Inducible Fgf13 ablation alleviates cardiac fibrosis via regulation of microtubule stability.

Fibroblast growth factor (FGF) isoform 13, a distinct type of FGF, boasts significant potential for therapeutic intervention in cardiovascular dysfunctions. However, its impact on regulating fibrosis remains unexplored. This study aims to elucidate the role and mechanism of FGF13 on cardiac fibrosis. Here, we show that following transverse aortic constriction (TAC) surgery, interstitial fibrosis and collagen content increase in mice, along with reduced ejection fraction and fractional shortening, augmented heart mass. However, following Fgf13 deletion, interstitial fibrosis is decreased, ejection fraction and fractional shortening are increased, and heart mass is decreased, compared with those in the TAC group. Mechanistically, incubation of cardiac fibroblasts with transforming growth factor ß (TGFß) increases the expressions of types I and III collagen proteins, as well as α-smooth muscle actin (α-SMA) proteins, and enhances fibroblast proliferation and migration. In the absence of Fgf13, the expressions of these proteins are decreased, and fibroblast proliferation and migration are suppressed, compared with those in the TGFß-stimulated group. Overexpression of FGF13, but not FGF13 mutants defective in microtubule binding and stabilization, rescues the decrease in collagen and α-SMA protein and weakens the proliferation and migration function of the Fgf13 knockdown group. Furthermore, Fgf13 knockdown decreases ROCK protein expression via microtubule disruption. Collectively, cardiac Fgf13 knockdown protects the heart from fibrosis in response to haemodynamic stress by modulating microtubule stabilization and ROCK signaling pathway.

Development and validation of machine learning models for nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) had become the most prevalent liver disease worldwide. Early diagnosis could effectively reduce NAFLD-related morbidity and mortality. This study aimed to combine the risk factors to develop and validate a novel model for predicting NAFLD. METHODS: We enrolled 578 participants completing abdominal ultrasound into the training set. The least absolute shrinkage and selection operator (LASSO) regression combined with random forest (RF) was conducted to screen significant predictors for NAFLD risk. Five machine learning models including logistic regression (LR), RF, extreme gradient boosting (XGBoost), gradient boosting machine (GBM), and support vector machine (SVM) were developed. To further improve model performance, we conducted hyperparameter tuning with train function in Python package 'sklearn'. We included 131 participants completing magnetic resonance imaging into the testing set for external validation. RESULTS: There were 329 participants with NAFLD and 249 without in the training set, while 96 with NAFLD and 35 without were in the testing set. Visceral adiposity index, abdominal circumference, body mass index, alanine aminotransferase (ALT), ALT/AST (aspartate aminotransferase), age, high-density lipoprotein cholesterol (HDL-C) and elevated triglyceride (TG) were important predictors for NAFLD risk. The area under curve (AUC) of LR, RF, XGBoost, GBM, SVM were 0.915 [95% confidence interval (CI): 0.886-0.937], 0.907 (95% CI: 0.856-0.938), 0.928 (95% CI: 0.873-0.944), 0.924 (95% CI: 0.875-0.939), and 0.900 (95% CI: 0.883-0.913), respectively. XGBoost model presented the best predictive performance, and its AUC was enhanced to 0.938 (95% CI: 0.870-0.950) with further parameter tuning. CONCLUSIONS: This study developed and validated five novel machine learning models for NAFLD prediction, among which XGBoost presented the best performance and was considered a reliable reference for early identification of high-risk patients with NAFLD in clinical practice.

[Effects of Extracellular Vesicles on the Drug Resistance of Lung Adenocarcinoma Cells by Modulating the ATP Binding Cassette Transporter G2].

Objective: To investigate the regulatory role of extracellular vesicles (EVs) carrying ATP binding cassette transporter G2 (ABCG2) on the drug resistance of lung adenocarcinoma cells and the relevant molecular mechanisms. Methods: A549 cells, human lung adenocarcinoma cells, were used to form cisplatin (or cis-Diaminedichloroplatinum, CDDP)-resistant lung adenocarcinoma cells, i.e., A549/CDDP cells. EVs from A549 and A549/CDDP cells were extracted by gradient centrifugation method and were hence named EVs 1 and EVs 2, respectively. The A549 cells were treated with EVs 1 and EVs 2 for 48 hours, and the cells were named A549-EVs 1 and A549-EVs 2 cells, respectively. A549/ ABCG2 cells were established by transfecting A549 cells with pCDNA3.1- ABCG2 recombinant plasmids. On the other hand, A549 cells transfected with empty vectors were named A549/pCDNA3.1 cells. MTT assay was conducted to calculate the 24-hour cell drug resistance index for CDDP. The ABCG2 gene expression in cells and EVs were assessed with real-time PCR. A549 and A549-EVs 2 cells were transplanted subcutaneously into nude mice, which were labeled the control group and the experimental group accordingly. After tumor formation, 3 mg/kg CDDP was intraperitoneally injected once a week for two times. The ABCG2 gene expression of subcutaneous transplanted tumor cells was examined by real-time PCR. The cell apoptosis rate of subcutaneous transplanted tumor cells was examined by flow cytometry. Results: Using the parental A549 cells as reference, the 24-h CDDP-resistance indexes of 549/CDDP, A549/ ABCG 2, A549/pCDNA3.1, A549-EVs 1, A549-EVs 2 cells were 7.17, 10.06, 1.02, 1.19 and 5.40, respectively. When comparing the ABCG2 gene expression levels in all cells and EVs, the findings were higher in A549/CDDP cells than those inA549 cells, higher in A549/ ABCG2 cells than those in A549/pCDNA3.1 or A549 cells, higher in EVs 2 than those in EVs 1, and higher in A549-EVs 2 than those in A549-EVs 1 cells ( P<0.01) . The volume of transplanted tumor and the ABCG2 gene expression level in the experimental group were higher than those in the control group, while the apoptosis rate was lower than that in the control group ( P<0.01). Conclusion: EVs carrying ABCG2 gene can regulate the drug resistance of lung adenocarcinoma cells.

The HNF1A-AS1/miR-92a-3p axis affects the radiosensitivity of non-small cell lung cancer by competitively regulating the JNK pathway.

BACKGROUND: It has been widely reported that long non-coding RNAs (lncRNAs) could affect the varieties of tumor response to radiotherapy. LncRNA HNF1A-AS1 is transcribed from HNF1A gene cluster's antisense strand. This work focused on the mechanism of how HNF1A-AS1 participated in the radiosensitivity of non-small cell lung cancer (NSCLC). METHODS: The mRNA or protein expression of HNF1A-AS1, miR-92a-3p MAP2K4, and JNK in NSCLC cells and tissues was detected by qRT-PCR or western blotting. RNA immunoprecipitation (RIP) detection and luciferase reporting system were used to evaluate the relationship between HNFA-AS1 and miR-92a-3p or between miR-92a-3p and MAP2K4. Flow cytometry assays, colony formation, and MTT were performed to analyze the function changes in A549 and Calu-1 cells. The rescue experiment was also conducted to explore the underlying mechanisms. RESULTS: HNF1A-AS1 was investigated in NSCLC cells and tissues and highly related to the advanced pathological stage. HNF1A-AS1 bound with miR-92a-3p, which was downregulated in NSCLC. It showed that miR-92a-3p was negatively related to HNF1A-AS1. Knockdown of HNF1A-AS1 impacted most cell biological behaviors in NSCLC cells, including restricting the proliferation and aggravating apoptosis. Furthermore, knockdown of HNF1A-AS1 dramatically enhanced radiotherapy sensitivity of NSCLC. Moreover, miR-92a-3p was found to target MAP2K4 and could reduce MAP2K4 expression. Inhibition of HNF1A-AS1 elevated radiotherapy sensitivity and retarded the progression of NSCLC cells, followed by decreasing expression levels of MAP2K4. Besides, MAP2K4 mimic rescued the si-HNF1A-AS1 effects on the biological behavior of NSCLC cells. CONCLUSION: HNF1A-AS1 is highly expressed in NSCLC. MiR-92a-3p is the target gene of HNF1A-AS1 and involved in tumor progression by regulating the MAP2K4/JNK pathway. HNF1AS1/miR-92a-3p/MAP2K4 axis plays important roles in radiotherapy resistance of NSCLC.

Association of C-reactive protein (CRP) rs1205 and rs2808630 variants and risk of cancer.

The correlation between rs1205, rs2808630 variants of C-reactive protein (CRP) gene and susceptibility of cancer has been assessed previously, but with conflicting results. We adopted odds ratios (ORs) with 95% confidence intervals (CIs), in silico tools and enzyme-linked immunosorbent assay (ELISA) analysis to evaluate this association. Totally, 10,614 cancer subjects and 33,294 controls were involved in the pooled analysis. When all the studies were pooled, no significant correlation was indicated between the two variants and cancer risk. However, in stratification analysis by ethnicity, we found that CRP rs1205 C>T polymorphism was associated with an elevated risk of cancer in Asians (T-allele vs. C-allele, OR = 1.20, 95% CI = 1.06-1.36, pheterogeneity = .226; TT vs. CC, OR = 1.48, 95% CI = 1.14-1.93, pheterogeneity = .089). Similar findings were observed for rs2808630 variant. In silico tools showed that lung adenocarcinoma participants with high CRP expression may have shorter overall survival time than low expression group. ELISA analysis indicated that CRP expression in prostate adenocarcinoma subjects with TT + TC genotypes was statistically higher than in those with CC genotypes. CRP rs1205 C>T and rs2808630 T>C polymorphism may be associated with cancer risk, especially for Asians.

The association between three AXIN2 variants and cancer risk.

Plenty of epidemiological studies have assessed the effects of AXIN2 polymorphisms on the risk of developing cancer, but the available results were somewhat inconclusive. Odds ratios (ORs) with 95% confidence intervals (CIs) were utilized to investigate the relationship between three AXIN2 variants (rs2240308 C/T, rs1133683 C/T, and rs4791171 A/G) and overall cancer susceptibility. In silico tools were undertaken to investigate the correlation of AXIN2 expression with cancer risk and survival time. Furthermore, we explored the serum expression of AXIN2 by enzyme-linked immunosorbent assay. A total of 4167 cancer patients and 3515 control subjects were evaluated. The overall results demonstrated that there was no major association of these polymorphisms on cancer risk. However, stratified analysis by cancer type showed evidence that rs2240308 C/T polymorphism had a lower risk in lung cancer (OR, 0.76; 95% CI, 0.63-0.92; Pheterogeneity = 0.865) and prostate cancer (OR, 0.54; 95% CI, 0.35-0.84; Pheterogeneity = 0.088) by heterozygote comparison. Similar results were indicated in Asian descendants and population-based studies. In silico analysis showed evidence that AXIN2 expressions in lung cancer and prostate cancer were lower than that in normal counterpart. High expression of AXIN2 may have longer overall survival time than low expression group for lung cancer participants. In addition, individuals who were CC/TC carriers had a higher serum expression level than TT carriers. In conclusion, this pooled analysis suggested that AXIN2 rs2240308 C/T variant may decrease both lung and prostate cancer susceptibility, particularly in Asian descendants and population-based studies. Future large scale and well-designed research are required to validate these effects in more detail.

VEGF gene rs3025039C/T and rs833052C/A variants are associated with bladder cancer risk in Asian descendants.

INTRODUCTION: Polymorphisms of vascular endothelial growth factor (VEGF) gene were evaluated in a number of studies to evaluate bladder cancer (BCa) susceptibility but with controversial conclusions. MATERIAL AND METHODS: We performed a pooled analysis and used odds ratios (ORs) with corresponding 95% confidence intervals (95% CIs) to investigate the correlation between VEGF gene rs3025039C/T and rs833052C/A variants and risk of BCa. Furthermore, we utilized in silico tools to demonstrate the relationship of VEGF expression correlated with BCa susceptibility and survival time. RESULTS: A total of eight studies including 4359 BCa patients and 5417 control subjects were enrolled in our study. For VEGF rs3025039C/T, a significant association was indicated between this variant and BCa risk in homozygote comparison (OR = 1.51; 95% CI = 1.13-2.02; P heterogeneity = 0.815) and recessive genetic model (OR = 1.49; 95% CI = 1.12-1.99; P heterogeneity = 0.874), in particular in an Asian population subgroup. For VEGF rs833052C/A, we observed a positive association between this variant and BCa susceptibility in Asian descendants. Results from in silico tool showed evidence that VEGF expression in bladder carcinoma tissue is higher than that in normal counterpart (transcripts per kilobase million = 7.21 vs 6.85; P < 0.05). CONCLUSIONS: The VEGF gene rs3025039C/T and rs833052C/A variants may contribute to the risk of developing BCa, especially in Asian descendants. Future larger sample studies should be continued to focus on this issue in more detail.

MMP-8 C-799 T, Lys460Thr, and Lys87Glu variants are not related to risk of cancer.

BACKGROUND: Several studies have focused on the relationship between MMP-8 variants and cancer risk, but they have been unsuccessful in drawing reliable conclusions. METHODS: We employed odds ratio (OR) together with 95% confidence interval (CI) to assess the correlation between MMP-8 C-799 T, Lys460Thr, and Lys87Glu polymorphisms and cancer risk. We further employed in silico tools to evaluate the effect of MMP-8 expression on cancer susceptibility and overall survival time. RESULTS: A total of 8140 patients with malignant carcinoma and 10,529 healthy individuals (control) were enrolled. Overall, the analysis showed that the relationship between three MMP-8 variants and cancer susceptibility was not significant (allelic contrast, C-799 T: OR = 0.98, 95% CI = 0.92-1.04, Pheterogeneity = 0.068; Lys460Thr: OR = 0.94, 95% CI = 0.67-1.32, Pheterogeneity = 0.905; Lys87Glu: OR = 1.05, 95% CI = 0.93-1.18, Pheterogeneity = 0.968). Similar results were observed in subgroup analysis by ethnicity, cancer type, and source of control. In silico analysis indicated that MMP-8 expression was elevated in bladder cancer tissue compared to that in the control. However, both the higher and lower MMP-8 expression groups did not show an impact on the overall survival time of the patients. CONCLUSIONS: MMP-8 C-799 T, Lys460Thr, and Lys87Glu variants are not participant with the susceptibility of cancer.

Living Donor Liver Transplantation in Biliary Atresia Children with Pulmonary Hypertension.

OBJECTIVE: Though living donor liver transplantation (LDLT) is commonly performed for pediatric patients with biliary atresia (BA), pulmonary hypertension (PH) is seldom encountered or reported previously. The aim of this study is mainly to identify the prevalence of PH in pediatric patients undergoing liver transplantation and assess whether PH significantly augment the operative risk and evaluate the outcomes in this series of patients. DESIGN: Retrospectively cohort study. SETTING: Renji hospital, Shanghai, China. PARTICIPANTS: This study comprised 161 pediatric patients undergoing LDLT. INTERVENTIONS: Patient diagnosed of PH in preoperative examination was compared to those without PH in intra- or post- operative complications or outcomes. MEASUREMENTS AND MAIN RESULTS: We collected clinical records of LDLT surgery for pediatric patients during the year of 2016 in our hospital. Results suggested that pediatric patients undergoing LDLT had a substantial number of PH with a prevalence of 16.1% in this study. No significant difference was identified between two groups of patients regarding intraoperative outcomes and postoperative complications and mortality. CONCLUSION: LDLT is a safe procedure in a selected group of BA patients with PH, however, further long-term clinical investigations and mechanical researches are needed.

Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation.

Ezh2 (Enhancer of zeste homolog 2) protein is the enzymatic component of the Polycomb repressive complex 2 (PRC2), which represses gene expression by methylating lysine 27 of histone H3 (H3K27) and regulates cell proliferation and differentiation during embryonic development. Recently, hot-spot mutations of Ezh2 were identified in diffused large B-cell lymphomas and follicular lymphomas. To investigate if tumor growth is dependent on the enzymatic activity of Ezh2, we developed a potent and selective small molecule inhibitor, EI1, which inhibits the enzymatic activity of Ezh2 through direct binding to the enzyme and competing with the methyl group donor S-Adenosyl methionine. EI1-treated cells exhibit genome-wide loss of H3K27 methylation and activation of PRC2 target genes. Furthermore, inhibition of Ezh2 by EI1 in diffused large B-cell lymphomas cells carrying the Y641 mutations results in decreased proliferation, cell cycle arrest, and apoptosis. These results provide strong validation of Ezh2 as a potential therapeutic target for the treatment of cancer.

AURKA knockdown inhibits esophageal squamous cell carcinoma progression through ferroptosis.

Aurora kinase A, as a pro-carcinogenic in gastric cancer and glioma kinase, is enhanced in several human tumors. However, it's regulatory mechanism in esophageal squamous cell carcinoma (ESCC) remains unclear. Thus, this study aimed to investigate the expression status, functional roles, and molecular mechanisms of AURKA in ESCC development. AURKA expression was analyzed by the screening of the GEO database and detected using an immunohistochemical method. The biological function of AURKA on ESCC was evaluated in vitro and in vivo. Western blot assay, malondialdehyde (MDA), iron, and glutathione (GSH) kits were utilized to assess changes in ferroptosis. Database analysis results showed that AURKA was a differential gene in ESCC and was highly expressed in human ESCC tissues. Functionally, AURKA knockdown decreased ESCC cell proliferation, invasion, and metastasis both in vitro and in vivo. Moreover, when AURKA was knockdown, cells were more correctly blocked in the G2/M phase, and the ferroptosis-related MDA and Fe increased, whereas the GSH reduced. Consistently, Glutathione peroxidase 4 (GPX4) and solute carrier family 7a member 11 (SLC7A11) expression were downregulated by AURKA knockdown. However, ferroptosis inhibitor partially restore ESCC cell proliferation, invasion, and metastasis caused by AURKA knockdown. AURKA knockdown enhances ferroptosis and acts against cancer progression in ESCC. AURKA acts as a tumor-promoting gene and may serve as potential target for ESCC treatment.

Trimethylamine-N-oxide aggravated the sympathetic excitation in D-galactose induced aging rats by down-regulating P2Y12 receptor in microglia.

This study aimed to determine whether trimethylamine N-oxide (TMAO) was involved in sympathetic activation in aging and the underlying mechanisms. Our hypothesis is TMAO reduces P2Y12 receptor (P2Y12R) and induces microglia-mediated inflammation in the paraventricular nucleus (PVN), then leading to sympathetic activation in aging. This study involved 18 young adults and 16 old adults. Aging rats were established by injecting D-galactose (D-gal, 200 mg/kg/d) subcutaneously for 12 weeks. TMAO (120 mg/kg/d) or 1% 3, 3-dimethyl-l-butanol (DMB) was administrated via drinking water for 12 weeks to investigate their effects on neuroinflammation and sympathetic activation in aging rats. Plasma TMAO, NE and IL-1ß levels were higher in old adults than in young adults. In addition, standard deviation of all normal to normal intervals (SDNN) and standard deviation of the average of normal to normal intervals (SDANN) were lower in old adults and negatively correlated with TMAO, indicating sympathetic activation in old adults, which is associated with an increase in TMAO levels. Treatment of rats with D-gal showed increased senescence-associated protein levels and microglia-mediated inflammation, as well as decreased P2Y12R protein levels in PVN. Plasma TMAO, NE and IL-1ß levels were increased, accompanied by enhanced renal sympathetic nerve activity (RSNA). While TMAO treatment exacerbated the above phenomenon, DMB mitigated it. These findings suggest that TMAO contributes to sympathetic hyperactivity in aging by downregulating P2Y12R in microglia and increasing inflammation in the PVN. These results may provide promising new target for the prevention and treatment of aging and aging-related diseases.

Hydrogen Sulfide Inhibited Sympathetic Activation in D-Galactose-Induced Aging Rats by Upregulating Klotho and Inhibiting Inflammation in the Paraventricular Nucleus.

The present study aimed to explore the central relationship between cardiovascular conditions and aging. D-galactose (D-gal) was utilized to induce an accelerated aging model and to evaluate the effects of hydrogen sulfide (H2S) on aging-related cardiovascular risk factors and mechanisms. Eight-week-old Sprague Dawley rats were given an intraperitoneal injection of 250 mg/kg D-gal every day with or without H2S (56 µmol/kg) for 12 weeks. We found that D-gal treatment induced a noticeably aging-related increase in p16, p53 and p21 protein levels and senescence-associated beta-galactosidase staining. In addition, the level of noradrenalin was increased, accompanied by enhanced blood pressure and renal sympathetic nerve activity in aged rats. The greater sympathetic responses were related with the increased level of inflammation. The decreased level of klotho in the paraventricular nucleus neuron also contributed to sympathetic activation in D-gal-induced aged rats. However, the exogenous administration of H2S attenuated the sympathetic activity in aged rats, as evidenced by the decreased blood pressure, renal sympathetic nerve activity and noradrenalin level. The ameliorated cellular senescence, inflammation and heightened klotho in the paraventricular nucleus were attributed to the protective effects of H2S. The present study provides further evidence for the drug development of H2S for the prevention or treatment of the aging-associated cardiovascular diseases.

Comparison of neoadjuvant immunotherapy versus routine neoadjuvant therapy for patients with locally advanced esophageal cancer: A systematic review and meta-analysis.

Background: The neoadjuvant use of immune checkpoint inhibitor combined with chemotherapy (nICT) or chemoradiotherapy (nICRT) in locally advanced esophageal cancer (EC) is currently an area of active ongoing research. Therefore, we carried out a comprehensive meta-analysis to compare the efficacy and safety of the new strategy with routine neoadjuvant strategy, which included neoadjuvant chemotherapy (nCT) and neoadjuvant chemoradiotherapy (nCRT). Patients and methods: MEDLINE (via PubMed), Embase (via OVID), ISI Web of Science database and Cochrane Library were included. And, all of them were searched for eligible studies between January, 2000 and February, 2023. The pathological complete response (pCR) and major pathological response (MPR) were primary outcome of our study. The second outcome of interest was R0 resection rate. Odds ratio (OR) and associated 95% CI were used as the effect indicators comparing the safety and efficiency of the neoadjuvant immunotherapy with the routine neoadjuvant therapy. Fixed-effect model (Inverse Variance) or random-effect model (Mantel-Haenszel method) was performed depending on the statistically heterogeneity. Results: There were eight trials with 652 patients were included in our meta-analysis. The estimated pCR rate was higher in the neoadjuvant immunotherapy group (OR =1.86; 95% CI, 1.25-2.75; I2 = 32.8%, P=0.166). The different results were found in the esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) subgroups, the estimated OR was 2.35 (95%CI, 1.00-2.72; I2 = 30.9%, P=0.215) in the EAC subgroup, and 2.35 (95% CI, 1.20-4.54; I2 = 45.3%, P=0.161) in the ESCC subgroup, respectively. The neoadjuvant immunotherapy also showed the advantage in the MPR rates (OR =2.66; 95% CI, 1.69-4.19; I2 = 24.3%, P=0.252). There was no obvious difference between the neoadjuvant immunotherapy and routine neoadjuvant therapy with respect to surgical resection rate, R0 resection rate, surgical delay rate; while more treatment-related adverse events were observed for the neoadjuvant immunotherapy for pneumonitis/pneumonia (OR=3.46, 95% CI, 1.31-9.16; I2 = 67.3%, P=0.005) and thyroid dysfunction (OR=4.69, 95% CI, 1.53-14.36; I2 = 56.5%, P=0.032). Conclusion: The pooled correlations indicated that the neoadjuvant immunotherapy (both nICT and nICRT) could significantly increase the rates of pCR and MPR, compared with routine neoadjuvant therapy (both nCT and nCRT) in the treatment of locally advanced EC. The neoadjuvant immunotherapy and routine neoadjuvant therapy were with acceptable toxicity. However, randomized studies with larger groups of patients need to performed to confirm these results. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42020155802.

A first-in-class HBO1 inhibitor WM-3835 inhibits castration-resistant prostate cancer cell growth in vitro and in vivo.

The prognosis and overall survival of castration-resistant prostate cancer (CRPC) patients are poor. The search for novel and efficient anti-CRPC agents is therefore extremely important. WM-3835 is a cell-permeable, potent and first-in-class HBO1 (KAT7 or MYST2) inhibitor. Here in primary human prostate cancer cells-derived from CRPC patients, WM-3835 potently inhibited cell viability, proliferation, cell cycle progression and in vitro cell migration. The HBO1 inhibitor provoked apoptosis in the prostate cancer cells. It failed to induce significant cytotoxicity and apoptosis in primary human prostate epithelial cells. shRNA-induced silencing of HBO1 resulted in robust anti-prostate cancer cell activity as well, and adding WM-3835 failed to induce further cytotoxicity in the primary prostate cancer cells. Conversely, ectopic overexpression of HBO1 further augmented primary prostate cancer cell proliferation and migration. WM-3835 inhibited H3-H4 acetylation and downregulated several pro-cancerous genes (CCR2, MYLK, VEGFR2, and OCIAD2) in primary CRPC cells. Importantly, HBO1 mRNA and protein levels are significantly elevated in CRPC tissues and cells. In vivo, daily intraperitoneal injection of WM-3835 potently inhibited pPC-1 xenograft growth in nude mice, and no apparent toxicities detected. Moreover, intratumoral injection of HBO1 shRNA adeno-associated virus (AAV) suppressed the growth of primary prostate cancer xenografts in nude mice. H3-H4 histone acetylation and HBO1-dependent genes (CCR2, MYLK, VEGFR2, and OCIAD2) were remarkably decreased in WM-3835-treated or HBO1-silenced xenograft tissues. Together, targeting HBO1 by WM-3835 robustly inhibits CRPC cell growth.

Update analysis of studies on the MMP-9 -1562 C>T polymorphism and cancer risk.

Polymorphisms in the matrix metalloproteinase (MMP) gene have been hypothesized to be functional and may contribute to genetic susceptibility to cancers. The common sequence variation in MMP-9 -1562 C>T (rs3918242), has been involved in cancer risk. However, results of the related published studies were somewhat controversial and underpowered in general. To clarify the role of MMP-9 -1562 C>T genotype in global cancer, we performed a meta-analysis of all the available published studies involving 4,124 cancer patients and 4,728 control subjects. The overall results indicated that there was no major association of the variant on cancer risk. However, stratified analysis by cancer type showed that the MMP-9 -1562 C>T polymorphism has a lower risk in colorectal cancer (OR = 0.80, 95%CI = 0.66-0.96, P (heterogeneity) = 0.391) and lung cancer (OR = 0.70, 95%CI = 0.51-0.96, P (heterogeneity) = 0.959) by allelic contrast. Furthermore, association of the MMP-9 -1562 C>T polymorphism and cancer risk was also observed in hospital-based studies under the dominant genetic model (OR = 0.87, 95%CI = 0.78-0.97, P (heterogeneity) = 0.355), allelic contrast (OR = 0.85, 95%CI = 0.75-0.96, P (heterogeneity) = 0.271) and heterozygote comparison (OR = 0.89, 95%CI = 0.79-0.99, P (heterogeneity) = 0.402). This pooled analysis showed evidence that the MMP-9 -1562 C>T polymorphism may decrease both the colorectal and lung cancer risk. Further prospective studies with larger numbers of participants worldwide are required to evaluate the association in more detail.

A systematic review of the efficacy of donepezil hydrochloride combined with nimodipine on treating vascular dementia.

BACKGROUND: Vascular dementia (VaD) is a comprehensive syndrome related to the damage of cognitive function and various cerebral vascular illnesses. VaD is also generally recognized as the second most common type of dementia after Alzheimer disease, contributing to 30% of the dementia population in Asia and developing countries. The ability of donepezil hydrochloride and nimodipine had been respectively proven in improving cognitive function in vascular dementia. However, whether the combined application of both drugs contribute to better efficacy remains as a research hotspot. Studies had shown definite satisfactory result with such combination, however evidence-based evaluation of the efficacy is still lacking. Therefore, meta-analysis is employed in this study to evaluate the efficacy and safety of using donepezil hydrochloride combined with nimodipine in treating VaD to provide references for clinical treatments. The efficacy of donepezil hydrochloride combined with nimodipine on treating vascular dementia is systematically reviewed to provide evidence-based references for clinical applications. METHODS: Both Chinese and English databases were searched from the start till August, 2020 for any RCT regarding the combined use of the 2 drugs in treating vascular dementia. Two investigators would later evaluate and screened out research and data based on an improved Jaded scale. Software Rev Man 5.3.0 was employed to carry out meta-analysis on clinical effificacy, mini-mental state examination (MMSE) ratings, activity of daily living (ADL) ratings, and clinical dementia scale (CDR) ratings. RESULTS: Donepezil hydrochloride combined with nimodipine had demonstrated satisfactory efficacy on the treatment of vascular dementia. Improvements were namely spotted on MMSE scale, ADL scale, and CDR scale, with the utmost efficacy by 12 weeks after intervention. CONCLUSIONS: Donepezil hydrochloride combined with nimodipine had good efficacy in the treatment of patients with vascular dementia, mainly in terms of improving the Simple MMSE scores, the ability to use daily living scale (ADL) scores and the CDR, and the best results were obtained after 12 weeks of intervention. Such conclusion should be cautiously evaluated.

Discovery of the Clinical Candidate MAK683: An EED-Directed, Allosteric, and Selective PRC2 Inhibitor for the Treatment of Advanced Malignancies.

Polycomb Repressive Complex 2 (PRC2) plays an important role in transcriptional regulation during animal development and in cell differentiation, and alteration of PRC2 activity has been associated with cancer. On a molecular level, PRC2 catalyzes methylation of histone H3 lysine 27 (H3K27), resulting in mono-, di-, or trimethylated forms of H3K27, of which the trimethylated form H3K27me3 leads to transcriptional repression of polycomb target genes. Previously, we have shown that binding of the low-molecular-weight compound EED226 to the H3K27me3 binding pocket of the regulatory subunit EED can effectively inhibit PRC2 activity in cells and reduce tumor growth in mouse xenograft models. Here, we report the stepwise optimization of the tool compound EED226 toward the potent and selective EED inhibitor MAK683 (compound 22) and its subsequent preclinical characterization. Based on a balanced PK/PD profile, efficacy, and mitigated risk of forming reactive metabolites, MAK683 has been selected for clinical development.

Porcine circovirus type 2 (PCV2) infection decreases the efficacy of an attenuated classical swine fever virus (CSFV) vaccine.

The Lapinized Philippines Coronel (LPC) vaccine, an attenuated strain of classical swine fever virus (CSFV), is an important tool for the prevention and control of CSFV infection and is widely and routinely used in most CSF endemic areas, including Taiwan. The aim of this study was to investigate whether PCV2 infection affects the efficacy of the LPC vaccine. Eighteen 6-week-old, cesarean-derived and colostrum-deprived (CDCD), crossbred pigs were randomly assigned to four groups. A total of 10(5.3) TCID50 of PCV2 was experimentally inoculated into pigs through both intranasal and intramuscular routes at 0 days post-inoculation (dpi) followed by LPC vaccination 12 days later. All the animals were challenged with wild-type CSFV (ALD stain) at 27 dpi and euthanized at 45 dpi. Following CSFV challenge, the LPC-vaccinated pigs pre-inoculated with PCV2 showed transient fever, viremia, and viral shedding in the saliva and feces. The number of IgM(+), CD4(+)CD8-CD25(+), CD4(+)CD8(+)CD25(+), and CD4(-)CD8(+)CD25(+) lymphocyte subsets and the level of neutralizing antibodies against CSFV were significantly higher in the animals with LPC vaccination alone than in the pigs with PCV2 inoculation/LPC vaccination. In addition, PCV2-derived inhibition of the CSFV-specific cell proliferative response of peripheral blood mononuclear cells (PBMCs) was demonstrated in an ex vivo experiment. These findings indicate that PCV2 infection decreases the efficacy of the LPC vaccine. This PCV2-derived interference may not only allow the invasion of wild-type CSFV in pig farms but also increases the difficulty of CSF prevention and control in CSF endemic areas.