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1.
BMC Cancer ; 21(1): 352, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33794808

RESUMO

BACKGROUND: Lung cancer survivors need more options to improve quality of life (QoL). It is unclear to what extent patients with advanced stage disease are willing to participate in home-based physical activity (PA) and if these interventions improve QoL. The goal of our study was to determine interest in participating in our 3-month home-based walking regimen in patients with advanced stage lung cancer. We used a randomized design to evaluate for potential benefit in PA and patient-reported outcomes. METHODS: We performed an open-label, 1:1 randomized trial in 40 patients with stage III/IV non-small cell lung cancer (NSCLC) evaluating enrollment rate, PA, QoL, dyspnea, depression, and biomarkers. Compared to usual care (UC), the intervention group (IG) received an accelerometer, in-person teaching session, and gain-framed text messages for 12 weeks. RESULTS: We enrolled 56% (40/71) of eligible patients. Participants were on average 65 years and enrolled 1.9 years from diagnosis. Most patients were women (75%), and receiving treatment (85%) for stage IV (73%) adenocarcinoma (83%). A minority of patients were employed part-time or full time (38%). Both groups reported low baseline PA (IG mean 37 (Standard deviation (SD) 46) vs UC 59 (SD 56) minutes/week; p = 0.25). The IG increased PA more than UC (mean change IG + 123 (SD 212) vs UC + 35 (SD 103) minutes/week; p = 0.051)). Step count in the IG was not statistically different between baseline (4707 step/day), week 6 (5605; p = 0.16), and week 12 (4606 steps/day; p = 0.87). The intervention improved EORTC role functioning domain (17 points; p = 0.022) with borderline improvement in dyspnea (- 13 points; p = 0.051) compared to UC. In patients with two blood samples (25%), we observed a significant increase in soluble PD-1 (219.8 (SD 54.5) pg/mL; p < 0.001). CONCLUSIONS: Our pilot trial using a 3-month, home-based, mobile health intervention enrolled over half of eligible patients with stage III and IV NSCLC. The intervention increased PA, and may improve several aspects of QoL. We also identified potential biomarker changes relevant to lung cancer biology. Future research should use a larger sample to examine the effect of exercise on cancer biomarkers, which may mediate the association between PA and QoL. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov ( NCT03352245 ).

2.
Gynecol Oncol ; 2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33773809

RESUMO

OBJECTIVES: Depression is one of the most prevalent mental disorders, and rates are higher among cancer survivors than the general population, and higher in ovarian cancer patients compared to cohorts of other cancer survivors. Physical activity has been associated with lower depressive symptoms in cancer survivors, yet no trial has examined this association in women with ovarian cancer. We examined the effect of exercise on depression symptomatology and serum brain derived neurotrophin factor (BDNF) which has been associated with depression, in women with ovarian cancer. METHODS: We conducted a 6-month home-based randomized trial of exercise vs. attention-control (AC) in 144 ovarian cancer survivors. Depressive symptomatology was measured via the Center for Epidemiologic Studies Depression Scale (CES-D). Serum total and free BDNF was measured at baseline and 6-months. Student's t-statistic and mixed-model repeated measures analysis was used to evaluate six-month change between arms in CES-D scores and BDNF. RESULTS: Women were 57.3 ±â€¯8.6 (mean ±â€¯SD) years old, 1.7 ±â€¯1.0 years post-diagnosis with a baseline CES-D score of 11.79 ±â€¯10.21. The majority (55%) were diagnosed with stage III/IV ovarian cancer. CES-D scores decreased in the exercise arm by 2.7 points (95% CI: -4.4, -0.9) or a 21% decrease compared to a 0.3 point decrease (-2.2, 1.5) (3% decrease) in the AC arm (P = 0.05). There was no difference in change in total or free BDNF between the exercise and AC arms. CONCLUSIONS: Ovarian cancer survivors are able to exercise at recommended levels, and exercise was associated with a significant reduction in depressive symptomatology.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33677781

RESUMO

PURPOSE: Our study examined whether common variants of obesity-associated genes FTO, MC4R, BDNF, and CREB1 moderated the effects of a lifestyle intervention on weight change among breast cancer survivors. METHODS: 151 breast cancer survivors with a body mass index ≥ 25 kg/m2 were randomly assigned to a 6-month weight loss intervention or usual care group. Genotyping of FTO rs9939609, MC4R rs6567160, BDNF rs11030104, CREB1 rs17203016 was performed. Linear mixed models were used including the main effects of genotype (assuming a dominant genetic model), treatment arm on weight and percent body fat changes, and genotype by treatment interaction variable. All statistical tests were evaluated against a Bonferroni-corrected alpha of 0.0125. RESULTS: Women in the intervention group achieved significantly greater weight loss than the usual care group (5.9% vs 0.4%, p < 0.001), regardless of genotype. Changes in weight and percent body fat did not differ significantly between carriers of the FTO rs9939609, MC4R rs6567160, BDNF rs11030104, and CREB1 rs17203016 risk alleles compared to non-carriers (p-interaction > 0.0125 for each single-nucleotide polymorphisms). CONCLUSIONS: Women who are genetically predisposed to obesity and recently diagnosed with breast cancer may achieve significant and clinically meaningful weight loss through healthy eating and exercise. CLINICAL TRIAL REGISTRATION: NCT02863887 (Date of Registration: August 11, 2016); NCT02110641 (Date of Registration: April 10, 2014).

4.
Artigo em Inglês | MEDLINE | ID: mdl-33563180

RESUMO

BACKGROUND: m6A-methyltransferaseMETTL3 anddemethylaseFTO regulate gene expressionby dynamically modifying RNAmethylation. However, theirclinical relevancein renal Clear Cell Carcinoma (CCRCC) hasnotbeenwell elucidated. OBJECTIVE: This study aimsto investigate prognostic values of FTO and METTL3mRNA and DNA methylation, their differential expression andassociations with chemokines and inflammation-related genes in CCRCC. METHOD: Kaplan-Meier survival curves and multivariate cox regression were performed for survival analyses, and random-effects meta-analysis was for differential expression of FTO and METTL3 in CCRCC. RESULTS: A significantly negative correlation existed between mRNA and DNA methylation for bothFTOandMETTL3.Survival analysis showed a superior survival in patients with either high FTOmRNA or low DNA methylation,or low METTL3mRNA or high DNA methylation. The adjusted hazard ratios were 0.67 (95% CI: 0.49-0.91, p=0.01) for high vs. low FTOmRNA, 2.17 (1.38-3.42, p=0.0008) for high vs. low FTODNA methylation, 1.97 (1.45-2.68, p<0.0001) for high vs. low METTL3mRNA, and 0.49 (0.31-0.79, p=0.003) for high vs. low METTL3DNA methylation, respectively. There was a significant interaction between FTO and METTL3mRNA levels (p =0.024). Upregulation of FTO and METTL3 with 1.64 folds (95% CI: 1.43-1.89) and 1.17 folds (1.02-1.35), respectively, was observed in CCRCCvs. normal kidney tissues.FTO and METTL3mRNA had opposite direction in association with the expression of CD8+ T cell migration-relatedchemokines. CONCLUSION: Dysregulated FTO and METTL3may beinvolved in the disease development and progression,and affect immune response in CCRCC.FTO and METTL3 expression and DNA methylation are potential prognostic markers of CCRCC.

5.
Int Immunopharmacol ; : 107167, 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33223469

RESUMO

The effect of immunosuppression blockade therapies depends on the infiltration of effector T cells and other immune cells in tumor. However, it is unclear how molecular pathways regulate the infiltration of immune cells, as well as how interactions between tumor-infiltrating immune cells and T cell activation affect breast cancer patient survival. CIBERSORT was used to estimate the relative abundance of 22 immune cell types. The association between mRNAs and immune cell abundance were assessed by Spearman correlation analysis. Enriched pathways were identified using MetaCore pathway analysis. The interactions between the T cell activation status and the abundance of tumor-infiltrating immune cells were evaluated using Kaplan-Meier survival and multivariate Cox regression models in a publicly available dataset of 1081 breast cancer patients. The role of tumor-infiltrating B cells in antitumor immunity, immune response of T cell subsets, and breakdown of CD4+ T cell peripheral tolerance were positively associated with M1 macrophage and CD8+ T cell but negatively associated with M2 macrophage. Abundant plasma cell was associated with prolonged survival (HR = 0.46, 95% CI: 0.32-0.67), and abundant M2 macrophage was associated with shortened survival (HR = 1.78, 95% CI: 1.23-2.60). There exists a significant interaction between the T cell activation status and the resting DC abundance level (p = 0.025). Molecular pathways associated with tumor-infiltrating immune cells provide future directions for developing cancer immunotherapies to control immune cell infiltration, and further influence T cell activation and patient survival in breast cancer.

6.
Nucleic Acids Res ; 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33035346

RESUMO

Transfer RNA-derived fragments (tRFs) are a new class of small non-coding RNAs and play important roles in biological and physiological processes. Prediction of tRF target genes and binding sites is crucial in understanding the biological functions of tRFs in the molecular mechanisms of human diseases. We developed a publicly accessible web-based database, tRFtarget (http://trftarget.net), for tRF target prediction. It contains the computationally predicted interactions between tRFs and mRNA transcripts using the two state-of-the-art prediction tools RNAhybrid and IntaRNA, including location of the binding sites on the target, the binding region, and free energy of the binding stability with graphic illustration. tRFtarget covers 936 tRFs and 135 thousand predicted targets in eight species. It allows researchers to search either target genes by tRF IDs or tRFs by gene symbols/transcript names. We also integrated the manually curated experimental evidence of the predicted interactions into the database. Furthermore, we provided a convenient link to the DAVID® web server to perform downstream functional pathway analysis and gene ontology annotation on the predicted target genes. This database provides useful information for the scientific community to experimentally validate tRF target genes and facilitate the investigation of the molecular functions and mechanisms of tRFs.

7.
Int J Cancer ; 2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33105052

RESUMO

A full-term pregnancy is associated with reduced endometrial cancer risk; however, whether the effect of additional pregnancies is independent of age at last pregnancy is unknown. The associations between other pregnancy-related factors and endometrial cancer risk are less clear. We pooled individual participant data from 11 cohort and 19 case-control studies participating in the Epidemiology of Endometrial Cancer Consortium (E2C2) including 16 986 women with endometrial cancer and 39 538 control women. We used one- and two-stage meta-analytic approaches to estimate pooled odds ratios (ORs) for the association between exposures and endometrial cancer risk. Ever having a full-term pregnancy was associated with a 41% reduction in risk of endometrial cancer compared to never having a full-term pregnancy (OR = 0.59, 95% confidence interval [CI] 0.56-0.63). The risk reduction appeared the greatest for the first full-term pregnancy (OR = 0.78, 95% CI 0.72-0.84), with a further ~15% reduction per pregnancy up to eight pregnancies (OR = 0.20, 95% CI 0.14-0.28) that was independent of age at last full-term pregnancy. Incomplete pregnancy was also associated with decreased endometrial cancer risk (7%-9% reduction per pregnancy). Twin births appeared to have the same effect as singleton pregnancies. Our pooled analysis shows that, while the magnitude of the risk reduction is greater for a full-term pregnancy than an incomplete pregnancy, each additional pregnancy is associated with further reduction in endometrial cancer risk, independent of age at last full-term pregnancy. These results suggest that the very high progesterone level in the last trimester of pregnancy is not the sole explanation for the protective effect of pregnancy.

8.
BMC Cancer ; 20(1): 856, 2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32894098

RESUMO

BACKGROUND: Germline copy number variants (CNVs) increase risk for many diseases, yet detection of CNVs and quantifying their contribution to disease risk in large-scale studies is challenging due to biological and technical sources of heterogeneity that vary across the genome within and between samples. METHODS: We developed an approach called CNPBayes to identify latent batch effects in genome-wide association studies involving copy number, to provide probabilistic estimates of integer copy number across the estimated batches, and to fully integrate the copy number uncertainty in the association model for disease. RESULTS: Applying a hidden Markov model (HMM) to identify CNVs in a large multi-site Pancreatic Cancer Case Control study (PanC4) of 7598 participants, we found CNV inference was highly sensitive to technical noise that varied appreciably among participants. Applying CNPBayes to this dataset, we found that the major sources of technical variation were linked to sample processing by the centralized laboratory and not the individual study sites. Modeling the latent batch effects at each CNV region hierarchically, we developed probabilistic estimates of copy number that were directly incorporated in a Bayesian regression model for pancreatic cancer risk. Candidate associations aided by this approach include deletions of 8q24 near regulatory elements of the tumor oncogene MYC and of Tumor Suppressor Candidate 3 (TUSC3). CONCLUSIONS: Laboratory effects may not account for the major sources of technical variation in genome-wide association studies. This study provides a robust Bayesian inferential framework for identifying latent batch effects, estimating copy number, and evaluating the role of copy number in heritable diseases.

9.
Pancreas ; 49(9): 1187-1194, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32898003

RESUMO

OBJECTIVES: The purpose of this study was to investigate the association of syndecan-1 (SDC1) and KRAS molecular characteristics with patient survival in pancreatic cancer. METHODS: Both SDC1 mRNA and methylation and KRAS mRNA and somatic mutations, as well as clinical data were retrieved from The Cancer Genome Alta pancreatic cancer data set for survival analyses. Kyoto Encyclopedia of Gene and Genomes pathway analysis for coexpressed genes for either SDC1 or KRAS was performed, respectively. RESULTS: A significantly negative correlation existed between SDC1 mRNA and DNA methylation. Patients with KRAS somatic mutations had a significantly higher SDC1 mRNA but lower methylation than those without the mutations. Compared with patients with KRASSDC1 signature, those with a high level of KRAS and SDC1 alone or both had a significantly elevated mortality. The adjusted hazard ratios (95% confidence interval) were 2.30 (1.16-4.54, P = 0.017) for KRASSDC1, 2.85 (1.48-5.49, P = 0.002) for KRASSDC1, and 2.48 (1.31-4.70, P = 0.005) for KRASSDC1, respectively. Several Kyoto Encyclopedia of Gene and Genomes pathways were shared, whereas there were distinct pathways between KRAS and SDC1 coexpressed genes. CONCLUSIONS: SDC1 interplays with KRAS, and targeting both KRAS and SDC1 in combination may be more beneficial to pancreatic cancer patients.

10.
Biosci Rep ; 40(9)2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32869851

RESUMO

Low expression of tumor suppressor microRNA (miRNA) and high expression of carcinogenic miRNA promote the occurrence and progression of human cancer. Most studies show that miR-145 is a tumor suppressor miRNA, and is closely related to the clinicopathology of breast cancer. However, the results are still inconsistent. Therefore, we conducted a meta-analysis on the basis of eligible studies to summarize the possible correlation between miR-145 and the clinicopathology and prognosis of breast cancer. Using PubMed, Embase, Web of Science, Wanfang and CNKI, we searched all published papers written in either English or Chinese on miR-145 expression in breast cancer from 1990 to November 2019 for meta-analysis. We used standardized mean difference (SMD) to evaluate the differential expression of miR-145 in breast cancer tissues and adjacent normal tissues or normal breast tissues. We found that miR-145 expression was significantly lower in breast cancer tissues than that in adjacent normal tissues (SMD = -2.93, P<0.0001) and in healthy women (SMD = -0.52, P=0.009). miR-145 expression was lower in breast cancer patients with ER-positive (SMD = 0.65, P<0.001), HER-2-positive (SMD = -1.04, P<0.001), compared with their counterparts, respectively. In addition, breast cancer patients with low expression of miR-145 had larger tumor diameters (SMD = -1.97, P<0.001) and lymph node metastasis (SMD = -1.75, P<0.001) that are unfavorable prognostic factors. Conclusion: Low miR-145 is observed in breast cancer, which is closely related to molecular subtypes and unfavorable factors of breast cancer. These findings indicate that miR-145 is tumor suppressor miRNA, and may be a potential diagnostic and prognostic marker in breast cancer.

11.
Cancers (Basel) ; 12(8)2020 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-32785169

RESUMO

Effector CD8+ T cell activation and its cytotoxic function are positively correlated with improved survival in breast cancer. tRNA-derived fragments (tRFs) have recently been found to be involved in gene regulation in cancer progression. However, it is unclear how interactions between expression of tRFs and T cell activation affect breast cancer patient survival. We used Kaplan-Meier survival and multivariate Cox regression models to evaluate the effect of interactions between expression of tRFs and T cell activation on survival in 1081 breast cancer patients. Spearman correlation analysis and weighted gene co-expression network analysis were conducted to identify genes and pathways that were associated with tRFs. tRFdb-5024a, 5P_tRNA-Leu-CAA-4-1, and ts-49 were positively associated with overall survival, while ts-34 and ts-58 were negatively associated with overall survival. Significant interactions were detected between T cell activation and ts-34 and ts-49. In the T cell exhaustion group, patients with a low level of ts-34 or a high level of ts-49 showed improved survival. In contrast, there was no significant difference in the activation group. Breast cancer related pathways were identified for the five tRFs. In conclusion, the identified five tRFs associated with overall survival may serve as therapeutic targets and improve immunotherapy in breast cancer.

12.
Cancers (Basel) ; 12(6)2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32575418

RESUMO

Cancer cells activate a telomere maintenance mechanism like telomerase in order to proliferate indefinitely. Telomerase can be reactivated by gain-of-function Telomerase Reverse Transcriptase (TERT) promoter mutations (TPMs) that occur in several cancer subtypes with high incidence and association with diagnosis, prognosis and epigenetics. However, such information about TPMs in sporadic pancreatic neuroendocrine neoplasms (pNENs) including tumor (pNET) and carcinoma (pNEC) is less well defined. We have studied two hot spot TPMs and telomere length (TL) in pNEN and compared the results with clinicopathological information and proliferation-associated miRNA/HDAC expression profiles. DNA was isolated from formalin-fixed paraffin-embedded (FFPE) tissue of 58 sporadic pNEN patients. T allele frequency of C250T and C228T TPM was analyzed by pyrosequencing, relative TL as telomeric content by qPCR. In total, five pNEN cases (9%) including four pNETs and one pNEC were identified with TPMs, four cases with exclusive C250T as predominant TPM and one case with both C250T and C228T. T allele frequencies of DNA isolated from adjacent high tumor cell content FFPE tissue varied considerably, which may indicate TPM tumor heterogeneity. Overall and disease-free survival was not associated with TPM versus wild-type pNEN cases. Binary category analyses indicated a marginally significant relationship between TPM status and longer telomeres (p = 0.086), and changes in expression of miR449a (p = 0.157), HDAC4 (p = 0.146) and HDAC9 (p = 0.149). Future studies with larger patient cohorts are needed to assess the true clinical value of these rare mutations in pNEN.

13.
J Clin Invest ; 130(9): 4985-4998, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32516139

RESUMO

The brain has evolved in an environment where food sources are scarce, and foraging for food is one of the major challenges for survival of the individual and species. Basic and clinical studies show that obesity or overnutrition leads to overwhelming changes in the brain in animals and humans. However, the exact mechanisms underlying the consequences of excessive energy intake are not well understood. Neurons expressing the neuropeptide hypocretin/orexin (Hcrt) in the lateral/perifonical hypothalamus (LH) are critical for homeostatic regulation, reward seeking, stress response, and cognitive functions. In this study, we examined adaptations in Hcrt cells regulating behavioral responses to salient stimuli in diet-induced obese mice. Our results demonstrated changes in primary cilia, synaptic transmission and plasticity, cellular responses to neurotransmitters necessary for reward seeking, and stress responses in Hcrt neurons from obese mice. Activities of neuronal networks in the LH and hippocampus were impaired as a result of decreased hypocretinergic function. The weakened Hcrt system decreased reward seeking while altering responses to acute stress (stress-coping strategy), which were reversed by selectively activating Hcrt cells with chemogenetics. Taken together, our data suggest that a deficiency in Hcrt signaling may be a common cause of behavioral changes (such as lowered arousal, weakened reward seeking, and altered stress response) in obese animals.

14.
Int J Gynaecol Obstet ; 150(3): 385-391, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32506422

RESUMO

OBJECTIVE: To establish the rate of occult ovarian micro-metastases in early stage disease and to provide an eligibility framework for providers to consider ovarian preservation in a patient population with presumed early stage disease. METHODS: A retrospective review from January 2005 to December 2010 identified women with presumed early stage endometrial cancer from a single institutional database. Inclusion criteria included: (1) FIGO grade 1 endometrioid endometrial cancer on endometrial biopsy; or (2) the same pathology as (1) on frozen section specimen with less than 50% myometrial biopsy; and (3) no evidence of metastatic disease on preoperative imaging or visible metastatic disease in the peritoneal cavity. RESULTS: Of the 52 patients, 86.5% were diagnosed with stage IA and 11.5% were diagnosed with stage II disease. One patient (1.9%) had microscopic adnexal involvement in a fallopian tube, which upstaged her to stage IIA disease. None of the patients had ovarian involvement. CONCLUSION: Preservation of the ovaries appears to be a safe and viable option for premenopausal women who are diagnosed with presumed early stage endometrioid endometrial cancer. It is believed that ovarian preservation in this select population will provide them with significant health benefits and improve their quality of life.

15.
Int Immunopharmacol ; 85: 106628, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32474388

RESUMO

Cancer immunotherapy has brought a great revolution in the treatment of advanced human cancer. Immune checkpoint inhibitors (ICIs) that target cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death protein 1 pathway (PD-1/PD-L1) have been widely administrated in the past years and demonstrated promising in a variety of malignancies. While some patients show benefit from ICIs, others do not respond or even develop resistance to these therapies. Among the responders, the treatments are consequently accompanied with immune-related adverse effects (irAEs), which are diverse in their effected organs, degree of severity and timing. Some of the toxicities are fatal and result in discontinuance of immunotherapy. The toxicity profile from anti-CTLA-4 to anti-PD-1/PD-L1 immunotherapies is distinct from those caused by conventional anticancer therapies, though their presentation may be similar. In order to better help clinicians recognize, monitor and manage irAEs in a growing population of cancer patients who are receiving ICI therapy, this article summarizes the FDA approved ICIs and focuses on (1) existing toxic evidence related to ICIs, (2) occurrence of irAEs, (3) factors influencing tumor responders treated with ICIs, (4) predictive biomarkers of irAEs, and (5) new potential mechanisms of resistance to ICI therapy.

16.
Oncol Rep ; 43(6): 2062-2072, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32186770

RESUMO

Breast cancer is the most common cancer type and the leading cause of cancer­associated mortality in women across the majority of countries. In general, the incidence of breast cancer has been decreasing in developed countries over the previous 20 years, while it has increased in the other areas, such as the Asian­Pacific region. MicroRNA­34a (miR­34a) targets stem cell­associated transcription factors E2F1/E2F3, and may have clinical relevance in breast cancer. The present study aimed to investigate the association between miR­34a/E2F1/E2F3 and patient survival in breast cancer, as well as the underlying molecular mechanism of miR­34a in suppressing factors associated with tumor aggressiveness in vitro. Kaplan­Meier survival curves were constructed and a meta­analysis was performed to analyze the association of miR­34a, E2F1 and E2F3 expression and overall survival in breast cancer, and the differential expression levels of E2F1 and E2F3 between breast cancer and normal breast tissues was assessed using publicly accessed datasets. Then 2D and 3D experiments on cell cultures were performed in vitro on both T­47D and MDA­MB­231 cells to investigate the cancer biology of miR­34a and its effect on E2F1 and E2F3 expression using reverse transcription­quantitative PCR. Then, caspase­3 (CASP3) activity was measured using a CaspACE™ assay system. E2F1 and E2F3 expression levels were upregulated in breast cancer, compared with normal breast tissues. Both high miR­34a, and low E2F1 and E2F3 mRNA levels were positively associated with longer survival times in patients with breast cancer. The in vitro 2D and 3D cell experiments revealed that overexpression of miR­34a significantly downregulated the expression of E2F1 and E2F3, and increased CASP3 activity in both T­47D and MDA­MB­231 cells, and that miR­34a treatment inhibited tumor cell proliferation, migration and invasiveness, as well as 3D spheroid formation. Thus, miR­34a influences the aggressiveness of breast cancer and patient survival, and is a potential therapeutic tool in the clinical management of breast cancer.


Assuntos
Neoplasias da Mama/mortalidade , Fator de Transcrição E2F1/genética , Fator de Transcrição E2F3/genética , MicroRNAs/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Movimento Celular , Proliferação de Células , Fator de Transcrição E2F1/metabolismo , Fator de Transcrição E2F3/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica , Análise de Sobrevida
17.
Cancer Causes Control ; 31(4): 321-332, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32060838

RESUMO

PURPOSE: HCC incidence has been continuously rising in the US for the past 30 years. To understand the increase in HCC risk, we conducted a case-control study in Connecticut, New Jersey and part of New York City. METHODS: Through rapid case ascertainment and random digit dialing, we recruited 673 incident HCC patients and 1,166 controls. Information on demographic and anthropometric characteristics, lifestyle factors, medical and family cancer histories, were ascertained through telephone interviews using a structured questionnaire. Saliva specimens were collected for testing hepatitis C virus (HCV) antibodies. Unconditional logistic regression models were utilized to calculate odds ratio (OR) and 95% confidence interval (CI) to determine HCC associations with risk factors. RESULTS: The study confirmed that HCV infection and obesity were important risk factors for HCC, ORs 110 (95% CI 59.2-204) and 2.13 (95% CI 1.52-3.00), respectively. High BMI and HCV infection had synergy in association with elevated HCC risk. Patients both obese and infected with HCV had HCC detected on average nearly 10 years earlier than those with neither factor. Diabetes, cigarette smoking and heavy alcohol intake were all associated with increased risk of HCC, whereas aspirin and other NSAID use were associated with reduced risk. HCC cases tended to attain less education, with lower household incomes, unmarried, and to have had more sexual partners than the controls. CONCLUSIONS: Individuals at risk of HCC in the US comprise a unique population with low socioeconomic status and unhealthy lifestyle choices. Given the multifactorial nature, a comprehensive approach is needed in HCC prevention.


Assuntos
Carcinoma Hepatocelular/epidemiologia , Neoplasias Hepáticas/epidemiologia , Adulto , Idoso , Estudos de Casos e Controles , Connecticut/epidemiologia , Diabetes Mellitus/epidemiologia , Feminino , Hepatite C/epidemiologia , Humanos , Incidência , Estilo de Vida , Masculino , Pessoa de Meia-Idade , New Jersey/epidemiologia , Cidade de Nova Iorque/epidemiologia , Obesidade/epidemiologia , Fatores de Risco
18.
Chemosphere ; 246: 125828, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31927381

RESUMO

People are inevitably exposed to phthalates (PEs) ubiquitously existing in environment. Our previous studies, simulating the actual situations of people exposure to PEs, have shown that the sub-chronic exposure to low-doses PEs mixture (MIXPs) impaired reproductive function in male rats. Zinc is an important element in maintaining male reproductive functions. However, it is still unknown whether zinc supplement could mitigate PEs-induced male reproductive toxicity or not with sub-chronic low-dose mixture exposure. This study aimed to explore the effect of zinc supplement on the reproductive toxicity caused by sub-chronic MIXPs exposure (160 mg/(kg•body weight)/d, for 90 days) in male rats, and further to reveal the underlying mechanisms. Testosterone (T), FSH and LH in serum, early toxicity indicators in urine, PIWI proteins (PIWIL1 and PIWIL2) expression in testes and pathological examination were performed for toxicity evaluation. Steroidogenic proteins (17ß-HSD, StAR, CYP17A1, P450scc and SRD5A) were measured for mechanisms of exploration. The results indicated that zinc supplement could inhibit the T, LH, FSH level decreases in serum, abolish the effect of 5 early toxicity indicators' levels in urine, restrain the alteration of PIWI proteins expression and improve the constructional injury of testes. These effects might be relevant with the suppressed alteration of the expression of steroidogenic proteins induced by MIXPs in rat testicular cells. This work may offer further insights into reducing health risks of MIXPs exposure.


Assuntos
Poluentes Ambientais/toxicidade , Ácidos Ftálicos/toxicidade , Reprodução/efeitos dos fármacos , Zinco/metabolismo , Animais , Proteínas Argonauta , Masculino , Proteínas/metabolismo , Ratos , Ratos Sprague-Dawley , Testículo/efeitos dos fármacos , Testosterona/sangue
19.
Oral Oncol ; 101: 104554, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31887619

RESUMO

OBJECTIVES: To investigate how T-cell activation interacts with NSUN2 to influence HNSCC patient survival. MATERIALS AND METHODS: The relationships between T-cell activation status (Activation, Intermediate, and Exhaustion), NSUN2 expression, and patient survival were evaluated using Kaplan-Meier survival curves and multivariate Cox regression models in a public dataset with 520 HNSCC patients. HPV status was determined based on a VirusScan analysis of RNA-seq data. RESULTS: Among the patients with high NSUN2 expression, the Activation group exhibited longer survival than the Exhaustion group (trend P = 0.056). Adjusted hazards ratios (HRs) were 0.77 (95% CI: 0.49-1.19) for the Intermediate vs Exhaustion, and 0.61 (0.36-1.03) for Activation vs. Exhaustion. In contrast, there is a positive association between T-cell activation score and mortality in the patients with low NSUN2 expression (trend P = 0.016). The adjusted HRs were 1.97 (1.12-3.47) for the Intermediate vs Exhaustion, and 2.06 (1.16-3.68) for the Activation vs Exhaustion. In multivariate cox models with or without HPV status, the interaction between T-cell activation status and NSUN2 expression was statistically significant (P = 0.004 for with HPV status, and P = 0.002 for without, respectively). When not controlling for NSUN2 expression, there was no significant association between T-cell activation score and patient mortality (P = 0.84). CONCLUSIONS: An interaction between NSUN2 expression and T-cell activation status affects patient survival in HNSCC regardless of HPV status, suggesting that NSUN2 is a potential precision marker for immune-checkpoint blockade, and a potential therapeutic target.


Assuntos
Regulação Neoplásica da Expressão Gênica , Ativação Linfocitária/genética , Metiltransferases/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Linfócitos T/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Linfócitos T/imunologia , Adulto Jovem
20.
Biomed Res Int ; 2020: 8826456, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33415160

RESUMO

N6-methyladenosine (m6A) plays an important role in many cancers. However, few studies have examined the role of m6A in colorectal CRC. To examine the effect of m6A on CRC, we studied the genome of 591 CRC cases from The Cancer Genome Atlas (TCGA). The relationship between the messenger RNA (mRNA) expression, copy number variation (CNVs), and mutations of m6A "Writers," "Readers," and "Erasers," prognosis, immune cell infiltration, and genetic mutations in CRC cases were analyzed. CNVs and mutations were found in thirteen m6A regulators. As expected, gain and amplification of m6A regulators increased the mRNA expression of these regulators, while deletion led to reduction in the mRNA expression. Moreover, CNVs and mutation of these regulators were significantly associated with APC, TP53, and microsatellite instability (MSI) status (p < 0.001, p < 0.001, and p = 0.029, respectively). CNVs of m6A regulators also correlated with inferred immune cell infiltration in CRC tissues, especially in colon tissues. Additionally, alterations of RBM15, YTHDF2, YTHDC1, YTHDC2, and METTL14 genes were related to the worse overall survival and disease-free survival (DFS) of CRC patients. Specifically, the deletion status of "Writers" was also correlated to the DFS of CRC patients (p = 0.02). Gene set enrichment analysis found that FTO was involved in mRNA 3' end processing, polyubiquitin binding, and RNA polymerase promoter elongation, while YTHDC1 was related to interferon-alpha and gamma response. In conclusion, a novel relationship was identified between CNVs and mutations of m6A regulators with prognosis and inferred immune function of CRC. These findings will improve the understanding of the relationship of m6A in CRC.

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