Chlorpyrifos is an organophosphorus (OP) pesticide widely used around the world for agricultural operations. Although studies have examined exposure in children, there is limited information on adolescents who are occupationally exposed. Furthermore, there is limited research addressing the change in exposure patterns and outcomes across the application season. The goal of the current study was to examine the impact of chlorpyrifos exposure on neurobehavioral performance in adolescents before, during and after the application season. The longitudinal study was conducted in Egypt from April 2010 to January 2011, quantifying exposure and neurobehavioral performance with repeated measures prior to, during, and following the application period. At each test session, participants completed a neurobehavioral test battery and urine was collected for analysis of the chlorpyrifos metabolite 3,5,6-trichloro-2 pyridinol (TCPy) (biomarker of exposure). Cumulative urinary TCPy over the study period was used to classify participants into low (
Pesticide; Chlorpyrifos; Adolescent; Neurobehavioral; Exposure
The genetic model plant Arabidopsis thaliana (arabidopsis) has been instrumental to recent advances in our understanding of the molecular function of the plant immune system. However, this work has not yet included plant associated and phytopathogenic yeasts largely due to a lack of yeast species known to interact with arabidopsis. The plant phylloplane is a significant habitat for neutral-residents, plant-growth and health-promoting species, and latent-pathogenic species. However, yeast phylloplane residents of arabidopsis remain underexplored. To address this, resident yeasts from the phyllosphere of wild arabidopsis collected in field conditions have been isolated and characterized. A total of 95 yeast strains representing 23 species in 9 genera were discovered, including potentially psychrophilic and pathogenic strains. Physiological characterization revealed thermotolerance profiles, sensitivity to the arabidopsis phytoalexin camalexin, the production of indolic compounds, and the ability to activate auxin responses in planta. These results indicate a rich diversity of yeasts present in the arabidopsis phylloplane and have created culture resources and information useful in the development of model systems for arabidopsis-yeast interactions.
Cancer results from the acquisition of somatic driver mutations. Several computational tools can predict driver genes from population-scale genomic data, but tools for analyzing personal cancer genomes are underdeveloped. Here we developed iCAGES, a novel statistical framework that infers driver variants by integrating contributions from coding, non-coding, and structural variants, identifies driver genes by combining genomic information and prior biological knowledge, then generates prioritized drug treatment. Analysis on The Cancer Genome Atlas (TCGA) data showed that iCAGES predicts whether patients respond to drug treatment (P = 0.006 by Fisher’s exact test) and long-term survival (P = 0.003 from Cox regression). iCAGES is available at http://icages.wglab.org.
Electronic supplementary material
The online version of this article (doi:10.1186/s13073-016-0390-0) contains supplementary material, which is available to authorized users.
Cancer genomics; Machine learning; Precision medicine; Precision oncology; TCGA
Metabolomics is a comprehensive assessment of endogenous metabolites of a biological system in a holistic context. In this study, we evaluated the in vivo anti-melanoma activity of aqueous extract of Forsythiae Fructus (FAE) and globally explored the serum metabolome characteristics of B16-F10 melanoma-bearing mice. UPLC/Q-TOF MS combined with pattern recognition approaches were employed to examine the comprehensive metabolic signatures and differentiating metabolites. The results demonstrated that FAE exhibited remarkable antitumor activity against B16-F10 melanoma in C57BL/6 mice and restored the disturbed metabolic profile by tumor insult. We identified 17 metabolites which were correlated with the antitumor effect of FAE. Most of these metabolites are involved in glycerophospholipid metabolisms. Notably, several lysophosphatidylcholines (LysoPCs) significantly decreased in tumor model group, while FAE treatment restored the changes of these phospholipids to about normal condition. Moreover, we found that lysophosphatidylcholine acyltransferase 1 (LPCAT1) and autotaxin (ATX) were highly expressed in melanoma, and FAE markedly down-regulated their expression. These findings indicated that modulation of glycerophospholipid metabolisms may play a pivotal role in the growth of melanoma and the antitumor activity of FAE. Besides, our results suggested that serum LysoPCs could be potential biomarkers for the diagnosis and prognosis of melanoma and other malignant tumors.
The serum concentration of soluble urokinase-type plasminogen activator receptor (suPAR) reflects immune activation. We performed a meta-analysis to evaluate the usefulness of suPAR for the diagnosis and prognosis of bacterial infections. PubMed, Embase and Cochrane Library databases were searched for studies reporting the detection of suPAR in adult patients with bacterial infections. Seventeen studies were selected from 671 studies. The pooled sensitivity and specificity of suPAR for diagnosing infection were 0.73 and 0.79, respectively, and the area under the summary receiver operating characteristic curve (AUC) was 0.82. Subgroup analyses revealed suPAR showed similar AUC values for diagnosing sepsis and bacteremia, but the AUC for differentiating sepsis from systemic inflammatory response syndrome (SIRS) was only 0.68. Elevated suPAR levels were significantly associated with a high risk of death, with a pooled risk ratio of 3.37 (95% confidence interval, 2.60–4.38). The pooled sensitivity and specificity for predicting mortality were 0.70 and 0.72, respectivfely, with an AUC of 0.77. Serum suPAR could be a biomarker for the diagnosis and prognosis of bacterial infection, but it is relatively ineffective for differentiating sepsis from SIRS. Further investigation is required to evaluate whether using of suPAR in combination with other biomarkers can improve diagnostic efficacy.
About 10–15% of adult, and most pediatric, gastrointestinal stromal tumors (GIST) lack mutations in KIT, PDGFRA, SDHx, or RAS pathway components (KRAS, BRAF, NF1). The identification of additional mutated genes in this rare subset of tumors can have important clinical benefit to identify altered biological pathways and select targeted therapies.
We performed comprehensive genomic profiling (CGP) for coding regions in more than 300 cancer-related genes of 186 GISTs to assess for their somatic alterations.
We identified 24 GIST lacking alterations in the canonical KIT/PDGFRA/RAS pathways, including 12 without SDHx alterations. These 24 patients were mostly adults (96%). The tumors had a 46% rate of nodal metastases. These 24 GIST were more commonly mutated at 7 genes: ARID1B, ATR, FGFR1, LTK, SUFU, PARK2 and ZNF217. Two tumors harbored FGFR1 gene fusions (FGFR1–HOOK3, FGFR1–TACC1) and one harbored an ETV6–NTRK3 fusion that responded to TRK inhibition. In an independent sample set, we identified 5 GIST cases lacking alterations in the KIT/PDGFRA/SDHx/RAS pathways, including two additional cases with FGFR1–TACC1 and ETV6–NTRK3 fusions.
Using patient demographics, tumor characteristics, and CGP, we show that GIST lacking alterations in canonical genes occur in younger patients, frequently metastasize to lymph nodes, and most contain deleterious genomic alterations, including gene fusions involving FGFR1 and NTRK3. If confirmed in larger series, routine testing for these translocations may be indicated for this subset of GIST. Moreover, these findings can be used to guide personalized treatments for patients with GIST.
Trial registration NCT 02576431. Registered October 12, 2015
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Gene sequencing; Mutation; GIST; FGFR1; ETV6–NTRK3
Gallbladder cancer (GBC), although considered as a relatively rare malignancy, is the most common neoplasm of the biliary tract system. The late diagnosis and abysmal prognosis present challenges to treatment. The overall 5-year survival rate for metastatic GBC patients is extremely low. BRCA1 and BRCA2 are the breast cancer susceptibility genes and their mutation carriers are at a high risk for cancer development, both in men and women. Olaparib, an oral poly ADP-ribose polymerase inhibitor, has been approved by the Food and Drug Administration and the European Commission for the treatment of ovarian cancer with any BRCA1/2 mutations. The first case of a BRCA1-mutated GBC patient who responded to olaparib treatment is reported here.
BRCA; Mutation; Olaparib; Poly ADP-ribose polymerase inhibitor; Gallbladder cancer
Although studies have examined the association between dietary magnesium intake and health outcome, the results are inconclusive. Here, we conducted a dose–response meta-analysis of prospective cohort studies in order to investigate the correlation between magnesium intake and the risk of cardiovascular disease (CVD), type 2 diabetes (T2D), and all-cause mortality.
PubMed, EMBASE, and Web of Science were searched for articles that contained risk estimates for the outcomes of interest and were published through May 31, 2016. The pooled results were analyzed using a random-effects model.
Forty prospective cohort studies totaling more than 1 million participants were included in the analysis. During the follow-up periods (ranging from 4 to 30 years), 7678 cases of CVD, 6845 cases of coronary heart disease (CHD), 701 cases of heart failure, 14,755 cases of stroke, 26,299 cases of T2D, and 10,983 deaths were reported. No significant association was observed between increasing dietary magnesium intake (per 100 mg/day increment) and the risk of total CVD (RR: 0.99; 95% CI, 0.88–1.10) or CHD (RR: 0.92; 95% CI, 0.85–1.01). However, the same incremental increase in magnesium intake was associated with a 22% reduction in the risk of heart failure (RR: 0.78; 95% CI, 0.69–0.89) and a 7% reduction in the risk of stroke (RR: 0.93; 95% CI, 0.89–0.97). Moreover, the summary relative risks of T2D and mortality per 100 mg/day increment in magnesium intake were 0.81 (95% CI, 0.77–0.86) and 0.90 (95% CI, 0.81–0.99), respectively.
Increasing dietary magnesium intake is associated with a reduced risk of stroke, heart failure, diabetes, and all-cause mortality, but not CHD or total CVD. These findings support the notion that increasing dietary magnesium might provide health benefits.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-016-0742-z) contains supplementary material, which is available to authorized users.
Magnesium; Cardiovascular disease; Type 2 diabetes; All-cause mortality; Meta-analysis
It is unclear whether and how whole-genome sequencing (WGS) data can be used to implement genomic medicine. Our objective is to retrospectively evaluate whether WGS can facilitate improving prevention and care for patients with susceptibility to cancer syndromes.
Methods and Findings
We analyzed genetic mutations in 60 autosomal dominant cancer-predisposition genes in 300 deceased patients with WGS data and nearly complete long-term (over 30 years) medical records. To infer biological insights from massive amounts of WGS data and comprehensive clinical data in a short period of time, we developed an in-house analysis pipeline within the SeqHBase software framework to quickly identify pathogenic or likely pathogenic variants. The clinical data of the patients who carried pathogenic and/or likely pathogenic variants were further reviewed to assess their clinical conditions using their lifetime EHRs. Among the 300 participants, 5 (1.7%) carried pathogenic or likely pathogenic variants in 5 cancer-predisposing genes: one in APC, BRCA1, BRCA2, NF1, and TP53 each. When assessing the clinical data, each of the 5 patients had one or more different types of cancers, fully consistent with their genetic profiles. Among these 5 patients, 2 died due to cancer while the others had multiple disorders later in their lifetimes; however, they may have benefited from early diagnosis and treatment for healthier lives, had the patients had genetic testing in their earlier lifetimes.
We demonstrated a case study where the discovery of pathogenic or likely pathogenic germline mutations from population-wide WGS correlates with clinical outcome. The use of WGS may have clinical impacts to improve healthcare delivery.
The large amount of repeats, especially high copy repeats, in the genomes of higher animals and plants makes whole genome assembly (WGA) quite difficult. In order to solve this problem, we tried to identify repeats and mask them prior to assembly even at the stage of genome survey. It is known that repeats of different copy number have different probabilities of appearance in shotgun data, so based on this principle, we constructed a statistical model and inferred criteria for mathematically defined repeats (MDRs) at different shotgun coverages. According to these criteria, we developed software MDRmasker to identify and mask MDRs in shotgun data. With repeats masked prior to assembly, the speed of assembly was increased with lower error probability. In addition, clone-insert size affects the accuracy of repeat assembly and scaffold construction. We also designed length distribution of clone-inserts using our model. In our simulated genomes of human and rice, the length distribution of repeats is different, so their optimal length distributions of clone-inserts were not the same. Thus with optimal length distribution of clone-inserts, a given genome could be assembled better at lower coverage.
mathematically defined repeat (MDR); clone-inserts; assembly
Recently, measurement of RNA at single cell resolution has yielded surprising insights. Methods for single-cell RNA sequencing (scRNA-seq) have received considerable attention, but the broad reliability of single cell methods and the factors governing their performance are still poorly known.
Here, we conducted a large-scale control experiment to assess the transfer function of three scRNA-seq methods and factors modulating the function. All three methods detected greater than 70% of the expected number of genes and had a 50% probability of detecting genes with abundance greater than 2 to 4 molecules. Despite the small number of molecules, sequencing depth significantly affected gene detection. While biases in detection and quantification were qualitatively similar across methods, the degree of bias differed, consistent with differences in molecular protocol. Measurement reliability increased with expression level for all methods and we conservatively estimate measurements to be quantitative at an expression level greater than ~5–10 molecules.
Based on these extensive control studies, we propose that RNA-seq of single cells has come of age, yielding quantitative biological information.
Electronic supplementary material
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Single-cell RNA-sequencing; Biotechnology; Bioinformatics; Genomics
Prediction of ligand binding sites is important to elucidate protein functions and is helpful for drug design. Although much progress has been made, many challenges still need to be addressed. Prediction methods need to be carefully developed to account for chemical and structural differences between ligands.
In this study, we present ligand-specific methods to predict the binding sites of protein-ligand interactions. First, a sequence-based method is proposed that only extracts features from protein sequence information, including evolutionary conservation scores and predicted structure properties. An improved AdaBoost algorithm is applied to address the serious imbalance problem between the binding and non-binding residues. Then, a combined method is proposed that combines the current template-free method and four other well-established template-based methods. The above two methods predict the ligand binding sites along the sequences using a ligand-specific strategy that contains metal ions, acid radical ions, nucleotides and ferroheme. Testing on a well-established dataset showed that the proposed sequence-based method outperformed the profile-based method by 4–19% in terms of the Matthews correlation coefficient on different ligands. The combined method outperformed each of the individual methods, with an improvement in the average Matthews correlation coefficients of 5.55% over all ligands. The results also show that the ligand-specific methods significantly outperform the general-purpose methods, which confirms the necessity of developing elaborate ligand-specific methods for ligand binding site prediction.
Two efficient ligand-specific binding site predictors are presented. The standalone package is freely available for academic usage at http://dase.ecnu.edu.cn/qwdong/TargetCom/TargetCom_standalone.tar.gz or request upon the corresponding author.
Electronic supplementary material
The online version of this article (doi:10.1186/s12859-016-1348-3) contains supplementary material, which is available to authorized users.
Binding residue prediction; Ensemble classifier; Protein function
microRNAs (miRNAs) have been demonstrated to contribute to tumor progression and metastasis, and have been proposed to be key regulators of diverse biological processes. In this study, we report that miR-4295 is deregulated in bladder cancer tissues and cell lines. To characterize the role of miR-4295 in bladder cancer cells, we performed functional assays. The overexpression of miR-4295 significantly promoted bladder cancer cell proliferation, colony formation, and migration. Moreover, its downregulation induced cell cycle arrest and apoptosis of bladder cancer cells. Furthermore, a luciferase reporter assay and rescue experiment indicated that miR-4295 directly targets BTG1 by binding its 3’UTR. In conclusion, these results demonstrate that miR-4295 acts as an oncogene and may be a potential biomarker for bladder cancer diagnosis and treatment.
MiR-4295; BTG1; bladder cancer; cell growth
The present study aimed to investigate the effect of genetic polymorphisms of catechol-O-methyl transferase (COMT), apolipoprotein E (APOE), and brain derived neurotrophic factor (BDNF) on the modulation of the chemotherapy-induced cognitive impairment (CICI) in breast cancer patients. Eighty triple negative breast cancer (TNBC) and 165 non-triple negative breast cancer (NTNBC) patients were selected, and subjected to a number of neuropsychological tests, including memory questionnaires, before and after chemotherapy. Six single-nucleotide polymorphisms (SNPs), including COMT (rs165599, rs4680, rs737865), APOE (rs429358, rs7412), and BDNF (rs6265), were evaluated. The scores of breast cancer patients after chemotherapy were poorer in comparison to those before chemotherapy (t = -5.317, z = -3.372, respectively, P < 0.01), and the scores of TNBC patients were poorer than those of NTNBC patients were after chemotherapy (t = -5.997, z = -5.284, respectively, P < 0.01). Patients with the COMT (rs165599) genotype had a significantly lower chance of developing cognitive decline than the patients with the G/G genotype, and this was linear with the retrospective memory (RM) questionnaires (β = -1.441, CI (95%) = -2.781~-0.101). However, there was no significant difference between the memory scores of APOE (rs429358, rs7412) and BDNF (rs6265) carriers before or after chemotherapy. This study suggests that CICI in TNBC patients was more prominent than that in NTNBC patients after chemotherapy, and the COMT (rs165599) polymorphism was linear to the retrospective memory (RM) questionnaires, and may be a potential genetic marker for increased vulnerability to CICI in TNBC patients.
Catechol-O-methyl transferase; polymorphisms; chemotherapy-induced cognitive impairment; breast cancer
Entanglement in multiple degrees of freedom has many benefits over entanglement in a single one. The former enables quantum communication with higher channel capacity and more efficient quantum information processing and is compatible with diverse quantum networks. Establishing multi-degree-of-freedom entangled memories is not only vital for high-capacity quantum communication and computing, but also promising for enhanced violations of nonlocality in quantum systems. However, there have been yet no reports of the experimental realization of multi-degree-of-freedom entangled memories. Here we experimentally established hyper- and hybrid entanglement in multiple degrees of freedom, including path (K-vector) and orbital angular momentum, between two separated atomic ensembles by using quantum storage. The results are promising for achieving quantum communication and computing with many degrees of freedom.
Establishing multi-degree-of-freedom entangled memories is important for high-capacity quantum communications and computing. Here, authors experimentally demonstrate hyper- and hybrid entanglement between two atomic ensembles in multiple degrees of freedom including path and orbital angular momentum.
Veronicastrum axillare is a traditional medical plant in China which is widely used in folk medicine due to its versatile biological activities, especially for its anti-inflammatory effects. However, the detailed mechanism underlying this action is not clear. Here, we studied the protective effects of V. axillare against acute lung injury (ALI), and we further explored the pharmacological mechanisms of this action. We found that pretreatment with V. axillare suppressed the release of proinflammatory cytokines in the serum of ALI mice. Histological analysis of lung tissue demonstrated that V. axillare inhibited LPS-induced lung injury, improved lung morphology, and reduced the activation of nuclear factor-κB (NF-κB) in the lungs. Furthermore, the anti-inflammatory actions of V. axillare were investigated in vitro. We observed that V. axillare suppressed the mRNA expression of interleukin-1β (IL-1β), IL-6, monocyte chemotactic protein-1 (MCP-1), cyclooxygenase-2 (COX-2), and tumor necrosis factor-α (TNF-α) in RAW264.7 cells challenged with LPS. Furthermore, pretreatment of V. axillare in vitro reduced the phosphorylation of p65 and IκB-α which is activated by LPS. In conclusion, our data firstly demonstrated that the anti-inflammatory effects of V. axillare against ALI were achieved through downregulation of the NF-κB signaling pathway, thereby reducing the production of inflammatory mediators.
Berberine (BBR) is a renowned natural compound that exhibits potent neuroprotective activities. However, the cellular and molecular mechanisms are still unclear. Hormesis is an adaptive mechanism generally activated by mild oxidative stress to protect the cells from further damage. Many phytochemicals have been shown to induce hormesis. This study aims to investigate whether the neuroprotective activity of BBR is mediated by hormesis and the related signaling pathways in 6-OHDA-induced PC12 cells and zebrafish neurotoxic models. Our results demonstrated that BBR induced a typical hormetic response in PC12 cells, i.e. low dose BBR significantly increased the cell viability, while high dose BBR inhibited the cell viability. Moreover, low dose BBR protected the PC12 cells from 6-OHDA-induced cytotoxicity and apoptosis, whereas relatively high dose BBR did not show neuroprotective activity. The hormetic and neuroprotective effects of BBR were confirmed to be mediated by up-regulated PI3K/AKT/Bcl-2 cell survival and Nrf2/HO-1 antioxidative signaling pathways. In addition, low dose BBR markedly mitigated the 6-OHDA-induced dopaminergic neuron loss and behavior movement deficiency in zebrafish, while high dose BBR only slightly exhibited neuroprotective activities. These results strongly suggested that the neuroprotection of BBR were attributable to the hormetic mechanisms via activating cell survival and antioxidative signaling pathways.
BBR, berberine; PD, Parkinson's disease; AD, Alzheimer's disease; HD, Huntington's disease; 6-OHDA, 6-hydroxydopamine; DMSO, dimethyl sulfoxide; Nom, nomifensine; MTT, thiazolyl blue tetrazolium bromide; PBS, phosphate buffered saline; PS, penicillin-streptomycin; FBS, fetal bovine serum; HS, horse serum; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; Nrf2, nuclear factor-E2-related factor 2; HO-1, heme oxygenase-1; FITC, fluorescein isothiocyanate; PI, propidium iodide; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling; ZnPP, zinc protoporphyrin IX; FCM, flow cytometry; dpf, day post fertilization; TH, tyrosine hydroxylase; DA, dopaminergic; NDD, neurodegenerative disorders; MAPK, mitogen-activated protein kinases; JNK, c-Jun N-terminal kinase; sMaf, small Maf; Berberine; Hormesis; Neuroprotection; PC12 cells; Zebrafish
Previous studies have shown that individuals with schizophrenia have a greater risk for psoriasis than a typical person. This suggests that there might be a shared genetic etiology between the 2 conditions. We aimed to characterize the potential shared genetic susceptibility between schizophrenia and psoriasis using genome-wide marker genotype data.
We obtained genetic data on individuals with psoriasis, schizophrenia and control individuals. We applied a marker-based coheritability estimation procedure, polygenic score analysis, a gene set enrichment test and a least absolute shrinkage and selection operator regression model to estimate the potential shared genetic etiology between the 2 diseases. We validated the results in independent schizophrenia and psoriasis cohorts from Singapore.
We included 1139 individuals with psoriasis, 744 with schizophrenia and 1678 controls in our analysis, and we validated the results in independent cohorts, including 441 individuals with psoriasis (and 2420 controls) and 1630 with schizophrenia (and 1860 controls). We estimated that a large fraction of schizophrenia and psoriasis risk could be attributed to common variants (h2SNP = 29% ± 5.0%, p = 2.00 × 10−8), with a coheritability estimate between the traits of 21%. We identified 5 variants within the human leukocyte antigen (HLA) gene region, which were most likely to be associated with both diseases and collectively conferred a significant risk effect (odds ratio of highest risk quartile = 6.03, p < 2.00 × 10−16). We discovered that variants contributing most to the shared heritable component between psoriasis and schizophrenia were enriched in antigen processing and cell endoplasmic reticulum.
Our sample size was relatively small. The findings of 5 HLA gene variants were complicated by the complex structure in the HLA region.
We found evidence for a shared genetic etiology between schizophrenia and psoriasis. The mechanism for this shared genetic basis likely involves immune and calcium signalling pathways.
In a large clinical trial, finasteride reduced the rate of low-grade prostate cancer (PCa) while increasing the incidence of high-grade cancer. Whether finasteride promotes the development of high-grade tumors remains controversial. We demonstrated the role of fibroblasts and c-Jun in chemopreventive and therapeutic effect of finasteride on xenograft models of PCa. LNCaP (PC3) cells or recombinants of cancer cells and fibroblasts were implanted in male athymic nude mice treated with finasteride. Tumor growth, cell proliferation, apoptosis, p-Akt, and p-ERK1/2 were evaluated. In LNCaP (PC3) mono-grafted models, finasteride did not change the tumor growth. In recombinant-grafted models, fibroblasts and c-Jun promoted tumor growth; finasteride induced proliferation of LNCaP cells and repressed PC3 cell apoptosis. When c-Jun was knocked out, fibroblasts and/or finasteride did not promote the tumor growth. Finasteride inhibited p-Akt and p-ERK1/2 in mono-culture cancer cells while stimulating the same signaling molecules in the presence of fibroblasts. Reduced p-Akt and p-ERK1/2 were noted in the presence of c-Jun−/− fibroblasts. Fibroblasts and c-Jun promote PCa growth; finasteride further stimulates tumor growth with promoted proliferation, repressed apoptosis, and up-regulated pro-proliferative molecular pathway in the presence of fibroblasts and c-Jun. Stromal-epithelial interactions play critical roles in finasteride's therapeutic effects on PCa. Our findings have preliminary implications in using finasteride as a chemopreventive or therapeutic agent for PCa patients.
chemoprevention; c-Jun; fibroblasts; finasteride; mouse model; prostate cancer