Exposure to heavy metal elements may significantly increase serum prostate-specific antigen levels with overdosed dietary zinc.

BACKGROUND: Serum prostate-specific antigen (PSA) is a primary metric for diagnosis and prognosis of prostate cancer (PCa). Exposure to heavy metals, such as lead, cadmium, mercury, and zinc can impact PSA levels in PCa patients. However, it is unclear whether this effect also occurs in men without PCa, which may lead to the overdiagnosis of PCa. METHOD: Data on a total of 5089 American men who had never been diagnosed with PCa were obtained from the National Health and Nutrition Examination Survey performed from 2003-2010. The relationship between serum PSA levels (dependent variable) and concentrations of lead (µmol/L), cadmium (nmol/L), and mercury (µmol/L) were investigated with dietary zinc intake being used as a potential modifier or covariate in a weighted linear regression model and a generalized additive model. A series of bootstrapping analyses were performed to evaluate sensitivity and specificity using these models. RESULTS: Regression analyses suggested that, in general, lead, cadmium, or mercury did not show an association with PSA levels, which was consistent with the results of the bootstrapping analyses. However, in a subgroup of participants with a high level of dietary zinc intake (≥14.12 mg/day), a significant positive association between cadmium and serum PSA was identified (1.06, 95% CI, P = 0.0268, P for interaction=0.0249). CONCLUSIONS: With high-level zinc intake, serum PSA levels may rise in PCa-free men as the exposure to cadmium increases, leading to a potential risk of an overdiagnosis of PCa and unnecessary treatment. Therefore, environmental variables should be factored in the current diagnostic model for PCa that is solely based on PSA measurements. Different criteria for PSA screening are necessary based on geographical variables. Further investigations are needed to uncover the biological and biochemical relationship between zinc, cadmium, and serum PSA levels to more precisely diagnose PCa.

Low expression of GRM4 is associated with poor prognosis and tumor immune infiltration in glioma.

INTRODUCTION: The metabotropic glutamate receptor 4 (mGlu4, GRM4) exhibits significant expression within the central nervous system (CNS) and has been implicated to be correlated with a poor prognosis. OBJECTIVE: This study was aimed to elucidate the relationship between the expression profile of GRM4 and the prognosis of glioma patients. METHODS: RNA-sequencing datasets from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and China Glioma Genome Atlas (CGGA) repositories were used to evaluate the potential relationship. The value of clinical prognostic about GRM4 was assessed using clinical survival data from CGGA and TCGA. The GEPIA database was used to select genes like GRM4. PPI network was constructed by the database of (STRING), GO and KEGG analyses were performed. TargetScan, TarBase, miRDB, and starBase were used to explore miRNAs that could regulate GRM4 expression. EWAS Data Hub, MethSurv, and MEXPRESS were used for the analysis and relationship between DNA methylation and GRM4 expression and prognosis in glioma. TIMER2.0 and CAMOIP databases were used to assess the association between immune cell infiltration and GRM4. Human GBM cell lines were used to validate the function of GRM4. RESULTS: Our study shows that GRM4 is under expressed among gliomas and accompanied by poorer OS. Multivariate analysis showed that low mRNA expression of GRM4 was an independent factor of prognostic for shorter OS in all glioma patients. MiR-1262 affects the malignant phenotype of gliomas through GRM4. Methylation of DNA plays an important role in the instruction of GRM4 expression, the methylation level of GRM4 in glioma tissue is higher in comparison to normal tissue, and the higher methylation level was accompanied with the worse prognosis. Further analysis showed that GRM4 mRNA expression in GBM linked negatively with common lymphoid progenitor, Macrophage M1, Macrophage, and T cell CD4+ Th2, but not with the tumor purity. Overexpression of GRM4 prevents the migration of human GBM cell lines in vitro. CONCLUSION: GRM4 may have a substantial impact on the infiltration of immune cells and serve as a valuable prognostic biomarker in gliomas.

Correlation of Reduced PTGER3 Expression with Prognosis and Immune Infiltration in Clear Cell Renal Carcinoma.

BACKGROUND: Prostaglandin E2 receptor 3 (PTGER3, EP3) is essential for many malignancies growth and metastasis. The role of PTGER3 in kidney renal clear cell carcinoma (KIRC) was assessed in terms of its prognosis and its association with immune infiltration. METHODS: Transcriptomic expression profiles of PTGER3 were acquired from The Cancer Genome Atlas (TCGA) database. Comparative analysis was performed to evaluate the disparity in PTGER3 expression between KIRC and normal tissues. The discriminative potential of PTGER3 as a distinguishing determinant was assessed through receiver operating characteristic (ROC) curves. Prognostic factors were evaluated employing COX regression and logistic models. Furthermore, the impact of PTGER3 on survival was ascertained utilizing the Kaplan-Meier method. A protein-protein interaction (PPI) network was constructed utilizing the STRING database. To investigate the correlation between immune infiltration levels and PTGER3 expression, a single-sample Gene Set Enrichment Analysis (GSEA) method was employed, employing the Gene Set Variation Analysis (GSVA) package and the Tumor Immune Estimation Resource (TIMER) database. RESULTS: Bioinformatics analysis unveiled a significant downregulation of PTGER3 expression in KIRC tissues compared to paraneoplastic tissues (p < 0.001). Furthermore, quantitative reverse transcription polymerase chain reaction (qRT-PCR) experiments demonstrated a reduction in PTGER3 expression in 786-O cells in contrast to paraneoplastic tissues (p < 0.01). The ROC curve, employing PTGER3 as a potential diagnostic biomarker, exhibited a substantial area under the curve (AUC) value of 0.929. According to the Kaplan-Meier survival analysis, reduced PTGER3 expression increased the chance of negative overall survival (OS) (p = 0.019). A PPI network was constructed, elucidating the interaction patterns between PTGER3 and the top 10 co-expressed genes. An examination of gene enrichment and immune infiltration levels found a link between PTGER3 transcription and immune infiltration levels. Notably, high B cell counts and low Mast cell counts were connected to a poor prognosis in KIRC patients. CONCLUSIONS: The expression of PTGER3 was found to be diminished in KIRC in comparison to paracancerous tissue. This observation exhibited a correlation with both prognosis and immune cell infiltration. As a result, our findings suggest that PTGER3 could be considered a promising biomarker to forecast KIRC prognosis and as a possible target for immunotherapy.

CRISPR-cas9 screening identified lethal genes enriched in Hippo kinase pathway and of predictive significance in primary low-grade glioma.

BACKGROUND: Low-grade gliomas (LGG) are a type of brain tumor that can be lethal, and it is essential to identify genes that are correlated with patient prognosis. In this study, we aimed to use CRISPR-cas9 screening data to identify key signaling pathways and develop a genetic signature associated with high-risk, low-grade glioma patients. METHODS: The study used CRISPR-cas9 screening data to identify essential genes correlated with cell survival in LGG. We used RNA-seq data to identify differentially expressed genes (DEGs) related to cell viability. Moreover, we used the least absolute shrinkage and selection operator (LASSO) method to construct a genetic signature for predicting overall survival in patients. We performed enrichment analysis to identify pathways mediated by DEGs, overlapping genes, and genes shared in the Weighted correlation network analysis (WGCNA). Finally, the study used western blot, qRT-PCR, and IHC to detect the expression of hub genes from signature in clinical samples. RESULTS: The study identified 145 overexpressed oncogenes in low-grade gliomas using the TCGA database. These genes were intersected with lethal genes identified in the CRISPR-cas9 screening data from Depmap database, which are enriched in Hippo pathways. A total of 19 genes were used to construct a genetic signature, and the Hippo signaling pathway was found to be the predominantly enriched pathway. The signature effectively distinguished between low- and high-risk patients, with high-risk patients showing a shorter overall survival duration. Differences in hub gene expression were found in different clinical samples, with the protein and mRNA expression of REP65 being significantly up-regulated in tumor cells. The study suggests that the Hippo signaling pathway may be a critical regulator of viability and tumor proliferation and therefore is an innovative new target for treating cancerous brain tumors, including low-grade gliomas. CONCLUSION: Our study identified a novel genetic signature associated with high-risk, LGG patients. We found that the Hippo signaling pathway was significantly enriched in this signature, indicating that it may be a critical regulator of tumor viability and proliferation in LGG. Targeting the Hippo pathway could be an innovative new strategy for treating LGG.

Overexpression of YTHDC2 contributes to the progression of prostate cancer and predicts poor outcomes in patients with prostate cancer.

YTH domain-containing protein 2 (YTHDC2), a member of N6-methyladenosine (m6A) readers, has been reported to be closely associated with multiple cancer types. However, very little is known about the YTHDC2 gene and its involvement in prostate cancer. YTHDC2 protein expression level was analyzed and correlated to clinical outcomes in prostate cancer patients who underwent prostatectomy in Guizhou Provincial People's Hospital. The YTHDC2 expression level was also detected in prostate cancer cell lines and an immortalized prostate epithelial cell line BPH-1 and RWPE1 by quantitative real-time reverse transcription polymerase chain reaction. Furthermore, we established stable cell lines (DU145 and PC-3) transfected with either empty vector or the full-length YTHDC2 gene and conducted cell function assays in vitro. Fisher's exact test and Pearson χ2 test were employed, Kaplan-Meier method was used for the survival analysis. Of 32 patient samples who enrolled in this study, YTHDC2 was significantly upregulated in prostate cancer (PCa) patients with higher Gleason scores and serum prostate-specific antigen levels. YTHDC2 expression was significantly elevated in all PCa cell lines compared to BPH-1 and RWPE1 (all p < 0.05). Functionally, the enforced expression of YTHDC2 markedly promoted cell growth, migration, and invasion efficacies in prostate cancer cells. Our data indicate that YTHDC2 upregulation may be potentially associated with the prognosis of prostate cancer patients.

Epidemiology of pediatric central nervous system tumors in Uyghur: experience from a single center.

PURPOSE: Retrospective analysis of clinical and epidemiological characteristics of central nervous system (CNS)tumors in Uyghur children from a single center in Xinjiang. METHODS: Between January 2013 and December 2021, 243 children (0-17 years old) with a clear pathological type of CNS tumor are collected and analyzed for tumor size, grade, and category, as well as their relationship with the child's gender, age, and region of origin according to the 2021 edition of the new WHO CNS tumor classification. OUTCOME: The 243 cases of CNS tumors in Uyghur children are predominantly from rural areas, with 144 cases (59.26%) of supratentorial tumors and 129 cases (53.09%) of low-grade tumors. With an overall male-to-female ratio of 1.43:1, a peak age of incidence of 6 to 8 years. CONCLUDING: The present study is based on a 9-year analysis of pediatric CNS data from a single center, and the center is the largest tertiary hospital in Xinjiang with large numbers of admitted patients, which may reflect some extent the clinical characteristics and epidemiological features characteristics of pediatric CNS tumors in Uyghur in Xinjiang.

Clinicopathological Characteristics and Prognosis of 91 Patients with Seromucinous and Mucinous Borderline Ovarian Tumors: a Comparative Study.

To explore the differences in clinicopathological characteristics and prognosis between seromucinous borderline ovarian tumors (SMBOTs) and mucinous borderline ovarian tumors (MBOTs). Ninety-one patients with SMBOTs and MBOTs who underwent surgery at the Obstetrics and Gynecology Hospital of Fudan University from July 2006 to January 2015 were included. The median onset age of patients with SMBOTs (29 years, 20-77) was younger than that of patients with MBOTs (37 years, 16-71). SMBOTs were more likely to be exogenous and show bilateral ovarian involvement and had a smaller average tumor size of 10.63 cm, while MBOTs were more prone to endogenous growth and show unilateral involvement and had a larger average tumor size of 18.55 cm (p < 0.05). Compared with MBOTs, SMBOTs were characterized by the expression of Mullerian differentiation markers (p < 0.05). Recurrence occurred in 15.8% patients with SMBOT and 9.1% patients with MBOT. One case of SMBOT (2.6%) and one case of MBOT (2.3%) progressed to malignancy during follow-up, but no disease-related death was observed. Age less than 40 years was a risk factor for recurrence, while the effect of fertility-sparing surgery (FSS) on recurrence requires a larger sample size to be validated. The clinical characteristics of SMBOTs and MBOTs are similar but also quite different. High expression of Mullerian differentiation markers in SMBOT may indicate a better response to hormone therapy. Repeated FSS should be performed with caution and fully informed because of the risk of recurrence and progression to malignancy.

ZFP36 Inhibits Tumor Progression of Human Prostate Cancer by Targeting CDK6 and Oxidative Stress.

Background: The expression of ZFP36 in previous study was reduced in prostate cancer (PCa) tissues as compared to benign prostate tissues, indicating the potential of ZFP36 as an auxiliary marker for PCa. Further evaluation was conducted in clinical samples for in vitro and in vivo experiments, to prove the potential possibility that ZFP36 dysregulation participated in the malignant phenotype of PCa, to determine its potential mechanism for tumor regulation, and to provide a new theoretical basis for gene therapy of PCa. Methods: First, the expression of ZFP36 in prostate tissue and PCa tissue was explored, and the relationship between ZFP36 and clinical features of PCa patients was illustrated. Subsequently, the impact of ZFP36 on the biology of PCa cells and relevant downstream pathways of ZFP36's biological impact on PCa were elucidated. Finally, whether oxidative stress mediated the regulation of ZFP36 in PCa was verified by the determination of oxidative stress-related indicators and bioinformatics analysis. Results: The downregulation of ZFP36 in PCa tissue had a positive correlation with high Gleason scores, advanced pathological stage, and biochemical recurrence. ZFP36 was identified as an independent prognostic factor for PCa patients' BCR-free survival (P = 0.022) by survival analysis. Following a subsequent experiment of function gain and loss, ZFP36 inhibited the proliferation, invasion, and migration in DU145 and 22RV1 cells and inhibits tumor growth in the mouse model. Additionally, high-throughput sequencing screened out CDK6 as the downstream target gene of ZFP36. Western blot/Q-PCR demonstrated that overexpression of ZFP36 could reduce the expression of CDK6 at both cellular and animal levels, and the dual-luciferase experiment and RIP experiment proved that CDK6 was the downstream target of ZFP36, indicating that CDK6 was a downstream target of ZFP36, which mediated tumor cell growth by blocking cell cycle at the G1 stage. Furthermore, ZFP36 inhibited oxidative stress in PCa cells. Conclusions: In PCa, ZFP36 might be a tumor suppressor that regulated growth, invasion, and migration of PCa cells. The lately discovered ZFP36-CDK6 axis demonstrated the molecular mechanism of PCa progression to a certain extent which might act as a new possible therapeutic target of PCa therapy.

Construction of a novel rabbit model of ureteral calculi implanted with flowable resin.

BACKGROUND: The purpose of this study was to characterize the pathophysiological changes of hydronephrosis caused by ureteral calculi obstruction in a new rabbit ureteral calculi model by implanting flowable resin. METHODS: Forty New Zealand rabbits were randomly divided into two groups: the calculi group and the sham control group. In the calculi group (n = 20), rabbits were operated at left lower abdomen and the left ureter was exposed. Then flowable resin (flowable restorative dental materials) was injected into the left ureter using a 0.45 mm diameter intravenous infusion needle. Then light-cured for 40 s by means of a dental curing light to form calculi. In the sham control group, normal saline was injected into the ureter. Rabbits underwent X-ray and routine blood and urine tests preoperatively, as well as X-ray, CT, dissection, HE staining and routine blood and urine tests on 1, 3, 5 and 7 days postoperatively. Stone formation was assessed by X-ray and unenhanced CT scan after surgery. The pathophysiological changes were evaluated through dissection, HE staining and routine blood and urine tests. RESULTS: Ureteral calculi models were successfully constructed in 17 rabbits. In calculi group, high-density shadows were observed in the left lower abdomen on postoperative day 1st, 3rd, 5th and 7th by X-ray and CT scan. Dissection found obstruction formation of the left ureters, dilatation of the renal pelvis and upper ureter during 7 days after surgery. The renal long-diameters of the left ureters increased only on the 1st postoperative day. HE staining found ureteral and kidney damage after surgery. In calculi group and sham group,the serum creatinine, urea nitrogen, white blood cells and urine red blood cells were raised at day 1 after surgery. However, the indicators returned to normal at day 3, 5, and 7. CONCLUSIONS: This is a stable, less complicated operation and cost-effective ureteral calculi model by implanting flowable resin. And this novel model may allow us to further understand the pathophysiology changes caused by ureteral calculi obstruction.

A Novel Classification Model for Lower-Grade Glioma Patients Based on Pyroptosis-Related Genes.

Recent studies demonstrated that pyroptosis plays a crucial role in shaping the tumor-immune microenvironment. However, the influence of pyroptosis on lower-grade glioma regarding immunotherapy and targeted therapy is still unknown. This study analyzed the variations of 33 pyroptosis-related genes in lower-grade glioma and normal tissues. Our study found considerable genetic and expression alterations in heterogeneity among lower-grade gliomas and normal brain tissues. There are two pyroptosis phenotypes in lower-grade glioma, and they exhibited differences in cell infiltration characteristics and clinical characters. Then, a PyroScore model using the lasso-cox method was constructed to measure the level of pyroptosis in each patient. PyroScore can refine the lower-grade glioma patients with a stratified prognosis and a distinct tumor immune microenvironment. Pyscore may also be an effective factor in predicting potential therapeutic benefits. In silico analysis showed that patients with a lower PyroScore are expected to be more sensitive to targeted therapy and immunotherapy. These findings may enhance our understanding of pyroptosis in lower-grade glioma and might help optimize risk stratification for the survival and personalized management of lower-grade glioma patients.

Bevacizumab confers significant improvements in survival for ovarian cancer patients with low miR-25 expression and high miR-142 expression.

BACKGROUND: Lymphovascular space invasion (LVSI) is the first step of hematogenous metastasis. Exploration of the differential miRNA expression profiles between LVSI-positive and LVSI-negative ovarian cancer tissues may help to identify key miRNAs involved in the hematogenous metastasis of ovarian cancer. This study is aimed to identify microRNAs (miRNAs) that are differentially expressed between LVSI-positive and LVSI-negative ovarian cancer tissues, followed by exploring their association with bevacizumab response in ovarian cancer patients. METHODS: The Cancer Genome Altas (TGGA) dataset was used to identify the differentially expressed miRNAs between LVSI-positive and LVSI-negative ovarian cancer tissues. The prognostic value of the differentially expressed miRNAs was determined using GSE140082 dataset. RESULTS: We showed that miR-25 and miR-142 were differentially expressed between LVSI-positive and LVSI-negative ovarian cancer tumors. Kaplan-Meier analysis indicated that high miR-25 expression was associated with increased progression free survival (PFS) and extended overall survival (OS). Moreover, patients with low miR-25 expression benefited significantly from bevacizumab treatment in terms of PFS. A similar trend was observed in terms of OS though without reaching statistical significance. In contrast, no significant survival benefits from bevacizumab were observed in patients with high miR-25 expression in terms of PFS and OS. There was no significant correlation between miR-142 expression and PFS. In contrast, high miR-142 expression was associated with reduced OS. Moreover, patients with high miR-142 expression benefited significantly from bevacizumab treatment in terms of PFS and OS. However, bevacizumab treatment conferred no significant improvements in both PFS and OS in patients with low miR-142 expression. The nomogram for PFS indicated that miR-25 expression had a larger contribution to PFS than debulking status and bevacizumab treatment. And the nomogram for OS illustrated both miR-25 expression and miR-142 expression as sharing a larger contribution to OS than bevacizumab treatment and debulking status. CONCLUSION: In conclusion, miR-25 expression correlates with a better PFS and OS in ovarian cancer. Patients with low miR-25 expression and high miR-142 expression could benefit from bevacizumab treatment significantly.

DNA methylation-based profiling reveals distinct clusters with survival heterogeneity in high-grade serous ovarian cancer.

High-grade serous ovarian cancer (HGSOC) is the most common type of epigenetically heterogeneous ovarian cancer. Methylation typing has previously been used in many tumour types but not in HGSOC. Methylation typing in HGSOC may promote the development of personalized care. The present study used DNA methylation data from The Cancer Genome Atlas database and identified four unique methylation subtypes of HGSOC. With the poorest prognosis and high frequency of residual tumours, cluster 4 featured hypermethylation of a panel of genes, which indicates that demethylation agents may be tested in this group and that neoadjuvant chemotherapy may be used to reduce the possibility of residual lesions. Cluster 1 and cluster 2 were significantly associated with metastasis genes and metabolic disorders, respectively. Two feature CpG sites, cg24673765 and cg25574024, were obtained through Cox proportional hazards model analysis of the CpG sites. Based on the methylation level of the two CpG sites, the samples were classified into high- and low-risk groups to identify the prognostic information. Similar results were obtained in the validation set. Taken together, these results explain the epigenetic heterogeneity of HGSOC and provide guidance to clinicians for the prognosis of HGSOC based on DNA methylation sites.

Failure of internal fixation of the anterior ring for unstable pelvic fractures, the experience of a single institute.

BACKGROUND: This study aimed to share our experience of anterior ring fixation failure for unstable pelvic fractures and propose corresponding treatment strategies. MATERIALS: From January 2009 to December 2018, 93 charts of patients with pelvic fractures were retrospectively reviewed. Patients with failure of the anterior ring internal fixation within 3 months after initial surgery were analyzed. Quality of reduction was evaluated using the Majeed scoring system. Patients aging ≥ 18 years, with unstable pelvic fractures, Tile classification type B and type C pelvic fractures, combined injury of other organs that did not affect the operation and without important neurovascular damage were included. The exclusion criteria included: (1) pathological fracture, or combined with pelvic bone tumor or severe osteoporosis; (2) femoral fracture and thoracolumbar fracture; (3) open pelvic fracture; (4) Morel-Lavallée injury; (5) complicated acetabular fracture. The quality of the reduction of the anterior pelvic ring injury was evaluated on the x-ray film using the Majeed scoring system. RESULTS: According to the Tile classification of fracture, there were 23 cases of type B1, 17 cases of type B2, 11 cases of type B3, 28 cases of type C1, 6 cases of type C2, and 8 cases of type C3. The duration from injury to pelvic internal fixation ranged from 5 to 28 days. Seven out of 93 patients experienced failure of internal fixation of the anterior pelvic ring within 3 months, including 2 patients fixed with an external fixator and 5 patients fixed with a plate. Five patients undergoing revision surgery were followed up for 6-36 months with an average of 18 months. According to Majeed's score at the last follow-up in the 5 patients undergoing revision surgery, there were 2 cases of excellent, 2 cases of good, 1 case of fair. The excellent and good rate reached 80%. CONCLUSION: The treatment of complicated unstable pelvic fractures requires performing internal fixation surgery within 2 weeks. It is necessary to make a preoperative plan and stabilize the posterior ring first, avoiding a single steel plate crossing the pubic symphysis.

HJURP is a prognostic biomarker for clear cell renal cell carcinoma and is linked to immune infiltration.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most prevalent and highly malignant pathological type of kidney cancer. Finding more precise biomarkers is critical for enhancing the prognosis of patients with ccRCC. Multiple studies have suggested that Holliday junction recognition protein (HJURP) promotes tumor progression and predicts poor prognosis in a variety of cancers. However, the role of HJURP in ccRCC remains unclear. METHODS: The ccRCC dataset was obtained from The Cancer Genome Atlas (TCGA), and the relationship between HJURP expression and ccRCC clinical features was investigated using R software. The effect of HJURP expression on survival was assessed using survival probabilities and Cox regression. Gene set enrichment analysis (GSEA) was used to identify HJURP-related signaling pathways in ccRCC. Finally, Tumor IMmune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA)were used to analyzethe correlation between HJURP expression and immunocyte infiltrates in ccRCC. RESULTS: HJURP expression was upregulated in ccRCC. Increased HJURP expression was associated with poor pathological features and correlated with poor prognosis in patients with ccRCC. Cox regression further found that HJURP expression was a high-risk factor for ccRCC patients. GSEA revealed that HJURP was closely linked to multiple immune-related signaling pathways. In ccRCC, HJURP expression was closely correlated with infiltration of various immune cells and expression of a wide range of immunocyte gene markers. CONCLUSION: HJURP is a potential independent prognostic marker in ccRCC that plays an essential role in the tumor microenvironment by regulating immunocyte infiltration.

Incaspitolide A extracted from Carpesium cernuum induces apoptosis in vitro via the PI3K/AKT pathway in benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a common disease that occurs mainly in older men. The pathogenesis of BPH is complex and patients face a prolonged treatment course, and novel drugs with better selectivity and lower toxicity are required. Incaspitolide A (compound TMJ-12) is a germacrane-type sesquiterpenoid compound extracted from the plant Carpesium carnuum. Extracts of C. carnuum are known to exert suppressive effects on BPH-1 cells. In the present study, we investigated the molecular mechanisms underlying the suppressive effect of TMJ-12 specifically on BPH-1 cells. A cytotoxicity assay indicated that TMJ-12 inhibited BPH-1 cell proliferation, while flow cytometry assays showed that TMJ-12 induced G2/M phase cell cycle arrest and the apoptosis of BPH-1 cells. TMJ-12 was also shown to regulate the expression of several apoptosis- and cell cycle-related proteins, namely Bcl-2, Bax, Bad, Caspase-9, Caspase-3, cyclin-dependent kinase 1 (CDK1), Cyclin B1, CDC25C, and c-Myc, among others. Collapse of the mitochondrial membrane potential (ΔΨm) following exposure to TMJ-12 was detected with the JC-1 staining assay. Further investigation revealed that treatment with TMJ-12 inhibited the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway by increasing the expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Taken together, the results suggest that TMJ-12 prevents BPH-1 cell proliferation via the PI3K/AKT pathway by inducing apoptosis and cell cycle arrest.

Expression and Role of Dickkopf-1 (Dkk1) in Tumors: From the Cells to the Patients.

Dickkopf-1 (Dkk1) is a secretory antagonist of the classical Wnt signaling pathway. Many studies have reported that Dkk1 is abnormally expressed in tumor cells, and abnormal expression of Dkk1 can inhibit cell proliferation or induce apoptosis through pro-apoptotic factors, However, due to the differences in tumor environment and the complex regulatory mechanisms in different tumors, Dkk1 has different effects on the progression of different tumors. In many tumors, high expression of Dkk1 may promote tumor metastasis. However, Dkk1, which is highly expressed in other tumors, can inhibit tumor invasion and metastasis. More and more evidence shows that Dkk1 plays a complex and different role in tumor occurrence, development and metastasis in different tumor environments and through a variety of complex regulatory mechanisms. Therefore, Dkk1 may not only be a useful biomarker of metastasis, but also a target for studying the metabolic mechanism of tumor cells and treating tumors in many tumor types. Therefore, this article reviews the research progress on the expression, mechanism and function of Dkk1 in different tumors, and at the same time, based on the public database data, we made a further analysis of the expression of Dkk1 in different tumors.

Association of Total Dietary Intake of Sugars with Prostate-Specific Antigen (PSA) Concentrations: Evidence from the National Health and Nutrition Examination Survey (NHANES), 2003-2010.

BACKGROUND: There is increasing evidence that dietary intake of sugars may be a risk factor for prostate cancer (PCa) and elevate the concentration of serum prostate-specific antigen (PSA). However, there is limited evidence of the correlation between total dietary intake of sugars and serum PSA concentrations for adult American males. Herein, we evaluated the association between total dietary intake of sugars and serum PSA concentrations in men without a malignant tumor diagnosis in the United States (US) National Health and Nutrition Examination Survey (NHANES) database. Material and Methods. In this secondary data analysis, a total of 6,403 men aged ≥40 years and without malignant tumor history were included from 2003 to 2010. The independent variable of this study was the total dietary intake of sugars, and the dependent variable was serum PSA concentrations. Covariates included dietary, comorbidity, physical examination, and demographic data. RESULTS: The average age of participants included in this study was 58.1 years (±13.6). After adjusting for the dietary, comorbidity, physical examination, and demographic data, we observed that a dietary intake increase of one gram of total dietary intake of sugars was associated with an increase of serum PSA concentrations by 0.003 ng/mL (after log2 transformed, 95% CI: 0.001 to 0.005) with a P value for trend less than 0.05. Sensitivity analysis using the generalized additive model (GAM) supported the linear association between total dietary intake of sugars and serum PSA concentrations. CONCLUSION: The total dietary intake of sugars is independently and positively associated with serum PSA concentrations in adult American males who are without a personal history of malignant tumors.

Immunogenomic Profiling and Classification of Prostate Cancer Based on HIF-1 Signaling Pathway.

The HIF-1 signaling pathway plays an important role in the pathogenesis of cancer. Many studies have explored the progression of prostate cancer (PCa) under hypoxic conditions based on transcriptome data; few have uncovered the immunogenomic profiling and prostate cancer classification based on the HIF-1 signaling pathway. This pathway may help to identify the optimal subset of PCa patients responsive to immunotherapy/chemotherapy. The immunogenomic PCa subsets were classified based on profiling of the HIF-1 signaling pathway, using four publicly available PCa datasets. Three PCa subtypes that named as HIF-1 High (HIF-1_H), HIF-1 Medium (HIF-1_M), and HIF-1 Low (HIF-1_L) were identified. Functional enrichment was analyzed in each subtype. Several cancer-associated and immune-related pathways were hyperactivated in the HIF-1_H subtypes. In contrast, HIF-1_L subtypes were enriched in cell cycle and cell repair. Compared with other subtypes, HIF-1_H subtypes have greater immune cell infiltration, anti-tumor immune activity, and better survival prognosis. The submap and TIDE algorithm were used to predict the clinical response to immune checkpoint blockade, and GDSC was employed to screen potential chemotherapeutic targets for the treatment of PCa. Several chemotherapy drugs were identified in the GDSC dataset, including ABT 888, Temsirolimus, and EHT 1864. Meanwhile, HIF-1_H was defined as an early PCa marker, which is more likely to respond to immunotherapy. The identification of immunogenomic PCa subtypes based on the HIF-1 signaling pathway has potential clinical implications for PCa treatment. Immunopositive PCa subtypes will help to explore the reasons for the poor response of PCa to immunotherapy, and it is expected that immunotherapy will guide the personalized treatment of PCa patients.

Dietary phosphorus intake and serum prostate-specific antigen in non-prostate cancer American adults: A secondary analysis of the National Health and Nutrition Examination Survey (NHANES), 2003-2010.

BACKGROUND AND OBJECTIVES: Previous study has reported phosphorus intake is associated prostate cancer (PCa), but the association between phosphorus intake and serum prostate specific antigen (PSA) levels hasn't been reported in non-history of PCa population. Therefore, we performed a secondary data analysis based on existing data from the public Nutrition Examination Survey (NHANES) (2003-2010) database. METHODS AND STUDY DESIGN: Totally 6403 participants were selected from NHANES (2003-2010) database. The interested independent and dependent variables were considered as dietary phosphorus intake and PSA level, respectively. Covariates included demographic data, dietary data, physical examination data, and comorbidities. Weighted linear regression and generalized additive models were used to addressing the linear and non-linear link of phosphorus intake to PSA level. RESULTS: Linear association between phosphorus intake and PSA was not detected [ß=0.016 (95% Confidence Interval (CI) -0.012, 0.045)]. But we found an existing nonlinearity. By the recursive algorithm, the inflection point was 1151 mg. On the left side of the inflection point, we did not find the correlation between dietary phosphorus intake (per 100 change) and PSA level [ß=-0.04 (95% CI -0.11, 0.02), p=0.2155], while dietary phosphorus intake (per 100 change) positively associated with PSA [ß=0.05 (95% CI 0.01, 0.09) p=0.0293] on the right side of inflection point. CONCLUSIONS: There is a non-linear correlation between dietary phosphorus intake and PSA. Dietary phosphorus intake was positively associated with increased PSA when dietary phosphorus intake is beyond 1151 mg after adjusting other covariates. Over 1151 mg per day dietary phosphorus intake may be the risk factor for PSA increasing.