[Effects of Long-Term Ethanol Consumption on Learning-Memory Functions in Mice and the Mechanisms Involved].

Objective: To investigate the effect of long-term ethanol consumption on learning-memory functions in mice and the mechanisms involved. Methods: Thirty male C57BL6/J mice were randomly assigned to 3 groups, with 10 mice in each group. The three groups included a control group in which the mice were given water ad libitum for 30 days, a long-term ethanol consumption group, or the EtOH group, in which the mice were given 6% (volume fraction) ethanol ad libitum for 30 days, and a long-term alcoholism group, or the EtOH+G group, in which the mice were given 5% (volume fraction) ethanol ad libitum for 30 days plus intermittent intragastric gavage of 20% ethanol at 3.5 g per kilogram body mass once every three days. After 30 days, the learning-memory functions of the mice were evaluated. At the conclusion of the experiment, the brain tissue of the mice was collected in order to examine the oxygen consumption rate (OCR) of mitochondria, the levels of pan-acetylation and protein oxidative stress in the hippocampal tissue, and the expression of sirtuin-3 (SIRT3) in hippocampus. Results: Morris water maze test showed that, compared with those of the control group, the times of crossing the platform and the percentage of platform time in the EtOH group and the EtOH+G group were both lower, and the EtOH+G group had the lowest results ( P<0.05). Western blot results showed that long-term ethanol intake increased the levels of protein oxidative stress and pan-acetylation in the hippocampal tissue and down-regulated SIRT3 expression of hippocampal mitochondria. The results of mitochondrial complex Ⅱ respiration showed that the brain mitochondrial 3-state respiration in the EtOH group and the EtOH+G group was lower than that in the control group ( P<0.05). Compared that with the control group, the mitochondrial maximum respiration in EtOH+G group was decreased ( P<0.05). Conclusions: Both long-term ethanol consumption and long-term alcoholism can reduce learning-memory functions and long-term alcoholism has the greater impact of the two. The potential mechanism may involve the down-regulation of the expression of SIRT3 protein in the hippocampus, which results in an increased level of pan-acetylation and enhanced expression of oxidative stress protein in the hippocampus, affects the mitochondrial functions of the brain, inhibits the oxidative phosphorylation capacity of mitochondrial complex Ⅱ, reduces the ATP energy supply of the brain tissue, and thus affects the learning-memory function.

[Effect of Ketone Body ß-Hydroxybutyrate to Attenuate Inflammation-Induced Mitochondrial Oxidative Stress in Vascular Endothelial Cells].

OBJECTIVE: To investigate the regulatory function and mechanism of ß-hydroxybutyrate (ß-OHB), a ketone body, on the mitochondrial oxidative stress of inflammatory human umbilical vein endothelial cells (HUVECs). METHODS: Lipopolysaccharide (LPS) and adenosine triphosphate (ATP) were used to induce macrophages to release proinflammatory factors, and the culture supernatant was collected as a macrophage-conditioned medium (MCM) to culture HUVECs. A total of 7 groups of cells were used in the study: ①control group, or normal cultured HUVECs; ②MCM group, or the MCM-cultured HUVECs; groups ③ to ⑦ were all HUVECs co-cultured with different reagents, including ③MCM+ß-OHB group, ④MCM+N-acetylcysteine (NAC) group, ⑤MCM+ß-OHB+NAC group, ⑥MCM+ß-OHB+histone deacetylase agonist ITSA1 group, and ⑦MCM+ß-OHB+histone deacetylase inhibitor Entinostat group. MitoSOX immunofluorescence staining was conducted to analyzes the mitochondrial superoxide levels, real-time fluorescent quantitative polymerase chain reaction (RT-qPCR) was performed to examine the mRNA expression of antioxidant genes, and Seahorse mitochondrial energy analyzer was used to measure mitochondrial aerobic respiration capacity. RESULTS: Compared with the control group, mitochondrial superoxide production was significantly increased in the MCM cultured HUVECs cells, while ß-OHB treatment significantly inhibited mitochondrial superoxide production, which was accompanied by an increase in the mRNA expression of antioxidant genes, and significant increase in the basal mitochondrial oxygen consumption rate and respiratory reserve capacity. NAC treatment did not further enhance the protective effect of ß-OHB on mitochondrial functions. In addition, ITSA1 treatment could completely offset the antioxidant and mitochondrial protective effects of ß-OHB, and these stated effects were still maintained after Entinostat treatment. CONCLUSION: The ketone body ß-OHB attenuates the mitochondrial oxidative stress of vascular endothelial cells through activating the antioxidant pathway and inhibiting histone deacetylase activity.

Erythrocyte membrane-coated gold nanocages for targeted photothermal and chemical cancer therapy.

Recently, red blood cell (RBC) membrane-coated nanoparticles have attracted much attention because of their excellent immune escapability; meanwhile, gold nanocages (AuNs) have been extensively used for cancer therapy due to their photothermal effect and drug delivery capability. The combination of the RBC membrane coating and AuNs may provide an effective approach for targeted cancer therapy. However, few reports have shown the utilization of combining these two technologies. Here, we design erythrocyte membrane-coated gold nanocages for targeted photothermal and chemical cancer therapy. First, anti-EpCam antibodies were used to modify the RBC membranes to target 4T1 cancer cells. Second, the antitumor drug paclitaxel (PTX) was encapsulated into AuNs. Then, the AuNs were coated with the modified RBC membranes. These new nanoparticles were termed EpCam-RPAuNs. We characterized the capability of the EpCam-RPAuNs for selective tumor targeting via exposure to near-infrared irradiation. The experimental results demonstrate that EpCam-RPAuNs can effectively generate hyperthermia and precisely deliver the antitumor drug PTX to targeted cells. We also validated the biocompatibility of the EpCam-RAuNs in vitro. By combining the molecularly modified targeting RBC membrane and AuNs, our approach provides a new way to design biomimetic nanoparticles to enhance the surface functionality of nanoparticles. We believe that EpCam-RPAuNs can be potentially applied for cancer diagnoses and therapies.

A novel lactylation-related gene signature for effectively distinguishing and predicting the prognosis of ovarian cancer.

Background: Lactylation has been found to regulate several types of biological processes in cancer. However, there is limited research on lactylation-related genes in predicting the prognosis of ovarian cancer (OC). This study aimed to explore the functional roles of lactylation-related genes in OC. Methods: Based on TCGA database, we obtained RNA sequencing data and clinical characteristics of patients with OC. Fourteen lactylation-related genes were screened for bioinformatic analysis in OC. Tumor classification of OC was constructed via a consistency cluster analysis. We examined the prognosis, immune-cell infiltration, and immunotherapy in relation to a lactylation-related model for OC. Results: A total of 707 prognostic genes and 14 key lactylation-related genes (SNRPA1, MPHOSPH6, POLDIP3, RB1, AHNAK, MAGOHB, CALM1, EP300, HDAC1, HDAC2, HDAC3, SIRT1, SIRT2, and SIRT3) were identified in TCGA-OC patients. Based on 14 genes involved in lactylation, TCGA-OC patients were split into low-risk (G1) and high-risk (G2) groups. Downregulated differentially expressed genes (DEGs) in the low-risk G1 group were associated with thermogenesis, oxidative phosphorylation, neutrophil extracellular trap formation, and interleukin 17 (IL-17) signaling pathway, whereas upregulated DEGs were associated with proteoglycans in cancer, focal adhesion, Wnt signaling pathway, extracellular matrix (ECM)-receptor interaction, and the adherens junction. The immune activity of the low-risk G1 group was lower than that of the high-risk G2 group. Gemcitabine, bleomycin, and doxorubicin had lower half-maximal inhibitory concentration (IC50) values in the high-risk G2 patients with OC, while cisplatin and paclitaxel had higher IC50 values compared to the low-risk G1 patients. The prognosis of patients with OC was also predicted with the help of an eight-lactylation-related gene prognostic model, comprising SNRPA1, MPHOSPH6, POLDIP3, RB1, HDAC1, CALM1, HDAC2, and SIRT2. Conclusions: The lactylation-related genes are closely related to tumor classification and immunity in patients with OC. There was good prognostic predictive performance for OC based on a lactylation-related signature. Our findings may offer new insights into the diagnosis and treatment of OC.

Obesity Enables NLRP3 Activation and Induces Myocardial Fibrosis via Hyperacetylation of HADHa.

Obesity increases the risk of myocardial fibrosis, a pathological change in most heart diseases, but the mechanism has not been fully elucidated. Here, we found that mice with high-fat diet-induced obesity had more severe myocardial fibrosis than control mice under normal and ischemia/reperfusion (I/R) conditions, which could be alleviated by neutralizing antibodies against interleukin (IL)-1ß and IL-18, downstream products of the nucleotide-binding oligomerization-like receptor protein 3 (NLRP3) inflammasome, and the NLRP3 inhibitor MCC950. Mechanistically, mitochondrial hyperacetylation in obese mouse hearts recruited apoptosis-associated speck-like protein containing a CARD (ASC) to mitochondria and thus facilitated NLRP3 inflammasome assembly. Acetylation of K255 on hydroxyl-CoA dehydrogenase α subunit (HADHa) was identified to trigger the mitochondrial localization of ASC. Blockade of HADHa-K255 acetylation downregulated mitochondrial ASC, suppressed the NLRP3 inflammasome, and attenuated post-I/R myocardial fibrosis in obese mouse hearts. In obese human patients, the extent of myocardial fibrosis according to T1 MRI was positively correlated with the plasma levels of IL-1ß and IL-18, supporting the connection of NLRP3 inflammation to obesity-induced myocardial fibrosis. In conclusion, our study demonstrates that the heart is susceptible to fibrosis under obesity through hyperacetylated HADHa-mediated activation of the NLRP3 inflammasome.

The relationship between polycystic ovary syndrome and infertility: a bibliometric analysis.

Background: Polycystic ovary syndrome (PCOS) is common and often causes infertility in women of childbearing age. This study adopted the method of bibliometrics to analyze the current research status of research on PCOS and infertility. Method: We conducted a literature search based on the Science Citation Index Expanded (SCI-E) database. All records of search results were exported and the records were cited r in plain text format to generate source files for analysis. CiteSpace software was then used to analyze the source files. The content of the analysis included: annual changes in the number of publications, the distribution of the countries and institutions of the authors of the literature, the distribution of the journals from which the literature was sourced, the distribution of authors, and the use of keywords. Results: There were a total of 2,716 documents retrieved, and the frequency of citations was 86,817. Both the number of documents and the number of citations showed an annually increasing trend. In this field of research, the United States was in a leading position, with many important research institutions and researchers. Emphasis was placed on top-level journals in the field of reproduction and top-level comprehensive journals. The use of keywords changed over time: in recent years, popular keywords included meta-analysis, follicular fluid, oxidative stress, and diagnostic criteria. Conclusions: There are obvious regional differences in PCOS and infertility research. International cooperation, especially cooperation with developing countries, should be strengthened.

Ketone Body ß-Hydroxybutyrate Prevents Myocardial Oxidative Stress in Septic Cardiomyopathy.

Septic cardiomyopathy is a life-threatening complication of severe sepsis and septic shock. Oxidative stress and mitochondrial dysfunction have been identified as significant abnormalities in septic cardiomyopathy. However, specific treatments are rare. This study aims to investigate the impact of ß-hydroxybutyrate (ß-OHB) on septic cardiomyopathy and explore the underlying mechanism(s). We found that pretreatment of D-ß-hydroxybutyrate-(R)-1,3 butanediol monoester (ketone ester, 3 mg/g body weight, once daily) by gavage for three days elevated the levels of ketone bodies, especially that of ß-hydroxybutyrate (ß-OHB) in the circulation and mouse hearts, which exerted a protective effect against lipopolysaccharide (LPS, 20 mg/kg)-induced septic cardiomyopathy in mice. In addition, an LPS-stimulated macrophage-conditioned medium (MCM) was used to mimic the pathological process of septic cardiomyopathy. Mechanistically, ß-OHB alleviated myocardial oxidative stress and improved mitochondrial respiratory function through the antioxidant FoxO3a/MT2 pathway activated via histone deacetylase (HDAC) inhibition, which ultimately enhanced heart performance in septic cardiomyopathy. Our results, therefore, suggested an unappreciated critical role of ß-OHB in septic heart protection as well as highlighted the potential of ß-OHB as a simple remedy for the septic cardiomyopathy population.

Integrated metabolomics revealed the fibromyalgia-alleviation effect of Mo2C nanozyme through regulated homeostasis of oxidative stress and energy metabolism.

Fibromyalgia (FM), the most common cause of chronic musculoskeletal pain in the general public, lacks advanced therapeutic methodology and detailed bioinformation. However, acting as a newly developed and important transition metal carbide or carbonitride, the Mo2C nanozyme has provided a novel iatrotechnique with excellent bioactivity in a cell/animal model, which also exhibits potential prospects for future clinical applications. In addition, high-content and high-throughput integrated metabolomics (including aqueous metabolomics, lipidomics, and desorption electrospray ionization-mass spectrometry imaging) also specializes in qualitative and quantitative analysis of metabolic shifts at the molecular level. In this work, the FM-alleviation effect of Mo2C nanozyme was investigated through integrated metabolomics in a mouse model. An advanced platform combining gas chromatography-mass spectrometry, liquid chromatography-mass spectrometry and bioinformatics was utilized to study the variation in the mouse metabolome and lipidome. The results revealed that Mo2C treatment could effectively enhance energy metabolism-related biological events impaired by FM, leading to homeostasis of oxidative stress and energy metabolism toward the control levels. During this process, Mo2C facilitated the elimination of ROS in plasma and cells and the rehabilitation of mice from oxidative stress and mitochondrial dysfunction. It was believed that such an integrated metabolomics study on the FM-alleviation effect of Mo2C nanozyme could provide another excellent alternative to traditional Mo2C-based research with numerous pieces of bioinformation, further supporting research area innovation, material modification, and clinical application.

Application of a Novel Prediction Model for Predicting 2-Year Risk of Non-Alcoholic Fatty Liver Disease in the Non-Obese Population with Normal Blood Lipid Levels: A Large Prospective Cohort Study from China.

PURPOSE: The purpose of this study was to develop and validate a nomogram to better assess the 2-year risk of non-alcoholic fatty liver disease (NAFLD) in non-obese population with normal blood lipid levels. PATIENTS AND METHODS: This study was a secondary analysis of a prospective study. We included 3659 non-obese adults with normal blood lipid levels without NAFLD at baseline. A total of 2744 participants were included in the development cohort and 915 participants were included in the validation cohort. The least absolute contraction selection operator (LASSO) regression model was used to identify the best risk factors. Multivariate Cox regression analysis was used to construct the prediction model. The performance of the prediction model was assessed using Harrell's consistency index (C-index), area under the receiver operating characteristic (AUROC) curve and calibration curve. Decision curve analysis was applied to evaluate the clinical usefulness of the prediction model. RESULTS: After LASSO regression analysis and multivariate Cox regression analysis on the development cohort, BMI, TG, DBIL, ALT and GGT were found to be risk predictors and were integrated into the nomogram. The C-index of development cohort and validation cohort was 0.819 (95% CI, 0.798 to 0.840) and 0.815 (95% CI, 0.781 to 0.849), respectively. The AUROC of 2-year NAFLD risk in the development cohort and validation cohort was 0.831 (95% CI, 0.811 to 0.851) and 0.797 (95% CI, 0.765 to 0.829), respectively. From calibration curves, the nomogram showed a good agreement between predicted and actual probabilities. The decision curve analysis indicated that application of the nomogram is more effective than the intervention-for-all-patients scheme. CONCLUSION: We developed and validated a nomogram for predicting 2-year risk of NAFLD in the non-obese population with normal blood lipid levels.

Hypoxic acclimation improves cardiac redox homeostasis and protects heart against ischemia-reperfusion injury through upregulation of O-GlcNAcylation.

Ischemia-reperfusion (I/R) injury is detrimental to cardiovascular system. Alteration in glucose metabolism has been recognized as an important adaptive response under hypoxic conditions. However, the biological benefits underlying this metabolic phenotype remain to be elucidated. This study was designed to investigate the impact of hypoxic acclimation (HA) on cardiac I/R injury and the antioxidative mechanism(s). Male adult mice were acclimated in a hypoxic chamber (10% oxygen [O2]) for 8 h/day for 14 days, and then subjected to cardiac I/R injury by ligation of left anterior descending coronary artery for 30 min and reperfusion for 24 h or 7 days. Our results showed that HA attenuated oxidative stress and reduced infarct size in the I/R hearts. This cardioprotective effect is coupled with an elevation of protein O-linked N-acetylglucosamine (O-GlcNAc) modification partially due to inflammatory stimulation. Hyperglycosylation activated glucose-6-phosphate dehydrogenase (G6PDH), the rate-limiting enzyme in the pentose phosphate pathway, resulting in an upregulation of NADPH/NADP+ and GSH/GSSG couples and enhancement of redox homeostasis in the heart. Pharmacological suppression of O-GlcNAcylation totally abolished the influence of HA on the G6PDH activity, redox balance and post-I/R damage in the hearts and cultured cardiomyocytes, whereby augmentation of O-GlcNAcylation further enhanced the benefits, suggesting a central role of O-GlcNAcylation in HA-initiated antioxidative and cardioprotective effects. These findings, therefore, identified HA as a promising anti-I/R strategy for the heart and proposed O-GlcNAc modification of G6PDH as a therapeutic target in ischemic heart disease.

Derivation and Validation of a Prediction Model for Predicting the 5-Year Incidence of Type 2 Diabetes in Non-Obese Adults: A Population-Based Cohort Study.

PURPOSE: The aim of this study was to derivate and validate a nomogram based on independent predictors to better evaluate the 5-year risk of T2D in non-obese adults. PATIENTS AND METHODS: This is a historical cohort study from a collection of databases that included 12,940 non-obese participants without diabetes at baseline. All participants were randomised to a derivation cohort (n = 9651) and a validation cohort (n = 3289). In the derivation cohort, the least absolute shrinkage and selection operator (LASSO) regression model was used to determine the optimal risk factors for T2D. Multivariate Cox regression analysis was used to establish the nomogram of T2D prediction. The receiver operating characteristic (ROC) curve, C-index, calibration curve, and decision curve analysis were performed by 1000 bootstrap resamplings to evaluate the discrimination ability, calibration, and clinical practicability of the nomogram. RESULTS: After LASSO regression analysis of the derivation cohort, it was found that age, fatty liver, γ-glutamyltranspeptidase, triglycerides, glycosylated hemoglobin A1c and fasting plasma glucose were risk predictors, which were integrated into the nomogram. The C-index of derivation cohort and validation cohort were 0.906 [95% confidence interval (CI), 0.878-0.934] and 0.837 (95% CI, 0.760-0.914), respectively. The AUC of 5-year T2D risk in the derivation cohort and validation cohort was 0.916 (95% CI, 0.889-0.943) and 0.829 (95% CI, 0.753-0.905), respectively. The calibration curve indicated that the predicted probability of nomogram is in good agreement with the actual probability. The decision curve analysis demonstrated that the predicted nomogram was clinically useful. CONCLUSION: Our nomogram can be used as a reasonable, affordable, simple, and widely implemented tool to predict the 5-year risk of T2D in non-obese adults. With this model, early identification of high-risk individuals is helpful to timely intervene and reduce the risk of T2D in non-obese adults.

The effect of comprehensive assessment and multi-disciplinary management for the geriatric and frail patient: A multi-center, randomized, parallel controlled trial.

BACKGROUND: A comprehensive geriatric assessment (CGA) of elderly patients is useful for detecting the patients vulnerabilities. Exercise and early rehabilitation, nutritional intervention, traditional Chinese medicine (TCM), standardized medication guidance, and patient education can, separately, improve and even reverse the physical frailty status. However, the effect of combining a CGA and multi-disciplinary management on frailty in elderly patients remains unclear. The present study assessed the effects of a CGA and multi-disciplinary management on elderly patients with frailty in China. METHODS: In this study, 320 in patients with frailty ≥70 years old will be randomly divided into an intervention group and a control group. The intervention group will be given routine management, a CGA and multi-disciplinary management involving rehabilitation exercise, diet adjustment, multi-drug evaluation, acupoint massage in TCM and patient education for 12 months, and the control group will be followed up with routine management for basic diseases. The primary outcomes are the Fried phenotype and short physical performance battery (SPPB). The secondary outcomes are the clinical frailty scale (CFS), non-elective hospital readmission, basic activities of daily living (BADL), 5-level European quality of life 5 dimensions index (EQ-5D), nutrition risk screening-2002 (NRS-2002), medical insurance expenses, fall events, and all-cause mortality. In addition, a cost-effectiveness study will be carried out. DISCUSSION: This paper outlines the protocol for a randomized, single-blind, parallel multi-center clinical study. This protocol, if beneficial, will demonstrate the interaction of various intervention strategies, will help improve elderly frailty patients, and will be useful for clinicians, nurses, policymakers, public health authorities, and the general population. TRIAL REGISTRATION: Chinese Clinical Trials Register, ChiCTR1900022623. Registered on April 19, 2019, http://www.chictr.org.cn/showproj.aspx?proj=38141.

Effect of age at first use of oral contraceptives on breast cancer risk: An updated meta-analysis.

BACKGROUND: We evaluated the relationship between the age at first use of oral contraceptives (OC) and breast cancer (BC) risk. METHODS: We searched PubMed, Embase, and related reviews published through June 28, 2018, and used summary relative risk (RR) and 95% confidence intervals (CIs) to evaluate the cancer risks, and fixed-effects dose-response meta-analysis to assess potential linear and non-linear dose-response relationships. RESULTS: We included 10 studies, with 8585 BC cases among 686,305 participants. The pooled RR for BC was 1.24 (95% CI: 1.10-1.41), with moderate heterogeneities (I = 66.5%, P < .001). No significant publication bias was found (P = .584 for Begg test, P = .597 for Egger test). A linear dose-response relationship between the age at first OC use and BC risk was detected (P = .518 for non-linearity). Subgroup analyses were restricted to studies done by BC subtypes, region, sample size, follow-up time and study quality. Inconsistent consequences with no statistical significance were explored when limited to studies from Western countries, study quality <7, sample size <10,000, follow-up time <5 years, and BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2) expression status in tumor tissue. Sensitivity analyses indicated that our results were stable and reliable after removing each study in turn and omitting studies of adjusted unreported variables. CONCLUSION: A significant linear relationship between the age at first OC use and BC risk was confirmed. No further consistent differences are noted in multiple aspects of BC subtypes defined by progesterone or ER status.

Erythrocyte-derived vesicles for circulating tumor cell capture and specific tumor imaging.

The precise diagnosis of cancer remains a great challenge; therefore, it is our research interest to develop safe, tumor-specific reagents. In this study, we designed nanovesicles derived from erythrocyte membranes; the nanovesicles are capable of recognizing tumor cells for both circulating tumor cell (CTC) capture and tumor imaging. The tumor-targeting molecules folic acid (FA) and fluorescein Cy5 were modified on the nanovesicle surface. The developed nanovesicles exhibit excellent tumor targeting ability both in vitro and in vivo for CTC capture and in tumor imaging. Compared with traditional immunomagnetic beads, the proposed nanovesicles are capable of avoiding non-specific adsorption as a derivative of red blood cells. Combined with a non-invasive means of micromanipulation, the nanometer-sized vesicles show a high purity of CTC capture (over 90%). In vivo, the nanovesicles can also be employed for efficient tumor imaging without obvious toxicity and side effects. In brief, the nanovesicles prepared herein show potential clinical application for integrated diagnosis in vitro and in vivo.

Capture and "self-release" of circulating tumor cells using metal-organic framework materials.

Capturing circulating tumor cells (CTCs) from peripheral blood for subsequent analyses has shown potential in precision medicine for cancer patients. Broad as the prospect is, there are still some challenges that hamper its clinical applications. One of the challenges is to maintain the viability of the captured cells during the capturing and releasing processes. Herein, we have described a composite material that could encapsulate a magnetic Fe3O4 core in a MIL-100 shell (MMs), which could respond to pH changes and modify the anti-EpCAM antibody (anti-EpCAM-MMs) on the surface of MIL-100. After the anti-EpCAM-MMs captured the cells, there was no need for additional conditions but with the acidic environment during the cell culture process, MIL-100 could realize automatic degradation, leading to cell self-release. This self-release model could not only improve the cell viability, but could also reduce the steps of the release process and save human and material resources simultaneously. In addition, we combined clinical patients' case diagnosis with the DNA sequencing and next generation of RNA sequencing technologies in the hope of precision medicine for patients in the future.

Cancer Cell Membrane Camouflaged Nanoparticles to Realize Starvation Therapy Together with Checkpoint Blockades for Enhancing Cancer Therapy.

Although anti-PD-1 immunotherapy is widely used to treat melanoma, its efficacy still has to be improved. In this work, we present a therapeutic method that combines immunotherapy and starvation therapy to achieve better antitumor efficacy. We designed the CMSN-GOx method, in which mesoporous silica nanoparticles (MSN) are loaded with glucose oxidase (GOx) and then encapsulate the surfaces of cancer cell membranes to realize starvation therapy. By functionalizing the MSN's biomimetic surfaces, we can synthesize nanoparticles that can escape the host immune system and homologous target. These attributes enable the nanoparticles to have improved cancer targeting ability and enrichment in tumor tissues. Our synthetic CMSN-GOx complex can ablate tumors and induce dendritic cell maturity to stimulate an antitumor immune response. We performed an in vivo analysis of these nanoparticles and determined that our combined therapy CMSN-GOx plus PD-1 exhibits a better antitumor therapeutic effect than therapies using CMSN-GOx or PD-1 alone. Additionally, we used the positron emission tomography imaging to measuring the level of glucose metabolism in tumor tissues, for which we investigate the effect with the cancer therapy in vivo.

Engineered red blood cells for capturing circulating tumor cells with high performance.

Filtration of circulating tumor cells (CTCs) in peripheral blood is of proven importance for early cancer diagnosis, treatment monitoring, metastasis diagnosis, and prognostic evaluation. However, currently available strategies for enriching CTCs, such as magnetic activated cell sorting (MACS), face serious problems with purity due to nonspecific interactions between beads and leukocytes in the process of capturing. In the present study, the tumor-targeting molecule folic acid (FA) and magnetic nanoparticles (MNPs) were coated on the surface of red blood cells (RBCs) by hydrophobic interaction and chemical conjugation, respectively. The resulting engineered RBCs rapidly adhered to CTCs and the obtained CTC-RBC conjugates were isolated in a magnetic field. After treatment with RBC lysis buffer and centrifugation, CTCs were released and captured. The duration of the entire process was less than three hours. Cell counting showed that the capture efficiency was above 90% and the purity of the obtained CTCs was higher than 75%. The performance of the proposed method exceeded that of MACS® beads (80% for capture efficiency and 20% for purity) under the same conditions. The obtained CTCs could be successfully re-cultured and proliferated in vitro. Our engineered RBCs have provided a novel method for enriching rare cells in the physiological environment.

Comparisons of weight changes between sodium-glucose cotransporter 2 inhibitors treatment and glucagon-like peptide-1 analogs treatment in type 2 diabetes patients: A meta-analysis.

AIMS/INTRODUCTION: To evaluate the efficacy of weight changes from baseline of the sodium-glucose cotransporter 2 (SGLT2) inhibitors treatment and glucagon-like peptide-1 (GLP-1) analogs treatment after comparisons with a placebo in type 2 diabetes patients, and the associated factors. MATERIALS AND METHODS: Studies were searched from when recording began, June 2004, until June 2015, and re-searched in July 2016, and placebo-controlled randomized trials in type 2 diabetes patients with a study length of ≥12 weeks were included. RESULTS: A total of 97 randomized controlled trials were included. Compared with a placebo, treatment with SGLT2 inhibitors was associated with a significantly greater decrease in weight change from baseline (weighted mean differences -2.01 kg, 95% confidence interval -2.18 to -1.83 kg, P < 0.001). Compared with a placebo, changes with GLP -1 treatment were also associated with a comparable decrease in weight change from baseline (weighted mean differences -1.59 kg, 95% confidence interval -1.86 to -1.32 kg, P < 0.001). Meta-regression analysis showed that the baseline age, sex, baseline glycated hemoglobin, diabetes duration or baseline body mass index were not associated with the weight change from baseline in SGLT2 inhibitors or in GLP-1 treatment corrected by placebo. Comparisons of weight changes from baseline corrected by placebo between SGLT2 inhibitors and GLP-1 treatment showed that the difference was not significant (P > 0.05). CONCLUSIONS: According to the present meta-analysis, treatment with SGLT2 inhibitors and treatment with GLP-1 analogs led to comparable weight changes from baseline, which are both with significance when compared with placebo treatment.

MTHFR gene polymorphisms and methotrexate toxicity in adult patients with hematological malignancies: a meta-analysis.

BACKGROUND: MTHFR gene polymorphisms has been shown to be associated with methotrexate (MTX) toxicity in adult hematological malignancies; however, the results remain inconclusive. MATERIALS & METHODS: To examine the role of common MTHFR variants in MTX toxicity prediction, we performed a meta-analysis via identifying relevant studies for quantitative data pooling. RESULTS: Our results showed a significant association between MTHFR C677T polymorphism and increased risk of MTX-induced all-grade (grade 1-4) and severe (grade 3-4) hepatic and gastrointestinal toxicities in Caucasian independent of MTX dosage. MTHFR 677T allele increased risk of severe mucositis and all-grade hematological toxicity. MTHFR A1298C polymorphism was not significantly associated with hepatic and hematological toxicity, whereas perhaps having a protective effect on mucositis and gastrointestinal toxicity. CONCLUSION: MTHFR C677T polymorphism may be a good predictor for MTX toxicity in adult hematological malignancies.

Similar efficacy and safety of daptomycin versus linezolid for treatment of vancomycin-resistant enterococcal bloodstream infections: a meta-analysis.

Daptomycin and linezolid are the most commonly used antibiotics for bloodstream infection caused by vancomycin-resistant enterococci (VRE-BSI). However, the best therapeutic agent to treat VRE-BSI remains to be established. In order to provide evidence for an optimal treatment decision, a systematic review and meta-analysis was performed comparing the efficacy and safety of daptomycin and linezolid for the treatment of VRE-BSI. After thorough searching of relevant studies from MEDLINE, EMBASE, Clinicaltrials.gov and international meetings up to November 2015, 11 retrospective cohort studies were finally included with a sample size of 1339 patients. Among these 11 included studies, all patients in the daptomycin group received standard or high-dose daptomycin treatment (≥6 mg/kg/day). Data were extracted and pooled risk ratios (RRs) and 95% confidence intervals (95% CIs) were calculated using a random-effects model. The meta-analysis indicated similar crude overall mortality between patients receiving daptomycin and those treated with linezolid (RR = 1.07, 95% CI 0.83-1.37). Moreover, no difference regarding clinical cure (RR = 1.11, 95% CI 0.88-1.42), microbiological cure (RR = 0.99, 95% CI 0.90-1.09) or relapse rate of VRE-BSI (RR = 1.08, 95% CI 0.76-1.52) was found between daptomycin and linezolid. Adverse event rates were not significantly different between the two groups. Currently available evidence indicates similar efficacy and safety of daptomycin and linezolid for the treatment of VRE-BSI. However, the findings in the meta-analysis are limited by heterogeneity between relatively small-scale retrospective studies and should be interpreted cautiously.