Immunostimulatory gene therapy combined with checkpoint blockade reshapes tumor microenvironment and enhances ovarian cancer immunotherapy.

Immune evasion has made ovarian cancer notorious for its refractory features, making the development of immunotherapy highly appealing to ovarian cancer treatment. The immune-stimulating cytokine IL-12 exhibits excellent antitumor activities. However, IL-12 can induce IFN-γ release and subsequently upregulate PDL-1 expression on tumor cells. Therefore, the tumor-targeting folate-modified delivery system F-DPC is constructed for concurrent delivery of IL-12 encoding gene and small molecular PDL-1 inhibitor (iPDL-1) to reduce immune escape and boost anti-tumor immunity. The physicochemical characteristics, gene transfection efficiency of the F-DPC nanoparticles in ovarian cancer cells are analyzed. The immune-modulation effects of combination therapy on different immune cells are also studied. Results show that compared with non-folate-modified vector, folate-modified F-DPC can improve the targeting of ovarian cancer and enhance the transfection efficiency of pIL-12. The underlying anti-tumor mechanisms include the regulation of T cells proliferation and activation, NK activation, macrophage polarization and DC maturation. The F-DPC/pIL-12/iPDL-1 complexes have shown outstanding antitumor effects and low toxicity in peritoneal model of ovarian cancer in mice. Taken together, our work provides new insights into ovarian cancer immunotherapy. Novel F-DPC/pIL-12/iPDL-1 complexes are revealed to exert prominent anti-tumor effect by modulating tumor immune microenvironment and preventing immune escape and might be a promising treatment option for ovarian cancer treatment.

Identification and Validation of Glomeruli Cellular Senescence-Related Genes in Diabetic Nephropathy by Multiomics.

Accumulating evidence indicates that cellular premature senescence of the glomerulus, including endothelial cells, mesangial cells, and podocytes leads to diabetic nephropathy (DN), and DN is regarded as a clinical model of premature senescence. However, the role of cellular senescence-associated genes in the glomerulus in DN progression remains unclear. Therefore, this work aims to identify and validate potential cellular aging-related genes in the glomerulus in DN to provide novel clues for DN treatment based on anti-aging. The microarray GSE96804 dataset, including 41 diabetic glomeruli and 20 control glomeruli, is retrieved from the Gene Expression Omnibus (GEO) database and cellular senescence-related genes (CSRGs) are obtained from the GeneCards database and literature reports. Subsequently, PPI, GO, and KEGG enrichment are analyzed by screening the intersection between differentially expressed genes (DEGs) and CSRGs. scRNA-seq dataset GSE127235 is used to verify core genes expression in glomerulocytes of mice. Finally, db/db mice are utilized to validate the hub gene expression in the glomeruli, and high glucose-induced mesangial cells are used to confirm key gene expression. This study reveals that FOS and ZFP36 may play an anti-aging role in DN to ameliorate cell intracellular premature aging in mesangial cells of glomeruli.

Metabolic reprogramming of proinflammatory macrophages by target delivered roburic acid effectively ameliorates rheumatoid arthritis symptoms.

Rheumatoid arthritis (RA) is a common chronic inflammatory disorder that usually affects joints. It was found that roburic acid (RBA), an ingredient from anti-RA herb Gentiana macrophylla Pall., displayed strong anti-inflammatory activity. However, its medical application is limited by its hydrophobicity, lack of targeting capability and unclear functional mechanism. Here, we constructed a pH responsive dual-target drug delivery system hitchhiking RBA (RBA-NPs) that targeted both CD44 and folate receptors, and investigated its pharmacological mechanism. In rat RA model, the nanocarriers effectively delivered RBA to inflammatory sites and significantly enhanced the therapeutic outcomes compared with free RBA, as well as strongly reducing inflammatory cytokine levels and promoting tissue repair. Following analysis revealed that M1 macrophages in the joints were reprogrammed to M2 phenotype by RBA. Since the balance of pro- and anti-inflammatory macrophages play important roles in maintaining immune homeostasis and preventing excessive inflammation in RA, this reprogramming is likely responsible for the anti-RA effect. Furthermore, we revealed that RBA-NPs drove M1-to-M2 phenotypic switch by down-regulating the glycolysis level via blocking ERK/HIF-1α/GLUT1 pathway. Thus, our work not only developed a targeting delivery system that remarkably improved the anti-RA efficiency of RBA, but also identified a potential molecular target to reversely reprogram macrophages though energy metabolism regulation.

Cost-effectiveness analysis of imatinib versus dasatinib in the treatment of pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia when combined with conventional chemotherapy in China.

BACKGROUND: Tyrosine kinase inhibitors combined with conventional chemotherapy (CC) in treating Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) has achieved promising efficacy and safety outcomes. The study was conducted to compare the cost-effectiveness between imatinib (HANSOH Pharma, Jiangsu, China) and dasatinib (CHIATAI TIANQING Pharma, Jiangsu, China) in treating pediatric Ph-positive ALL when combined with CC from the perspective of the health system in China. METHODS: A Markov model was established to simulate a hypothetical cohort of pediatric Ph-positive ALL patients receiving imatinib or dasatinib, combined with CC. The model was designed using a 10-year horizon, a 3- month cycle, and a 5% discount rate. Three health states were included: alive with progression-free survival, progressed disease, and death. Patient characteristics and transition probabilities were estimated based on clinical trials. Other relevant data, such as direct treatment costs and health utility data were extracted from published literature and Sichuan Province's centralized procurement and supervision platform. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to assess the robustness of the results. The willingness-to-pay (WTP) was set as three times China's GDP per capita in 2021. RESULTS: In the base-case analysis, the total medical costs were $89,701 and $101,182, and the quality-adjusted life years (QALYs) gained were 1.99 and 2.70, for imatinib and dasatinib regimens, respectively. The incremental cost-effectiveness ratio for dasatinib versus imatinib was $16,170/QALY. The probabilistic sensitivity analysis indicated that treatment with dasatinib combined with CC achieved a 96.4% probability of cost-effectiveness at a WTP threshold of $37,765/QALY. CONCLUSIONS: Dasatinib combined with CC is likely to be a cost-effective strategy compared to imatinib combination therapy for pediatric Ph-positive ALL in China at a WTP threshold of $37,765/QALY.

Human Serum Albumin-enriched Clopidogrel Bisulfate Nanoparticle Alleviates Cerebral Ischemia-Reperfusion Injury in Rats.

PURPOSE: Cerebral ischemia-reperfusion (I/R) injury remains a leading cause of mobility and mortality among patients with ischemic stroke. This study aims to develop a human serum albumin (HSA)-enriched nanoparticle platform for solubilizing clopidogrel bisulfate (CLP) for intravenous administration, and to explore the protective effect of HSA-enriched nanoparticles loaded with CLP (CLP-ANPs) against cerebral I/R injury in transient middle cerebral artery occlusion (MCAO) rat model. METHODS: CLP-ANPs were synthesized via a modified nanoparticle albumin-bound technology, lyophilized, and then characterized by morphology, particle size, zeta potential, drug loading capacity, encapsulation efficiency, stability and in vitro release kinetics. In vivo pharmacokinetic studies were conducted using Sprague-Dawley (SD) rats. Also, an MCAO rat model was established to explore the therapeutic effect of CLP-ANPs on cerebral I/R injury. RESULTS: CLP-ANPs remained spherical particles with a layer of proteins forming protein corona. Lyophilized CLP-ANPs after dispersion displayed an average size of about 235.6 ± 6.6 nm (PDI = 0.16 ± 0.08) with a zeta potential of about - 13.5 ± 1.8 mV. CLP-ANPs achieved sustained release for up to 168 h in vitro. Next, a single injection of CLP-ANPs dose-dependently reversed the histopathological changes induced by cerebral I/R injury possibly via attenuating apoptosis and reducing oxidative damages in the brain tissues. CONCLUSIONS: CLP-ANPs represent a promising and translatable platform system for the management of cerebral I/R injury during ischemic stroke.

Efficacy and safety of esketamine for sedation among patients undergoing gastrointestinal endoscopy: a systematic review and meta-analysis.

BACKGROUND: Patients who undergo gastrointestinal endoscopy often require propofol-based sedation combined with analgesics. At present, the efficacy and safety of esketamine as an adjunct to propofol for sedation during endoscopic procedures in patients remains controversial. Moreover, there is no universal agreement regarding the appropriate dose of esketamine supplementation. This study aimed to assess the efficacy and safety of esketamine as an adjunct to propofol for sedation during endoscopic procedures in patients. METHODS: Seven electronic databases and three clinical trial registry platforms were searched and the deadline was February 2023. Randomized controlled trials (RCTs) evaluating the efficacy of esketamine for sedation were included by two reviewers. Data from the eligible studies were combined to calculate the pooled risk ratio or standardized mean difference. RESULTS: Eighteen studies with 1962 esketamine participants were included in the analysis. As an adjunct to propofol, the administration of esketamine reduced the recovery time compared to normal saline (NS). However, there was no significant difference between the opioids group and ketamine group. For propofol dosage, the administration of esketamine required a lower propofol dosage compared to the NS group and opioids group].For complications, the esketamine group had fewer complications compared to the NS group and opioid group in patients, but there were no significant differences between the esketamine group and ketamine group. Notably, the coadministration of esketamine was associated with a higher risk of visual disturbance compared to the NS group. In addition, we used subgroup analysis to investigate whether 0.2-0.5 mg/kg esketamine was effective and tolerable for patients. CONCLUSION: Esketamine as an adjunct to propofol, is an appropriate effective alternative for sedation in participants undergoing gastrointestinal endoscopy. However, considering the possibility of its psychotomimetic effects, esketamine should be used with caution.

Degradable Temperature-Sensitive Hydrogel Loaded with Heparin Effectively Prevents Post-Operative Tissue Adhesions.

Tissue adhesions could occur following surgeries, and severe tissue adhesions can lead to serious complications. Medical hydrogels could be applied at surgical sites as a physical barrier to prevent tissue adhesion. For practical reasons, spreadable, degradable, and self-healable gels are highly demanded. To meet these requirements, we applied carboxymethyl chitosan (CMCS) to poloxamer-based hydrogels to generate low Poloxamer338 (P338) content gels displaying low viscosity at refrigerator temperature and improved mechanical strength at body temperature. Heparin, an effective adhesion inhibitor, was also added to construct P338/CMCS-heparin composite hydrogel (PCHgel). PCHgel presents as a flowable liquid below 20 °C and could rapidly transform into gel when spread on the surface of damaged tissue due to temperature change. The introduction of CMCS enabled hydrogels to form a stable self-healable barrier at injured positions and slowly release heparin during the wound healing period before being degraded after ∼14 days. Ultimately, PCHgel significantly reduced tissue adhesion in model rats and displayed higher efficiency than P338/CMCS gel without heparin. Its adhesion suppression mechanism was verified, and it also displayed good biosafety. Therefore, PCHgel showed good clinical transformation potential with high efficacy, good safety, and ease of use.

A cross-sectional study on knowledge and behavior regarding medication usage among guardians of left-behind children: evidence from China.

PURPOSE: The primary objective of this study was to evaluate knowledge and behavior of medication use among guardians of left-behind children (LBC) and non-left-behind children (NLBC). METHODS: A cross-sectional study was conducted in Chengdu, the major city of southwestern China from May 2020 to August 2020. A logistic regression model was conducted to assess medication-related knowledge and behavior of guardians between the LBC group and NLBC group, adjusted for confounders. Stratified analysis was further performed. RESULTS: The overall mean scores for knowledge and for behavior were 20.22 (standard deviation = 4.472) and 15.77 (standard deviation = 3.604), respectively. No significant difference was found in medication-related knowledge and behavior scores between LBC and NLBC guardians (P > 0.05). A significant difference was only observed after adjusting for past medical history and history of present illness (HPI). CONCLUSION: There was no significant difference in the awareness and behavior of medication use between guardians of LBC and NLBC in this study, having more contact with the doctor was an effective method of health education that could possibly improve their health literacy.

Curcumin and Its Analogs in Non-Small Cell Lung Cancer Treatment: Challenges and Expectations.

Researchers have made crucial advances in understanding the pathogenesis and therapeutics of non-small cell lung cancer (NSCLC), improving our understanding of lung tumor biology and progression. Although the survival of NSCLC patients has improved due to chemoradiotherapy, targeted therapy, and immunotherapy, overall NSCLC recovery and survival rates remain low. Thus, there is an urgent need for the continued development of novel NSCLC drugs or combination therapies with less toxicity. Although the anticancer effectiveness of curcumin (Cur) and some Cur analogs has been reported in many studies, the results of clinical trials have been inconsistent. Therefore, in this review, we collected the latest related reports about the anti-NSCLC mechanisms of Cur, its analogs, and Cur in combination with other chemotherapeutic agents via the Pubmed database (accessed on 18 June 2022). Furthermore, we speculated on the interplay of Cur and various molecular targets relevant to NSCLC with discovery studio and collected clinical trials of Cur against NSCLC to clarify the role of Cur and its analogs in NSCLC treatment. Despite their challenges, Cur/Cur analogs may serve as promising therapeutic agents or adjuvants for lung carcinoma treatment.

Effects of vitamin D supplementation during pregnancy on bone health and offspring growth: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Whether vitamin D supplementation during pregnancy is beneficial to bone health and offspring growth remains controversial. Moreover, there is no universal agreement regarding the appropriate dose and the time of commencement of vitamin D supplementation during pregnancy. OBJECTIVE: We aimed to systematically review the effects of vitamin D supplementation during pregnancy on bone development and offspring growth. METHODS: A literature search for randomized controlled trials (RCTs) was performed in 7 electronic databases to identify relevant studies about the effects of vitamin D supplementation during pregnancy on bone development and offspring growth from inception to May 22, 2022. A Cochrane Risk Assessment Tool was used for quality assessment. Vitamin D supplementation was compared with placebo or standard supplements. The effects are presented as the mean differences (MDs) with 95% CIs. The outcomes include bone mineral content (BMC), bone mineral density (BMD), bone area (BA), femur length (FL) and humeral length (HL); measurement indicators of growth, including length, weight and head circumference; and secondary outcome measures, including biochemical indicators of bone health, such as the serum 25(OH)D concentration. Additionally, subgroup analyses were carried out to evaluate the impact of different doses and different initiation times of supplementation with vitamin D. RESULTS: Twenty-three studies with 5390 participants met our inclusion criteria. Vitamin D supplementation during pregnancy was associated with increased humeral length (HL) (MD 0.13, 95% CI 0.06, 0.21, I2 = 0, P = 0.0007) during the fetal period (third trimester). Vitamin D supplementation during pregnancy was associated with a significantly increased length at birth (MD 0.14, 95% CI 0.04, 0.24, I2 = 24%, P = 0.005) and was associated with a higher cord blood 25(OH)D concentration (MD 48.74, 95% CI 8.47, 89.01, I2 = 100%, P = 0.02). Additionally, subgroup analysis revealed that birth length was significantly higher in the vitamin D intervention groups of ≤1000 IU/day and ≥4001 IU/day compared with the control group. Prenatal (third trimester) vitamin D supplementation was associated with a significant increase in birth length, while prenatal (second trimester) vitamin D supplementation was associated with a significant increase in birth weight. CONCLUSION: Vitamin D supplementation during pregnancy may be associated with increased humeral length (HL) in the uterus, increased body length at birth and higher cord blood 25(OH)D concentration. Evidence of its effect on long-term growth in children is lacking. Additional rigorous high-quality, long-term and larger randomized trials are required to more fully investigate the effects of vitamin D supplementation during pregnancy.

Live Macrophage-Delivered Doxorubicin-Loaded Liposomes Effectively Treat Triple-Negative Breast Cancer.

Triple-negative breast cancer is often aggressive and resistant to various cancer therapies, especially corresponding targeted drugs. It is shown that targeted delivery of chemotherapeutic drugs to tumor sites could enhance treatment outcome against triple-negative breast cancer. In this study, we exploited the active tumor-targeting capability of macrophages by loading doxorubicin-carrying liposomes on their surfaces via biotin-avidin interactions. Compared with conventional liposomes, this macrophage-liposome (MA-Lip) system further increased doxorubicin accumulation in tumor sites, penetrated deeper into tumor tissue, and enhanced antitumor immune response. As a result, the MA-Lip system significantly lengthened the survival rate of 4T1 cell-bearing mice with low toxicity. Besides, the MA-Lip system used highly biocompatible and widely approved materials, which ensured its long-term safety. This study provides a system for triple-negative breast cancer treatment and offers another macrophage-based strategy for tumor delivery.

A Simple and Sensitive UPLC-UV Method for Simultaneous Determination of Isoniazid, Pyrazinamide, and Rifampicin in Human Plasma and Its Application in Therapeutic Drug Monitoring.

As the first-line clinical drugs for tuberculosis (TB), isoniazid (INH), pyrazinamide (PZA), and rifampicin (RMP) are playing important roles for preventing the rapid spread of TB. Precise quantification of these drugs in biological samples is crucial to evaluate or improve the efficacy of advanced TB drug delivery systems, which are designed for reducing drug resistance, minimizing side effects, etc. Herein, a simple and sensitive method based on UPLC-UV was established and investigated for simultaneous quantification of PZA, INH, and RMP in human plasma and was applied to anti-TB drug therapeutic drug monitoring. The analytes were implemented on an HSS T3 C18 column at 40°C. The separation was performed with a gradient elution with methanol-acetonitrile-water (3:3:94) at 0.1 ml/min. The analysis only involved plasma with a small volume of 100 µL and a rapid one-step protein precipitation with methanol-acetonitrile (1:1). The results showed that the calibration curves for INH, PZA, and RMP were linear in a range of 0.5-20 µg/ml, 5-60 µg/ml, and 5-60 µg/ml, respectively. The intra- and inter-day precisions were both smaller than 15%, and the lower limit of quantitation (LLOQ) was identifiable and reproducible at 0.5 µg/ml for INH and 5 µg/ml for both PZA and RMP, respectively. The target drugs in plasma were stable after 21 days of storage at -80°C. The results indicated that our developed method is suitable for the simultaneous monitoring of INH, PZA, and RMP in human plasma.

Curcumin and Its Analogs as Potential Epigenetic Modulators: Prevention of Diabetes and Its Complications.

BACKGROUND: The pathobiology of diabetes and associated complications has been widely researched in various countries, but effective prevention and treatment methods are still insufficient. Diabetes is a metabolic disorder of carbohydrates, fats, and proteins caused by an absence of insulin or insulin resistance, which mediates an increase of oxidative stress, release of inflammatory factors, and macro- or micro-circulation dysfunctions, ultimately developing into diverse complications. SUMMARY: In the last decade through pathogenesis research, epigenetics has been found to affect metabolic diseases. Particularly, DNA methylation, histone acetylation, and miRNAs promote or inhibit diabetes and complications by regulating the expression of related factors. Curcumin has a wide range of beneficial pharmacological activities, including anti-inflammatory, anti-oxidation, anticancer, anti-diabetes, anti-rheumatism, and increased immunity. Key Messages: In this review, we discuss the effects of curcumin and analogs on diabetes and associated complications through epigenetics, and we summarize the preclinical and clinical researches for curcumin and its analogs in terms of management of diabetes and associated complications, which may provide an insight into the development of targeted therapy of endocrine diseases.

Co-Delivery of Paclitaxel and shMCL-1 by Folic Acid-Modified Nonviral Vector to Overcome Cancer Chemotherapy Resistance.

Acquired chemoresistance presents a major clinical impediment, which is an urgent problem to be solved. Interestingly, myeloma cell leukemia-1 (MCL-1) and folate receptor expression levels are higher in chemotherapy-resistant patients than in pretreatment patients. In this study, a multifunctional folic acid (FA)-targeting core-shell structure is presented for simultaneous delivery of shMCL-1 and paclitaxel (PTX). The transfection efficiency of shMCL-1 with the FA-targeting delivery system is higher than with a nontargeting delivery system in Skov3 and A2780T cells. The FA-targeting system significantly inhibits cell growth, blocks cell cycles, and promotes apoptosis of cancer cells in vitro. The mechanisms involved in inhibiting growth are related to Bcl-2/Bax and cdc2/Cyclin B1 pathways. An analysis of RNA sequencing suggests that shMCL-1 reverses chemoresistance through regulating genes such as regulator of chromosome condensation 2 (RCC2). The synergetic effect of shMCL-1 and PTX effectively inhibits tumor growth in both PTX-resistant and normal cancer models by inducing tumor apoptosis, inhibiting proliferation, and limiting tumor angiogenesis. The study results indicate that a FA-targeting delivery system combining shMCL-1 with PTX can simultaneously target tumor sites and restore the sensitivity of chemotherapy-resistant cancer to PTX. These findings have important implications for patients with normal or PTX-resistant cancer.

Use of tyrosine kinase inhibitors for paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia: a systematic review and meta-analysis.

OBJECTIVES: To investigate the effectiveness and safety of tyrosine kinase inhibitors (TKIs) in the management of paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ALL). DESIGN: A systematic review and meta-analysis. DATA SOURCES: Electronic searches were conducted on CENTRAL, MEDLINE, EMBASE, SIOP, ASPHO, ASCO, ASH and four Chinese databases from inception to 8 March 2020. Language of publications was restricted in English and Chinese. ELIGIBILITY CRITERIA: Prospective and retrospective comparative studies were included. DATA EXTRACTION AND SYNTHESIS: Two authors independently assessed and extracted data. Quality of studies was assessed by the Cochrane Collaboration's tool and Newcastle-Ottawa Scale. Subgroup analysis was performed by comparing different types of TKIs. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Two randomised controlled trials (RCTs) and four cohort studies enrolling 536 patients were included. For RCTs, the pooled HR was 0.68 (95% CI 0.26 to 1.78) in overall survival (OS), 0.63 (95% CI 0.28 to 1.42) in event-free survival (EFS), respectively, comparing TKI arm with non-TKI arm for treatment of paediatric Ph+ALL. There was significant difference in OS and EFS between imatinib arm and dasatinib arm (HR 2.26, 95% CI 1.02 to 5.01; HR 2.36; 95% CI 1.27 to 4.39, respectively). For cohort studies, the pooled HR was 0.25 (95% CI 0.14 to 0.47) in OS, 0.25 (95% CI 0.12 to 0.56) in EFS, respectively, comparing TKI arm with non-TKI arm. There was no significance difference in adverse drug reaction between TKI group and without TKI group (risk ratio (RR) 0.82, 95% CI 0.63 to 1.08 in RCT; RR 1.01, 95% CI 0.64 to 1.59 in cohort studies; respectively), and imatinib versus dasatinib (RR 0.97, 95% CI 0.77 to 1.23). The quality of evidence was rated as low for OS, EFS and adverse drug reaction (ADR). CONCLUSIONS: The combination of TKIs with chemotherapy is likely to improve the OS and EFS rates in paediatric Ph+ALL, and dasatinib is superior than imatinib. Large sample size and prospective controlled studies are warranted. PROSPERO REGISTRATION NUMBER: CRD42018104107.

Co-Delivery of Docetaxel and Curcumin via Nanomicelles for Enhancing Anti-Ovarian Cancer Treatment.

INTRODUCTIONS: Ovarian cancer is a stubborn malignancy of gynecological system with a high mortality rate. Docetaxel (DTX), the second-generation of anti-tumor drug Taxane, has shown superior efficacy over classic paclitaxel (PTX) in certain cancers. However, its clinical application is hindered by poor bioavailability. The natural spice extract curcumin (Cur) has been discovered to improve the bioavailability of DTX. Therefore, it is meaningful to develop a combined drug strategy of DTX and Cur with methoxy poly (ethylene glycol)-poly (L-lactic acid) (MPEG-PLA) copolymers in ovarian cancer therapy. METHODS: Injectable DTX-Cur/M nanomicelles were synthesized and characterized in the study. The molecular interactions between DTX, Cur and copolymer were simulated and the drug release behavior was investigated. The anti-tumor activity and anti-tumor mechanisms of DTX-Cur/M were evaluated and explored in both cells and mice model of xenograft human ovarian cancer. RESULTS: DTX-Cur/M nanomicelles with an average particle size of 37.63 nm were obtained. The drug release experiment showed sustained drug release from DTX-Cur/M nanomicelles. The MTT assay and apoptotic study indicated that DTX-Cur/M exhibited stronger inhibition and pro-apoptotic effects on A2780 cells compared with DTX or Cur alone. In vivo anti-tumor experiment results confirmed that the DTX-Cur/M played the most effective role in anti-ovarian cancer therapy by inhibiting tumor proliferation, suppressing tumor angiogenesis and promoting tumor apoptosis. CONCLUSION: We designed injectable DTX-Cur/M nanomicelles for co-delivery of DTX and Cur agents to the tumor site through systemic administration. The DTX-Cur/M nanomicelle would be a biodegradable, sustainable and powerful anti-tumor drug candidate with great potential in ovarian cancer treatment.

Comparison of dexmedetomidine with chloral hydrate as sedatives for pediatric patients: A systematic review and meta-analysis.

BACKGROUND: Dexmedetomidine (Dex) and chloral hydrate (CH) are the most frequently used sedative agents in pediatric patients. We aimed to systematically review the literature comparing the efficacy and safety of Dex and CH for sedation in pediatric patients. METHODS: Seven electronic databases and 3 clinical trial registry platforms were searched for articles published prior to October 2019. Randomized controlled trials (RCTs) evaluating the efficacy and safety of Dex versus CH for sedation in children were examined by 2 reviewers. The extracted information included the success rate of sedation, sedation latency, sedation duration, sedation recovery time, and adverse events. Moreover, the extracted data included 5 subgroups: the effects of 1, 1.5, 2, 2.5, and 3 µg/kg doses of Dex were compared with the effect of CH on the success rate of sedation. We also formed separate subgroups for different types of adverse events (incidence of vomiting, hypotension, bradycardia, etc). The outcomes were analyzed by Review Manager 5.3 software and are expressed as relative risks (RR) or the mean difference (MD) with the 95% confidence interval (CI). Heterogeneity was assessed with I-squared (I) statistics. RESULTS: A total of 15 RCTs involving 2128 children with Dex versus CH for sedation were included in the meta-analysis. The dose range of Dex ranged from 1 to 3 µg/kg. Compared with CH, the Dex group had a significantly higher success rate of sedation (RR = 1.14, 95% CI [1.05, 1.25], I = 79%, P = .003). Additionally, subgroup analysis revealed that there was no significant difference in the success rate of sedation between the CH group and the 1, 1.5, 2.5, and 3 µg/kg Dex groups; only the 2 µg/kg Dex group had a significantly higher success rate than the CH group (RR = 1.15, 95% CI [1.03, 1.29], I = 80%, P = .02). There was no significant difference in the number of subjects who required 2 doses or the duration of sedation between the CH and Dex groups. Furthermore, compared with the Dex group, the CH group had a significantly longer sedation latency (MD = -3.54, 95% CI [-5.94, -1.15], I = 95%, P = .004), sedation recovery time (MD = -30.08, 95% CI [-46.77, -13.39], I = 99%, P = .0004), and total time from sedative administration to discharge (MD = -12.73, 95% CI [-15.48, -9.97], I = 0%, P < .05), as well as a higher number of adverse events in total (RR = 0.25, 95% CI [0.11, 0.61], I = 89%, P = .002). Moreover, the subgroup analysis of adverse events revealed that CH was associated with higher risks of vomiting (RR = 0.07, 95% CI [0.03, 0.17], I = 0%, P < .0001), crying or resisting (RR = 0.22, 95% CI [0.07, 0.71], I = 60%, P = .01), and cough (RR = 0.15, 95% CI [0.05, 0.44], I = 0%, P = .0006); there was no significant difference in the risk of hypotension, supplemental oxygen, or respiratory events between CH and Dex. However, Dex was associated with a higher risk of bradycardia (RR = 4.08, 95% CI [1.63, 10.21], I = 0%, P = .003). CONCLUSIONS: Dex is an appropriate effective alternative to CH for sedation in pediatrics. However, considering the possibility of bradycardia, Dex should be used with caution.

A comparative evaluation of dexmedetomidine and midazolam in pediatric sedation: A meta-analysis of randomized controlled trials with trial sequential analysis.

BACKGROUND: The present study with trial sequential analysis (TSA) was conducted to evaluate comprehensively the efficacy and safety of dexmedetomidine and midazolam in pediatric sedation, and to investigate whether the outcomes achieved the required information size to draw the conclusions. METHODS: PubMed, Embase, and Cochrane Library were searched from inception to October 2019. All randomized controlled trials used dexmedetomidine and midazolam in pediatric sedation were enrolled. Sedative efficacy, postoperative analgesic effect, and incidence of emergence agitation were considered as the co-primary outcomes. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was applied to rate the quality of evidences. RESULTS: We acquired data from 34 studies involving 2281 pediatric patients. The results indicated that administration of dexmedetomidine was associated with less incidence of emergence agitation (RR = 0.78, with 95% CI [0.65, 0.92]) and more satisfactory sedation at parental separation (RR = 0.31, with 95% CI [0.24, 0.41]) compared to midazolam, and the current sample sizes were sufficient with unnecessary further trials. Two groups did not differ significantly in sedation level at mask induction (RR = 0.86, with 95% CI [0.74, 1.00]). And using of dexmedetomidine was associated with less incidence of postoperative analgesic rescue (RR = 0.57, with 95% CI [0.35, 0.93]), but the number of patients was too few to achieve the required information size and to draw reliable conclusions. Premedication of dexmedetomidine was associated with significant less value of SBP, heart rate, increased incidence of bradycardia, and a lower rate of shivering. And there were no differences about onset of sedation and recovery time between two groups. CONCLUSIONS: Given that more satisfactory sedation at separation from parents and less incidence of emergence agitation, dexmedetomidine is preferred for pediatric sedation. However, compared with midazolam, the superiority of dexmedetomidine in providing adequate sedation at mask induction and postoperative analgesic effects has not yet been defined.

Correction: A fast-dissolving microneedle array loaded with chitosan nanoparticles to evoke systemic immune responses in mice.

Correction for 'A fast-dissolving microneedle array loaded with chitosan nanoparticles to evoke systemic immune responses in mice' by Zhilin Li et al., J. Mater. Chem. B, 2020, DOI: 10.1039/c9tb02061f.

Comparison of effects and safety in providing controlled hypotension during surgery between dexmedetomidine and magnesium sulphate: A meta-analysis of randomized controlled trials.

BACKGROUND: Effectiveness of controlled hypotension has been proven in alleviating intraoperative bleeding. Many recent studies emphasized the efficacy of dexmedetomidine and magnesium in providing controlled hypotension during various surgeries. The present meta-analysis of randomized controlled trials (RCTs) was performed to evaluate comprehensively the effects and safety of these two medications. METHODS: Literature search was performed in four databases from inception to April 2019. All RCTs that used dexmedetomidine and magnesium as hypotensive agents were enrolled. The outcomes contained bleeding condition of surgical site, hemodynamic parameters, duration of surgeries, number of patients requiring opioid/analgesia administration, recovery period, and adverse events emerged during surgeries. RESULTS: Ten studies with 663 patients met with our inclusion criteria. The results indicated that both bleeding score and values of mean arterial pressure (MAP) and heart rate (HR) were significantly lower in patients receiving dexmedetomidine (SMD 1.65 with 95% CI [0.90,2.41], P<0.00001) compared to the patients receiving magnesium. The effect in decreasing the necessity of using opioid/analgesia was affirmative in dexmedetomidine group (29.13% with magnesium vs 10.78% with dexmedetomidine), and the condition was more favorable in magnesium group in reducing recovery period (SMD -1.98 with 95% CI [-4.27,0.30], P = 0.09). Compared with magnesium, using of dexmedetomidine was associated with higher incidence of bradycardia but lower incidence of nausea and vomiting. CONCLUSION: Compared with magnesium, dexmedetomidine is more effective to provide promising surgical field condition, favorable controlled hypotension, and less necessity of opioid or analgesia administration. But long recovery period and high-probability bradycardia should be deliberated.