Neuroprotective effects of Shenghui decoction via inhibition of the JNK/p38 MAPK signaling pathway in an AlCl3-induced zebrafish (Danio rerio) model of Alzheimer's disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD) is a multi-factorial degenerative disease, and multi-targeted therapies targeting multiple pathogenic mechanisms should be explored. Shenghui decoction (SHD) is an ancient traditional Chinese medicine (TCM) formula used clinically to alleviate AD. However, the precise mechanism of action of SHD as a therapeutic agent for AD remains unclear. AIM OF THE STUDY: This study investigated the neuroprotective properties and potential mechanisms of action of SHD in mitigating AD-like symptoms induced by AlCl3 in a zebrafish model. MATERIALS AND METHODS: Active components of SHD were detected using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Zebrafish were exposed to AlCl3 (200 µg/L) for 30 days to establish an AD zebrafish model. AlCl3-exposed zebrafish were treated with SHD or donepezil. Behavioral tests were used to assess learning and memory, locomotor activity, and AD-related anxiety and aggression in AlCl3-exposed zebrafish. Nissl staining and transmission electron microscopy were used to evaluate histological alterations in brain neurons. The concentrations of pro-inflammatory cytokines (tumor necrosis factor-α, TNF-α; interleukin-1ß, IL-1ß) were quantified using Enzyme-linked immunosorbent assay (ELISA). Markers of oxidative stress and cholinergic activity (acetylcholinesterase, AChE) were detected using biochemical assays. Western blotting and immunofluorescence were used to detect the protein expression levels of Aß, p-tau, PSD-95, synaptophysin, TLR4, phosphorylation of NF-κB p65, p38, and JNK. RESULTS: Fifteen SHD compounds were identified by UPLC-MS/MS analysis. SHD improved AlCl3-induced dyskinesia, learning and memory impairment, anxiety-like behavior, and aggressive behavior in zebrafish. AlCl3-exposed zebrafish showed AD-like pathology, overexpression of Aß, hyperphosphorylated tau protein, marked neuronal damage, decreased expression of synaptic proteins, synaptophysin, and PSD-95, and impairment of synaptic structural plasticity. These effects were reversed by the SHD treatment. We also observed that SHD ameliorated oxidative stress and decreased AChE activity and inflammatory cytokine levels. These effects are similar to those observed for donepezil. Meanwhile, SHD could decrease the protein expression of TLR4 and inhibit phosphorylation of NF-κB, JNK, and p38 MAPK. These results demonstrate that SHD has the potential to exert neuroprotective effects, which may be partly mediated via inhibition of the JNK/p38 MAPK signaling pathway. CONCLUSIONS: Our findings revealed the therapeutic mechanism of SHD in mitigating AD progression and suggested that SHD is a potent neuroprotectant that contributes to the future development of TCM modernization and broader clinical applications.

Phase II study of apatinib plus exemestane in estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer.

PURPOSE: Apatinib is a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR)-2. This study was conducted to assess the efficacy and safety of apatinib combined with exemestane in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). METHODS: This single-center, single-arm phase II study enrolled patients with ER+/HER2- MBC progressed on previous letrozole or anastrozole. Stratified analysis was performed according to the number of chemotherapy regimens for metastatic disease. The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), overall survival (OS) and toxicity. Patients received apatinib at a starting dose of 500 mg/d and exemestane 25 mg/d on days 1-28 of each 4-week cycle. RESULTS: Thirty patients were enrolled with median four prior anticancer therapies. Eighty percent of patients received chemotherapy for metastatic disease. The median PFS (mPFS) and OS were 5.6 (95%CI: 4.3-6.9) months and 15.7 (95% CI: 9.7-21.7) months, respectively. The ORR, DCR, and CBR were 21.4%, 71.4%, and 46.4%, respectively. Patients with 0-1 line chemotherapy for MBC showed a slightly longer mPFS compared to those with ≥2 lines chemotherapy (mPFS: 6.4 months vs 4.8 months, P = .090). Most of the AEs were grade 1/2. One patient (3.3%) who suffered bone marrow metastases experienced grade 4 thrombocytopenia, and 14 experienced grade 3 AEs. Fifty percent of patients were given reduced dose for apatinib. CONCLUSIONS: Apatinib plus exemestane exhibited objective efficacy in patients with ER+/HER2- MBC who have failed multiple lines of treatment. The AEs of apatinib required close monitoring and most of patients were well tolerated.

Association of serum water-soluble vitamin exposures with the risk of metabolic syndrome: results from NHANES 2003-2006.

Introduction: Existing evidence suggests an association between certain vitamins and metabolic syndrome (MetS), but few epidemiological studies have focused on the effects of multivitamin co-exposure on MetS. This study aims to investigate the associations of the individual or multiple water-soluble vitamins (i.e., vitamin C (VC), vitamin B9 (VB9), and vitamin B12 (VB12)) with co-exposure to MetS, as well as the dose-response relationships among them. Methods: A cross-sectional study was conducted by employing the National Health and Examination Surveys (NHANESs) 2003-2006. Multivariate-adjusted logistic regression models were used to explore the association between individual serum water-soluble vitamins and the risk of MetS and its components, including waist circumference, triglyceride, high-density lipoprotein, blood pressure, and fasting plasma glucose. Restricted cubic splines were performed to explore the dose-response relationships among them. The quantile g-computation method was adopted to explore the associations of multiple water-soluble vitamins co-exposure with MetS risk and MetS components. Results: A total of 8983 subjects were involved in the study, of whom 1443 were diagnosed with MetS. The MetS groups had a higher proportion of participants with age ≥60 years, BMI ≥30 kg/m2, and insufficient physical activity. Compared with the lowest quartile, the third (OR=0.67, 95% CI: 0.48, 0.94) and highest quartiles (OR=0.52, 95%CI: 0.35, 0.76) of VC were associated with lower MetS risk. Restricted cubic splines showed negative dose-response relationships among VC, VB9 and VB12, and MetS. Regarding MetS components, higher VC quartiles were associated with lower waist circumference, triglyceride, blood pressure, and fasting plasma glucose, while higher VC and VB9 quartiles were associated with higher high-density lipoprotein (HDL). Co-exposure to VC, VB9, and VB12 was significantly inversely associated with MetS, with ORs (95% CI) of 0.81 (0.74, 0.89) and 0.84 (0.78, 0.90) in the conditional and marginal structural models, respectively. Furthermore, we found that VC, VB9, and VB12 co-exposure were negatively associated with waist circumference and blood pressure, while VC, VB9, and VB12 co-exposure were positively associated with HDL. Conclusion: This study revealed negative associations of VC, VB9, and VB12 with MetS, while the high water-soluble vitamin co-exposure was associated with a lower MetS risk.

Effect of Low-Frequency Electrical Stimulation Combined with Tonifying Kidney and Blood Pills on Uterine Rejuvenation after Abortion.

Objective: This study aimed to observe the clinical efficacy of low-frequency electrical stimulation therapy combined with tonifying the kidney and activating blood pills to promote uterine recovery after abortion and its effect on heat-shock protein (HSP)70 and HSP90. Methods: All cases were women with early pregnancy who underwent an abortion at the Third Affiliated Hospital of Nanchang University from September 2019 to September 2020. They were divided into two groups in accordance with the principle of patient voluntariness: 237 cases in the experimental group and 143 cases in the control group. Patients in both groups were given low-frequency electrical stimulation after surgery. In addition, patients in the experimental group began to take the Dingkun pill orally (one pill per time, two times per day) from the first day of surgery and continued to take it until their menstruation returned to normal. Abdominal pain, the duration of vaginal bleeding, and the amount of bleeding were observed in both groups. Uterine size, endometrial thickness, and urinary human chorionic gonadotropin (HCG) status were also observed at 2 weeks postoperatively to determine preoperative and postoperative HSP70 and HSP90 serum levels. The time of menstrual resumption, menstrual period, and menstrual volume were observed and compared with preoperative menstruation. The occurrence of complications, such as a residual uterine cavity, uterine effusion, menstrual irregularities, and reproductive tract infections, during the follow-up period was also recorded in both groups. Results: Comparison of the endometrial thickness (mm) and uterine size (sum of the three diameters) on uterine adnexal ultrasound at 2-week postoperative review was better in the experimental group than in the control group (p < 0.05). No statistically significant difference was found between the two groups in terms of residual uterine cavity and blood accumulation in the uterine cavity and the results of the urine pregnancy test (p > 0.05). Serum HSP70 and HSP90 levels were significantly higher in the control group than in the experimental group 2 weeks after surgery (p < 0.05). Postoperative HSP70 and HSP90 levels were significantly higher than preoperative levels in both groups (p < 0.05). The degree of postoperative abdominal pain in the experimental group was less severe than that in the control group, and the duration was shorter (p < 0.05). No statistically significant differences were observed when comparing the duration of postoperative vaginal bleeding and the amount of bleeding (p > 0.05). The time of the first menstrual resumption and menstrual volume were more satisfactory in the experimental group than in the control group (p < 0.05). No adverse reactions occurred in either group of patients receiving treatment. Conclusion: Low-frequency electrical stimulation combined with tonifying the kidney and invigorating blood pills could effectively promote uterine rejuvenation after abortion, conducive to improving patients' postoperative abdominal pain, promoting menstrual recovery and maintaining menstrual flow.

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.

Screening and Identification of Human Endogenous Retrovirus-K mRNAs for Breast Cancer Through Integrative Analysis of Multiple Datasets.

Objective: Human endogenous retroviruses (HERVs) make up 8% of the human genome. HERVs are biologically active elements related to multiple diseases. HERV-K, a subfamily of HERVs, has been associated with certain types of cancer and suggested as an immunologic target in some tumors. The expression levels of HERV-K in breast cancer (BCa) have been studied as biomarkers and immunologic therapeutic targets. However, HERV-K has multiple copies in the human genome, and few studies determined the transcriptional profile of HERV-K copies across the human genome for BCa. Methods: Ninety-one HERV-K indexes with entire proviral sequences were used as the reference database. Nine raw sequencing datasets with 243 BCa and 137 control samples were mapped to this database by Salmon software. The differential proviral expression across several groups was analyzed by DESeq2 software. Results: First, the clustering of each dataset demonstrated that these 91 HERV-K proviruses could well cluster the BCa and control samples when the normal controls were normal cells or healthy donor tissues. Second, several common HERV-K proviruses that are closely related with BCa risk were significantly differentially expressed (p adj < 0.05 and absolute log2FC > 1.5) in the tissues and cell lines. Additionally, almost all the HERV-K proviruses had higher expression in BCa tissue than in healthy donor tissue. Notably, we first found the expression of 17p13.1 provirus that located with TP53 should regulate TP53 expression in ER+ and HER2+ BCa. Conclusion: The expression profiling of these 91 HERV-K proviruses can be used as biomarkers to distinguish individuals with BCa and healthy controls. Some proviruses, especially 17p13.1, were strongly associated with BCa risk. The results suggest that HERV-K expression profiles may be appropriate biomarkers and targets for BCa.

Association of depressive symptoms with marital status among the middle-aged and elderly in Rural China-Serial mediating effects of sleep time, pain and life satisfaction.

OBJECTIVE: This study aimed to explore the potential effect of sleep time, pain and life satisfaction on the association between marital status and depressive symptoms. METHODS: This study included 9780 individuals aged 45 years and older from the China Health and Retirement Longitudinal Study (CHARLS) in 2015. Regression analysis was used to explore the mediating effect of targeted mediators on the association between marital status and depressive symptoms. Bootstrap method was used to examine the statistical significance of the mediating effects. RESULTS: In the mediation model incorporating sleep time, pain and life satisfaction as mediators between marital status and depressive symptoms, the direct effect of marital status on depressive symptoms was statistically significant (p < 0.001, 95% CI = 0.699, 1.428). Approximately 39.28% (Indirect effect/Total effect) of the significant association between marital status and depressive symptoms was mediated by sleep time, pain, and life satisfaction. LIMITATIONS: Limitations include non-representativeness other than rural residents and unclear cause-and-effect relationship. CONCLUSIONS: Those separated/divorced/widowed/never-married middle-aged and elderly individuals might be high risk population of depressive symptoms. It could be possible to relieve the depressive symptoms of these people by guaranteeing sufficient sleep, relieving pain and improving life satisfaction.

Epimedii Folium and Curculiginis Rhizoma ameliorate lipopolysaccharides-induced cognitive impairment by regulating the TREM2 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Neuroinflammation induced by microglia is closely related to a variety of neurodegenerative diseases including Alzheimer's disease (AD). Previous study has found that aqueous extract of Epimedii Folium and Curculiginis Rhizoma (EX) had anti-inflammatory effect on AD by activating the NLRP3 inflammasome and inhibiting NF-κB/MAPK pathway. However, whether the anti-neuroinflammatory effect of EX is related to microglia or not remains unclear. AIM OF THE STUDY: The present study aimed to investigate the protective effect of EX on cognitive impairment induced by LPS and explore the underlying mechanism of EX. MATERIALS AND METHODS: High performance liquid chromatography-tandem mass spectrometry (HPLC-MS) was performed to qualify the major components of EX, EX in the serum and cerebrospinal fluid. To evaluate the anti-inflammatory effects of EX in vivo, the mice were orally administrated with EX (2.34, 4.68 g kg-1•d-1) for 28 days before cotreatment with LPS (1 mg kg-1•d-1, i.p.). The leaning and memory abilities of mice were examined by Morris water maze test. The expression of inflammatory related proteins and the activation of microglia were detected by ELISA, immunofluorescence, real-time PCR and Western blotting. RESULTS: HPLC-MS analysis confirmed and quantified 9 components in EX, 5 components in the serum and 4 components in the cerebrospinal fluid. In a LPS-induced neuroinflammatory mouse model, EX was found to exert anti-inflammatory activity by reducing the levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß), regulating the expression of different phenotypes of microglia, and increasing the expression of proteins related with TREM2 in the hippocampus tissue. Moreover, LPS-induced microglia activation was markedly attenuated in the hippocampus. CONCLUSIONS: These findings demonstrate that EX exerts anti-neuroinflammatory effects via reducing the production of inflammatory mediators, regulating the conversion of microglia and activating the proteins related with TREM2. EX might become a novel herb pairs to treat neuroinflammatory diseases.

Waist-to-height ratio, an optimal anthropometric indicator for metabolic dysfunction associated fatty liver disease in the Western Chinese male population.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has been entitled as metabolic-dysfunction associated fatty liver disease (MAFLD). Therefore anthropometric indicators of adiposity may provide a non-invasive predictive and diagnostic tool for this disease. This study intended to validate and compare the MAFLD predictive and diagnostic capability of eight anthropometric indicators. METHODS: The study involved a population-based retrospective cross-sectional design. The Fangchenggang area male health and examination survey (FAMHES) was used to collect data of eight anthropometric indicators, involving body mass index (BMI), waist-to-height ratio (WHtR), waist-hip ratio (WHR), body adiposity index (BAI), cardiometabolic index (CMI), lipid accumulation product (LAP), visceral adiposity index (VAI), and abdominal volume index (AVI). Receiver operating characteristics (ROC) curves and the respective areas under the curves (AUCs) were utilized to compare the diagnostic capacity of each indicator for MAFLD and to determine the optimal cutoff points. Binary logistic regression analysis was applied to identify the odds ratios (OR) with 95% confidence intervals (95% CI) for all anthropometric indicators and MAFLD. The Spearman rank correlation coefficients of anthropometric indicators, sex hormones, and MAFLD were also calculated. RESULTS: All selected anthropometric indicators were significantly associated with MAFLD (P < 0.001), with an AUC above 0.79. LAP had the highest AUC [0.868 (95% CI, 0.853-0.883)], followed by WHtR [0.863 (95% CI, 0.848-0.879)] and AVI [0.859 (95% CI, 0.843-0.874)]. The cutoff values for WHtR, LAP and AVI were 0.49, 24.29, and 13.61, respectively. WHtR [OR 22.181 (95% CI, 16.216-30.340)] had the strongest association with MAFLD, regardless of potential confounders. Among all the anthropometric indicators, the strongest association was seen between LAP and sex hormones. CONCLUSION: All anthropometric indicators were associated with MAFLD. WHtR was identified as the strongest predictor of MAFLD in young Chinese males, followed by LAP and AVI. The strongest association was found between LAP and sex hormones.

Efficacy and Safety of Scalp Acupuncture for Insomnia: A Systematic Review and Meta-Analysis.

OBJECTIVE: To systematically evaluate the efficacy and safety of scalp acupuncture in the treatment of insomnia. METHODS: CNKI, Wanfang database, CQVIP database, CBM, Web of Science, Cochrane Library, and PubMed were searched for the literature on the treatment of insomnia by scalp acupuncture from the establishment of the database to July 23, 2020. Two researchers independently screened the literatures and extracted the data, then evaluated the quality of the literatures, and used RevMan 5.3 software for statistical analysis. RESULTS: A total of 21 studies including 1606 cases were included. 21 studies were included in the analysis of effective rate. The heterogeneity test showed that there was no significant heterogeneity. The fixed effect model was used, P < 0.00001. The effective rate of scalp acupuncture in the treatment of insomnia was significantly higher than that of the control group. The analysis of PSQI score was finally included in 19 studies. The heterogeneity test showed that there was obvious heterogeneity. The random effect model was used, and the subgroup analysis was conducted according to the different intervention measures of the control group. The P values of the drug group and the blank group were both less than 0.05, indicating that the improvement of PSQI score in the scalp acupuncture treatment of insomnia was significantly better than that in the drug group and the blank group; P = 0.05 in other acupuncture groups, suggesting in scalp acupuncture treatment, there was no difference between insomnia and other acupuncture in improving the PSQI score. Six studies were included in the analysis of adverse events. The heterogeneity test showed no significant heterogeneity. The fixed effect model was used, P = 0.04 < 0.05, indicating that the adverse events of scalp acupuncture in the treatment of insomnia were better than those of the control group. No publication bias analysis was conducted due to the small number of adverse events included. Publication bias was analyzed for effective rate and PSQI score. Egger's TSTs test (effective rate P = 0.001, PSQI score P = 0.001) and funnel plot showed publication bias. CONCLUSION: Scalp acupuncture is effective and safe in the treatment of insomnia, which is worthy of clinical application. However, due to the limited number of included literature, the methodology of some studies is slightly low and the quality of literature is slightly poor. In the future, we need to design rigorous, large sample, multiple center randomized controlled study to further verify the conclusion of this study.

Suan-Zao-Ren Decoction ameliorates synaptic plasticity through inhibition of the Aß deposition and JAK2/STAT3 signaling pathway in AD model of APP/PS1 transgenic mice.

BACKGROUND: Suan-Zao-Ren Decoction (SZRD) has been widely used to treat neurological illnesses, including dementia, insomnia and depression. However, the mechanisms underlying SZRD's improvement in cognitive function remain unclear. In this study, we examined SZRD's effect on APP/PS1 transgenic mice and mechanisms associated with SZRD's action in alleviating neuroinflammation and improving synaptic plasticity. METHODS: The APP/PS1 mice were treated with different dosages of SZRD (12.96 and 25.92 g/kg/day, in L-SZRD and H-SZRD groups, respectively) for 4 weeks. Morris water maze was conducted to determine changes in behaviors of the mice after the treatment. Meanwhile, in the samples of the hippocampus, Nissl staining and Golgi-Cox staining were used to detect synaptic plasticity. ELISA was applied to assess the expression levels of Aß1-40 and Aß1-42 in the hippocampus of mice. Western blot (WB) was employed to test the protein expression level of Aß1-42, APP, ADAM10, BACE1, PS1, IDE, IBA1, GFAP, PSD95 and SYN, as well as the expressions of JAK2, STAT3 and their phosphorylation patterns to detect the involvement of JAK2/STAT3 pathway. Besides, we examined the serum and hippocampal contents of IL-1ß, IL-6 and TNF-α through ELISA. RESULTS: Compared to the APP/PS1 mice without any treatment, SZRD, especially the L-SZRD, significantly ameliorated cognitive impairment of the APP/PS1 mice with decreases in the loss of neurons and Aß plaque deposition as well as improvement of synaptic plasticity in the hippocampus (P < 0.05 or 0.01). Also, SZRD, in particular, the L-SZRD markedly inhibited the serum and hippocampal concentrations of IL-6, IL-1ß and TNF-α, while reducing the expression of p-JAK2-Tyr1007 and p-STAT3-Tyr705 in the hippocampus of the APP/PS1 mice (P < 0.05 or 0.01). CONCLUSIONS: The SZRD, especially the L-SZRD, may improve the cognitive impairment and ameliorate the neural degeneration in APP/PS1 transgenic mice through inhibiting Aß accumulation and neuroinflammation via the JAK2/STAT3 pathway.

Efficacy and safety of continuous infusion of Rh-endostatin combined with platinum-based chemotherapy for advanced triple-negative breast cancer.

BACKGROUND: This study aimed to prospectively evaluate and investigate the efficacy and safety of recombinant human endostatin (Rh-endostatin) combined with platinum-based regimens for advanced triple-negative breast cancer (TNBC) patients. METHODS: This study was a prospective, single-arm, single-center, open-label trial. From January 2017 to August 2019, 21 women aged 18-70 years with histologically confirmed advanced TNBC were enrolled. Rh-endostatin at 30 mg/d was continuously pumped for 7 days and used synchronously with the chemotherapy cycle. The primary endpoint of this study was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), overall survival (OS), and toxicity. RESULTS: The median PFS (mPFS) was 8.8 months (95% CI: 7.2-10.4 months), and the median OS was 13.3 months (95% CI: 11.6-15.0 months). The ORR and CBR for the whole population were 47.6% and 52.4%, respectively. Patients sensitive to anthracycline and taxane drugs showed a significantly longer mPFS compared to those who were resistant to anthracycline and taxane drugs (mPFS: 8.8 vs. 5.3 months, P=0.038). For patients who received first- and second-line therapy or beyond, the mPFS was 8.8 and 5.3 months, respectively, with a significant difference (P=0.025). No statistically significant differences in the mPFS between pemetrexed combined with platinum and gemcitabine/taxanes combined with platinum were observed. The most common grade 3-4 hematologic toxicities were neutropenia (14.3%) and anemia (14.3%). One patient (4.8%) experienced febrile neutropenia. No grade 3-4 non-hematologic toxicities were observed, and no treatment-related deaths were reported in this study. CONCLUSIONS: This study revealed that Rh-endostatin might enhance the antitumor effects of platinum-based chemotherapy for advanced TNBC patients with well-tolerated toxicities, which may provide a new basis and novel idea for the treatment of TNBC. However, further investigations and validation of its long-term efficacy and toxicity are warranted in the future.

Mesenchymal Stem Cell-Secreted Exosome Promotes Chemoresistance in Breast Cancer via Enhancing miR-21-5p-Mediated S100A6 Expression.

Emerging evidence has shown the role of mesenchymal stem cell-derived exosome (MSC-exo) in inducing resistance of cancer cells to chemotherapy. However, it remains unclear whether the change of MSC-exo in response to chemotherapy also contributes to chemoresistance. In this study, we investigated the effect of a standard-of-care chemotherapeutic agent, doxorubicin (Dox), on MSC-exo and its contribution to the development of Dox resistance in breast cancer cells (BCs). We found that the exosome secreted by Dox-treated MSCs (Dt-MSC-exo) induced a higher degree of Dox resistance in BCs when compared with non-treated MSC-exo. By analysis of the MSC-exo-induced transcriptome change in BCs, we identified S100A6, a chemoresistant gene, as a top-ranked gene induced by MSC-exo in BCs, which was further enhanced by Dt-MSC-exo. Furthermore, we found that Dox induced the expression of miR-21-5p in MSCs and MSC-exo, which was required for the expression of S100A6 in BCs. Importantly, silencing of miR-21-5p expression in MSCs and MSC-exo abolished the resistance of BCs to Dox, indicating an exosomal miR-21-5p-regulated S100A6 in chemoresistance. Our study thus uncovered a novel mechanistic insight into the role of MSC-secreted exosome in the development of chemoresistance in the tumor microenvironment.

A three-gene signature based on tumour microenvironment predicts overall survival of osteosarcoma in adolescents and young adults.

Evidences shows that immune and stroma related genes in the tumour microenvironment (TME) play a key regulator in the prognosis of Osteosarcomas (OSs). The purpose of this study was to develop a TME-related risk model for assessing the prognosis of OSs. 82 OSs cases aged ≤25 years from TARGET were divided into two groups according to the immune/stromal scores that were analyzed by the Estimate algorithm. The differentially expressed genes (DEGs) between the two groups were analyzed and 122 DEGs were revealed. Finally, three genes (COCH, MYOM2 and PDE1B) with the minimum AIC value were derived from 122 DEGs by multivariate cox analysis. The three-gene risk model (3-GRM) could distinguish patients with high risk from the training (TARGET) and validation (GSE21257) cohort. Furthermore, a nomogram model included 3-GRM score and clinical features were developed, with the AUC values in predicting 1, 3 and 5-year survival were 0.971, 0.853 and 0.818, respectively. In addition, in the high 3-GRM score group, the enrichment degrees of infiltrating immune cells were significantly lower and immune-related pathways were markedly suppressed. In summary, this model may be used as a marker to predict survival for OSs patients in adolescent and young adults.

Aspirin might reduce the incidence of breast cancer: An updated meta-analysis of 38 observational studies.

BACKGROUND: Many epidemiologic studies were performed to clarify the protective effect of regular aspirin use on breast cancer risks, but the results remain inconsistent. Here, we conducted an updated meta-analysis of 38 studies to quantitatively assess the association of regular aspirin use with risk of breast cancer. METHOD: We performed a bibliographic database search in PubMed, Embase, Web of Science, Cochrane library, Scopus, and Google Scholar from January 1939 to December 2019. Relative risk (RR) estimates were extracted from eligible case-control and cohort studies and pooled using a random effects model. Subgroup analysis was conducted based on study design, aspirin exposure assessment, hormone receptor status, menopausal status, cancer stage as well as aspirin use duration or frequency. Furthermore, sensitivity and publication bias analyses were performed. RESULTS: Thirty eight studies of 1,926,742 participants involving 97,099 breast cancer cases contributed to this meta-analysis. Compared with nonusers, the aspirin users had a reduced risk of breast cancer (RR = 0.91, 95% confidence interval [CI]: 0.87-0.95, P value of significance [Psig] < .001) with heterogeneity (P value of heterogeneity [Phet] < .001, I = 82.6%). Subgroup analysis revealed a reduced risk in case-control studies (RR = 0.83, 95% CI: 0.78-0.89, Psig < .001), in hormone receptor positive tumors (RR = 0.91, 95% CI: 0.88-0.94, Psig < .001), in situ breast tumors (RR = 0.79, 95% CI: 0.71-0.88, Psig < .001), and in postmenopausal women (RR = 0.89, 95% CI: 0.83-0.96, Psig = .002). Furthermore, participants who use aspirin for >4 times/wk (RR = 0.88, 95% CI: 0.82-0.96, Psig = .003) or for >10 years (RR = 0.94, 95% CI: 0.89-0.99, Psig = .025) appeared to benefit more from the reduction in breast cancer caused by aspirin. CONCLUSIONS: Our study suggested that aspirin use might be associated with a reduced risk of breast cancer, particularly for reducing the risk of hormone receptor positive tumors or in situ breast tumors, and the risk of breast cancer in postmenopausal women.

rs2274911 polymorphism in GPRC6A associated with serum E2 and PSA in a Southern Chinese male population.

BACKGROUND: rs2274911 (Pro91Ser, G > A) is a missense mutation located on the second exon of the GPRC6A gene. Increasing evidence revealed a significant association between the A allele of rs2274911 and male diseases, such as oligospermia, cryptorchidism, and prostate tumor. However, the function of rs2274911 in healthy males is unclear. SUBJECTS AND METHODS: A total of 1742 healthy men were selected from the Fangchenggang Area Male Health and Examination Survey (FAMHES). The association between rs2274911 and phenotype was evaluated. The cell characteristics of rs2274911 mutation (mu), wild-type GPRC6A (WT), and RFP control in human embryonic kidney (293T) and human prostate cancer (PC3) cells were analyzed. RNA sequencing was performed on PC3 cells. RESULTS: E2 and PSA serum levels increased with the accumulation of the A allele (E2: G vs. A, -0.029 [-0.050, -0.008], P < 0.01, P trend = 0.027; PSA: G vs. A, -0.040 [-0.079, 0.000], P < 0.05, P trend = 0.048). rs2274911 enhanced the proliferation and invasion ability of PC3 or 293T cells and activated the ERK pathway. The genes were identified as rs2274911 mu-affected genes through RNA sequential analysis of rs2274911 mu, GPRC6A WT, and RFP control of PC3 cells. Most of these genes were related to cancer development processes, cAMP, and the ERK cell signaling pathway. CONCLUSION: This project represents that rs2274911 is associated with E2 and PSA serum levels in Southern Chinese men. Rs2274991 mutation promotes 293T and PC3 cell proliferation in vitro. These results suggest that rs2274911 is a functional variant of GPRC6A.

Efficacy and safety of acupuncture combined with western medicine for anxiety: A systematic review protocol.

BACKGROUND: As a common clinical mental disorder, the prevalence rate of anxiety disorder increased yearly, devastating both physical health and social-economic prospect. The most common treatment relied on the use of western medications which is yet to fulfill ideal performance. While acupuncture is adopted as a treatment for anxiety disorders, the combination treatment of acupuncture and western medicines becomes more acknowledged. Albeit a spike in related literatures, the curative effect and safety of the treatment are still in lack of evidence. Therefore, this systematic review and meta-analysis protocol is planned to evaluate the efficacy and safety of the combination treatment of acupuncture and western medications. METHODS: Six English databases (PubMed, Web of science, Medline, EBASE, Springer Cochrane Library and WHO International Clinical Trials Registry Platform) and four Chinese databases (Wan fang Database, Chinese Scientific Journal Database, China National Knowledge Infrastructure Database (CNKI) and Chinese Biomedical Literature Database) will be searched normatively according to the rule of each database from the inception to June 1, 2020. Two reviewers will independently conduct article selection, data collection, and risk of bias evaluation. Any disagreement will be resolved by discussion with the third reviewer. Either the fixed-effects or random-effects model will be used for data synthesis based on the heterogeneity test. The change in the scores on the Hamilton Anxiety Scale (HANA) and the self-rating anxiety scale (SAS) will be used as the main outcome measure, quality of life scale (SF-36), changes of symptoms in TCM, hormone levels and clinical global impression (CGI) as the secondary outcome. treatment emergent symptom scale (TESS), general physical examination(temperature, pulse, respiration, blood pressure), Routine examination of blood, urine and stool, Electrocardiogram, Liver and kidney function examination as the security indexes. RevMan 5.3.5 will be used for meta-analysis. RESULTS: This study will provide high-quality evidence to assess the effectiveness and safety of acupuncture combined with western medicine for anxiety. CONCLUSION: This systematic review will explore whether acupuncture combined with western medicine is an effective and safe intervention for anxiety. ETHICS AND DISSEMINATION: Ethical approval is not required for this study. The systematic review will be published in a peer-reviewed journal, presented at conferences, and will be shared on social media platforms. This review will be disseminated in a peer-reviewed journal or conference presentation. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42020149746.

Leptin promotes bone metastasis of breast cancer by activating the SDF-1/CXCR4 axis.

Obesity is associated with an increased risk of tumorigenesis, and increased leptin levels can promote tumor metastasis. However, the effects of leptin on bone metastasis in breast cancer are not fully understood. Here, we examined leptin receptor expression and bone metastasis in tissue samples from 96 breast cancer patients. In addition, we investigated the effects of leptin on the metastatic capacity of breast cancer cells invitro using a transwell assays. The results indicated that higher leptin receptor levels in breast cancer cells are associated with increased incidence of bone metastasis in breast cancer patients. Additionally, leptin promoted migration and invasion of breast cancer cells. The SDF-1/CXCR4 axis activated by leptin also promoted bone metastasis of breast cancer. Finally, increased CXCR4 expression was accompanied by high leptin receptor expression in bone metastatic tissues from breast cancer patients. These results indicate that leptin induces bone metastasis of breast cancer by activating the SDF-1/CXCR4 axis.

Drinking Frequency but not Years may be Associated with Lower Urinary Tract Symptoms: Result from a Large Cross-Sectional Survey in Chinese Men.

OBJECTIVE: To evaluate the effect of the drinking frequency and years on lower urinary tract symptoms (LUTS) in a large Chinese male population. METHODS: The current data were obtained from a consecutive series of 3,229 men aged 18-79 who participated in a routine physical examination in Fangchenggang First People's Hospital, Guangxi, China. During a face-to-face interview, the detailed demographic variables about alcohol consumption, potential confounding factors were collected. LUTS were assessed by International Prostate Symptom Score (IPSS) and defined as total LUTS, irritative (IRR) and obstructive (OBS) symptoms, respectively. Multivariate logistic regression analysis was used to evaluate the risk of total LUTS, IRR and OBS symptoms affected by alcohol consumption. RESULTS: The prevalence of moderate to severe LUTS was 8.3% and apparently increased with age (P<0.001). A significant distribution presented in age, alcohol consumption, BMI, cigarette smoking, education attainment and hypertension among different strata of LUTS severity (P<0.05). Men who drank 1-2 times per week were less likely to have OBS symptoms (OR=0.45, 95%CI=0.29-0.70) regardless of age (OR=0.52, 95%CI=0.33-0.82) or multivariate adjusted (OR=0.52, 95%CI=0.33-0.83). Nevertheless, we did not observe a significant negative or positive association presented between drinking years and the risk of total LUTS, OBS and IRR symptoms. CONCLUSION: The current results imply that moderate drinking frequency may be protective against LUTS, and drinking years did not relate to worsening or improving LUTS.

Aspirin alleviates hepatic fibrosis by suppressing hepatic stellate cells activation via the TLR4/NF-κB pathway.

Hepatic fibrosis arises from a sustained wound-healing response to chronic liver injury. Because the occurrence and development of hepatic fibrosis is always associated with chronic inflammation, controlling inflammation within the liver may be an effective means of controlling the development and progression of hepatic fibrosis. Aspirin is a non-steroidal anti-inflammatory drug used to relieve both inflammatory symptoms and pain. The results of our study showed that aspirin significantly attenuated hepatic inflammation and fibrosis. Aspirin effectively inhibited the activation and proliferation of hepatic stellate cells (HSCs), which led to downregulation of inflammatory factors, including IL-6 and TNF-α in those cells. Aspirin also downregulated expression of Toll-like receptor-4 (TLR4) on HSCs, as well as its downstream mediators, MyD88 and NF-κB. The results of our study demonstrate aspirin's potential to inhibit the development of hepatic fibrosis and the molecular mechanism by which it acts. They suggest aspirin may be an effective therapeutic agent for the treatment of hepatic fibrosis.