Ellagic acid inhibits tumor growth and potentiates the therapeutic efficacy of sorafenib in hepatocellular carcinoma.

Background: Sorafenib is a classic molecular targeted drug approved for hepatocellular carcinoma (HCC) therapy. However, a poor response rate and increasing resistance to sorafenib make its therapeutic efficacy suboptimal. Combination treatment with an agent capable of potentiating sorafenib sensitivity may be a promising solution. Aim: The aim of this study was to determine the synergistic effect of ellagic acid (EA), a natural polyphenol, and sorafenib on HCC. Methods: CCK-8, EdU incorporation and colony formation assays were used to study the effect of EA on HCC cell proliferation. Apoptosis was detected by flow cytometry in HCC cells and TUNEL assay in xenograft tumors. Transcriptome analysis was utilized to investigate alterations in signaling pathways with EA treatment. A xenograft mouse model was used to confirm the synergistic effect of sorafenib and EA on HCC tumors in vivo. Results: We found that EA inhibited growth and induced apoptosis in both HCC cells and xenograft tumors. Mechanistically, EA treatment reduced the activation of the MAPK and Akt/mTOR signaling pathways in HCC cells. Furthermore, combined EA and sorafenib treatment further inhibited the MAPK and Akt/mTOR signaling pathways compared to EA or sorafenib alone. EA synergistically potentiated the anticancer activity of sorafenib against HCC both in vitro and in vivo. Conclusion: EA inhibits HCC growth by inducing apoptosis through attenuation of the MAPK and Akt/mTOR signaling pathways. EA potentiates the response of HCC tumors to sorafenib both in vitro and in vivo, an effect that may be attributed to further inhibition of the MAPK and Akt/mTOR signaling pathways. These results suggest that EA is an effective adjuvant option for sorafenib therapy.

Comparison of nomogram for Primary Nonfunctional Pancreatic Neuroendocrine Tumors based on the 7th vs 8th edition of the AJCC cancer staging manual.

BACKGROUND: Our study aimed to construct and validate prognostic nomograms for predicting survival for patients with Nonfunctional Pancreatic neuroendocrine tumor (NF-pNET). METHODS: This retrospective study included 1824 patients diagnosed with NF-pNET in the Surveillance, Epidemiology and End Results database between 2004 and 2016. Randomization divided the patients into training (n = 1278) and validation (n = 546) cohorts. Prognostic factors were determined using Cox regression analyses, nomograms based on AJCC 7th and 8th staging system were constructed separately. The prediction models were validated using internal validation and external validation. RESULTS: Age, year of diagnosis, primary tumor site, grade, 7th or 8th TNM stage, surgery, tumor size were determined as prognostic indicator to construct two nomograms. Harrell's concordance index (C-index) of two nomograms exhibited a clinical predictive ability of 0.828 (95%CI, 0.808~0.849) vs 0.828 (95% CI, 0.808~0.849) in the internal verification. The c-index in the external validation was 0.812 (95%CI, 0.778~0.864) vs 0.814 (95% CI, 0.779~0.848). The predictive power of the two nomograms is comparable. CONCLUSIONS: Our nomogram may be a effective tool for predicting overall survival in patients with NF-pNET. The AJCC 8th-edition system provides discrimination similar to that of the 7th-edition system.

Basal cell carcinoma of the prostate with squamous metaplasia: A case report and literature review.

Basal cell carcinoma of the prostate (BCCP) is a rare tumor with a total incidence of 140 cases to date. However, BCCP with squamous metaplasia has not been reported as of date. In this paper, we report the first case of BCCP with squamous metaplasia. The patient was hospitalized for progressive dyspareunia and had been treated for recurrent urinary retention four times in 5 years. Rectal examination showed that the prostate was medium in texture with no palpable nodules. The levels of total prostate specific antigen (tPSA), free prostate specific antigen (fPSA), and fPSA/tPSA (f/t) ratio were 1.29 ng/mL, 0.4 ng/mL, and 0.31, respectively. Ultrasound of the urinary tract showed that the prostate gland was 51 mm*40 mm*38 mm in size. We performed transurethral resection of the prostate. Histopathology confirmed the diagnosis of basal cell carcinoma with focal squamous differentiation, and immunohistochemical staining was positive for P63 and 34ßE12. A laparoscopic radical prostatectomy was performed 45 days after the first surgery and the postoperative pathology showed a small amount of residual tumor with negative margins and no involvement of the seminal vesicles and vas deferens. The patient was followed up for 50 months and was doing well by the end of our study. We describe the clinical symptoms, pathological features, treatment, and prognosis of patients with BCCP with squamous metaplasia. The relevant published literature is also briefly reviewed.

Causal association of cardiovascular disease with erectile dysfunction: a two-sample bidirectional Mendelian randomization analysis.

BACKGROUND: The association between cardiovascular diseases (CVD), including ischemic stroke (IS), heart failure (HF), myocardial infarction (MI), and coronary heart disease (CHD), and erectile dysfunction (ED) remains unclear from observational studies. OBJECTIVES: We explored the potential bidirectional association between CVD and ED by Mendelian randomization (MR). METHODS: Data from genome-wide association studies for CVD in individuals with European ancestry were obtained from several databases, with 1,711,875-977,323 participants, while that for ED included 223,805 participants. We conducted univariate MR (UVMR), inverse variance-weighting (IVW), weighted median, MR-Egger, and multivariate MR (MVMR) analyses to explore the bidirectional causal effects between CVD and ED. RESULTS: UVMR indicated that IS (odds ratios [OR] = 1.34, 95% confidence interval [CI]: 1.08-1.21, P = 0.007), HF (OR = 1.36, 95% CI 1.07-1.74, P = 0.013), and CHD (OR = 1.15, 95% CI 1.09-1.18, P = 0.022) were associated with ED. By MVMR, IS estimates remained significant after accounting for combining single nucleotide polymorphisms from CVDs (OR = 1.42, 95%CI: 1.13-1.79, P = 0.002). Moreover, the effect of a genetic susceptibility to IS on ED was not mediated by type 2 diabetes or triglycerides; that of HF was not mediated by type 2 diabetes, and that of CHD was not mediated by body mass index. Bidirectional analyses showed that genetic susceptibility to ED did not confer any increased CVD risk. CONCLUSIONS: Our results, based on MR, indicated that genetic susceptibility to IS, HF, and CHD was causally associated with ED. These findings can inform prevention and intervention strategies for ED in IS, HF, and CHD patients.

Succession of the Gut Microbiome in the Tibetan Population of Minjiang River Basin.

Tibetans are one of the oldest ethnic groups in China and South Asia. Based on the analysis of 1,059 Tibetans in the Minjiang River basin at an altitude of 500-4,001 m, we found that the dominant phyla of the Tibetan population were Bacteroidota and Firmicutes, and the main genera were Prevotella and Bacteroides, which were mostly in consistent with other nationalities. We further evaluated in total 115 parameters of seven categories, and results showed that altitude was the most important factor affecting the variation in the microbial community. In the process of emigration from high altitudes to the plain, the gut microbial composition of late emigrants was similar to that of plateau aborigines. In addition, regarding immigration from low altitude to high altitude, the microbial community became more similar to that of high altitude population with the increase of immigration time. Changes in these microbes are related to the metabolism, disease incidence and cell functions of the Tibetan population. The results of other two cohorts (AGP and Z208) also showed the impact of altitude on the microbial community. Our study demonstrated that altitude of habitation is an important factor affecting the enterotype of the microflora in the Tibetan population and the study also provided a basis to explore the interaction of impact parameters with gut microbiome for host health and diseases.

Comprehensive Analysis of Differentially Expressed Profiles of mRNA N6-Methyladenosine in Colorectal Cancer.

Aim: To comprehensively profile the landscape of the mRNA N6-methyladenosine (m6A) modification in human colorectal cancer (CRC). Methods: Methylated RNA immunoprecipitation sequencing (MeRIP-seq) was explored to compare the difference in mRNA N6-methyladenosine (m6A) methylation between CRC tissues and adjacent normal control (NC) tissue. RNA-sequencing (RNA-seq) was performed to transcribe differentially expressed mRNAs. Conjoint analysis of MeRIP-seq and RNA-seq data was conducted to predict RNA-binding proteins (RBPs). Results: MeRIP-seq identified 1110 differentially m6A methylated sites (DMMSs) and 980 differentially m6A methylated genes (DMMGs) in CRC, with 50.13% of all modified genes showing unique m6A-modified peaks in CRC. RNA-seq showed 915 upregulated genes and 1463 downregulated genes in CRC. QRT-PCR verified the RNA-seq results by detecting the expression of some mRNAs. Conjoint analysis of MeRIP-seq and RNA-seq identified 400 differentially m6A methylated and expressed genes (DEGs), and pathway analysis detected that DMMGs and DEGs were closely related to cancer. After analyzing these DMMGs and DEGs through the GEPIA database, we found that the expression of B3GNT6, DKC1, SRPK1, and RIMKLB were associated with prognosis, and the expression of B3GNT6 and RIMKLB were associated with clinical stage. 17 RBPs were identified based on the DMMGs and DEGs, among which FXR1, FXR2, FMR1, IGF2BP2, IGF2BP3, and SRSF1 were obviously highly expressed in CRC, and FMR1, IGF2BP2, and IGF2BP3 were closely related to methylation, and might be involved in the development of CRC. Conclusion: This study comprehensively profiled m6A modification of mRNAs in CRC, which revealed possible mechanisms of m6A-mediated gene expression regulation.

hTERT promotes gastric intestinal metaplasia by upregulating CDX2 via NF-κB signaling pathway.

BACKGROUND: hTERT has been reported involved in the proliferation and metastasis of gastric cancer, but the role of hTERT in gastric intestinal metaplasia, a premalignant lesion of the gastric mucosa was unknown. The aim of the present study was to investigate the role of hTERT in GIM and the effect of hTERT on CDX2 expression in gastric cells. RESULTS: Experiments showed that expression of hTERT was significantly higher in GIM than in normal gastric mucosa. Moreover, hTERT increased the KLF4 level via NF-κB during GIM. Furthermore, KLF4 is involved in the up-regulation of CDX2 induced by hTERT, and hTERT can interact with p50, thereby increasing the level of CDX2. MATERIALS AND METHODS: Immunohistochemistry was used to detect the expression of hTERT in gastric intestinal metaplasia tissue. Then, effect of hTERT on the expression of CDX2 was detected by qRT-PCR, WB and dual luciferase experiment. The role of p65 and p50 in the regulation of CDX2 were further detected by WB, CO-IP and ChIP. CONCLUSIONS: We may conclude that hTERT promotes GIM by up-regulating CDX2 via NF-κB signaling pathway.

The reverse-mode NCX1 activity inhibitor KB-R7943 promotes prostate cancer cell death by activating the JNK pathway and blocking autophagic flux.

We explored the effects of KB-R7943, an inhibitor of reverse-mode NCX1 activity, in prostate cancer (PCa). NCX1 was overexpressed in PCa tissues and cell lines, and higher NCX1 levels were associated higher PCa grades. At concentrations greater than 10 µM, KB-R7943 dose-dependently decreased PC3 and LNCaP cell viability. KB-R7943 also increased cell cycle G1/S phase arrest and induced apoptosis in PC3 cells. KB-R7943 increased autophagosome accumulation in PCa cells as indicated by increases in LC3-II levels and eGFP-LC3 puncta. Combined treatment with chloroquine (CQ) and KB-R7943 decreased P62 and increased LC3-II protein levels in PC3 cells, indicating that KB-R7943 blocked autophagic flux. KB-R7943 induced autophagosome accumulation mainly by downregulating the PI3K/AKT/m-TOR pathway and upregulating the JNK pathway. In xenograft experiments, KB-R7943 inhibited tumor growth. Combined treatment with KB-R7943 and an autophagy inhibitor inhibited growth and increased apoptosis. These results indicate that KB-R7943 promotes cell death in PCa by activating the JNK signaling pathway and blocking autophagic flux.

The FOXM1-induced resistance to oxaliplatin is partially mediated by its novel target gene Mcl-1 in gastric cancer cells.

Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein that belongs to the Bcl-2 family. The aberrant expression of Mcl-1 is important for sensitivity to chemotherapy drugs in gastric cancer. However, the regulatory mechanism of Mcl-1 in gastric cancer cells remains unclear. In this study, we first found that Forkhead box M1 (FOXM1) and Mcl-1 expression levels were positively correlated in human gastric cancer specimens and that both are associated with poor prognosis of patients treated with oxaliplatin. Second, we demonstrated that the expression level of Mcl-1 was correlated with FOXM1 expression in gastric cancer cells. Third, reporter assays showed that FOXM1 upregulated the promoter activity of the Mcl-1 gene. Electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP) assays further demonstrated that FOXM1 could bind to a particular site (-635acaaacaa-628) in the promoter region of the Mcl-1 gene. Moreover, CCK-8 assays and analyses of apoptosis revealed that the suppression of the FOXM1/Mcl-1 pathway induced apoptosis and thus increased sensitivity to oxaliplatin in gastric cancer cells, whereas the enhancement of the FOXM1/Mcl-1 pathway inhibited apoptosis and decreased sensitivity to oxaliplatin in gastric cancer cells. Taken together, this study is the first to not only show that Mcl-1 is a novel target gene of FOXM1 but also suggest that targeting FOXM1/Mcl-1 may be a novel strategy to enhance sensitivity to oxaliplatin in gastric cancer.

PLCE1 polymorphism and upper gastrointestinal cancer risk: a meta-analysis.

BACKGROUND: In recent years, the PLCE1 rs2274223 polymorphism has been extensively investigated as a potential risk factor for upper gastrointestinal cancers, including squamous cell carcinoma (ESCC) and gastric cancer. However, the results of these studies have been inconsistent. METHODS: A meta-analysis of 13 case-control studies was performed including more than 11,000 subjects with genotyped PLCE1 rs2274223 polymorphisms. Odds ratios (OR) with 95% confidence intervals (CI) were employed to assess the association of the PLCE1 rs2274223 polymorphism with a susceptibility to ESCC or gastric cancer. RESULTS: A statistically significant increase in the risk of ESCC was associated with the PLCE1 rs2274223 polymorphism. This included the homozygous genetic model (OR = 1.46), heterozygous genetic model (OR = 1.25) and allelic genetic model (OR = 1.23). Similar results were consistently found for gastric cancer. In a subgroup analysis, the PLCE1 rs2274223 polymorphism was found to be a very sensitive marker for gastric cardia cancer as shown by the homozygous genetic model (OR = 2.23), heterozygous genetic model(OR = 1.59) and allelic genetic model (OR = 1.47). The risk associations of all of the gastric cardia cancer models were statistically significant. In contrast, none of the genetic models for non-cardia gastric cancer were significant. CONCLUSIONS: In this meta-analysis, the PLCE1 rs2274223 polymorphism was confirmed to have a statistically significant association with an increasing risk of ESCC and gastric cancer. The increase risk was especially observed for gastric cardia cancer.

[Efficacy and safety of different dosages of intravesical epirubicin instillation for prevention of primary superficial bladder carcinoma from recurrence].

OBJECTIVE: To investigate the efficiency and safety of different regimens by intravesical instillation of epirubicin, a derivative of adriamycin, for the prevention of primary superficial bladder carcinoma from recurrence. METHODS: Ninety patients supplemented with intravesical epirubicin instillation after operation were randomly divided into three groups: Group A--80 mg in one dose; Group B--repeated epirubicin 40 mg q wk x 4-8 sessions followed by q month to the end of the second year; or Group C--50 mg q month to the same duration. All patients were followed up for two years by observing the recurrence rates and side effects. RESULTS: The recurrence rate of groups A, B and C at one year was 16.7%, 13.3% and 16.7%, respectively, without any significant difference observed. However, it was 50.0%, 36.7% and 36.7% at two years, at which time the recurrence rate of group A was significantly higher than those of groups B and C. The side effects rate was 23.3%, 40.0% and 33.3% for groups A, B and C, respectively. The more instillations the patients had, the more severe side effects were. CONCLUSION: Early postoperative single high dose intravesical instillation of epirubicin combined with repeated lower doses of the same drug every month may be an efficient and safe regimen to prevent the primary superficial bladder carcinoma from recurrence.