Dual roles of HK3 in regulating the network between tumor cells and tumor-associated macrophages in neuroblastoma.

Neuroblastoma (NB) is the most common and deadliest extracranial solid tumor in children. Targeting tumor-associated macrophages (TAMs) is a strategy for attenuating tumor-promoting states. The crosstalk between cancer cells and TAMs plays a pivotal role in mediating tumor progression in NB. The overexpression of Hexokinase-3 (HK3), a pivotal enzyme in glucose metabolism, has been associated with poor prognosis in NB patients. Furthermore, it correlates with the infiltration of M2-like macrophages within NB tumors, indicating its significant involvement in tumor progression. Therefore, HK3 not only directly regulates the malignant biological behaviors of tumor cells, such as proliferation, migration, and invasion, but also recruits and polarizes M2-like macrophages through the PI3K/AKT-CXCL14 axis in neuroblastoma. The secretion of lactate and histone lactylation alterations within tumor cells accompanies this interaction. Additionally, elevated expression of HK3 in M2-TAMs was found at the same time. Modulating HK3 within M2-TAMs alters the biological behavior of tumor cells, as demonstrated by our in vitro studies. This study highlights the pivotal role of HK3 in the progression of NB malignancy and its intricate regulatory network with M2-TAMs. It establishes HK3 as a promising dual-functional biomarker and therapeutic target in combating neuroblastoma.

Integrative analysis with machine learning identifies diagnostic and prognostic signatures in neuroblastoma based on differentially DNA methylated enhancers between INSS stage 4 and 4S neuroblastoma.

INTRODUCTION: Accumulating evidence demonstrates that aberrant methylation of enhancers is crucial in gene expression profiles across several cancers. However, the latent effect of differently expressed enhancers between INSS stage 4S and 4 neuroblastoma (NB) remains elusive. METHODS: We utilized the transcriptome and methylation data of stage 4S and 4 NB patients to perform Enhancer Linking by Methylation/Expression Relationships (ELMER) analysis, discovering a differently expressed motif within 67 enhancers between stage 4S and 4 NB. Harnessing the 67 motif genes, we established the INSS stage related signature (ISRS) by amalgamating 12 and 10 distinct machine learning (ML) algorithms across 113 and 101 ML combinations to precisely diagnose stage 4 NB among all NB patients and to predict the prognosis of NB patients. Based on risk scores calculated by prognostic ISRS, patients were categorized into high and low-risk groups according to median risk score. We conducted comprehensive comparisons between two risk groups, in terms of clinical applications, immune microenvironment, somatic mutations, immunotherapy, chemotherapy and single-cell analysis. Ultimately, we empirically validated the differential expressions of two ISRS model genes, CAMTA2 and FOXD1, through immunochemistry staining. RESULTS: Through leave-one-out cross-validation, in both feature selection and model construction, we selected the random forest algorithm to diagnose stage 4 NB, and Enet algorithm to develop prognostic ISRS, due to their highest average C-index across five NB cohorts. After validations, the ISRS demonstrated a stable predictive capability, outperforming the previously published NB signatures and several clinic variables. We stratified NB patients into high and low-risk group based on median risk score, which showed the low-risk group with a superior survival outcome, an abundant immune infiltration, a decreased mutation landscape, and an enhanced sensitivity to immunotherapy. Single-cell analysis between two risk groups reveals biologically cellular variations underlying ISRS. Finally, we verified the significantly higher protein levels of CAMTA2 and FOXD1 in stage 4S NB, as well as their protective prognosis value in NB. CONCLUSION: Based on multi-omics data and ML algorithms, we successfully developed the ISRS to enable accurate diagnosis and prognostic stratification in NB, which shed light on molecular mechanisms of spontaneous regression and clinical utilization of ISRS.

Meta-analysis of efficacy, safety, stability and predictability of Small Incision Lenticule Extraction (SMILE) for myopia.

In order to investigate the postoperative efficacy, safety, stability, and predictability of SMILE surgery as a treatment for myopia, a comprehensive search was conducted in April 2023 across prominent databases, including PubMed, EMBASE, Web of Science, and Cochrane Library. The search aimed to select relevant studies of randomized controlled trials (RCTs) comparing clinical outcomes between SMILE and other corneal refractive surgeries for myopia. Upon conducting the initial search, a total of 324 records were retrieved from the aforementioned databases. These records were subjected to a meticulous selection process, adhering to predetermined inclusion criteria, resulting in 17 studies being ultimately included for analysis. By pooling the results of these studies, the comparison between SMILE surgery and alternative corneal refractive surgeries demonstrated similar outcomes in terms of efficacy, safety, stability, predictability, and higher-order aberrations (HOAs) concerning the correction of myopia. Furthermore, it was observed that the SMILE procedure exhibited a lesser impact on corneal sensation and corneal nerve density compared to other corneal refractive surgeries. Based on these findings, SMILE surgery may be considered as a treatment option with a slight superiority over conventional corneal surgery for myopia.

Physicochemical stability and antibacterial mechanism of theabrownins prepared from tea polyphenols catalyzed by polyphenol oxidase and peroxidase.

Tea polyphenols were used as substrates and oxidized successively by polyphenol oxidase and peroxidase to prepare theabrownins (TBs-dE). The conversion rate of catechins to TBs-dE was 90.91%. The ultraviolet and infrared spectroscopic properties and zeta potential of TBs-dE were characterized. TBs-dE is more stable at pH 5.0-7.0, about 25 °C or in dark environment. Ultraviolet light and sunlight can deepen its color due to the further oxidative polymerization. Mg2+, Cu2+, and Al3+ had a significant effect on the stability of TBs-dE. The inhibitory rates of TBs-dE (1 mg/mL) against Staphylococcus aureus and Escherichia coli DH5α were 51.45% and 45.05%, respectively. After TBs-dE treatment, the cell morphology of both bacteria changed, some cell walls were blurred, and the cytoplasmic content leaked. The research results can provide theoretical support for the industrialization of theabrownins.

Doxycycline hydrochloride inhibits the progress of malignant rhabdoid tumor of kidney by targeting MMP17 and MMP1 through PI3K-Akt signaling pathway.

OBJECTIVE: To identify therapeutic targets for malignant rhabdoid tumors of kidney (MRTK) and to investigate the effects and underlying mechanism of doxycycline hydrochloride on these tumors. METHODS: Gene expression and clinical data of MRTK were retrieved from the TARGET database. Differentially expressed genes (DEGs) and prognostic-related genes (PRGs) were selected through a combination of statistical analyses. The functional roles of MMP17 and MMP1 were elucidated through RNA overexpression and intervention experiments. Furthermore, in vitro and in vivo studies provided evidence for the inhibitory effect of doxycycline hydrochloride on MRTK. Additionally, transcriptome sequencing was employed to investigate the underlying molecular mechanisms. RESULTS: 3507 DEGs and 690 PRGs in MRTK were identified. Among these, we focused on 41 highly expressed genes associated with poor prognosis and revealed their involvement in extracellular matrix regulatory pathways. Notably, MMP17 and MMP1 stood out as particularly influential genes. When these genes were knocked out, a significant inhibition of proliferation, invasion and migration was observed in G401 cells. Furthermore, our study explored the impact of the matrix metalloproteinase inhibitor, doxycycline hydrochloride, on the malignant progression of G401 both in vitro and in vivo. Combined with sequencing data, the results indicated that doxycycline hydrochloride effectively inhibited MRTK progression, due to its ability to suppress the expression of MMP17 and MMP1 through the PI3K-Akt signaling pathway. CONCLUSION: Doxycycline hydrochloride inhibits the expression of MMP17 and MMP1 through the PI3K-Akt signaling pathway, thereby inhibiting the malignant progression of MRTK in vivo and in vitro.

Safety of photodynamic therapy combined with surgical excision in patients with actinic keratosis and risk factors for secondary cutaneous squamous cell carcinoma.

OBJECTIVE: To investigate the efficacy of photodynamic therapy combined with surgical excision on the prognosis of patients with actinic keratosis (AK) and to analyze the risk factors for secondary cutaneous squamous cell carcinoma (cSCC). METHODS: Clinical data of 114 patients with AK treated at the West China Hospital from March 2014 to November 2018 were enrolled to this retrospective analysis. Among them 55 patients who underwent surgical resection alone were the control group (CG) and the other 59 who received photodynamic therapy combined with surgical resection were in the research group (RG). The treatment efficacy, lesion area, quality of life, incidence of adverse effects, and incidence of secondary sSCC in 3 years were compared, and the risk factors for sSCC were analyzed by multivariate logistics analysis. RESULTS: The treatment efficacy of the RG was dramatically higher than that of the CG (P<0.05), and there was no obvious difference in the incidence of adverse reactions between the two groups (P>0.05). The lesion area and dermatology life quality index of the RG were dramatically lower than those of the CG after treatment (P<0.05), and the 3-year incidence of secondary cSCC in the RG was not statistically different from that of the OG (P>0.05). A greater number of lesion sites, a family history of tumor, and a history of skin disease were independent risk factors for secondary cSCC. CONCLUSION: Photodynamic therapy combined with surgical excision has better therapeutic efficacy in AK with a high safety.

BKM120 inhibits malignant rhabdoid tumor of the kidney through induction of apoptosis and G0/G1 phase arrest.

Malignant rhabdoid tumor of the kidney (MRTK) has an inferior prognosis and is insensitive to radiotherapy and chemotherapy. Search for novel, potent medicinal agents is urgent. Herein, data on the gene expression and clinical characteristics of malignant rhabdoid tumors (MRT) were retrieved from the TARGET database. Prognosis-related genes were identified by differential analysis and one-way cox regression analysis, and prognosis-related signalling pathways were identified by enrichment analysis. The prognosis-related genes were imported into the Connectivity Map database for query, and BKM120 was predicted and screened as a potential therapeutic agent for MRTK. A combination of high-throughput RNA sequencing and Western blot verified that the PI3K/Akt signaling pathway is associated with MRTK prognosis and is overactivated in MRTK. Our results outlined that BKM120 inhibited the proliferation, migration, and invasion ability of G401 cells and induced apoptosis and cell cycle G0/G1 phase arrest. In vivo, BKM120 inhibited tumor growth and had no significant toxic side effects. Western blot and immunofluorescence results confirmed that BKM120 could reduce the expression of PI3K and p-AKT, critical proteins of the PI3K/Akt signaling pathway. BKM120 inhibits MRTK by inhibiting PI3K/Akt signalling pathway to induce apoptosis and cell cycle G0/G1 phase arrest, which is anticipated to give the clinical treatment of MRTK a new direction.

Selectivity of osilodrostat as an inhibitor of human steroidogenic cytochromes P450.

Osilodrostat (LCI699) is a potent inhibitor of the human steroidogenic cytochromes P450 11ß-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2). LCI699 is FDA-approved for the treatment of Cushing disease, which is characterized by chronic overproduction of cortisol. While phase II and III clinical studies have proven the clinical efficacy and tolerability of LCI699 for treating Cushing disease, few studies have attempted to fully assess the effects of LCI699 on adrenal steroidogenesis. To this end, we first comprehensively analyzed LCI699-mediated inhibition of steroid synthesis in the NCI-H295R human adrenocortical cancer cell line. We then studied LCI699 inhibition using HEK-293 or V79 cells stably expressing individual human steroidogenic P450 enzymes. Our studies using intact cells confirm the potent inhibition of CYP11B1 and CYP11B2 with negligible inhibition of 17-hydroxylase/17,20-lyase (CYP17A1) and 21-hydroxylase (CYP21A2). Furthermore, partial inhibition of the cholesterol side-chain cleavage enzyme (CYP11A1) was observed. To calculate the dissociation constant (Kd) of LCI699 with the adrenal mitochondrial P450 enzymes, we successfully incorporated P450s into lipid nanodiscs and carried out spectrophotometric equilibrium and competition binding assays. Our binding experiments confirm the high affinity of LCI699 to CYP11B1 and CYP11B2 (Kd ≈ 1 nM or less) and much weaker binding for CYP11A1 (Kd = 18.8 µM). Our results confirm the selectivity of LCI699 for CYP11B1 and CYP11B2 and demonstrate partial inhibition of CYP11A1 but not CYP17A1 and CYP21A2.

BI-D1870 Induces Mitotic Dysfunction and Apoptosis in Neuroblastoma by Regulating the PI3K-Akt-mTORC1 Signal Axis.

Introduction: Neuroblastoma (NB) is one of the most common extracranial solid malignant tumors in children. The 5-year survival rate of high-risk or refractory NB is less than 50%. Therefore, developing new effective therapeutics for NB remains an urgent challenge. Materials and Methods: Based on the NB dataset TARGET-NBL in the TCGA database, the prognosis-related genes were analyzed using univariate cox regression (p < 0.01). The protein network interaction of prognostic genes was analyzed using STRING to obtain 150 hub genes with HR > 1 and 150 hub genes with HR < 1. The Connectivity Map database was used to predict a therapeutic drug: BI-D1870, a ribosomal S6 kinase inhibitor. The inhibitory effect of BI-D1870 on NB was investigated through in vivo and in vitro experiments, and its inhibitory mechanism was explored. Results: Both the in vivo and in vitro experiments showed that BI-D1870 could inhibit tumor proliferation and induce tumor apoptosis. Furthermore, we proved that BI-D1870 caused G2/M phase arrest and mitosis damage in cells. RNA-seq of cells showed that BI-D1870 may inhibit the growth of NB by inhibiting the PI3K-Akt-mTOR axis. Western blot and immunofluorescence testing showed that BI-D1870 inhibited the PI3K-Akt-mTORC1 signal pathway to regulate the phosphorylation of RPS6 and 4E BP1 proteins, inhibit protein translation, and inhibit microtubule formation, thus preventing mitotic proliferation and inducing apoptosis. Conclusions: This study provides strong support that BI-D1870 may be a potential adjuvant therapy for NB.

Graphene oxide as a multi-functional additive for compatilizer, enhancer, and barrier in ethylene vinyl alcohol copolymer/aramid pulp composites.

To improve the thermal, mechanical, and barrier properties of ethylene vinyl alcohol copolymer (EVOH)/aramid pulp (AP), graphene oxide (GO) was used as a compatilizer, enhancer, and barrier to fabricate EVOH-based composites. The results showed that graphene oxide serves as an ideal compatilizer to reinforce the interfacial action between the EVOH matrix and aramid pulp. The EVOH/AP/GO composite presented the best combination of thermal stability, tensile strength, oxygen barrier, and heat deformation temperature by adding only 1 wt% graphene oxide, compared to those of pure EVOH. Moreover, both scanning electron microscopy (SEM) and polarized optical microscopy (POM) photographs demonstrated that the aramid pulp dispersed homogeneously into the EVOH resin with the addition of 1 wt% graphene oxide. Our work provides a novel and facile way for producing a prominent EVOH-based composite, which can be potentially used in packaging fields in the future.

Identification of hub genes and pathways of ferroptosis in Fusarium keratitis by bioinformatics methods.

Background: Fungal keratitis is a common blinding eye disease, and Fusarium is one of the main species that cause fungal keratitis. As is well known, oxidative stress plays an important role in Fusarium keratitis and it is also a significant initiating factor of ferroptosis. But the relationship between Fusarium keratitis and ferroptosis is currently unclear. This study aimed to speculate and validate potential ferroptosis-related genes in Fusarium keratitis using bioinformatics analysis, which provided ideas for further research on its specific mechanism and new targets for its treatment. Methods: The microarray expression profiling dataset (GSE58291) came from Gene Expression Omnibus (GEO). The differentially expressed genes (DEGs) were obtained by the limma package of the R software. The DEGs were performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Then, the DEGs were intersected with the genes in the ferroptosis database. The top 5 hub genes were obtained by the protein-protein interaction (PPI) network analysis and the cytoHubba plug-in of Cytoscape software. The hub genes were subjected to GSEA analysis. Then we analyzed the immune infiltration of the samples by CIBERSORT and ssGSEA algorithm. Finally, we validated the mRNA of hub genes by qPCR. Results: A total of 1,368 DEGs were identified and 26 ferroptosis-related DEGs were obtained. At the same time, ferroptosis-related pathways were enriched by GO and KEGG using DEGs. HMOX1, CYBB, GPX2, ALOX5 and SRC were obtained by the PPI network analysis and the cytoHubba plug-in of Cytoscape software. The iron metabolism and immune response related pathways were enriched using GSEA. They included hematopoietic cell lineage, lysosome and FC gamma R mediated phagocytosis. T cells follicular helper, monocytes, macrophages and mast cells might play an important role in Fusarium keratitis using analysis of immune infiltration. Finally, qPCR confirmed that the expression of HMOX1, CYBB, ALOX5 mRNA in the DON group was significantly elevated, while the expression of GPX2 were significantly decreased. Conclusions: Ferroptosis may play an important role in Fusarium keratitis. HMOX1, CYBB, ALOX5 and GPX2 may be key ferroptosis-related genes in the pathogenesis of Fusarium keratitis.

Cinnamate-Functionalized Cellulose Nanocrystals as Interfacial Layers for Efficient and Stable Perovskite Solar Cells.

The poor interfacial contact and imperfections between the charge transport layer and perovskite film often result in carrier recombination, inefficient charge collection, and inferior stability of perovskite solar cells (PSCs). Therefore, interface engineering is quite crucial to achieve high-performance and stable PSCs. Here, we introduced a cinnamate-functionalized cellulose nanocrystals (Cin-CNCs) interfacial layer between SnO2 and perovskite active layer for enhancing carrier transport ability and crystal growth of perovskite, meanwhile endowing additional functional of long-term device stability against ultraviolet light. The enhancement of interfacial contact between SnO2 and perovskite layer and cascade energy alignment are realized, which is beneficial for obtaining the desirable perovskite film morphology, passivating the interfacial defects, and restraining charge recombination in the SnO2/perovskite interface. An efficiency as high as 23.18%, with an open-circuit voltage of 1.15 V and a significantly enhanced fill factor of 81.07%, is achieved. In addition, the unencapsulated PSCs maintain 75% of the initial PCE after aging for over 1500 h under 25 °C and 30% relative humidity, with better light-soaking stability. These results exhibit the vital role for Cin-CNCs in interfacial modification and constructing high-performance perovskite solar cells.

Comparison of Caregiver- and Child-Reported Quality of Life in Children With Sleep-Disordered Breathing.

OBJECTIVE: Caregivers frequently report poor quality of life (QOL) in children with sleep-disordered breathing (SDB). Our objective is to assess the correlation between caregiver- and child-reported QOL in children with mild SDB and identify factors associated with differences between caregiver and child report. STUDY DESIGN: Analysis of baseline data from a multi-institutional randomized trial SETTING: Pediatric Adenotonsillectomy Trial for Snoring, where children with mild SDB (obstructive apnea-hypopnea index <3) were randomized to observation or adenotonsillectomy. METHODS: The Pediatric Quality of Life Inventory (PedsQL) assessed baseline global QOL in participating children 5 to 12 years old and their caregivers. Caregiver and child scores were compared. Multivariable regression assessed whether clinical factors were associated with differences between caregiver and child report. RESULTS: PedsQL scores were available for 309 families (mean child age, 7.0 years). The mean caregiver-reported PedsQL score was higher at 75.2 (indicating better QOL) than the mean child-reported score of 67.9 (P < .001). The agreement between caregiver and child total PedsQL scores was poor, with intraclass correlation coefficients of 0.03 (95% CI, -0.09 to 0.15) for children 5 to 7 years old and 0.21 (95% CI, 0.03-0.38) for children 8 to 12 years old. Higher child age and health literacy were associated with closer agreement between caregiver and child report. CONCLUSION: Caregiver- and child-reported global QOL in children with SDB was weakly correlated, more so for young children. In pediatric SDB, child-perceived QOL may be poorer than that reported by caregivers. Further research is needed to assess whether similar trends exist for disease-specific QOL metrics.

Doxycycline Hydrochloride Regulates Cytoskeletal Rearrangement and Epithelial-To-Mesenchymal Transition in Malignant Rhabdoid Tumour of the Kidney.

Objective: As a highly malignant tumour, malignant rhabdoid tumours of the kidney (MRTK) are prone to metastasis and invasion, while tumour metastasis and invasion are inseparable from matrix metalloproteinases (MMPs) and epithelial-mesenchymal transformation (EMT). Moreover, the key to EMT is remodelling of the cytoskeleton. Therefore, our study is aimed at investigating whether doxycycline hydrochloride (DCH), an inhibitor of MMPs, could reverse EMT in MRTK to exert an antitumour effect by regulating MMPs and the cytoskeleton. Methods: The existence of EMT in MRTK cells was verified by bioinformatics analysis, immunofluorescence, and western blotting (WB). In vitro, the proliferation, migration, and invasion abilities of G401 cells were examined by Cell Counting Kit-8 (CCK-8), scratch, and Transwell assays, respectively. The effect of DCH on tumour growth in tumour-bearing mice was explored in in vivo experiments, and the expression of MMP2 and MMP9 and EMT correlation indexes was measured by immunofluorescence and WB, and the changes in cytoskeletal F-actin and ß-tubulin were measured by fluorescence. Results: The altered extracellular matrix (ECM) composition, EMT, and high expression of MMP2 and MMP9 existed in MRTK. DCH inhibited the proliferation, migration, and invasion of G401 cells in vitro. In vivo, DCH inhibited tumour growth in mice, downregulated the expression of MMP2 and MMP9, and partially reversed EMT. Alternatively, DCH resulted in cytoskeletal rearrangements of G401 cells. Conclusions: DCH, as an MMP inhibitor, is used for the first time in MRTK research, showing good antitumour effects by reversing EMT and potentially providing new therapeutic measures for MRTK treatment.

Exosome mimetics derived from bone marrow mesenchymal stem cells deliver doxorubicin to osteosarcoma in vitro and in vivo.

Osteosarcoma is a bone tumor with a high incidence in children and adolescents. Chemotherapy for osteosarcoma is limited, and effective targeted drugs are urgently needed to treat osteosarcoma. Exosomes as a natural nano drug delivery platform have been widely studied and proven to have good drug delivery performance. However, the low production of exosomes hinders its development as a carrier. Exosome mimetics (EMs) as an alternative product of exosomes solve the problem of low production of exosomes and maintain the good performance of exosomes as carriers. In this study, bone marrow mesenchymal stem cells (BMSCs) were sequentially extruded to generate EMs to encapsulate doxorubicin (EM-Dox) to treat osteosarcoma. The results showed that we successfully prepared EMs of BMSC, and EM-Dox was prepared using an active-loading approach. Our engineered EM-Dox demonstrated significantly more potent tumor inhibition activity and fewer side effects than free doxorubicin. This novel biological nanomedicine system provides a promising opportunity to develop novel precision medicine for osteosarcoma.

Epigenomic landscape study reveals molecular subtypes and EBV-associated regulatory epigenome reprogramming in nasopharyngeal carcinoma.

BACKGROUND: Epstein-Barr virus (EBV) latent infection is associated with genome-wide epigenomic changes in several malignancies, but its role in epigenetic dysregulation remains unclear in nasopharyngeal carcinoma (NPC). METHODS: To investigate EBV-associated epigenetic dysregulation, we performed a multi-omics study by integrating whole-genome bisulfite sequencing (WGBS), assay for transposase-accessible chromatin using sequencing (ATAC-Seq), whole-exome sequencing (WES), and single-cell RNA sequencing (scRNA-Seq) data. FINDINGS: In addition to the known global DNA hypermethylated subtype, we discovered a novel subtype with global hypomethylation in EBV + NPC. The consistent EBV-specific differentially methylated regions (EBV-DMRs) in the human genome were identified from both subtypes and associated with loss of CTCF binding (P < 2.2e-16). Importantly, CTCF is a master chromatin regulator and CTCF protein was reduced in 45% of NPC cases, especially in those with advanced NPC (Stage IV vs. others: 62% vs. 38%, P = 0.034). This result links EBV with chromatin changes. The ATAC-Seq data suggest regulatory epigenome reprogramming through chromatin accessibility changes in EBV + NPC with altered CTCF binding and the switch of transcription factor binding from differentiation-associated KLF/SP family to the innate and adaptive immunity-related NF-ĸB and IRF families. Detailed chromatin accessibility analysis identified a potential EBV target gene CD74, which mediated EBV-specific cell-cell communications in the tumor microenvironment (TME) and was strongly correlated with T cell exhaustion (r2 = 0.55). INTERPRETATION: Our study reveals the unexpected epigenetic heterogeneity, providing insights into NPC pathogenesis and highlighting the involvement of host factors in virus-associated epigenetic changes. EBV infection is associated with epigenome reprogramming and may promote immune evasion. FUNDING: This study was funded by the Hong Kong Research Grants Council grant (AoE/M-06/08) to MLL, General Research Fund (17103218 and 17102619) and seed funding for basic research (201611159158) to WD, and General Research Fund (17119618) to HC.

The effect of aggressive management of intraoperative body temperature on postoperative APACHE II score and prognosis in high-risk patients undergoing thoracoscopic surgery.

Background: Intraoperative hypothermia is related with postoperative complication, longer length of stay (LoS) and mortality. Acute Physiology and Chronic Health Evaluation II (APACHE II) it the most commonly used evaluation system for assessing the severity and clinical prognosis of patients. This study sought to examine the effect of intraoperative body temperature on postoperative APACHE II scores and the prognosis of high-risk patients undergoing thoracoscopic surgery. Methods: This study used the clinical data of patients from a multicenter randomized controlled trial who had undergone thoracoscopic surgery at our center (NCT03111875). In our center were randomly assigned (1:1) to receive either aggressive warming to a target core temperature of 37 ℃ or routine thermal management to a target of 35.5 ℃ during non-cardiac surgery. Randomisation was computer-generated. Eligible patients (aged ≥45 years) had at least one cardiovascular risk factor, were scheduled for inpatient noncardiac surgery expected to last 2-6 h with general anaesthesia. We retrieved medical information through the electronic medical record system. The primary outcome was the postoperative APACHE II scores, APACHE II score variation. The secondary outcome was Quality of Recovery-15 (QoR-15) scores, LoS in hospital, postoperative complications, infections, and deaths of the patients were recorded, and a logistic regression analysis was conducted to stratify the risk factors for the APACHE II score. Results: Group R comprised 121 patients and Group A comprised 84 patients. Group A had lower postoperative APACHE II scores (P=0.046) and a lower probability of a grade increase than Group R (P=0.005). However, no significant differences were found in terms of the QoR-15 scores, LoS, postoperative complications, infections, and deaths between the 2 groups. The logistic regression showed that aggressive warming, age, and the American Society of Anesthesiologists (ASA) grade were risk factors for the deterioration of postoperative APACHE II scores. Conclusions: The active adoption of various passive and aggressive warming strategies to keep the core body temperature ≥37 ℃ during thoracoscopic surgery significantly reduced increases in APACHE II scores, which is different from age and ASA grade, and was the only intervention factor.

Exosome mimetics derived from bone marrow mesenchymal stem cells ablate neuroblastoma tumor in vitro and in vivo.

PURPOSE: To develop exosome-mimetics derived from bone marrow mesenchymal stem cells (EM) as a novel nanoscale drug delivery system(nanoDDS) with improved tumor targeting activity, therapeutic effect, and biosafety, and to evaluate the therapeutic effect of doxorubicin loaded EM (EM-Dox) on neuroblastoma (NB) in vitro and in vivo. METHODS: EM was prepared by serial extrusion of bone marrow mesenchymal stem cells (BMSCs), ammonium sulfate gradient method was used to promote the active loading of doxorubicin, and EM-Dox was obtained after removal of free doxorubicin by dialysis. The obtained EM and EM-Dox were characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), Western Blot assay(WB), and the yield of exosomes and EM was further compared. Confocal fluorescent microscopy was used to verify the uptake of EM-Dox and free doxorubicin (Free-Dox) by NB cells. CCK-8 assay, cell cycle assay, and cell apoptosis assay were used to evaluate the antitumor effect of EM-Dox on NB cells in vitro. In addition, the targeted therapeutic effect and biosafety of EM-Dox against NB were evaluated in tumor-bearing nude mice. RESULTS: TEM, NTA, and WB verified that both EM and EM-Dox feature highly similar morphology, size and marker protein expression in comparison with naturally occurred exosomes, but the particle size of EM-Dox increased slightly after loading doxorubicin. The protein yield and particle yield of EM-Dox were 16.8 and 26.3-folds higher than those of exosomes, respectively. Confocal fluorescent microscopy showed that EM and doxorubicin had a definite co-localization. EM-Dox was readily internalized in two well-established human NB cell lines. The intracellular content of doxorubicin in cells treated with EM-Dox was significantly higher than that treated with Free-Dox. CCK-8 assay and flow cytometry confirmed that EM-Dox could inhibit NB cell proliferation, induce G2/M phase cell cycle arrest, and promote NB cell apoptosis in vitro. In vivo bioluminescence imaging results demonstrated that EM-Dox effectively targets NB tumors in vivo. Compared with Free-Dox, EM-Dox had a significantly increased inhibitory effect against NB tumor proliferation and progression in vivo, without inducing any myocardial injury. CONCLUSIONS: EM-Dox showed significantly increased anti-tumor activity in comparison with free doxorubicin in vitro and in vivo, and scalable EMs may represent a new class of NanoDDS that can potentially replace naturally occurred exosomes in preclinical or clinical translations.

Effect of hypotension prediction index in the prevention of intraoperative hypotension during noncardiac surgery: A systematic review.

Intraoperative hypotension (IOH) is common in noncardiac surgery and is associated with serious postoperative complications. Hypotension Prediction Index (HPI) has shown high sensitivity and specificity for predicting hypotension and may reduce IOH in noncardiac surgery. We conducted a systematic review of randomized controlled trials (RCTs) to evaluate the applications and effects of HPI in reducing hypotension during noncardiac surgery. We comprehensively searched the PubMed, Embase, Cochrane Library, Google Scholar, and http://ClinicalTrials.gov databases to identify RCTs conducted before May 2022. The primary outcome measures were the time-weighted average (TWA) of hypotension and the area under the hypotensive threshold (65 mmHg). Secondary outcomes were the incidence and duration of hypotension and the percentage of hypotensive time during surgery. The Cochrane Risk of Bias (RoB) tool was used to assess the quality of selected studies. We conducted data synthesis for median differences and assessed the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. We included five studies with a total of 461 patients. Limited evidence suggested that HPI-guided intraoperative hemodynamics management leads to lower a) TWA of hypotension (median of difference of medians [MDM], -0.27 mmHg; 95% confidence interval [CI], -0.38, -0.01), b) area under the hypotensive threshold (MDM, -60.28 mmHg*min; 95% CI, -74.00, -1.30), c) incidence of hypotension (MDM, -4.50; 95% CI, -5.00, -4.00), d) total duration of hypotension (MDM, -12.80 min; 95% CI, -16.11, -3.39), and e) percentage of hypotension (MDM, -5.80; 95% CI, -6.65, -4.82) than routine hemodynamic management during noncardiac surgery. However, only very low- to low-quality evidence on the benefit of intraoperative HPI-based hemodynamic management is available. Our review revealed that HPI has the potential to reduce the occurrence, duration, and severity of IOH during noncardiac surgery compared to standard intraoperative care with proper adherence to the protocol. Systematic review registration PROSPERO CRD42022333834.

Development and validation of a nomogram to predict cancer-specific survival in elderly patients with papillary thyroid carcinoma: a population-based study.

OBJECTIVE: Thyroid carcinoma (TC) is the most common endocrine tumor in the human body. Papillary thyroid carcinoma (PTC) accounts for more than 80% of thyroid cancers. Accurate prediction of elderly PTC can help reduce the mortality of patients. We aimed to construct a nomogram predicting cancer-specific survival (CSS) in elderly patients with PTC. METHODS: Patient information was downloaded from the Surveillance, Epidemiology, and End Results (SEER) program. Univariate and multivariate Cox regression models were used to screen the independent risk factors for patients with PTC. The nomogram of elderly patients with PTC was constructed based on the multivariate Cox regression model. We used the concordance index (C-index), the area under the receiver operating characteristic curve (AUC) and the calibration curve to test the accuracy and discrimination of the prediction model. Decision curve analysis (DCA) was used to test the clinical value of the model. RESULTS: A total of 14,138 elderly patients with PTC were included in this study. Patients from 2004 to 2015 were randomly divided into a training set (N = 7379) and a validation set (N = 3141), and data from 2016 to 2018 were divided into an external validation set (N = 3618). Proportional sub-distribution hazard model showed that age, sex, tumor size, histological grade, TNM stage, surgery and chemotherapy were independent risk factors for prognosis. In the training set, validation set and external validation set, the C-index was 0.87(95%CI: 0.852-0.888), 0.891(95%CI: 0.866-0.916) and 0.931(95%CI:0.894-0.968), respectively, indicating that the nomogram had good discrimination. Calibration curves and AUC suggest that the prediction model has good discrimination and accuracy. CONCLUSIONS: We constructed a new nomogram to predict CSS in elderly patients with PTC. Internal cross-validation and external validation indicate that the model has good discrimination and accuracy. The predictive model can help doctors and patients make clinical decisions.