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1.
J Infect Dis ; 2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33735375

RESUMO

BACKGROUND: Human papillomavirus (HPV) infection is a major cause of cervical cancer. Studies showed the onset of HPV carcinogenesis may be induced by oxidative stress affecting the host immune system. The association between antioxidants and oncogenic HPV remains unclear. In this study, we aim to identify antioxidants associated with vaginal HPV infection in women. METHODS: The associations between the 15 antioxidants and vaginal HPV infection status (no, low-risk, and high-risk HPV [LR- and HR-HPV]) were evaluated using 11,070 women who participated in the 2003-2016 National Health and Nutrition Examination Survey (NHANES). RESULTS: We identified serum albumin and four dietary antioxidants (vitamin-A, -B2, -E, and folate) inversely associated with HR-HPV infection. Women with a low level of albumin (≤39 g/L) have a significantly higher risk of HR-HPV (OR=1.4, p=0.009 vs. >44 g/L). A nutritional antioxidant score (NAS) was developed based on these four dietary antioxidants. The women with the lowest quartile NAS had a higher chance of HR-HPV (OR=1.3, p=0.030) and LR-HPV (OR=1.4, p=0.002) compared with the women with the highest quartile NAS. CONCLUSIONS: We identified five antioxidants negatively associated with vaginal HR-HPV infection in women. Our findings provide valuable insights into understanding antioxidants' impact on HPV carcinogenesis.

2.
J Cell Mol Med ; 25(6): 2795-2805, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33539648

RESUMO

Although the Eukaryotic Translation Initiation Factor 4 Gamma 1 (EIF4G1) has been found overexpressed in a variety of cancers, its role in non-small cell lung cancers (NSCLC) pathogenesis especially in immunoregulatory functions, its clinical relevance and therapeutic potential remain largely unknown. By using cancer patients tissue assays, the results indicate that EIF4G1 expressional levels are much higher in NSCLC tissues than in adjacent or normal lung tissues, which are also associated with NSCLC patient survival. By using an RNA-Sequencing based pipeline, the data show that EIF4G1 has a significant association with immune checkpoint molecules such as PD-1/PD-L1 in NSCLC. EIF4G1 small-molecule inhibitors effectively repress NSCLC growth in cell culture and xenograft animal models. Protein array results identify the signature of proteins controlled by EIF4G1 in NSCLC cells, in which new candidates such as MUC1 and NRG1 are required for NSCLC survival and tumorigenesis with clinical relevance. Taken together, these results have for the first time demonstrated the immunoregulatory functions, clinical relevance and therapeutic potential of the EIF4G1 network in NSCLC, which may represent a promising and novel target to improve lung cancer treatment.

3.
Public Health Nutr ; : 1-13, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33541468

RESUMO

OBJECTIVE: To evaluate age-related differences in the independent/combined association of added sugar intake from soda and body adiposity with hyperuricaemia in gender-stratified US adults. DESIGN: Consumption of added sugar from soda was calculated from 24-h dietary interviews and categorised into none, regular and excessive consumption. Hyperuricaemia was defined as serum uric acid levels >417 mmol/l in men and >357 mmol/l in women. Multiple regression models with interaction terms and logistic models adjusted for covariates were conducted under survey-data modules. SETTING: National Health and Nutrition Examination Survey during 2007-2016. PARTICIPANTS: 15 338 adults without gout, failing kidneys, an estimated glomerular filtration rate < 30 or diabetes were selected. RESULTS: The age-stratified prevalence rate of hyperuricaemia was 18·8-20·4 % in males and 6·8-17·3 % in females. Hyperuricaemia prevalence of approximately 50 % was observed in young and middle age males who consumed excessive added sugar from soda. Excessive added sugar intake was observed to be associated with 1·5- to 2·0-fold and 2·0- to 2·3-fold increased risk of the probability of hyperuricaemia in young and middle age males and middle age females, respectively. Study participants, regardless of age or gender, who were obese and consumed excessive added sugar from soda had the highest risk of having hyperuricaemia. CONCLUSIONS: Our study revealed that the association between hyperuricaemia and consumption of excessive added sugar from soda may vary by age and gender. Obese adults who consumed excessive added sugar from soda had the highest risk of hyperuricaemia, a finding that was found across all age-specific groups for both genders.

4.
Int J Cancer ; 148(1): 99-105, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32930425

RESUMO

Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46) showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify single nucleotide polymorphisms (SNPs) that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Ten iterations of a 10-fold cross-validation search were conducted to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African was compared using the same cross-validated approach. Three SNPs (rs76229939, rs74421890 and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47-4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65-0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans.

5.
In Vivo ; 34(4): 1759-1764, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606144

RESUMO

BACKGROUND/AIM: Interleukin-16 (IL-16) is reported to play an important role in inflammation, carcinogenesis and tumoricidal processes, however, the contribution of IL-16 genotype to oral carcinogenesis is still largely unrevealed. Thus, the study aimed to investigate the contribution of IL-16 genotypes to Taiwan oral cancer risk. MATERIALS AND METHODS: The genotypes of IL-16 rs4778889, rs11556218, and rs4072111 were revealed among 958 oral cancer cases and 958 control subjects by polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP). RESULTS: First, the distributions of genotypic (p=0.0004) and allelic (p=0.0001) frequencies of IL-16 rs11556218 were significantly different between the case and control groups. In detail, the frequencies of IL-16 rs11556218 TG and GG were 28.1 and 5.8%, respectively, among oral cancer patients, significantly higher compared to those among controls (25.0% and 2.7%, respectively). Second, no difference was observed regarding IL-16 rs4778889 or IL-16 rs4072111. Last, there was a synergistic effect of betel quid chewing behavior and risky IL-16 rs11556218 genotype on oral cancer risk. CONCLUSION: The study indicates that the IL-16 rs11556218 G allele synergistically interacts with betel quid chewing behavior, contributing to increased risk of oral cancer in Taiwanese.

6.
Cancer Epidemiol Biomarkers Prev ; 29(9): 1731-1738, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32581112

RESUMO

BACKGROUND: A polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening. METHODS: United Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups. RESULTS: The expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age. CONCLUSIONS: PHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS. IMPACT: Personalized genetic risk assessments could inform prostate cancer screening decisions.

7.
Eur J Hum Genet ; 28(10): 1467-1475, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32514134

RESUMO

We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated for random sizes of the training set. The performance of a representative Established-SNP model was estimated for random sizes of the testing set. Mean HR98/50 (hazard ratio of top 2% to average in test set) of the Established-SNP model increased from 1.73 [95% CI: 1.69-1.77] to 2.41 [2.40-2.43] when the number of training samples was increased from 1 thousand to 30 thousand. Corresponding HR98/50 of the Discovery-SNP model increased from 1.05 [0.93-1.18] to 2.19 [2.16-2.23]. HR98/50 of a representative Established-SNP model using testing set sample sizes of 0.6 thousand and 6 thousand observations were 1.78 [1.70-1.85] and 1.73 [1.71-1.76], respectively. We estimate that a study population of 20 thousand men is required to develop Discovery-SNP PHS models while 10 thousand men should be sufficient for Established-SNP models.

8.
Molecules ; 25(3)2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31979200

RESUMO

Compound 1 is a curcumin di-O-2,2-bis(hydroxymethyl)propionate that shows significant in vitro and in vivo inhibitory activity against MDA-MB-231 cells with eight to ten-fold higher potency than curcumin. Here, we modified the α-position (C-4 position) of the central 1,3-diketone moiety of 1 with polar or nonpolar functional groups to afford a series of 4,4-disubstituted curcuminoid 2,2-bis(hydroxymethyl)propionate derivatives and evaluated their anticancer activities. A clear structure-activity relationship of compound 1 derivatives focusing on the functional groups at the C-4 position was established based on their anti-proliferative effects against the MDA-MB-231 and HCT-116 cell lines. Compounds 2-6 are 4,4-dimethylated, 4,4-diethylated, 4,4-dibenzylated, 4,4-dipropargylated and 4,4-diallylated compound 1, respectively. Compounds 2m-6m, the ester hydrolysis products of compounds 2-6, respectively, were synthesized and assessed for anticancer activity. Among all compound 1 derivatives, compound 2 emerged as a potential chemotherapeutic agent for colon cancer due to the promising in vivo anti-proliferative activities of 2 (IC50 = 3.10 ± 0.29 µM) and its ester hydrolysis product 2m (IC50 = 2.17 ± 0.16 µM) against HCT-116. The preliminary pharmacokinetic evaluation of 2 implied that 2 and 2m are main contributors to the in vivo efficacy. Compound 2 was further evaluated in an animal study using HCT-116 colon tumor xenograft bearing nude mice. The results revealed a dose-dependent efficacy that led to tumor volume reductions of 27%, 45%, and 60% at 50, 100, and 150 mg/kg doses, respectively. The established structure-activity relationship and pharmacokinetic outcomes of 2 is the guidance for future development of 4,4-disubstituted curcuminoid 2,2-bis(hydroxymethyl)- propionate derivatives as anticancer drug candidates.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida , Curcumina/química , Células HCT116 , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Camundongos , Camundongos Nus , Ratos Sprague-Dawley , Relação Estrutura-Atividade
9.
Int J Public Health ; 65(1): 45-53, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31982934

RESUMO

OBJECTIVES: This study aims to (1) assess the associations between sugar-sweetened beverages (SSB) consumption and C-reactive protein (CRP) levels, and (2) evaluate the modifying effect of body mass index (BMI) on the association between SSB consumption and CRP levels. METHODS: A total of 6856 eligible adults were selected from the 2007-2010 National Health and Nutrition Examination Survey (NHANES). Average quantity of SSB consumption was calculated from 2-day 24-h dietary recalls. All data analyses were performed with appropriate sampling weights. RESULTS: Compared with non-SSB drinkers, a 0.26 mg/l higher CRP was observed in heavy SSB drinkers after adjusting for demographic characteristics, lifestyle patterns, and BMI. An effect modification of BMI on SSB intake and CRP levels was detected (P < 0.05). Medium and heavy SSB consumers with obesity had 0.58 and 0.50 higher CRP than non-SSB consumers, respectively (P = 0.014 and 0.013). No association was found in SSB drinkers who were normal weight or overweight. CONCLUSIONS: These findings emphasize that SSB intake is positively associated with CRP levels. Obesity might strengthen CRP levels in individuals with medium/heavy amount of SSB consumption.


Assuntos
Índice de Massa Corporal , Proteína C-Reativa/análise , Inflamação/epidemiologia , Sobrepeso/epidemiologia , Bebidas Adoçadas com Açúcar/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupos de Populações Continentais , Dieta , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Obesidade/epidemiologia , Fatores Socioeconômicos , Adulto Jovem
10.
J Infect Dis ; 221(8): 1331-1341, 2020 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-31111897

RESUMO

Collectively, viruses are the principal cause of cancers arising in patients with immune dysfunction, including human immunodeficiency virus (HIV)-positive patients. Kaposi sarcoma (KS) etiologically linked to Kaposi sarcoma-associated herpesvirus (KSHV) continues to be the most common AIDS-associated tumor. The involvement of the oral cavity represents one of the most common clinical manifestations of this tumor. HIV infection incurs an increased risk among individuals with periodontal diseases and oral carriage of a variety of pathogenic bacteria. However, whether interactions involving periodontal bacteria and oncogenic viruses in the local environment facilitate replication or maintenance of these viruses in the oral cavity of HIV-positive patients remain largely unknown. We previously showed that pathogen-associated molecular patterns (PAMPs) from specific periodontal bacteria promoted KSHV entry into oral cells and subsequent establishment of latency. In the current study, we demonstrate that Staphylococcus aureus, one of common pathogens causing infection in HIV-positive patients, and its PAMPs can effectively induce KSHV lytic reactivation from infected oral cells, through the Toll-like receptor reactive oxygen species and cyclin D1-Dicer-viral microRNA axis. This investigation provides further clinical evidence about the relevance of coinfection due to these 2 pathogens in the oral cavities of a cohort HIV-positive patients and reveals novel mechanisms through which these coinfecting pathogens potentially promote virus-associated cancer development in the unique niche of immunocompromised patients.

11.
Transl Cancer Res ; 8(Suppl 4): S334-S345, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31497514

RESUMO

Background: Alcohol intake is a leading modifiable cause related to cancer-specific deaths. Various alcohol intake patterns have shown to impact cancer progression differently, however, many studies only evaluated simplified patterns (such as heavy vs. non-heavy drinking) of alcohol intake for cancer survivors. The objective of this study is to provide population-based prevalence of the complex alcohol drinking patterns for cancer survivors, and compare it with that of non-cancer individuals. Additionally, we evaluated the impact of cancer related factors (binary, alcohol-related cancer type, and length of cancer history) to the alcohol intake patterns adjusted for the selected factors. Methods: A total of 193,197 individuals, including 16,504 cancer survivors, with age ≥18 years old in the 2012-2017 National Health Interview Survey (NHIS) were included in this study. The population-based prevalence of alcohol patterns was estimated. To evaluate cancer related factors associated with the alcohol intake patterns, we applied multinomial logistic models with the appropriate sampling weights and adjusted the selected demographic factors and smoking status. Results: There were 62.1% of cancer survivors and 66.0% of non-cancer individuals who were current alcohol drinkers in the past year. The prevalence of heavy drinking was identical for 5.2% of cancer and non-cancer individuals. For frequent binge drinking, cancer survivors tended to have less frequent binge than non-cancer individuals (2.8% vs. 4.9%). After adjusting for the selected demographic factors and smoking status, the cancer survivors were less likely to have the intermediate level of alcohol intake (light/moderate or occasional binge drinking) compared with non-cancer individuals, but no difference for the excessive alcohol intake (heavy or frequent binge drinking) was observed for those with and without cancer. As for cancer type, those with non-alcohol related cancer tended to be a current drinker compared with those with alcohol-related cancer. Compared with cancer survivors with a short cancer history (2-4 years), survivors with a cancer history of 5-9 years were more likely to be current drinkers after adjusting for the selected factors. Cancer status, alcohol-related cancer type and length of cancer history had no impact on excessive alcohol intake. Conclusions: In summary, cancer survivors have similar excessive alcohol drinking patterns but were less likely to have the intermediate level of alcohol intake compared to non-cancer individuals. Alcohol intake may enhance cancer progression, interfere with cancer treatments and increase cancer-related mortality. To improve cancer survivors' health, custom alcohol interventions and cessation programs should be conducted to minimize alcohol intake for cancer survivors, especially for excessive alcohol drinkers.

12.
Virology ; 536: 16-19, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31394407

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV) causes several cancers such as Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). PD-1/PD-Ls immune checkpoint molecules play important roles in cancer cell immune escape. The expression of PD-1/PD-Ls and their regulation by oncogenic viruses, in particular KSHV, remain largely undefined. Here we demonstrate strong PD-1/PD-L1/PD-L2 expression in KS tissues from a cohort of HIV + patients. We found that induction of KSHV lytic reactivation significantly upregulates PD-L1 expression on infected tumor cells, potentially through several major cellular signaling pathways and IL-1ß, which may represent a novel mechanism for virus-associated tumor cell immune escape.


Assuntos
Antígeno B7-H1/genética , Infecções por HIV/genética , Herpesvirus Humano 8/genética , Interações Hospedeiro-Patógeno/genética , Proteína 2 Ligante de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/genética , Sarcoma de Kaposi/genética , Adulto , Antígeno B7-H1/imunologia , Linhagem Celular Tumoral , Estudos de Coortes , Coinfecção , Regulação da Expressão Gênica , Células HEK293 , HIV/imunologia , HIV/patogenicidade , Infecções por HIV/imunologia , Infecções por HIV/virologia , Herpesvirus Humano 8/imunologia , Herpesvirus Humano 8/patogenicidade , Interações Hospedeiro-Patógeno/imunologia , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Masculino , Pessoa de Meia-Idade , Proteína 2 Ligante de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/imunologia , Sarcoma de Kaposi/imunologia , Sarcoma de Kaposi/virologia , Transdução de Sinais , Evasão Tumoral/genética , Ativação Viral , Latência Viral
13.
Int J Mol Sci ; 20(7)2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30925760

RESUMO

Interleukin-18 (IL-18) is a multi-functional immuno-mediator in the development and progression of many types of infectious and inflammatory diseases. In this study, we evaluated the contribution of IL-18 genotypes to renal cell carcinoma (RCC) in Taiwan via the genotyping of IL-18 -656 (A/C), -607 (A/C), and -137 (G/C). Moreover, we analyzed their interactions with smoking, alcohol drinking, hypertension, and diabetes status. The results showed an association of the AC and CC genotypes of IL-18 -607 with a significant decrease in the risk of RCC compared with the AA genotype (odds ratio (OR) = 0.44 and 0.35, 95% confidence interval (CI) = 0.27⁻0.72 and 0.18⁻0.66, p = 0.0008 and 0.0010, respectively). Furthermore, a significantly lower frequency of the C allele at -607 was observed in the RCC group (35.3% vs. 49.8%; OR = 0.53; 95% CI = 0.35⁻0.71, p = 0.0003). However, IL-18 -656 and -137 did not exhibit a likewise differential distribution of these genotypes between the control and case groups. Stratifying the population according to smoking, alcohol drinking, hypertension, and diabetes status revealed a different distribution of IL-18 -607 genotypes among non-smokers, non-drinkers, and patients without diabetes, but not among smokers, drinkers, or patients with diabetes. These findings suggest that IL-18 -607 genotypes may play a role in the etiology and progression of RCC in Taiwan and may serve as a useful biomarker for early detection.


Assuntos
Carcinoma de Células Renais/genética , Interleucina-18/genética , Neoplasias Renais/genética , Polimorfismo de Nucleotídeo Único , Idoso , Carcinoma de Células Renais/epidemiologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Neoplasias Renais/epidemiologia , Masculino , Pessoa de Meia-Idade , Taiwan/epidemiologia
14.
Cancer Epidemiol Biomarkers Prev ; 28(6): 1067-1075, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30914434

RESUMO

BACKGROUND: African American (AA) men have a higher risk of developing prostate cancer than white men. SNPs are known to play an important role in developing prostate cancer. The impact of PVT1 and its neighborhood genes (CASC11 and MYC) on prostate cancer risk are getting more attention recently. The interactions among these three genes associated with prostate cancer risk are understudied, especially for AA men. The objective of this study is to investigate SNP-SNP interactions in the CASC11-MYC-PVT1 region associated with prostate cancer risk in AA men. METHODS: We evaluated 205 SNPs using the 2,253 prostate cancer patients and 2,423 controls and applied multiphase (discovery-validation) design. In addition to SNP individual effects, SNP-SNP interactions were evaluated using the SNP Interaction Pattern Identifier, which assesses 45 patterns. RESULTS: Three SNPs (rs9642880, rs16902359, and rs12680047) and 79 SNP-SNP pairs were significantly associated with prostate cancer risk. These two SNPs (rs16902359 and rs9642880) in CASC11 interacted frequently with other SNPs with 56 and 9 pairs, respectively. We identified the novel interaction of CASC11-PVT1, which is the most common gene interaction (70%) in the top 79 pairs. Several top SNP interactions have a moderate to large effect size (OR, 0.27-0.68) and have a higher prediction power to prostate cancer risk than SNP individual effects. CONCLUSIONS: Novel SNP-SNP interactions in the CASC11-MYC-PVT1 region have a larger impact than SNP individual effects on prostate cancer risk in AA men. IMPACT: This gene-gene interaction between CASC11 and PVT1 can provide valuable information to reveal potential biological mechanisms of prostate cancer development.


Assuntos
Afro-Americanos/genética , Grupo com Ancestrais do Continente Europeu/genética , Neoplasias da Próstata/genética , RNA Longo não Codificante/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Epistasia Genética , Seguimentos , Genes myc , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Prognóstico , Estudos Prospectivos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Longo não Codificante/metabolismo , Fatores de Risco
15.
Phytomedicine ; 53: 28-36, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30668408

RESUMO

BACKGROUND: Excision repair cross-complementary 1 (ERCC1) overexpression in lung cancer cells is strongly correlated with its resistance to platinum-based chemotherapy. Overexpression of thymidine phosphorylase (TP) reverts platinum-induced cancer cell death. PURPOSE: Curcumin has been reported to enhance antitumor properties through the suppression of TP and ERCC1 in non-small cell lung carcinoma cells (NSCLC). Nevertheless, whether two other curcuminoids, demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) from Curcuma longa demonstrate antitumor activity like that of curcumin remain unknown. METHODS: MTT assay was conducted to determine the cell cytotoxicity. Western blotting was used to determine the protein expressions. Docking is the virtual screening of a database of compounds and predicting the strongest binders based on various scoring functions. BIOVIA Discovery Studio 4.5 (D.S. 4.5) were used for docking. RESULTS: Firstly, when compared with curcumin and BDMC, DMC exhibited the most potent cytotoxic effect on NSCLC, most importantly, MRC-5, a lung fetal fibroblast, was insensitive to DMC (under 30 µM). Secondly, DMC alone significantly inhibited on-target cisplatin (CDDP) resistance protein, ERCC1, via PI3K-Akt-snail pathways, and TP protein expression in A549 cells. Thirdly, DMC treatment markedly increased post-target CDDP resistance pathway including Bax and cytochrome c. DMC significantly decreased Bcl-2 protein expressions. Finally, MTT assay indicated that DMC significantly increased CDDP-induced cytotoxicity and was confirmed with an increased Bax/Bcl-2 ratio, indicating upregulation of caspase-3. CONCLUSIONS: We concluded that enhancement of the cytotoxicity to CDDP by coadminstration with DMC was mediated by down-regulation of the expression of TP and ERCC1, regulated by PI3K-Akt-Snail pathway inactivation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Curcumina/análogos & derivados , Proteínas de Ligação a DNA/metabolismo , Endonucleases/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Células A549 , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Cisplatino/farmacologia , Curcuma/química , Curcumina/administração & dosagem , Curcumina/química , Curcumina/metabolismo , Curcumina/farmacologia , Diarileptanoides , Regulação para Baixo/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Timidina Fosforilase/antagonistas & inibidores , Timidina Fosforilase/metabolismo
16.
Ann Epidemiol ; 30: 44-49.e1, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30555003

RESUMO

PURPOSE: Smoking in young adults identifies the population at risk for future tobacco-related disease. We investigated smoking in a young adult population and within high-risk groups using emergency department (ED) data in a metropolitan area. METHODS: Using the electronic health record, we performed a retrospective study of smoking in adults aged 18-30 years presenting to the ED. RESULTS: Smoking status was available for 55,777 subjects (90.9% of the total ED cohort); 60.8% were women, 55.0% were black, 35.3% were white, and 8.1% were Hispanic; 34.4% were uninsured. Most smokers used cigarettes (95.1%). Prevalence of current smoking was 21.7% for women and 42.5% for men. The electronic health record contains data about diagnosis and social history that can be used to investigate smoking status for high-risk populations. Smoking prevalence was highest for substance use disorder (58.0%), psychiatric illness (41.3%) and alcohol use (39.1%), and lowest for pregnancy (13.5%). In multivariable analyses, male gender, white race, lack of health insurance, alcohol use, and illicit drug use were independently associated with smoking. Smoking risk among alcohol and drug users varied by gender, race, and/or age. CONCLUSIONS: The ED provides access to a large, demographically diverse population, and supports investigation of smoking risk in young adults.


Assuntos
Grupo com Ancestrais do Continente Africano/estatística & dados numéricos , Registros Eletrônicos de Saúde/estatística & dados numéricos , Serviço Hospitalar de Emergência/estatística & dados numéricos , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Hispano-Americanos/estatística & dados numéricos , Produtos do Tabaco , Fumar Tabaco/epidemiologia , Uso de Tabaco/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Feminino , Humanos , Masculino , Nova Orleans/epidemiologia , Prevalência , Estudos Retrospectivos , Distribuição por Sexo , Fumar Tabaco/efeitos adversos , Fumar Tabaco/etnologia , População Urbana , Adulto Jovem
17.
Molecules ; 23(12)2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30563166

RESUMO

Demethoxycurcumin (DMC), through a self-assembled amphiphilic carbomethyl-hexanoyl chitosan (CHC) nanomatrix has been successfully developed and used as a therapeutic approach to inhibit cisplatin-induced drug resistance by suppressing excision repair cross-complementary 1 (ERCC1) in non-small cell lung carcinoma cells (NSCLC). Previously, DMC significantly inhibited on-target cisplatin resistance protein, ERCC1, via PI3K-Akt-snail pathways in NSCLC. However, low water solubility and bioavailability of DMC causes systemic elimination and prevents its clinical application. To increase its bioavailability and targeting capacity toward cancer cells, a DMC-polyvinylpyrrolidone core phase was prepared, followed by encapsulating in a CHC shell to form a DMC-loaded core-shell hydrogel nanoparticles (DMC-CHC NPs). We aimed to understand whether DMC-CHC NPs efficiently potentiate cisplatin-induced apoptosis through downregulation of ERCC1 in NSCLC. DMC-CHC NPs displayed good cellular uptake efficiency. Dissolved in water, DMC-CHC NPs showed comparable cytotoxic potency with free DMC (dissolved in DMSO). A sulforhodamine B (SRB) assay indicated that DMC-CHC NPs significantly increased cisplatin-induced cytotoxicity by highly efficient intracellular delivery of the encapsulated DMC. A combination of DMC-CHC NPs and cisplatin significantly inhibited on-target cisplatin resistance protein, ERCC1, via the PI3K-Akt pathway. Also, this combination treatment markedly increased the post-target cisplatin resistance pathway including bax, and cytochrome c expressions. Thymidine phosphorylase (TP), a main role of the pyrimidine salvage pathway, was also highly inhibited by the combination treatment. The results suggested that enhancement of the cytotoxicity to cisplatin via administration of DMC-CHC NPs was mediated by down-regulation of the expression of TP, and ERCC1, regulated via the PI3K-Akt pathway.


Assuntos
Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Quitosana , Curcumina/análogos & derivados , Neoplasias Pulmonares/genética , Nanopartículas , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quitosana/química , Cisplatino/farmacologia , Curcumina/administração & dosagem , Diarileptanoides , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Microscopia Confocal , Nanopartículas/química , Nanopartículas/ultraestrutura , Proteínas Proto-Oncogênicas c-akt/metabolismo
18.
Molecules ; 23(12)2018 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-30469543

RESUMO

P-glycoprotein (P-gp) effluxes lots of chemotherapeutic agents and leads to multidrug resistance (MDR) in cancer treatments. The development of P-gp inhibitors from natural products provide a potential strategy for the beneficial clinical outcomes. This study aimed to evaluate the effects of the natural flavonoid taxifolin, luteolin, (-)-gallocatechin, and (-)-catechin on human P-gp activity. The kinetic interactions and underlying mechanisms of taxifolin-mediated transporter inhibition were further investigated. The transporter inhibition ability was evaluated in human P-gp stable expression cells (ABCB1/Flp-InTM-293) by calcein-AM uptake assays. The kinetics study for P-gp inhibition was evaluated by doxorubicin and rhodamine123 efflux assays. The MDR reversal ability of taxifolin were performed by SRB assays to detect the cell viability in sensitive cancer cell line (HeLaS3), and resistant cancer cell line (KB-vin). Cell cycle analysis and ABCB1 real-time RT-PCR were used for mechanical exploration. The results demonstrated that taxifolin decreased ABCB1 expression in a concentration-dependent manner. The function of P-gp was inhibited by taxifolin through uncompetitive inhibition of rhodamine 123 and doxorubicin efflux. The combination of taxifolin significantly resensitized MDR cancer cells to chemotherapeutic agents. These results suggested that taxifolin may be considered as a potential P-gp modulator for synergistic treatment of MDR cancers.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Quercetina/análogos & derivados , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação para Baixo , Doxorrubicina/farmacologia , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Quercetina/farmacologia
19.
J Neurosci Methods ; 309: 161-174, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30184473

RESUMO

BACKGROUND: Technological advances are enabling us to collect multimodal datasets at an increasing depth and resolution while with decreasing labors. Understanding complex interactions among multimodal datasets, however, is challenging. NEW METHOD: In this study, we tested the interaction effect of multimodal datasets using a novel method called the kernel machine for detecting higher order interactions among biologically relevant multimodal data. Using a semiparametric method on a reproducing kernel Hilbert space, we formulated the proposed method as a standard mixed-effects linear model and derived a score-based variance component statistic to test higher order interactions between multimodal datasets. RESULTS: The method was evaluated using extensive numerical simulation and real data from the Mind Clinical Imaging Consortium with both schizophrenia patients and healthy controls. Our method identified 13-triplets that included 6 gene-derived SNPs, 10 ROIs, and 6 gene-specific DNA methylations that are correlated with the changes in hippocampal volume, suggesting that these triplets may be important for explaining schizophrenia-related neurodegeneration. COMPARISON WITH EXISTING METHOD(S): The performance of the proposed method is compared with the following methods: test based on only first and first few principal components followed by multiple regression, and full principal component analysis regression, and the sequence kernel association test. CONCLUSIONS: With strong evidence (p-value ≤0.000001), the triplet (MAGI2, CRBLCrus1.L, FBXO28) is a significant biomarker for schizophrenia patients. This novel method can be applicable to the study of other disease processes, where multimodal data analysis is a common task.


Assuntos
Aprendizado de Máquina , Análise Multivariada , Neuroimagem/métodos , Esquizofrenia/diagnóstico , Adulto , Algoritmos , Simulação por Computador , Feminino , Humanos , Masculino , Curva ROC , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/genética
20.
Clin Lymphoma Myeloma Leuk ; 18(9): 569-575.e1, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30122201

RESUMO

BACKGROUND: The proteasome inhibitor bortezomib has demonstrated marked preclinical activity when combined with the histone deacetylase inhibitor vorinostat in leukemia, multiple myeloma, and mantle cell lymphoma (MCL) cells. The present study evaluated the efficacy and safety of the combination in patients with relapsed or refractory MCL and diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: The present multicenter, nonrandomized phase II trial used a Simon 2-stage design with 3 cohorts: cohort A, MCL with no previous bortezomib (including untreated MCL); cohort B, MCL with previous bortezomib; and cohort C, relapsed or refractory DLBCL with no previous bortezomib. Vorinostat (400 mg) was administered orally on days 1 to 5 and 8 to 12 before bortezomib (1.3 mg/m2), which was administered intravenously on days 1, 4, 8, and 11 of each 21-day cycle. RESULTS: For the 65 treated patients (22 in cohort A, 4 in cohort B, and 39 in cohort C), the overall response rate was 31.8%, 0%, and 7.7%, respectively. The median progression-free survival was 7.6 months for cohort A and 1.8 months for cohort C. In cohort A, 7 patients had a partial response (PRs), 5 had stable disease (SD), 7 had progressive disease (PD), 1 was not assessed, and 2 were not evaluable. In cohort B, 2 had SD and 2 had PD. In cohort C, 3 had a PR, 8 had SD, 23 had PD, and 5 were not assessed. Baseline NF-κB activation, measured as nuclear RelA by immunohistochemistry, did not correlate with clinical response. CONCLUSION: The combination of bortezomib and vorinostat is safe and has modest activity in MCL and limited activity in DLBCL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma de Célula do Manto/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Terapia de Salvação , Adulto , Idoso , Idoso de 80 Anos ou mais , Bortezomib/administração & dosagem , Feminino , Seguimentos , Humanos , Linfoma Difuso de Grandes Células B/patologia , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Vorinostat/administração & dosagem
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