An oral polyphenol host-guest nanoparticle for targeted therapy of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a global public health challenge that affects millions of people. Current medical treatments for IBD are not fully effective and may cause undesirable side effects on patients. Thus, there is an urgent need for safe, simple, and efficacious strategies to treat IBD in clinical settings. Here, we develop an oral polyphenol nanoparticle (PDT) by assembling dexamethasone sodium phosphate (DSP)-loaded poly-ß-cyclodextrin with tannic acid via host-guest interactions for treating IBD. This one-step assembly process is rapid (within 10 s), reproducible, and free of harmful chemical agents, which can facilitate its clinical translation. PDT is negatively charged due to the three components, which enable it to specifically target the positively charged inflamed colonic mucosa through electrostatic attraction, thus localizing the drug at the inflamed site to reduce systemic exposure and side effects. Furthermore, PDT exhibits a strong reactive oxygen species (ROS)-scavenging ability derived from the tannic acid component, which can alleviate ROS-mediated inflammatory responses and ameliorate IBD symptoms. Compared with free DSP, PDT demonstrates sustained DSP release behavior in vitro and in vivo, as well as enhanced therapeutic efficacy in a colitis mouse model. These results suggest that PDT might be a potential therapeutic agent for the treatment of IBD. Moreover, this facile polyphenol host-guest assembly strategy may provide a promising drug-delivery platform for treating various diseases STATEMENT OF SIGNIFICANCE: To develop safe and effective treatments for inflammatory bowel disease (IBD), we have designed an oral polyphenol nanoparticle (PDT) using the host-guest assembly of dexamethasone sodium phosphate (DSP)-loaded poly-ß-cyclodextrin with tannic acid. Through in vitro and in vivo experiments, PDT has demonstrated remarkable inflammation-targeting, ROS-scavenging, and anti-inflammatory properties, along with sustained release of DSP. Moreover, in an IBD mouse model, PDT has shown significantly improved therapeutic efficacy compared to free DSP. The host-guest assembly strategy employed for PDT is noteworthy for its rapidity, reproducibility, and safety due to the absence of harmful chemicals, holding great promise for designing a diverse range of nanomedicines customized for treating various diseases.

Posterior unilateral small fenestration of lamina combined with a custom-made Y-shaped fracture reduction device for the treatment of severe thoracolumbar burst fracture: a prospective comparative study.

BACKGROUND: The purpose was to evaluate the clinical effect of a custom-made Y-shaped fracture fragment reduction device and to assist in posterior unilateral small fenestration of lamina to reduce the fracture fragments. METHODS: In this study, 40 patients were assigned to one of two groups: the traditional reduction device group (TRG) or the Y-shaped reduction device group (YRG). All patients underwent posterior unilateral small fenestration of the lamina and direct decompression through the spinal canal. And the operation time (OT), intraoperative bleeding (IB), preoperative, postoperative, and final follow-up data on the spinal stenosis rate (SSR), Cobb angle, the anterior compression ratio of injured vertebrae (ACRIV), and ASIA neurological function grade were compared between the two groups. RESULT: There were no complications, including vascular and nerve injury, serious postoperative infection, internal fixation fracture, or loosening, for any of the patients. And the average follow-up time of the two groups was 14.2 months, the average operation time of the TRG was 236.6 min, and the average intraoperative blood loss was 357.20 ml. Moreover, the average operation time of the YRG was 190.6 min, and the average intraoperative blood loss was 241.5 ml. There were significant differences between the two groups in terms of operation duration and intraoperative blood loss. The YRG's was lower than that of the TRG. Besides, there was no difference in SSR, Cobb angle, ACRIV, or neurological recovery between the two groups before or immediately after the operation or at the last follow-up. CONCLUSION: The Y-shaped fracture reduction device can reduce the fracture fragments and the OT and IB stably; it also has satisfactory postoperative curative effects and clinical utility.

Safety and efficacy of dexmedetomidine hydrochloride combined with midazolam in fiberoptic bronchoscopy in children: a prospective randomized controlled study. / ç›é ¸å³ç¾Žæ‰˜å’ªå®šè”åˆå’ªè¾¾å”‘ä»‘åœ¨å„¿ç«¥çº¤ç»´æ”¯æ°”ç®¡é•œæ£€æŸ¥ä¸­çš„å®‰å ¨æ€§å’Œæœ‰æ•ˆæ€§­­å‰çž»æ€§éšæœºå¯¹ç §ç ”究.

OBJECTIVES: To study the safety and efficacy of dexmedetomidine hydrochloride combined with midazolam in fiberoptic bronchoscopy in children. METHODS: A total of 118 children who planned to undergo fiberoptic bronchoscopy from September 2018 to February 2021 were enrolled. They were divided into a control group (n=60) and an observation group (n=58) using a random number table. The observation group received intravenous pumping of dexmedetomidine hydrochloride (2 µg/mL) at 1 µg/kg and then intravenous injection of midazolam at 0.05 mg/kg, followed by dexmedetomidine hydrochloride pumped intravenously at 0.5-0.7 µg/(kg·h) 10 minutes later to maintain anesthesia. The control group was given intravenous pumping of propofol at 2 mg/kg and then intravenous injection of midazolam at 0.05 mg/kg, followed by propofol pumped intravenously at 4-6 mg/(kg·h) 10 minutes later to maintain anesthesia. Fiberoptic bronchoscopy was performed after the children were unconscious. Heart rate (HR), respiratory rate, blood oxygen saturation, and mean arterial pressure (MAP) were recorded before inserting the bronchoscope (T0), at the time of inserting the bronchoscope (T1), when the bronchoscope reached the glottis (T2), when the bronchoscope reached the carina (T3), and when the bronchoscope entered the bronchus (T4). The intraoperative peak airway pressure (Ppeak), examination time, degree of sedation, extent of amnesia, incidence of adverse reactions, postoperative awakening time, and postoperative agitation score were also recorded. RESULTS: Compared with the control group, the observation group had significantly decreased MAP at T1 to T4 and HR at T1 to T3 (P<0.05). Compared with that at T0, MAP was significantly increased at T1 to T4 in the control group and at T3 in the observation group (P<0.05). HR was significantly higher at T1 to T3 than at T0 (P<0.05). Compared with the control group, the observation group showed significantly lower intraoperative Ppeak value, incidence of intraoperative adverse reactions, and postoperative agitation score, significantly shorter examination time, and better effects of amnesia and anesthesia (P<0.05). There was no significant difference in the degree of intraoperative sedation and postoperative awakening time between the two groups (P>0.05). CONCLUSIONS: Dexmedetomidine hydrochloride combined with midazolam is a safe and effective way to administer general anesthesia for fiberoptic bronchoscopy in children, which can ensure stable vital signs during examination, reduce intraoperative adverse reactions and postoperative agitation, shorten examination time, and increase amnesic effect.

The nine ADAMs family members serve as potential biomarkers for immune infiltration in pancreatic adenocarcinoma.

BACKGROUND: The functional significance of ADAMs family members in the immune infiltration of pancreatic adenocarcinoma (PAAD) awaits elucidation. METHODS: ADAMs family members with significant expression were identified among differentially expressed genes of PAAD based on The Cancer Genome Atlas (TCGA) database followed by a verification based on the Oncomine database. The correlation of ADAMs in PAAD was estimated with the Spearman's rho value. The pathway enrichment of ADAMs was performed by STRING and GSEALite, respectively. The protein-protein interaction and Gene Ontology analyses of ADAMs and their similar genes were exanimated in STRING and visualized by Cytoscape. Subsequently, the Box-Whisker plot was used to show a correlation between ADAMs and different tumor grade 1/2/3/4 with Student's t-test. TIMER was applied to estimate a correlation of ADAMs expressions with immune infiltrates and immune checkpoint blockade (ICB) immunotherapy-related molecules. Furthermore, the effect of copy number variation (CNV) of ADAMs genes was assessed on the immune infiltration levels. RESULT: ADAM8/9/10/12/15/19/28/TS2/TS12 were over-expressed in PAAD. Most of the nine ADAMs had a significant correlation. ADAM8/12/15/19 expression was remarkably increased in the comparison between grade 1 and grade 2/3 of PAAD. ADAM8/9/10/12/19/28/TS2/TS12 had a positive correlation with almost five immune infiltrates. ADAM12/19/TS2/TS12 dramatically related with ICB immunotherapy-related molecules. CNV of ADAMs genes potentially influenced the immune infiltration levels. CONCLUSION: Knowledge of the expression level of the ADAMs family could provide a reasonable strategy for improved immunotherapies to PAAD.

The potential drug for treatment in pancreatic adenocarcinoma: a bioinformatical study based on distinct drug databases.

BACKGROUND: The prediction of drug-target interaction from chemical and biological data can advance our search for potential drug, contributing to a therapeutic strategy for pancreatic adenocarcinoma (PAAD). We aim to identify hub genes of PAAD and search for potential drugs from distinct databases. The docking simulation is adopted to validate our findings from computable perspective. METHODS: Differently expressed genes (DEGs) of PAAD were performed based on TCGA. With two Cytoscape plugins of CentiScaPe and MCODE, hub genes were analyzed and visualized by STRING analysis of Protein-protein Interaction (PPI). The hub genes were further selected with significant prognostic values. In addition, we examined the correlation between hub genes and immune infiltration in PAAD. Subsequently, we searched for the hub gene-targeted drugs in Connectivity map (Cmap) and cBioportal, which provided a large body of candidate drugs. The hub gene, which was covered in the above two databases, was estimated in Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Herbal Ingredients' Targets (HIT) database, which collected natural herbs and related ingredients. After obtaining molecular structures, the potential ingredient from TCMSP was applied for a docking simulation. We finalized a network connectivity of ingredient and its targets. RESULTS: A total of 2616 DEGs of PAAD were identified, then we further determined and visualized 24 hub genes by a connectivity analysis of PPI. Based on prognostic value, we identified 5 hub genes including AURKA (p = 0.0059), CCNA2 (p = 0.0047), CXCL10 (p = 0.0044), ADAM10 (p = 0.00043), and BUB1 (p = 0.0033). We then estimated tumor immune correlation of these 5 hub genes, because the immune effector process was one major result of GO analysis. Subsequently, we continued to search for candidate drugs from Cmap and cBioportal database. BUB1, not covered in the above two databases, was estimated in TCMSP and HIT databases. Our results revealed that genistein was a potential drug of BUB1. Next, we generated two docking modes to validate drug-target interaction based on their 3D structures. We eventually constructed a network connectivity of BUB1 and its targets. CONCLUSIONS: All 5 hub genes that predicted poor prognosis had their potential drugs, especially our findings showed that genistein was predicted to target BUB1 based on TCMSP and docking simulation. This study provided a reasonable approach to extensively retrieve and initially validate putative therapeutic agents for PAAD. In future, these drug-target results should be investigated with solid data from practical experiments.

Clinical efficacy and safety of synthetic thymic peptides with chemotherapy for non-small cell lung cancer in China: A systematic review and meta-analysis of 27 randomized controlled trials following the PRISMA guidelines.

BACKGROUND: Synthetic thymic peptides (sTPs) are used with chemotherapy to treat non-small cell lung cancer (NSCLC). In this study, we have performed a systematic review and meta-analysis of published trials to confirm the clinical efficacy and safety of sTPs, and determine the optimal types, usages, and sTP/chemotherapy combinations to produce the desired responses. MATERIALS AND METHODS: We collected all studies regarding combined sTP therapy and chemotherapy for NSCLC from the Chinese and English databases (up to October 2018). Bias risk was evaluated for each. Data for meta-analysis was extracted using a pre-designed form. Evidence quality was rated using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: We included 27 randomized controlled trials containing 1925 patients, most with unclear bias risk. Combining sTPs with chemotherapy significantly increased the objective response rate [1.28, (1.13 to 1.45)], disease control rate [1.10, (1.01 to 1.18)], quality of life (QOL) [2.05, (1.62, 2.60)], and 1-year overall survival rate [1.43, (1.15 to 1.78)], with decreased risks of neutropenia, thrombocytopenia, and gastrointestinal reactions. Optimal conditions included treatment in combination with gemcitabine or navelbine and cisplatin, twice a week, with one 3-week cycle. In these conditions, thymosin α1 improved both antitumor immunity and tumor response. Most results had good robustness, and their quality ranged from moderate to very low. CONCLUSIONS: The results suggest that treatment with sTPs, especially thymosin α1, and concomitant chemotherapy is beneficial to the patient, and provide evidence for optimal treatment regimens that may increase patient QOL and survival.

Molecular characterization of the viral structural gene of the first dengue virus type 1 outbreak in Xishuangbanna: A border area of China, Burma and Laos.

BACKGROUND: Xishuangbanna, a border area of China, Burma and Laos, had its first major DENV-1 outbreak in 2017. This study aims to explore the genetic characterization, potential source and evolution of the viruses in outbreak. METHODS: The structural protein C/prM/E genes of viruses isolated from local residents or Burmese travelers were sequenced followed by mutation, phylogenetic, homologous recombination, molecular clock and demographic reconstruction analysis. RESULTS: Phylogenetic analysis revealed that all of the strains were classified as three cluster of DENV-1. Cluster 1, 2 and 3 were most similar to China Guangzhou 2011, China Hubei 2014 and Laos 2008 strain, respectively. Among 236 base mutations, 31 caused nonsynonymous mutations when compared with the DENV-1SS. No homologous recombination signal was discovered. The structural protein of these strains had similar three-dimensional structure. Only site 434 showed differences among five predicted protein binding sites. Molecular clock phylogenetic and demographic reconstruction analysis showed that DENV-1 became highly diversified in 1972 followed by a slightly decreased period until 2017. CONCLUSIONS: Dengue isolated strains show diversification between Burma and China. Amino acid substitution (I440T) may lead to weakened virulence of the epidemic strains. DENV-1 became highly diversified in 1972 followed by a slightly decreased period.

A comparative proteomic study identified calreticulin and prohibitin up-regulated in adrenocortical carcinomas.

BACKGROUND: Identifying novel tumor biomarkers to develop more effective diagnostic and therapeutic strategies for patients with ACC is urgently needed. The aim of the study was to compare the proteomic profiles between adrenocortical carcinomas (ACC) and normal adrenocortical tissues in order to identify novel potential biomarkers for ACC. METHODS: The protein samples from 12 ACC tissues and their paired adjacent normal adrenocortical tissues were profiled with two-dimensional electrophoresis; and differentially expressed proteins were identified by mass spectrometry. Expression patterns of three differently expressed proteins calreticulin, prohibitin and HSP60 in ACC, adrenocortical adenomas (ACA) and normal adrenocortical tissues were further validated by immunohistochemistry. RESULTS: In our proteomic study, we identified 20 up-regulated and 9 down-regulated proteins in ACC tissues compared with paired normal controls. Most of the up-regulated proteins were focused in protein binding and oxidoreductase activity in Gene Ontology (GO) molecular function classification. By immunohistochemistry, two biomarkers calreticulin and prohibitin were validated to be overexpressed in ACC compared with adrenocortical adenomas (ACA) and normal tissues, but also calreticulin overexpression was significantly associated with tumor stages of ACC. CONCLUSION: For the first time, calreticulin and prohibitin were identified to be novel candidate biomarkers for ACC, and their roles during ACC carcinogenesis and clinical significance deserves further investigation. VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1897372598927465.

Cell cycle dependent telomere regulation by telomerase in human bone marrow mesenchymal stem cells.

Human bone marrow mesenchymal stem cells (hMSCs) are a promising source for clinical stem cell transplantation. However, telomere regulation mechanisms, as one of the possible major mechanisms by which hMSCs sustain their stem cell characteristics, remain unknown. We isolated hMSCs by plastic adhesion and characterized these cells by morphology, immune phenotype and differentiation capacity. Telomerase was found negative in hMSCs, but slightly up-regulated in hMSC-derived adipocytes by the Telomeric Repeat Amplification Protocol (TRAP) assay. Moreover, hMSCs lack the alternative lengthening of telomeres (ALT) mechanism, because the hallmarks of ALT, such as very long and heterogeneous telomeres, extra-chromosome telomere repeat DNA (ECTR), and ALT-associated promyelocytic leukemia bodies (APBs), were not evident. However, when hMSCs were arrested in S phase with a combination of serum deprivation and aphidicolin, previously undetectable telomerase activity became predominantly positive. Meanwhile, the expression level of hTERT protein and mRNA increased, paralleled with the appearance of a large cohort of synchronized hMSCs at S phase. These findings provide a profile of telomere regulation by cell cycle dependent expression of telomerase in hMSCs and may lead to a better understanding of the stem cell nature of these cells.