Comprehensive analyses of solute carrier family members identify SLC12A2 as a novel therapy target for colorectal cancer.

As the largest transporter family impacting on tumor genesis and development, the prognostic value of solute carrier (SLC) members has not been elucidated in colorectal cancer (CRC). We aimed to identify a prognostic signature from the SLC members and comprehensively analyze their roles in CRC. Firstly, we downloaded transcriptome data and clinical information of CRC samples from GEO (GSE39582) and TCGA as training and testing dataset, respectively. We extracted the expression matrix of SLC genes and established a prognostic model by univariate and multivariate Cox regression. Afterwards, the low-risk and high-risk group were identified. Then, the differences of prognosis traits, transcriptome features, clinical characteristics, immune infiltration and drug sensitivity between the two groups were explored. Furthermore, molecular subtyping was also implemented by non-negative matrix factorization (NMF). Finally, we studied the expression of the screened SLC genes in CRC tumor tissues and normal tissues as well as investigated the role of SLC12A2 by loss of function and gain of function. As a result, we developed a prognostic risk model based on the screened 6-SLC genes (SLC39A8, SLC2A3, SLC39A13, SLC35B1, SLC4A3, SLC12A2). Both in the training and testing sets, CRC patients in the high-risk group had the poorer prognosis and were in the more advanced pathological stage. What's more, the high-risk group were enriched with CRC progression signatures and immune infiltration. Two groups showed different drug sensitivity. On the other hand, two distinct subclasses (C1 and C2) were identified based on the 6 SLC genes. CRC patients in the high-risk group and C1 subtype had a worse prognosis. Furthermore, we found and validated that SLC12A2 was steadily upregulated in CRC. A loss-of-function study showed that knockdown of SLC12A2 expression restrained proliferation and stemness of CRC cells while a gain-of-function study showed the contrary results. Hence, we provided a 6-SLC gene signature for prognosis prediction of CRC patients. At the same time, we identified that SLC12A2 could promote tumor progression in CRC, which may serve as a potential therapeutic target.

From bench to bedside: current development and emerging trend of KRAS-targeted therapy.

Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) is the most frequently mutated oncogene in human cancers with mutations predominantly occurring in codon 12. These mutations disrupt the normal function of KRAS by interfering with GTP hydrolysis and nucleotide exchange activity, making it prone to the GTP-bound active state, thus leading to sustained activation of downstream pathways. Despite decades of research, there has been no progress in the KRAS drug discovery until the groundbreaking discovery of covalently targeting the KRASG12C mutation in 2013, which led to revolutionary changes in KRAS-targeted therapy. So far, two small molecule inhibitors sotorasib and adagrasib targeting KRASG12C have received accelerated approval for the treatment of non-small cell lung cancer (NSCLC) harboring KRASG12C mutations. In recent years, rapid progress has been achieved in the KRAS-targeted therapy field, especially the exploration of KRASG12C covalent inhibitors in other KRASG12C-positive malignancies, novel KRAS inhibitors beyond KRASG12C mutation or pan-KRAS inhibitors, and approaches to indirectly targeting KRAS. In this review, we provide a comprehensive overview of the molecular and mutational characteristics of KRAS and summarize the development and current status of covalent inhibitors targeting the KRASG12C mutation. We also discuss emerging promising KRAS-targeted therapeutic strategies, with a focus on mutation-specific and direct pan-KRAS inhibitors and indirect KRAS inhibitors through targeting the RAS activation-associated proteins Src homology-2 domain-containing phosphatase 2 (SHP2) and son of sevenless homolog 1 (SOS1), and shed light on current challenges and opportunities for drug discovery in this field.

Promising preclinical patient-derived organoid (PDO) and xenograft (PDX) models in upper gastrointestinal cancers: progress and challenges.

Gastrointestinal (GI) cancers (gastric cancer, oesophageal cancer, liver cancer, colorectal cancer, etc.) are the most common cancers with the highest morbidity and mortality in the world. The therapy for most GI cancers is difficult and is associated with a poor prognosis. In China, upper GI cancers, mainly gastric cancer (GC) and oesophageal cancer (EC), are very common due to Chinese people's characteristics, and more than half of patients are diagnosed with distant metastatic or locally advanced disease. Compared to other solid cancers, such as lung cancer and breast cancer, personalized therapies, especially targeted therapy and immunotherapy, in GC and EC are relatively lacking, leading to poor prognosis. For a long time, most studies were carried out by using in vitro cancer cell lines or in vivo cell line-derived xenograft models, which are unable to reproduce the characteristics of tumours derived from patients, leading to the possible misguidance of subsequent clinical validation. The patient-derived models represented by patient-derived organoid (PDO) and xenograft (PDX) models, known for their high preservation of patient tumour features, have emerged as a very popular platform that has been widely used in numerous studies, especially in the research and development of antitumour drugs and personalized medicine. Herein, based on some of the available published literature, we review the research and application status of PDO and PDX models in GC and EC, as well as detail their future challenges and prospects, to promote their use in basic and translational studies or personalized therapy.

Efficacy of breast reconstruction for N2-3M0 stage female breast cancer on breast cancer-specific survival: A population-based propensity score analysis.

BACKGROUND: The efficacy of breast reconstruction for patients with N2-3M0 stage female breast cancer (FBC) remained unclear due to the lack of randomized clinical trials. This retrospective study aimed to explore the efficacy of breast reconstruction for patients with N2-3M0 stage FBC. METHODS: Two thousand five hundred forty-five subjects with FBC staged by N2-3M0 from 2010 to 2016 were retrieved from the Surveillance, Epidemiology, and End Results database. Generalized boosted model (GBM) and propensity score matching (PSM) analyses and multivariable Cox analyses were employed to assess the clinical prognostic effect of postmastectomy reconstruction for patients with N2-3M0 stage FBC in breast cancer-specific survival (BCSS). RESULTS: Totally, 1784 candidates underwent mastectomy alone (mastectomy group), and 761 candidates underwent postmastectomy reconstruction (PMbR group), with 418 breast-specific deaths after a median follow-up time of 57 months (ranging from 7 to 227 months). BCSS in the mastectomy group showed no statistical difference from that in the PMbR group in the PSM cohort (HR = 0.93, 95% CI: 0.70-1.25, p = 0.400) and GBM cohort (HR = 0.75, 95% CI: 0.56-1.01, p = 0.057). In the multivariate analyses, there was no difference in the effect of PMbR and mastectomy on BCSS in the original cohort (HR = 0.85, 95% CI: 0.66-1.09, p = 0.197), PSM cohort (HR = 0.86, 95% CI: 0.64-1.15, p = 0.310), and GBM cohort (HR = 0.84, 95% CI: 0.61-1.17, p = 0.298). Triple-negative breast cancer (TNBC) was a detrimental factor affecting BCSS for patients in the PMbR group. CONCLUSIONS: Our study demonstrated that PMbR is an oncologically safe surgical treatment and can be widely recommended in clinics for females with non-TNBC staged by T0-3N2-3M0.

Global disease burden attributed to unsafe sex in 204 countries and territories from 1990 to 2019: results from the Global Burden of Disease Study 2019.

Unsafe sex has become a public safety problem that endangers society, and research on deaths and disability-adjusted life years (DALYs) related to unsafe sex is valuable for global policy-making. We aimed to estimate the deaths and DALYs attributable to unsafe sex by country, gender, age group, and sociodemographic status from 1990 to 2019. We extracted data on disease burden from the Global Disease Burden 2019 (GBD 2019) database for unsafe sex, including deaths, DALYs and age-standardized rates (ASRs). Comparative analyses were performed on data about deaths, DALYs and the responding ASRs attributable to unsafe sex in different countries and regions using the Social Demographic Index (SDI). The global age-standardized mortality rate (ASMR) and age-standardized DALY rate (ASDR) attributable to unsafe sex were 11.98 (95% uncertainty intervals (UI): 10.97-13.52) per 100,000 people and 570.78 (95% UI: 510.24-658.10) per 100,000 people, respectively. Both the ASMRs and ASDRs were the highest in southern sub-Saharan Africa and lowest in Australasia and decreased with increasing SDI levels. About unsafe-sex-related disease, HIV/AIDS has the highest ASMR [8.48 (95% UI: 7.62-9.95)/100,000 people] and ASDR [447.44 (95% UI: 394.82-533.10)/100,000 people], followed by Cervical cancer [ASMR: 3.40 (95% UI: 2.90-3.81)/100,000 people and ASDR: 107.2 (95% UI: 90.52-119.43)/100,000 people] and sexually transmitted infections excluding HIV [ASMR: 0.10 (95% UI: 0.08-0.11)/100,000 people and ASDR: 16.14 (95% UI: 10.51-25.83)/100,000 people]. The death and DALY burden caused by these three diseases were more serious in the over 75 years old age group. The 40-44 age group for men and the 35-39 age group for women had the highest population of unsafe sex-related deaths and DALYs, respectively. In addition, the burden of unsafe sex in women was more serious than those in men. Unsafe sex is an important risk factor for global disease burden and a leading cause of substantial health loss. We found that the risk of ASMRs and ASDRs attributable to unsafe sex had negative correlation with SDI levels. These results demonstrate that the need for revised policies that focus on efforts to reduce overall unsafe sex worldwide.

High expression of CETN2 is associated with platinum resistance and poor prognosis in epithelial ovarian cancer.

PURPOSE: The poor prognosis of ovarian cancer is largely due to platinum resistance. It has been demonstrated that nucleotide excision repair (NER) involving centrin-2(CETN2) is connected to platinum resistance in ovarian cancer. The molecular mechanism of CETN2 in ovarian cancer and the mechanism affecting the outcome of chemotherapy are unknown. METHODS: The protein-protein interaction (PPI) network was mapped after obtaining the interacting proteins of CETN2, and the interacting genes were subjected to enrichment analysis. To examine the relationship between CETN2 and platinum resistance, gene microarray data and clinical data related to platinum resistance in ovarian cancer were downloaded. The possible signaling pathway of CETN2 was investigated by Gene set enrichment analysis (GSEA). Immune infiltration analysis was performed. Immunohistochemistry (IHC) and quantitative real-time PCR (QRT-PCR) were used to examine the expression of CETN2 in clinical samples in relation to the effectiveness of chemotherapy. The capacity of CETN2 to predict chemotherapy results was proven by receiver operating characteristic (ROC) curves after the construction of two prediction models, the logistic regression model and the decision tree model. The impact of CETN2 on prognosis was examined using the Kaplan-Meier technique. RESULTS: CETN2 was associated with NER, oxidative phosphorylation (OXPHOS) and cell cycle pathways in ovarian cancer drug-resistant samples. In clinical samples, CETN2 showed its possible correlation with immune infiltration. The protein expression level of CETN2 was significantly higher in platinum-resistant patients than that in platinum-sensitive patients, and the expression level had some predictive value for chemotherapy outcome, and high CETN2 protein expression was associated with poorer progression-free survival. CONCLUSIONS: CETN2 protein had a significant effect on ovarian cancer platinum sensitivity and prognosis, which may be related to the activation of NER, OXPHOS and cell cycle pathways upon CETN2 upregulation. Further research is necessary to determine the therapeutic application value of CETN2, which may be a new biomarker of chemoresponsiveness.

Hydroxyls on the B ring and gallic acyl are essential for catechins to restrain ADP-induced thrombosis.

Platelet hyperactivation could lead to various cardiovascular and cerebrovascular diseases, while epidemiological analyses have found that long-term tea drinking could prevent and restrain cardiovascular diseases. Existing studies have shown that catechins, especially epigallocatechin gallate (EGCG), are the main functional factors of tea in alleviating thrombosis, which could inhibit arterial thrombosis and platelet aggregation induced by a variety of agonists. However, their structure-activity relationship and the underlying mechanisms are still unclear. Based on the above background, this study took six typical catechins as research objects, constructed platelet activation models with different inducers, and explored the inhibitory effects and potential mechanisms of catechins with different structures on platelet aggregation through flow cytometry, immunoblotting, cell spreading, and other experiments. It was found that ester catechins could inhibit platelet aggregation induced by adenosine diphosphate (ADP), while epigallocatechin (EGC) with three hydroxyls on the B ring in non-ester catechins was also able to effectively inhibit platelet aggregation. Our data suggested that gallic acyl on the C ring and three hydroxyls on the B ring were the main functional groups affecting the antithrombotic effect of catechins, and the effect of gallic acyl on platelets was significantly stronger than that of the hydroxyl.

Nomogram for predicting overall survival in patients with invasive micropapillary carcinoma after breast-conserving surgery: A population-based analysis.

Background: Due to the loss of prediction of overall survival (OS) for patients with invasive micropapillary carcinoma (IMPC) after breast-conserving surgery (BCS), this study aimed to construct a nomogram for predicting OS in IMPC patients after BCS. Methods: In total, 481 eligible cases staged 0-III IMPC from 2000 to 2016 were retrieved from the SEER database. A nomogram was built based on the variables selected by LASSO regression to predict the 3-year and 5-year probabilities of OS. Results: A total of 336 patients were randomly assigned to the training cohort and 145 cases in the validation cohort. The LASSO regression revealed that six variables (age at diagnosis, AJCC stage, marital status, ER status, PR status, and chemotherapy) were predictive variables of OS, and then a nomogram model and an easy-to-use online tool were constructed. The C-indices 0.771 in the training cohort and 0.715 in the validation cohort suggested the robustness of the model. The AUC values for 3-year and 5-year OS in the training cohort were 0.782, 0.790, and 0.674, and 0.682 in the validation cohort, respectively. Based on the cutoff values of 147.23 and 222.44 scores calculated by X-tile analysis, participants in the low-risk group (≤147.23 scores) had a more favorable OS in comparison with those in the medium (>147.23, but <222.44 scores)- and high-risk groups (≥222.44 scores). Conclusions: By risk stratification, this model is expected to provide a precise and personalized prediction of the cumulative risk and guide treatment decision-making in improving OS strategies for IMPC patients.

Epidemiological trends of female breast and gynecologic cancers in adolescents and young adults in China from 1990 to 2019: Results from the Global Burden of Disease Study 2019.

Background: Research on the incidence, mortality, and disability-adjusted life years (DALYs) of female breast and gynecologic cancers (FeBGCs) and the relevant risk factors for adolescents and young adults (AYAs) are valuable for policy-making in China. We aimed to estimate the incidence, deaths, and DALYs and predict epidemiological trends of FeBGCs among AYAs in China between 1990 and 2019. Methods: Data from the 2019 Global Burden of Disease (GBD) study between 1990 and 2019 in 195 countries and territories were retrieved. Data about the number of FeBGC incident cases, deaths, DALYs, age-standardized rates (ASRs), and estimated annual percentage changes (EAPCs) were extracted. A comparative risk assessment framework was performed to estimate the risk factors attributable to breast cancer deaths and DALYs, and autoregressive integrated moving average (ARIMA) models were fitted for time-series analysis to predict female cancer morbidity and mortality among Chinese AYAs until 2030. Results: In 2019, there are 61,038 incidence cases, 8,944 deaths, and 529,380 DALYs of FeBGCs among the AYAs in China, respectively. The estimated annual percentage change (EAPC) values were positive scores (>0) in ASIRs and negative scores (<0) in ASMR and ASDR. Furthermore, in 2030, the incidence rate of FeBGCs would grow to 30.49 per 100,000 in China, while the mortality rate would maintain a steady state. Of the deaths and DALYs, diet high in red meat was the greatest contributor to breast cancer, while a high body mass index (BMI) was the greatest contributor to cervical, ovarian, and uterine cancers. Conclusion: The increasing Chinese FeBGC burden is mainly observed in AYAs and non-red meat diet, and the control of body weight could reduce FeBGC burden in China.

Effect of the Nipple-Excising Breast-Conserving Therapy in Female Breast Cancer: A Competing Risk Analysis and Propensity Score Matching Analysis of Results Based on the SEER Database.

Introduction: Due to the lack of randomized controlled trial, the effectiveness and oncological safety of nipple-excising breast-conserving therapy (NE-BCT) for female breast cancer (FBC) remains unclear. We aimed to explore and investigate the prognostic value of NE-BCT versus nipple-sparing breast-conserving therapy (NS-BCT) for patients with early FBC. Methods: In this cohort study, data between NE-BCT and NS-BCT groups of 276,661 patients diagnosed with tumor-node-metastasis (TNM) stage 0-III FBC from 1998 to 2015 were retrieved from the Surveillance, Epidemiology, and End Results database. Propensity score matching analysis, Kaplan-Meier, X-tile, Cox proportional hazards model, and competing risk model were performed to evaluate the effectiveness and oncological safety for patients in NE-BCT and NS-BCT groups. Results: A total of 1,731 (0.63%) patients received NE-BCT (NE-BCT group) and 274,930 (99.37%) patients received NS-BCT (NS-BCT group); 44,070 subjects died after a median follow-up time of 77 months (ranging from 1 to 227 months). In the propensity score matching (PSM) cohort, NE-BCT was found to be an adversely independent prognostic factor affecting overall survival (OS) [hazard ratio (HR), 1.24; 95% CI, 1.06-1.45, p=0.0078]. Subjects in NE-BCT group had similar breast-cancer-specific survival (BCSS) (HR, 1.15; 95%CI, 0.88-1.52, p=0.30) and worse other-causes-specific death (OCSD) (HR, 1.217; 95%CI, 1.002-1.478, p=0.048<0.05) in comparison with those in the NS-BCT group. Conclusions: Our study demonstrated that the administration of NE-BCT is oncologically safe and reliable and can be widely recommended in clinics for women with non-metastatic breast cancer.

Research on the cutoff tumor size of omitting radiotherapy for BCSS after breast conserving surgery in women aged 65 years or oder with low-risk invasive breast carcinoma: Results based on the SEER database.

BACKGROUND: Radiotherapy after breast-conserving surgery (BCS) is not always necessary in older women staged T1N0M0 with low-risk invasive breast cancer, but few studies have concluded the detailed tumor size as a reference for avoiding radiotherapy. The study was conducted to explore and identify the optimal cutoff tumor size. METHODS: The study population was from the Surveillance, Epidemiology, and End Results (SEER) database in 2010-2016. Propensity score matching was used to balance the confounders between groups. Predictors associated with survival were analyzed by Kaplan-Meier, X-tile, Cox proportional hazards model and competing risk model. RESULTS: A total of 52049 women and 3846 deaths were included in the cohort with a median follow-up of 34 months. Based on the cutoff value determined by X-tile analysis, the study population were divided into small tumor group (≤14 mm in diameter) and large tumor group (>14 mm in diameter). Small tumors and radiotherapy were correlated with better breast cancer-specific survival (BCSS). In subgroup analysis, the absolute benefit of BCSS in 6 years attributed to radiotherapy was only 0.90% (RT vs. non- RT:98.77% vs. 97.87%) for patients with small tumors but up to 3.33% (RT vs. non- RT:97.10% vs. 93.77%) for those with large tumors. CONCLUSION: Small tumors and adjuvant radiotherapy were associated with improved long-term prognosis, and 14 mm in diameter was the cutoff tumor size of omitting radiotherapy for patients aged 65 or older with T1N0M0 stage, ER+ and HER2-breast carcinoma after BCS.

Research on the Role of Marriage Status Among Women Underwent Breast Reconstruction Following Mastectomy: A Competing Risk Analysis Model Based on the SEER Database, 1998-2015.

BACKGROUND: Marital status is an important foundation of social public relations in modern society, but little is known about the role of marriage status among women who underwent breast reconstruction following mastectomy. This research mainly aimed to investigate the prognostic value of marital status in breast cancer women who underwent breast reconstruction. METHODS: The demographic and clinical data of patients were obtained from the Surveillance, Epidemiology, and End Results (SEER) Program database. The eligible population was assessed on overall survival (OS), breast cancer-specific survival (BCSS), and breast cancer-specific death (BCSD) through propensity score matching (PSM) method, multivariate Cox proportional hazards model analysis, competing risk model analysis, multivariate competing risk regression model analysis, and subgroup analysis. RESULTS: Of the 54,683 women included in the current study, a total of 38,110 participants were married patients (married group), and 16,573 participants were unmarried patients (unmarried group). Patients in the married group tended to have better OS (hazard ratio [HR] = 1.397, 95% CI: 1.319-1.479, p < 0.001), BCSS (HR = 1.332, 95% CI: 1.244-1.426, p < 0.001), cumulative BCSD incidence (Gray's test, p < 0.001), and other causes-specific death (OCSD) incidence (Gray's test, p < 0.001) than those in the unmarried group. In subgroup analysis, subjects with HR+/HER2- subtype breast cancer in the married group showed improved OS (1.589, 95% CI: 1.363-1.854, p < 0.001) and BCSS (HR = 1.512, 95% CI: 1.255-1.82, p < 0.001) than those in the unmarried group. CONCLUSIONS: Our study demonstrated that the inexistence of marriage was associated with poorer OS and BCSS, especially for HR+/HER2- breast cancer women who underwent breast reconstruction.

Identification of NEO1 as a prognostic biomarker and its effects on the progression of colorectal cancer.

BACKGROUND: Due to the high morbidity and poor clinical outcomes, early predictive and prognostic biomarker identification is desiderated in colorectal cancer (CRC). As a homologue of the Deleted in Colorectal Cancer (DCC) gene, the role of Neogenin-1 (NEO1) in CRC remained unveiled. This study was designed to probe into the effects and potential function of NEO1 in CRC. METHODS: Online databases, Gene Set Enrichment Analysis (GSEA), quantitative real-time PCR and western blotting were used to evaluate NEO1 expression in colorectal cancer tissues. Survival analysis was performed to predict the prognosis of CRC patients based on NEO1 expression level. Then, cell proliferation was detected by colony formation and Cell Counting Kit 8 (CCK-8) assays. CRC cell migration and invasion were examined by transwell assays. Finally, we utilized the Gene Set Variation Analysis (GSVA) and GSEA to dig the potential mechanisms of NEO1 in CRC. RESULTS: Oncomine database and The Cancer Genome Atlas (TCGA) database showed that NEO1 was down-regulated in CRC. Further results validated that NEO1 mRNA and protein expression were both significantly lower in CRC tumor tissues than in the adjacent tissues in our clinical samples. NEO1 expression was decreased with the progression of CRC. Survival and other clinical characteristic analyses exhibited that low NEO1 expression was related with poor prognosis. A gain-of-function study showed that overexpression of NEO1 restrained proliferation, migration and invasion of CRC cells while a loss-of-function showed the opposite effects. Finally, functional pathway enrichment analysis revealed that NEO1 low expression samples were enriched in inflammation-related signaling pathways, EMT and angiogenesis. CONCLUSION: A tumor suppressor gene NEO1 was identified and verified to be correlated with the prognosis and progression of CRC, which could serve as a prognostic biomarker for CRC patients.

Research on the Role of Combined Chemotherapy and Radiotherapy in Patients With N+ Non-Metastatic Metaplastic Breast Carcinoma: A Competing Risk Analysis Model Based on the SEER database, 2000 to 2015.

PURPOSE: Due to the rarity of metaplastic breast carcinoma (MpBC), no randomized trials have investigated the role of combined chemotherapy and radiotherapy (CCRP) in this condition. We aimed to explore and identify the effectiveness of CCRP in patients with regional lymph node metastasis (N+) non-metastatic MpBC. MATERIALS AND METHODS: Data were obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program database. We assessed the effects of CCRP on overall survival (OS), breast cancer-specific survival (BCSS), and breast cancer-specific death (BCSD) using Kaplan-Meier analysis, competing risk model analysis, and competing risk regression mode analysis. RESULTS: A total of 707 women and 361 death cases were included in the unmatched cohort, of which 76.45% (276/361) were BCSD, and 23.55% (85/361) were non-breast cancer-specific deaths (non-BCSD). Both the ChemT and CCRP groups had better OS (ChemT group: HR: 0.59, 95% CI: 0.45-0.78, P<0.001; CCRP group: HR: 0.31, 95% CI: 0.23-0.41, P<0.001) and BCSS (ChemT group: HR: 0.63, 95% CI: 0.45-0.87, P<0.001; CCRP group: HR: 0.32, 95%CI: 0.22-0.46, P<0.001) than the non-therapy group. Subjects in the CCRP group tended to have significantly lower cumulative BCSD (Gray's test, P=0.001) and non-BCSD (Gray's test, P<0.001) than the non-therapy group or ChemT group. In competing risk regression model analysis, subjects in the CCRP group had a better prognosis in BCSD (HR: 0.710, 95% CI: 0.508-0.993, P=0.045) rather than the ChemT group (HR: 1.081, 95% CI: 0.761-1.535, P=0.660) than the non-therapy group. CONCLUSION: Our study demonstrated that CCRP could significantly decrease the risk of death for both BCSD and non-BCSD and provided a valid therapeutic strategy for patients with N+ non-metastatic MpBC.

PACAP ameliorates hepatic metabolism and inflammation through up-regulating FAIM in obesity.

Obesity is considered a chronic inflammatory disease, the inflammatory factors, such as interleukin 6 (IL-6), monocyte chemoattractant protein 1 (MCP-1) and small inducible cytokine A5 (RANTES), are elevated in obese individuals. Pituitary adenylate cyclase-activating polypeptide (PACAP) suppresses anti-inflammatory cytokines and ameliorates glucose and lipid metabolism. Our previous study showed that Fas apoptosis inhibitory molecule (FAIM) is a new mediator of Akt2 signalling, increases the insulin signalling pathway and lipid metabolism. In this study, we found that PACAP promoted the expression of FAIM protein in a human hepatocyte cell line (L02). Overexpression of FAIM with lentivirus suppressed the expression of the inflammatory factor interleukin 6 (IL-6), monocyte chemoattractant protein 1 (MCP-1) and tumour necrosis factor alpha (TNF-α). Following treatment of obese mice with FAIM or PACAP for 2 weeks, inflammation was alleviated and the bodyweight and blood glucose levels were decreased. Overexpression of FAIM down-regulated the expression of adipogenesis proteins, including SREBP1, SCD1, FAS, SREBP2 and HMGCR, and up-regulated glycogen synthesis proteins, including Akt2 (Ser474) phosphorylation, GLUT2 and GSK-3ß, in the liver of obese mice. However, down-regulation of FAIM with shRNA promotes obesity. Altogether, our data identified that FAIM mediates the function of PACAP in anti-inflammation, glucose regulation and lipid metabolism in obese liver.

[Cognitive Impairments and Associated Factors in Community-dwelling Elderly in Chengdu, Sichuan].

OBJECTIVE: To determine the prevalence and associated factors of cognitive impairments in the community-dwelling elderly aged 60 years or older in Chengdu of Sichuan province. METHODS: A random cluster sampling strategy was adopted to select 621 community-dwelling elderly. Face-to-face interviews were conducted to assess the cognitive status of the participants. 2 tests and logistic regression analyses were performed to identify factors associated with cognitive impairments. RESULTS: About 40.9% of the participants had cognitive impairments. Those attended primary schools had a lower risk of cognitive impairments [odds ratio OR)=0.369, P<0.001] compared with the illiterate ones. Older age OR=1.505 for 70-79 years, P=0.042; OR=3.069 for ≥80 years, P<0.001), cerebrovascular disease OR=2.159, P=0.003) and smoking OR=2.388, P<0.001) were risk factors of cognitive impairments. Men had lower risk OR=0.489, P=0.005) of cognitive impairments than women. CONCLUSION: The prevalence of cognitive impairments in community-dwelling elderly in Chengdu is high in comparison with those in other cities. Illiteracy, older age (over 70 years), women, smoking, and cerebrovascular disease are risk factors of cognitive impairments.

Two new bioactive steroids from a mangrove-derived fungus Aspergillus sp.

Two unusual naturally Diels-Alder additive steroids, ergosterdiacids A and B (1 and 2), constructing a 6/6/6/6/5 pentacyclic steroidal system, together with three known compounds (3-5) were obtained from the mangrove-derived fungus Aspergillus sp. Their structures were elucidated based on the comprehensive spectroscopic analysis, including 1D, 2D NMR and HRESIMS, as well as the quantum chemical ECD calculations. The plausible biosynthetic pathways of 1 and 2 were discussed. In the bioactivity assays, 1 and 2 exhibited potential in vitro inhibition activity against Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) with an IC50 value of 15.1 and 30.1 µM, respectively. The inhibitory kinetic experiments indicated that both of them acted via a noncompetitive inhibition mechanism. Moreover, 1 and 2 showed strong in vitro anti-inflammatory effects by suppressing the NO production at 4.5 and 3.6 µM, respectively.

Delivery of a TNF-α-derived peptide by nanoparticles enhances its antitumor activity by inducing cell-cycle arrest and caspase-dependent apoptosis.

Prostate cancer is the second-most common malignancy of the male genitourinary system. TNF-α has attracted intense attention as a potential therapeutic agent against various cancers. However, its therapeutic application is restricted by short half life and severe toxic side-effects. In this study, we constructed a stable nanodrug, called TNF-α-derived polypeptide (P16)-conjugated, chitosan (CTS)-modified selenium nanoparticle (SC; SCP), which is composed of SC as a slow-release carrier conjugated to P16. SCP had significant inhibitory effects on multiple types of tumor cells, especially DU145 prostate cancer cells, but not on RWPE-1 normal human prostate epithelial cells. SCP could induce G0/G1 cell-cycle arrest and apoptosis in DU145 cells more effectively than could P16 and TNF-α. In DU145 xenograft tumor models, SCP exerted much stronger antitumor effects than P16 or estramustine (the clinical drug for prostate cancer) but caused fewer toxic side-effects. In addition, SCP significantly inhibited proliferation and accelerated apoptosis in DU145 xenograft tumors. Further mechanistic studies revealed that SCP exerted antitumor effects via activation of the p38 MAPK/JNK pathway, thus inducing G0/G1 cell-cycle arrest and caspase-dependent apoptosis. These findings suggest that SCP may represent a potential long-lasting therapeutic agent for human prostate cancer with fewer side effects.-Yan, Q., Chen, X., Gong, H., Qiu, P., Xiao, X., Dang, S., Hong, A., Ma, Y. Delivery of a TNF-α-derived peptide by nanoparticles enhances its antitumor activity by inducing cell-cycle arrest and caspase-dependent apoptosis.

A new and important relationship between miRNA-147a and PDPK1 in radiotherapy.

It was found that the expression level of miR-147a was significantly increased and the pathway of PI3K/AKT was dramatically inhibited after radiation. In view of the relationship between miRNA and target genes, we put forward the question, what is the relationship between PI3K/AKT and miR-147a? In order to find the answer to the question, we used bioinformatics techniques to analyze the relationship between miR-147 (a or b) and PI3K/AKT signaling pathway. miR-147a overexpression plasmid and PDPK1 3'UTR luciferase reporter gene plasmid were constructed. Dual luciferase reporter gene system validation experiments were carried out on miR-147a and PDPK1 relationship. The verification experiments were also carried out. Bioinformatics analysis showed that there is a miR-147a binding site in the non-coding region (3'UTR) of PDPK1. In the experimental groups transfected with wild type PDPK1 gene of 3'UTR plasmid, the luciferase activity decreased (or increased) significantly in miR-147a (or inhibitor) group compared with miR-NC (or anti-miR-NC); There was no significant difference between the miR-147a group (or inhibitor) and the miR-NC group (or anti-miR-NC) in the transfection of PDPK1-3'UTR-Mut gene vector. PDPK1 was a target gene for direct regulation of miR-147a downstream. Verifying test results showed that the expression of PDPK1 mRNA and protein was reduced after overexpression of miR-147a, which was up-regulated after silencing miR-147a in TC, and V79 cells. These results suggest that miR-147a could be involved in the regulation of PDPK1 transcription by binding to the target site in PDPK1 mRNA 3'UTR, and then regulated AKT.