) from American melanoma-prone families (22 with germline CDKN2A or CDK4 mutations). We found that the global burden of overall CNVs (or deletions or duplications separately) was not significantly associated with case-control or CDKN2A/CDK4 mutation status after accounting for the familial dependence. However, we identified several rare CNVs that either involved known melanoma genes (e.g., PARP1, CDKN2A) or cosegregated with melanoma (duplication on 10q23.23, 3p12.2 and deletions on 8q424.3, 2q22.1) in families without mutations in known melanoma high-risk genes. Some of these CNVs were correlated with expression changes in disrupted genes based on RNASeq data from a subset of melanoma cases included in the CNV study. These results suggest that rare cosegregating CNVs may influence melanoma susceptibility in some melanoma-prone families and genes found in our study warrant further evaluation in future genetic analyses of melanoma.


Assuntos
Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença/epidemiologia , Mutação em Linhagem Germinativa , Melanoma/genética , Neoplasias Cutâneas/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Incidência , Masculino , Melanoma/patologia , Linhagem , Reação em Cadeia da Polimerase em Tempo Real/métodos , Medição de Risco , Análise de Sequência de RNA , Neoplasias Cutâneas/patologia
10.
Medicine (Baltimore) ; 95(31): e4290, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27495031

RESUMO

The impact of major lung resections on myocardial function has not been well-investigated. We aimed to identify this impact through the use of speckle tracking echocardiography (STE) to evaluate the right and left ventricular myocardial function in patients who underwent lung resections.Thirty patients who had lung resections were recruited for this study. Ten patients who underwent pneumonectomies were matched by age and sex, with 20 patients who underwent lobectomies. STE was performed on both right and left ventricle (RV and LV). Strain values of pre and postlung resections were compared in both the pneumonectomy group and the lobectomy group. Comparison between the pneumonectomy group and the lobectomy group was also studied.Left ventricular ejection fraction remained normal (>55%), but significantly decreased after lung resection in both the pneumonectomy group and the lobectomy group. An accelerated heart rate was observed in both groups after lung resection, with the pneumonectomy group demonstrating extra rapid heart rate (P < 0.05). Strain values in the RV and LV decreased in both groups after lung resection, with the pneumonectomy group exhibiting a further decrease in longitudinal strain in LV and RV when compared with the lobectomy group (P < 0.05).Right and left ventricular dysfunction can occur after lung resection regardless of pneumonectomy or lobectomy, and lobectomy may have a less significant impact on myocardial functions. This study demonstrated that STE is able to detect acute cardiac dysfunction after lung resection.


Assuntos
Ecocardiografia Doppler em Cores/métodos , Interpretação de Imagem Assistida por Computador/métodos , Pneumonectomia/efeitos adversos , Disfunção Ventricular Direita/diagnóstico , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Pneumonectomia/métodos , Estudos Prospectivos , Índice de Gravidade de Doença , Disfunção Ventricular Direita/etiologia
11.
Haematologica ; 101(7): 853-60, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27365461

RESUMO

Hodgkin lymphoma shows strong familial aggregation but no major susceptibility genes have been identified to date. The goal of this study was to identify high-penetrance variants using whole exome sequencing in 17 Hodgkin lymphoma prone families with three or more affected cases or obligate carriers (69 individuals), followed by targeted sequencing in an additional 48 smaller HL families (80 individuals). Alignment and variant calling were performed using standard methods. Dominantly segregating, rare, coding or potentially functional variants were further prioritized based on predicted deleteriousness, conservation, and potential importance in lymphoid malignancy pathways. We selected 23 genes for targeted sequencing. Only the p.A1065T variant in KDR (kinase insert domain receptor) also known as VEGFR2 (vascular endothelial growth factor receptor 2) was replicated in two independent Hodgkin lymphoma families. KDR is a type III receptor tyrosine kinase, the main mediator of vascular endothelial growth factor induced proliferation, survival, and migration. Its activity is associated with several diseases including lymphoma. Functional experiments have shown that p.A1065T, located in the activation loop, can promote constitutive autophosphorylation on tyrosine in the absence of vascular endothelial growth factor and that the kinase activity was abrogated after exposure to kinase inhibitors. A few other promising mutations were identified but appear to be "private". In conclusion, in the largest sequenced cohort of Hodgkin lymphoma families to date, we identified a causal mutation in the KDR gene. While independent validation is needed, this mutation may increase downstream tumor cell proliferation activity and might be a candidate for targeted therapy.


Assuntos
Exoma , Estudos de Associação Genética , Predisposição Genética para Doença , Doença de Hodgkin/genética , Mutação , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Adulto , Biologia Computacional/métodos , Família , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Doença de Hodgkin/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Anotação de Sequência Molecular , Linhagem , Conformação Proteica , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Adulto Jovem
12.
J Natl Cancer Inst ; 108(9)2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27130930

RESUMO

BACKGROUND: HPV16 is a common sexually transmitted infection although few infections lead to cervical precancer/cancer; we cannot distinguish nor mechanistically explain why only certain infections progress. HPV16 can be classified into four main evolutionary-derived variant lineages (A, B, C, D) that have been previously suggested to have varying disease risks. METHODS: We used a high-throughput HPV16 whole-genome sequencing assay to investigate variant lineage risk among 3215 HPV16-infected women. Using sublineages A1/A2 as the reference, we assessed all variant lineage associations with infection outcome over three or more years of follow-up: 1107 control subjects (

Assuntos
Carcinoma/virologia , Papillomavirus Humano 16/classificação , Papillomavirus Humano 16/genética , Infecções por Papillomavirus/virologia , Lesões Pré-Cancerosas/virologia , Neoplasias do Colo do Útero/virologia , Adenocarcinoma/etnologia , Adenocarcinoma/virologia , Adenocarcinoma in Situ/etnologia , Adenocarcinoma in Situ/virologia , Adulto , Assistência ao Convalescente , California/epidemiologia , Carcinoma/etnologia , Carcinoma de Células Escamosas/etnologia , Carcinoma de Células Escamosas/virologia , Neoplasia Intraepitelial Cervical/etnologia , Neoplasia Intraepitelial Cervical/virologia , Feminino , Genoma , Sequenciamento de Nucleotídeos em Larga Escala , Papillomavirus Humano 16/patogenicidade , Humanos , Pessoa de Meia-Idade , Infecções por Papillomavirus/etnologia , Filogenia , Lesões Pré-Cancerosas/etnologia , Fatores de Risco , Neoplasias do Colo do Útero/etnologia , Adulto Jovem
14.
Papillomavirus Res ; 1: 3-11, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26645052

RESUMO

For unknown reasons, there is huge variability in risk conferred by different HPV types and, remarkably, strong differences even between closely related variant lineages within each type. HPV16 is a uniquely powerful carcinogenic type, causing approximately half of cervical cancer and most other HPV-related cancers. To permit the large-scale study of HPV genome variability and precancer/cancer, starting with HPV16 and cervical cancer, we developed a high-throughput next-generation sequencing (NGS) whole-genome method. We designed a custom HPV16 AmpliSeq™ panel that generated 47 overlapping amplicons covering 99% of the genome sequenced on the Ion Torrent Proton platform. After validating with Sanger, the current "gold standard" of sequencing, in 89 specimens with concordance of 99.9%, we used our NGS method and custom annotation pipeline to sequence 796 HPV16-positive exfoliated cervical cell specimens. The median completion rate per sample was 98.0%. Our method enabled us to discover novel SNPs, large contiguous deletions suggestive of viral integration (OR of 27.3, 95% CI 3.3-222, P=0.002), and the sensitive detection of variant lineage coinfections. This method represents an innovative high-throughput, ultra-deep coverage technique for HPV genomic sequencing, which, in turn, enables the investigation of the role of genetic variation in HPV epidemiology and carcinogenesis.

15.
Medicine (Baltimore) ; 94(47): e2085, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26632719

RESUMO

Aortic stenosis (AS) and aortic regurgitation (AR) are associated with congenital isolated bicuspid aortic valve (BAV) disease. The chronic pressure overload of AS and the volume overload of AR are known to impair the left ventricular function. This study assessed whether two-dimensional speckle tracking echocardiography (2D-STE) is capable of detecting the myocardial dysfunction associated with BAV caused by various aortic valve lesions in patients retaining normal ejection fraction (EF).Thirty-two isolated BAV patients and 20 healthy tricuspid aortic valve (TAV) volunteers were recruited. BAV patients were divided into 4 subgroups based on aortic valvular lesion types: normal function (NF) group, isolated AS group, isolated AR group, and a group who had both AS&AR. Myocardial strain and degree of twist were analyzed and compared between the BAV and TAV groups, as well as between valvular lesion groups and the NF group.Compared with healthy TAV controls, global radial strain (GRS), global circumferential strain (GCS), global longitudinal strain (GLS), and twist angle absolute values were lower in the BAV group (P < 0.05). The AS, AR, and AS&AR groups all demonstrated a significant decrease in GRS and GCS when compared with the TAV group. The AS and AS&AR groups demonstrated lower GLS than the TAV group, and the smallest degree of twist was detected in the AR group. There were no significant differences between the NF and TAV groups. The AR and AS&AR groups demonstrated significant differences in multiple parameters of cardiac mechanics compared with the NF group.2D-STE is able to detect altered cardiac mechanics associated with aortic lesion types in BAV patients with normal EF compared with normal TAV controls, and so can provide valuable information for clinical decision-making.


Assuntos
Insuficiência da Valva Aórtica/complicações , Estenose da Valva Aórtica/complicações , Valva Aórtica/anormalidades , Ecocardiografia/métodos , Doenças das Valvas Cardíacas/complicações , Doenças das Valvas Cardíacas/diagnóstico por imagem , Adulto , Valva Aórtica/diagnóstico por imagem , Feminino , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , Volume Sistólico
16.
Gigascience ; 4: 50, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26543556

RESUMO

BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes account for 20-25 % of inherited breast cancers and about 10 % of all breast cancer cases. Detection of BRCA mutation carriers can lead to therapeutic interventions such as mastectomy, oophorectomy, hormonal prevention therapy, improved screening, and targeted therapies such as PARP-inhibition. We estimate that African Americans and Hispanics are 4-5 times less likely to receive BRCA screening, despite having similar mutation frequencies as non-Jewish Caucasians, who have higher breast cancer mortality. To begin addressing this health disparity, we initiated a nationwide trial of BRCA testing of Latin American women with breast cancer. Patients were recruited through community organizations, clinics, public events, and by mail and Internet. Subjects completed the consent process and questionnaire, and provided a saliva sample by mail or in person. DNA from 120 subjects was used to sequence the entirety of BRCA1 and BRCA2 coding regions and splice sites, and validate pathogenic mutations, with a total material cost of $85/subject. Subjects ranged in age from 23 to 81 years (mean age, 51 years), 6 % had bilateral disease, 57 % were ER/PR+, 23 % HER2+, and 17 % had triple-negative disease. RESULTS: A total of seven different predicted deleterious mutations were identified, one newly described and the rest rare. In addition, four variants of unknown effect were found. CONCLUSIONS: Application of this strategy on a larger scale could lead to improved cancer care of minority and underserved populations.


Assuntos
Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Hispano-Americanos/genética , Feminino , Humanos
17.
Endocr Relat Cancer ; 22(6): 909-17, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26459559

RESUMO

Germline inactivating mutations of isoform 4 of phosphodiesterase (PDE) 11A (coded by the PDE11A gene) have been associated with familial adrenocortical tumors and familial testicular cancer. Testicular tissue is unique in expressing all four isoforms of PDE11A. In a prior candidate gene study of 94 familial testicular germ cell tumor (TGCT) subjects, we identified a significant association between the presence of functionally abnormal variants in PDE11A and familial TGCT risk. To validate this novel observation, we sequenced the PDE11A coding region in 259 additional TGCT patients (both familial and sporadic) and 363 controls. We identified 55 PDE11A variants: 20 missense, four splice-site, two nonsense, seven synonymous, and 22 intronic. Ten missense variants were novel; nine occurred in transcript variant 4 and one in transcript variant 3. Five rare mutations (p.F258Y, p.G291R, p.V820M, p.R545X, and p.K568R) were present only in cases and were significantly more common in cases vs controls (P=0.0037). The latter two novel variants were functionally characterized and shown to be functionally inactivating, resulting in reduced PDE activity and increased cAMP levels. In further analysis of this cohort, we focused on white participants only to minimize confounding due to population stratification. This study builds upon our prior reports implicating PDE11A variants in familial TGCT, provides the first independent validation of those findings, extends that work to sporadic testicular cancer, demonstrates that these variants are uncommonly but reproducibly associated with TGCT, and refines our understanding regarding which specific inactivating PDE11A variants are most likely to be associated with TGCT risk.


Assuntos
Proteínas de Neoplasias/genética , Neoplasias Embrionárias de Células Germinativas/genética , Diester Fosfórico Hidrolases/genética , Neoplasias Testiculares/genética , Substituição de Aminoácidos , Estudos de Casos e Controles , AMP Cíclico/metabolismo , DNA de Neoplasias/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Genótipo , Células HEK293 , Humanos , Íntrons/genética , Masculino , Mutagênese Sítio-Dirigida , Mutação de Sentido Incorreto , Proteínas de Neoplasias/fisiologia , Neoplasias Embrionárias de Células Germinativas/enzimologia , Diester Fosfórico Hidrolases/fisiologia , Mutação Puntual , Isoformas de Proteínas/genética , Sítios de Splice de RNA/genética , Risco , Neoplasias Testiculares/enzimologia , Transfecção , Estados Unidos
19.
Clin Cancer Res ; 21(23): 5360-70, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26080840

RESUMO

PURPOSE: Cervical cancer is one of the most common causes of cancer mortality for women living in poverty, causing more than 28,000 deaths annually in Latin America and 266,000 worldwide. To better understand the molecular basis of the disease, we ascertained blood and tumor samples from Guatemala and Venezuela and performed genomic characterization. EXPERIMENTAL DESIGN: We performed human papillomavirus (HPV) typing and identified somatically mutated genes using exome and ultra-deep targeted sequencing with confirmation in samples from Mexico. Copy number changes were also assessed in the exome sequence. RESULTS: Cervical cancer cases in Guatemala and Venezuela have an average age of diagnosis of 50 years and 5.6 children. Analysis of 675 tumors revealed activation of PIK3CA and other PI3K/AKT pathway genes in 31% of squamous carcinomas and 24% of adeno- and adenosquamous tumors, predominantly at two sites (E542K, E545K) in the helical domain of the PIK3CA gene. This distribution of PIK3CA mutations is distinct from most other cancer types and does not result in the in vitro phosphorylation of AKT. Somatic mutations were more frequent in squamous carcinomas diagnosed after the age of 50 years. Frequent gain of chromosome 3q was found, and low PIK3CA mutation fractions in many tumors suggest that PI3K mutation can be a late event in tumor progression. CONCLUSIONS: PI3K pathway mutation is important to cervical carcinogenesis in Latin America. Therapeutic agents that directly target PI3K could play a role in the therapy of this common malignancy.


Assuntos
Genoma Humano , Genômica , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/etiologia , Adulto , Idoso , Alphapapillomavirus/classificação , Alphapapillomavirus/genética , Biomarcadores Tumorais , Mapeamento Cromossômico , Classe I de Fosfatidilinositol 3-Quinases , Variações do Número de Cópias de DNA , Exoma , Feminino , Expressão Gênica , Guatemala/epidemiologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , México/epidemiologia , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Risco , Transdução de Sinais , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Venezuela/epidemiologia
20.
Hum Genet ; 134(7): 775-87, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25939664

RESUMO

Juvenile myelomonocytic leukemia (JMML) is a pediatric myeloproliferative neoplasm that arises from malignant transformation of the stem cell compartment and results in increased production of myeloid cells. Somatic and germline variants in CBL (Casitas B-lineage lymphoma proto-oncogene) have been associated with JMML. We report an incompletely penetrant CBL Y371C mutation discovered by whole-exome sequencing in three individuals with JMML in a large pedigree with 35 years of follow-up. The Y371 residue is highly evolutionarily conserved among CBL orthologs and paralogs. In silico bioinformatics prediction programs suggested that the Y371C mutation is highly deleterious. Protein structural modeling revealed that the Y371C mutation abrogated the ability of the CBL protein to adopt a conformation that is required for ubiquitination. Clinically, the three mutation-positive JMML individuals exhibited variable clinical courses; in two out of three, primary hematologic abnormalities persisted into adulthood with minimal clinical symptoms. The penetrance of the CBL Y371C mutation was 30% for JMML and 40% for all leukemia. Of the 8 mutation carriers in the family with available photographs, only one had significant dysmorphic features; we found no evidence of a clinical phenotype consistent with a "CBL syndrome". Although CBL Y371C has been previously reported in familial JMML, we are the first group to follow a complete pedigree harboring this mutation for an extended period, revealing additional information about this variant's penetrance, function and natural history.


Assuntos
Mutação em Linhagem Germinativa , Leucemia Mielomonocítica Juvenil/genética , Mutação de Sentido Incorreto , Linhagem , Proteínas Proto-Oncogênicas c-cbl/genética , Ubiquitinação/genética , Adolescente , Adulto , Criança , Pré-Escolar , Exoma , Feminino , Seguimentos , Humanos , Lactente , Masculino , Modelos Moleculares , Penetrância , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-cbl/química
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