Few trials have examined the effect of lifestyle behavioral interventions on tissue markers in patients with cancer. The purpose of this study was to examine the feasibility and impact of a 6-month ...weight loss intervention on breast tissue and serum biomarkers in women with breast cancer. Fifty-one women who completed breast cancer treatment and had a BMI ≥ 25.0 kg/m
were randomized to a weight loss intervention or usual care. Breast tissue biopsies, fasting blood draw and body composition were collected at baseline and 6 months, with between-group changes examined using analysis of covariance method. Baseline and post-intervention biopsies were conducted in 49 and 42 women, respectively, with pre- and post-epithelial tissue available from 25 tissue samples. Average 6-month weight loss was 6.7% for the weight loss group and 2.0% increase for the usual care group (p < 0.0001). At baseline, body fat and serum insulin levels were inversely associated with breast tissue insulin receptor levels and CD68 (p < 0.05). At 6 months, favorable changes were observed in serum leptin and adiponectin levels and tissue CD163 among women randomized to weight loss vs. adverse change in women randomized to usual care (p < 0.05). Breast tissue biopsies are feasible to collect in a clinical research setting among breast cancer survivors, with weight loss favorably impacting metabolic and inflammatory markers associated with breast cancer.
•PXR is significantly activated by BDE-47 in PXR-overexpressing HepG2 cells.•Thyroid receptor isoforms are downregulated in response to BDE-47.•Expression of PXR downstream target CYP3A4, UGT1A3, and ...SULT2A1 are increased by BDE-47.•Activation of hPXR may play a critical role in BDE-47–induced thyroid hormone disruption.
2,2′,4,4′-Tetra-bromodiphenyl ether (BDE-47), an important congener among polybrominated diphenyl ether (PBDE) compounds, has been predominantly in environmental samples and human tissue. Thyroid disruption is the most sensitive endpoint effect among a number of health effects of exposure to BDE-47 in animals and humans. However, the detailed underlying mechanisms in humans are not well understood. In the present study, human pregnane X receptor (hPXR)-overexpressing HepG2 cell model and a dual-luciferase reporter assay system were constructed to investigate the role of hPXR in BDE-47–induced alterations of expression of metabolic enzymes and TR in vitro. The results showed that hPXR was significantly activated by BDE-47, and expression levels of both mRNA and protein of the thyroid receptor (TR) isoforms TRα1 and TRβ1 were decreased in hPXR-overexpressing HepG2 cells after BDE-47 treatment. However, the increased expression of hepatic microsomal phase I enzyme CYP3A4 and phase II enzymes, UGT1A3 and SULT2A1 were also found. Taken together, the results indicated that BDE-47 was a strong hPXR activator, activation of hPXR played an important role in BDE-47–induced down-regulation of TR, and up-regulations of CYP3A4, UGT1A3, and SULT2A1 participated in the process, which may provide more toxicological evidence on mechanisms of disruption of thyroid hormone induced by BDE-47.
Several genome-wide association studies (GWASs) reported tens of risk genes for alcohol dependence, but most of them have not been replicated or confirmed by functional studies. The present study ...used a GWAS to search for novel, functional and replicable risk gene regions for alcohol dependence. Associations of all top-ranked SNPs identified in a discovery sample of 681 African-American (AA) cases with alcohol dependence and 508 AA controls were retested in a primary replication sample of 1,409 European-American (EA) cases and 1,518 EA controls. The replicable associations were then subjected to secondary replication in a sample of 6,438 Australian family subjects. A functional expression quantitative trait locus (eQTL) analysis of these replicable risk SNPs was followed-up in order to explore their cis-acting regulatory effects on gene expression. We found that within a 90 Mb region around PHF3-PTP4A1 locus in AAs, a linkage disequilibrium (LD) block in PHF3-PTP4A1 formed the only peak associated with alcohol dependence at p<10(-4). Within this block, 30 SNPs associated with alcohol dependence in AAs (1.6×10(-5)≤p≤0.050) were replicated in EAs (1.3×10(-3)≤p≤0.038), and 18 of them were also replicated in Australians (1.8×10(-3)≤p≤0.048). Most of these risk SNPs had strong cis-acting regulatory effects on PHF3-PTP4A1 mRNA expression across three HapMap samples. The distributions of -log(p) values for association and functional signals throughout this LD block were highly consistent across AAs, EAs, Australians and three HapMap samples. We conclude that the PHF3-PTP4A1 region appears to harbor a causal locus for alcohol dependence, and proteins encoded by PHF3 and/or PTP4A1 might play a functional role in the disorder.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The stage at diagnosis is a major factor in making treatment strategies and cancer control policies. However, the stage distribution for liver cancer in China was not well studied. In this ...multi-center hospital-based study, we aimed to identify the distribution and factors associated with stage at diagnosis for liver cancer in China.
We included patients diagnosed with primary liver cancer in 13 hospitals of 10 provinces covering various geographic and socioeconomic populations during 2016–2017 in China. The stage distribution overall, and by sex and age at diagnosis were analyzed. We used logistic regression to identify the factors associated with stage III-IV disease. We further compared these estimates with data from the USA.
We included 2,991 patients with known stage at diagnosis in China. The proportion of patients diagnosed with stage I, II, III, and IV was 17.5%, 25.6%, 29.3%, and 27.6%, respectively. The proportion of stage III-IV cases was higher in women 65.1% vs 54.9%, adjusted odds ratio (OR) = 1.5, 95% CI: 1.2, 1.8 and those ≥ 60 years (61.6% vs 52.8%, OR = 1.4, 95% CI: 1.2, 1.6). We found an increased risk of stage III-IV among drinkers and those without a family history of cancer. Compared to the USA, our study population had a substantially higher proportion of stage III-IV cases (56.9% vs 45.6%).
The disparities in liver cancer stage at diagnosis among different populations within China, and between China and the USA, imply the necessity for improving cancer awareness and early detection for liver cancer in China.
•Uterine adenosarcoma appears to have relatively good prognosis, especially in the absence of high-risk factors.•Lymphadenectomy and adjuvant therapy have an unclear benefit for Mullerian ...adenosarcoma.•Ovarian preservation can be considered in premenopausal patients with presumed uterine-confined disease.
To examine clinicopathologic characteristics and oncologic outcomes of patients diagnosed with Mullerian adenosarcoma and to evaluate ovarian preservation as a practical management option in early-stage disease.
A retrospective review was performed of 31 patients treated for uterine, ovarian, or cervical adenosarcoma at our institution between 1/2000–3/2020. Recurrence-free survival (RFS) and overall survival (OS) were analyzed with Kaplan-Meier estimates, the log-rank test, and Cox proportional hazards regression.
Median age was 51 years (IQR: 41–68). Primary sites included uterine corpus (n = 23, 74.2%), uterine cervix (n = 7, 22.6%), and ovary (n = 1, 3.2%). Surgical management primarily consisted of total hysterectomy +/- bilateral adnexectomy +/- lymph node dissection. Fifteen (48.1%) patients underwent lymph node dissection; no patients had positive nodes. Ovaries were preserved in 6 (19.4%). Twenty-two (71.0%) patients received no adjuvant therapy, 4 (12.9%) received chemotherapy, 1 (3.2%) received chemoradiation, and 3 (9.7%) received hormonal therapy. Sarcomatous overgrowth (p = 0.04), high grade histology (p = 0.002), and greater depth of myometrial invasion (p = 0.001) were associated with decreased RFS. None of the 6 patients with ovarian preservation had recurrences. At last follow up, 21 patients (67.7%) had no evidence of disease, 7 (22.6%) were deceased due to disease, and 3 (9.7%) were deceased due to non-cancerous reasons.
Uterine adenosarcoma appears to have a relatively good prognosis, especially in the absence of risk factors, such as sarcomatous overgrowth, high grade histology, and deep myometrial invasion. Ovarian preservation may be a feasible management option with non-inferior outcomes for premenopausal women with early-stage disease. Future studies including larger patient cohorts are needed for this rare disease.
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.
Genome-wide association studies (GWAS) have identified common variants that predispose individuals to a higher body mass index (BMI), an independent risk factor for endometrial cancer. Composite ...genotype risk scores (GRS) based on the joint effect of published BMI risk loci were used to explore whether endometrial cancer shares a genetic background with obesity. Genotype and risk factor data were available on 3,376 endometrial cancer case and 3,867 control participants of European ancestry from the Epidemiology of Endometrial Cancer Consortium GWAS. A BMI GRS was calculated by summing the number of BMI risk alleles at 97 independent loci. For exploratory analyses, additional GRSs were based on subsets of risk loci within putative etiologic BMI pathways. The BMI GRS was statistically significantly associated with endometrial cancer risk (P = 0.002). For every 10 BMI risk alleles a woman had a 13% increased endometrial cancer risk (95% CI: 4%, 22%). However, after adjusting for BMI, the BMI GRS was no longer associated with risk (per 10 BMI risk alleles OR = 0.99, 95% CI: 0.91, 1.07; P = 0.78). Heterogeneity by BMI did not reach statistical significance (P = 0.06), and no effect modification was noted by age, GWAS Stage, study design or between studies (P≥0.58). In exploratory analyses, the GRS defined by variants at loci containing monogenic obesity syndrome genes was associated with reduced endometrial cancer risk independent of BMI (per BMI risk allele OR = 0.92, 95% CI: 0.88, 0.96; P = 2.1 x 10-5). Possessing a large number of BMI risk alleles does not increase endometrial cancer risk above that conferred by excess body weight among women of European descent. Thus, the GRS based on all current established BMI loci does not provide added value independent of BMI. Future studies are required to validate the unexpected observed relation between monogenic obesity syndrome genetic variants and endometrial cancer risk.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
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.
Purpose
Immune checkpoints cytotoxic T lymphocyte antigen 4 (CTLA4) and programmed cell death 1 receptor (PD-1) negatively regulate CD8
+
T cell functions, impeding the capacity of effector T cells ...to kill tumors. Here, we study the prognostic significance of CTLA4, PD-1 and T cell activation status in breast cancer.
Methods
Using a publicly accessed RNA-seq dataset including 1087 breast cancer patients, we performed Kaplan–Meier survival curves and multivariate Cox regression models to evaluate the associations of CTLA4, PD-1, and weighted T cell activation score with patients’ overall survival.
Results
Survival analyses showed that high CTLA4 but low PD-1 expression was associated with a poor overall survival, and that high T cell activation score was associated with an improved survival. The median survival was 216.6 months (95% CI 114.1–244.9) for the T activation group, 127.0 months (95% CI 112.3–212.1) for the intermediate, and 120.5 months (95% CI 93.8 to ∞) for the exhaustion (Log-rank
p
= 0.084). This association was verified in multivariate Cox regression analysis. The hazard ratios were 0.81 (95% CI 0.56–1.19) for the intermediate group, and 0.48 (95% CI 0.26–0.86) for the activation group, respectively, in comparison to the exhaustion group (
p
value for trend = 0.016).
Conclusions
T cell activation score has significantly positive relationship with patients’ overall survival, and may serve as a marker of personalized immunotherapy in breast cancer patients. Cocktail rather than single immune checkpoint blockade may yield more benefit for breast cancer patients.
Breast cancer is the most common cancer type and the leading cause of cancer‑associated 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 Asian‑Pacific region. MicroRNA‑34a (miR‑34a) targets stem cell‑associated transcription factors E2F1/E2F3, and may have clinical relevance in breast cancer. The present study aimed to investigate the association between miR‑34a/E2F1/E2F3 and patient survival in breast cancer, as well as the underlying molecular mechanism of miR‑34a in suppressing factors associated with tumor aggressiveness in vitro. Kaplan‑Meier survival curves were constructed and a meta‑analysis was performed to analyze the association of miR‑34a, 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 T‑47D and MDA‑MB‑231 cells to investigate the cancer biology of miR‑34a and its effect on E2F1 and E2F3 expression using reverse transcription‑quantitative PCR. Then, caspase‑3 (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 miR‑34a, 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 miR‑34a significantly downregulated the expression of E2F1 and E2F3, and increased CASP3 activity in both T‑47D and MDA‑MB‑231 cells, and that miR‑34a treatment inhibited tumor cell proliferation, migration and invasiveness, as well as 3D spheroid formation. Thus, miR‑34a influences the aggressiveness of breast cancer and patient survival, and is a potential therapeutic tool in the clinical management of breast cancer.
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