OBJECTIVE: To investigate the characteristics of gut microbiota changes in patients with acute myeloid leukemia (AML) undergoing induction chemotherapy and to explore the relationship between infectious complications and gut microbiota. METHODS: Fecal samples were collected from 37 newly diagnosed AML patients at four time points: before induction chemotherapy, during chemotherapy, during the neutropenic phase, and during the recovery phase. Metagenomic sequencing was used to analyze the dynamic changes in gut microbiota. Correlation analyses were conducted to assess the relationship between changes in gut microbiota and the occurrence of infectious complications. RESULTS: During chemotherapy, the gut microbiota α-diversity (Shannon index) of AML patients exhibited significant fluctuations. Specifically, the diversity decreased significantly during induction chemotherapy, further declined during the neutropenic phase (P < 0.05, compared to baseline), and gradually recovered during the recovery phase, though not fully returning to baseline levels.The abundances of beneficial bacteria, such as Firmicutes and Bacteroidetes, gradually decreased during chemotherapy, whereas the abundances of opportunistic pathogens, including Enterococcus, Klebsiella, and Escherichia coli, progressively increased.Analysis of the dynamic changes in gut microbiota of seven patients with bloodstream infections revealed that the bloodstream infection pathogens could be detected in the gut microbiota of the corresponding patients, with their abundance gradually increasing during the course of infection. This finding suggests that bloodstream infections may be associated with opportunistic pathogens originating from the gut microbiota.Compared to non-infected patients, the baseline samples of infected patients showed a significantly lower relative abundance of Bacteroidetes (P < 0.05). Regression analysis indicated that Bacteroidetes abundance is an independent predictive factor for infectious complications (P < 0.05, OR =13.143). CONCLUSION During induction chemotherapy in AML patients, gut microbiota α-diversity fluctuates significantly, and the abundance of opportunistic pathogens increase, which may be associated with bloodstream infections. Patients with lower baseline Bacteroidetes abundance are more prone to infections, and its abundance can serve as an independent predictor of infectious complications.
Humans ; Gastrointestinal Microbiome ; Leukemia, Myeloid, Acute/microbiology* ; Induction Chemotherapy ; Feces/microbiology* ; Male ; Female ; Middle Aged

OBJECTIVES: To determine the pharmacological impact of hesperidin, the main component of Citri Reticulatae Pericarpium, on depressive behavior and elucidate the mechanism by which hesperidin treats depression, focusing on the gut-brain axis. METHODS: Fifty-four Sprague Dawley male rats were randomly allocated to 6 groups using a random number table, including control, model, hesperidin, probiotics, fluoxetine, and Citri Reticulatae Pericarpium groups. Except for the control group, rats in the remaining 5 groups were challenged with chronic unpredictable mild stress (CUMS) for 21 days and housed in single cages. The sucrose preference test (SPT), immobility time in the forced swim test (FST), and number in the open field test (OFT) were performed to measure the behavioral changes in the rats. Enzyme-linked immunosorbent assay was used to determine the levels of 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF) in brain tissue, and the histopathology was performed to evaluate the changes of colon tissue, together with sequencing of the V3-V4 regions of 16S rRNA gene on feces to explore the changes of intestinal flora in the rats. RESULTS: Compared to the control group, the rats in the model group showed notable reductions in body weight, SPF, and number in OFT (P<0.01). Hesperidin was found to ameliorate depression induced by CUMS, as seen by improvements in body weight, SPT, immobility time in FST, and number in OFT (P<0.05 or P<0.01). Regarding neurotransmitters, it was found that at a dose of 50 mg/kg hesperidin treatment upregulated the levels of 5-HT and BDNF in depressed rats (P<0.05). Compared to the control group, the colon tissue of the model group exhibited greater inflammatory cell infiltration, with markedly reduced numbers of goblet cells and crypts and were significantly improved following treatment with hesperidin. Simultaneously, the administration of hesperidin demonstrated a positive impact on the gut microbiome of rats treated with CUMS, such as Shannon index increased and Simpson index decreased (P<0.01), while the abundance of Pseudomonadota and Bacteroidota increased in the hesperidin-treated group (P<0.05). CONCLUSION The mechanism responsible for the beneficial effects of hesperidin on depressive behavior in rats may be related to inhibition of the expressions of BDNF and 5-HT and preservation of the gut microbiota.
Animals ; Hesperidin/therapeutic use* ; Rats, Sprague-Dawley ; Depression/drug therapy* ; Male ; Stress, Psychological/drug therapy* ; Brain/metabolism* ; Brain-Derived Neurotrophic Factor/metabolism* ; Serotonin/metabolism* ; Gastrointestinal Microbiome/drug effects* ; Behavior, Animal/drug effects* ; Rats ; Brain-Gut Axis/drug effects* ; Chronic Disease ; Colon/drug effects*

This consensus will introduce the characteristics of fillers used in the surgical cavities of domestic nasal surgery patients based on relevant literature and expert opinions. It will also provide recommendations for the selection of cavity fillers for different nasal diseases, with chronic sinusitis as a representative example.
Humans ; Nasal Cavity/surgery* ; Nasal Surgical Procedures ; China ; Consensus ; Sinusitis/surgery* ; Dermal Fillers

Sigma-1 receptor (σ ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K _i < 4 nmol/L) and selective σ ₁R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ ₁R in relation to σ ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.

This study aimed to comprehensively examine the association of gallstones, cholecystectomy, and cancer risk. Multivariable logistic regressions were performed to estimate the observational associations of gallstones and cholecystectomy with cancer risk, using data from a nationwide cohort involving 239 799 participants. General and gender-specific two-sample Mendelian randomization (MR) analysis was further conducted to assess the causalities of the observed associations. Observationally, a history of gallstones without cholecystectomy was associated with a high risk of stomach cancer (adjusted odds ratio (aOR)=2.54, 95% confidence interval (CI) 1.50-4.28), liver and bile duct cancer (aOR=2.46, 95% CI 1.17-5.16), kidney cancer (aOR=2.04, 95% CI 1.05-3.94), and bladder cancer (aOR=2.23, 95% CI 1.01-5.13) in the general population, as well as cervical cancer (aOR=1.69, 95% CI 1.12-2.56) in women. Moreover, cholecystectomy was associated with high odds of stomach cancer (aOR=2.41, 95% CI 1.29-4.49), colorectal cancer (aOR=1.83, 95% CI 1.18-2.85), and cancer of liver and bile duct (aOR=2.58, 95% CI 1.11-6.02). MR analysis only supported the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer. This study added evidence to the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer, highlighting the importance of cancer screening in individuals with gallstones.
Humans ; Mendelian Randomization Analysis ; Gallstones/complications* ; Female ; Male ; Cholecystectomy/statistics & numerical data* ; Middle Aged ; Risk Factors ; Aged ; Adult ; Neoplasms/etiology* ; Stomach Neoplasms/epidemiology*

After entering the body from the drug delivery site, antitumor nanomedicines need to cross a series of physiopathological barriers to reach the target site of action to effectively exert antitumor therapeutic effects. The ligand modification strategy is a classic method to enhance the efficiency of nanomedicine delivery in vivo, but the contradiction between the single ligand modification strategy, which is characterized by unity and stage, and the in vivo delivery process, which is characterized by versatility and whole-process characteristics, determines that nanomedicines modified by a single ligand alone cannot satisfy the target efficacy requirements. Therefore, the use of multiligand combinatorial modification strategies by virtue of nanomedicine surface area advantages is key to advancing the next generation of smart nanomedicines. In this paper, on the basis of summarizing and classifying the commonly used functional ligands for in vivo delivery, the advantages and research progress of multiligand combination modification of antitumor nanomedicines are discussed with special focus, and the multiligand combination modification is classified as synergistic and complementary according to the combination of the ligands, which is of great significance to ensure that antitumor nanomedicines can overcome the multiple physiopathological barriers to achieve precise delivery.

Objective To investigate disease characteristics and hospitalization costs of children with Mycoplasma Pneumoniae pneumonia(MPP)admitted to Shanghai municipal medical hospitals from 2019 to 2023.Methods Depending on the Shanghai Municipal Hospital Pediatric Alliance,we retrospectively investigated community acquired MPP pediatric patients hospitalized in 22 municipal hospitals with pediatric qualifications(including 4 children's hospitals)in Shanghai from Jan 2019 to Dec 2023.We collected the patients'diagnosis codes,gender,age,length of hospital stay,hospitalization costs,and whether they progressed to severe Mycoplasma pneumoniae pneumonia(SMPP).Results From 2019 to 2023,a total of 29 045 hospitalized children with MPP were treated,with 6 035 cases(20.8%)identified as SMPP in the 22 hospitals.Trend analysis revealed a rising trend with years in the proportion of SMPP patients(χ2trend=365.498,P<0.001).Among the 4 children's hospitals,there were 18 710 cases with MPP,including 4 078 cases(21.8%)of SMPP.The proportion of SMPP patients also showed an increasing trend with years(χ2trend=14.548,P<0.001),and the proportion in 2023(23.0%)was higher than that in previous years with statistical significance.There were statistical differences in the seasonal distribution of MPP cases between different years,with higher proportions in summer and autumn overall.The age distribution of hospitalized MPP children varied among different years,with school-age children accounting for the majority(56.8%)in 2023.There was no difference in the distribution of severe cases between different genders,but there were differences in the proportion of severe cases among different age groups in different years,with a gradual increase in severe cases among children aged 1 to 3 years(χ2trend=191.567,P<0.001).The average length of hospital stay for MPP during the epidemic was higher than that during non-epidemic periods,and there were statistically significant differences in the average length of hospital stay between different years(P<0.001).The individual hospitalization costs during the epidemic were higher than in other years,and there were statistically significant differences in individual hospitalization costs between different years(P<0.001).The total hospitalization costs were still higher in 2019 and 2023.The individual hospitalization costs for SMPP were higher than for non-SMPP cases.Conclusion MPP outbreaks occurred in Shanghai in 2019 and 2023,with the higher proportions in summer and autumn overall.Compared to previous years,the number of hospitalized MPP children in Shanghai was higher in 2023,with a higher proportion of SMPP cases,especially among children under 3 years old.The individual per capita hospitalization expenses for SMPP cases were higher than for non-SMPP cases.

Objective To investigate the effect of hemoperfusion combined with sequential hemodiafiltration on pancreatic islet β cell function,nutritional status and inflammatory response in patients with diabetic nephropathy(DN).Methods One hundred patients with DN admitted to Nanyang Central Hospital from February 2022 to February 2023 were selected as the research subjects.They were divided into the control group and the observation group according to the random number table method,with 50 patients in each group.The patients in the control group were treated with sequential hemodiafil-tration,and the patients in the observation group were treated with sequential hemodiafiltration combined with hemoperfusion.The weight and height of patients in the two groups were measured before treatment and after 6-month treatment to calculate body mass index(BMI).The triceps skinfold(TSF)thickness was measured by using a skinfold caliper.The nutritional status of patients were evaluated by subjective global assessment(SCA)scores.Fasting venous blood was collected from patients in the two groups to measure the levels of fasting insulin(FINS)and fasting plasma glucose(FPG)by radioimmunoassay,and the homeostasis model assessment of insulin resistance(HOMA-IR)and homeostasis model assessment of beta-cell function(HOMA-β)were calculated;the levels of total cholesterol(TC),triglyceride(TG),high-density lipoprotein cholesterol(HDL-C)and low-density lipoprotein cholesterol(LDL-C)were measured by using the fully automatic biochemical analyzer,and the levels of serum C-reactive protein(CRP),tumor necrosis factor-α(TNF-α)and interleukin-6(IL-6)were measured by using the enzyme-linked immunosorbent assay.Results There was no significant difference in HOMA-β,FINS and HOMA-IR of patients between the control group and the observation group before treatment(P＞0.05).FINS and HOMA-IR of patients after treatment were significantly lower than those before treatment,while HOMA-β was significantly higher than that before treatment in the two groups(P＜0.05).After treatment,FINS and HOMA-IR of patients in the observation group were significantly lower than those in the control group,while HOMA-β was significantly higher than that in the control group(P＜0.05).There was no significant difference in BMI,TSF and SGA of patients between the control group and the observation group before treatment(P＞0.05).After treatment,BMI,TSF and SGA of patients in both groups were significantly higher than those before treatment;and BMI,TSF and SGA of patients in the observation group were significantly higher than those in the control group(P＜0.05).There was no significant difference in the levels of TC,TG,LDL-C and HDL-C of patients between the control group and the observation group before treatment(P＞0.05).After treatment,the levels of TC,TG and LDL-C of patients in both groups were significantly lower than those before treatment,while the HDL-C level of patients was significantly higher than that before treatment(P＜0.05).After treatment,the levels of TC,TG and LDL-C of patients in the observation group were significantly lower than those in the control group,while the HDL-C level of patients was significantly higher than that in the control group(P＜0.05).There was no significant difference in the levels of serum CRP,TNF-α and IL-6 of patients between the control group and the observation group before treatment(P＞0.05).After treatment,the levels of serum CRP,TNF-α and IL-6 of patients in both groups were significantly lower than those before treatment;and the levels of serum CRP,TNF-α and IL-6 of patients in the observation group were significantly lower than those in the control group(P＜0.05).Conclusion Sequential hemodiafiltration combined with hemoperfusion can significantly improve pancreatic islet βcell function,nutritional status and lipid metabolism in patients with DN and inhibit inflammatory response.

Objective:To investigate the effects of cerium oxide nanoenzyme-gelatin methacrylate anhydride (GelMA) hydrogel (hereinafter referred to as composite hydrogel) in the repair of infected full-thickness skin defect wounds in mice.Methods:This study was an experimental study. Cerium oxide nanoenzyme with a particle size of (116±9) nm was prepared by hydrothermal method, and GelMA hydrogel with porous network structure and good gelling performance was also prepared. The 25 μg/mL cerium oxide nanoenzyme which could significantly promote the proliferation of human skin fibroblasts and had high superoxide dismutase activity was screened out. It was added to GelMA hydrogel to prepare composite hydrogel. The percentage of cerium oxide nanoenzyme released from the composite hydrogel was calculated after immersing it in phosphate buffer solution (PBS) for 3 and 7 d. The red blood cell suspension of mice was divided into PBS group, Triton X-100 group, cerium oxide nanoenzyme group, GelMA hydrogel group, and composite hydrogel group, which were treated with corresponding solution. The hemolysis of red blood cells was detected by microplate reader after 1 h of treatment. The bacterial concentrations of methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli were determined after being cultured with PBS, cerium oxide nanoenzyme, GelMA hydrogel, and composite hydrogel for 2 h. The sample size in all above experiments was 3. Twenty-four 8-week-old male BALB/c mice were taken, and a full-thickness skin defect wound was prepared in the symmetrical position on the back and infected with MRSA. The mice were divided into control group without any drug intervention, and cerium oxide nanoenzyme group, GelMA hydrogel group, and composite hydrogel group applied with corresponding solution, with 6 mice in each group. The wound healing was observed on 3, 7, and 14 d after injury, and the remaining wound areas on 3 and 7 d after injury were measured (the sample size was 5). The concentration of MRSA in the wound exudation of mice on 3 d after injury was measured (the sample size was 3), and the blood flow perfusion in the wound of mice on 5 d after injury was observed using a laser speckle flow imaging system (the sample size was 6). On 14 d after injury, the wound tissue of mice was collected for hematoxylin-eosin staining to observe the newly formed epithelium and for Masson staining to observe the collagen situation (the sample size was both 3). Results:After immersion for 3 and 7 d, the release percentages of cerium oxide nanoenzyme in the composite hydrogel were about 39% and 75%, respectively. After 1 h of treatment, compared with that in Triton X-100 group, the hemolysis of red blood cells in PBS group, GelMA hydrogel group, cerium oxide nanoenzyme group, and composite hydrogel group was significantly decreased ( P<0.05). Compared with that cultured with PBS, the concentrations of MRSA and Escherichia coli cultured with cerium oxide nanoenzyme, GelMA hydrogel, and composite hydrogel for 2 h were significantly decreased ( P<0.05). The wounds of mice in the four groups were gradually healed from 3 to 14 d after injury, and the wounds of mice in composite hydrogel group were all healed on 14 d after injury. On 3 and 7 d after injury, the remaining wound areas of mice in composite hydrogel group were (29±3) and (13±5) mm 2, respectively, which were significantly smaller than (56±12) and (46±10) mm 2 in control group and (51±7) and (38±8) mm 2 in cerium oxide nanoenzyme group (with P values all <0.05), but was similar to (41±5) and (24±9) mm 2 in GelMA hydrogel group (with P values both >0.05). On 3 d after injury, the concentration of MRSA on the wound of mice in composite hydrogel group was significantly lower than that in control group, cerium oxide nanoenzyme group, and GelMA hydrogel group, respectively (with P values all <0.05). On 5 d after injury, the volume of blood perfusion in the wound of mice in composite hydrogel group was significantly higher than that in control group, cerium oxide nanoenzyme group, and GelMA hydrogel group, respectively ( P<0.05). On 14 d after injury, the wound of mice in composite hydrogel group basically completed epithelization, and the epithelization was significantly better than that in the other three groups. Compared with that in the other three groups, the content of collagen in the wound of mice in composite hydrogel group was significantly increased, and the arrangement was also more orderly. Conclusions:The composite hydrogel has good biocompatibility and antibacterial effect in vivo and in vitro. It can continuously sustained release cerium oxide nanoenzyme, improve wound blood perfusion in the early stage, and promote wound re-epithelialization and collagen synthesis, therefore promoting the healing of infected full-thickness skin defect wounds in mice.

Objective To investigate the expression of Midkine(MDK)in cholangiocarcinoma(CCA)and its value in predicting the prognosis of CCA,as well as the potential mechanism of the effect of MDK on the progression of CCA.Methods The data of CCA samples were obtained from TCGA database to analyze the difference in the expression of MDK between cancer tissue and paracancerous tissue and its association with clinical features,and the data collected from GEO database and 11 CCA patients who underwent surgical resection in The Fifth Medical Center of Chinese PLA General Hospital from June 2018 to September 2021 were used for validation.STRING and Cytoscape were used to construct a protein-protein interaction network,and gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses were used to investigate the biological functions and tumor-related pathways involving MDK-related genes.In addition,TIMER and TISIDB databases were used to analyze the correlation between MDK expression and immune cell infiltration in CCA tissue.The independent-samples t test or the Mann-Whitney U test was used for comparison of continuous data between two groups,and the Fisher's exact test was used for comparison of categorical data between two groups.The Kaplan-Meier method was used to plot survival curves,and the Log-rank test was used for comparison between groups.The Spearman correlation analysis was used to investigate the correlation between two variables.Results The expression level of MDK in cancer tissue and paracancerous tissue of CCA patients was compared based on TCGA database,and the results of the non-paired and paired analyses showed that the expression level of MDK in CCA tumor tissue was significantly higher than that in paracancerous tissue(P<0.001).Transcriptome sequencing was performed for the tumor tissue and its corresponding paracancerous tissue from 11 CCA patients,and the results showed that the expression level of MDK in CCA tumor tissue was significantly higher than that in corresponding paracancerous tissue(P<0.01).High expression of MDK was associated with lymph node metastasis(P=0.045)and vascular invasion(P=0.044).Survival analysis showed that compared with the CCA patients with low MDK expression,the CCA patients with high MDK expression had significantly shorter overall survival time(χ2=5.30,P=0.028)and disease-specific survival time(χ2=6.25,P=0.019).The GO and KEGG enrichment analyses showed that the 30 MDK-related genes were closely associated with ubiquitin-mediated proteolysis and affected the prognosis of CCA patients.The TIMER analysis showed that the expression level of MDK was positively correlated with the infiltration of B cells(r=0.356,P=0.035 6)and dendritic cells(r=0.409,P=0.014 7)in tumor microenvironment of CCA;the TISIDB analysis showed that the expression level of MDK was positively correlated with CXCL16(r=0.465,P=0.004 67)and was negatively correlated with CXCL12(r=-0.389,P=0.019 7)and CXCR5(r=-0.393,P=0.018 5),and it was also negatively correlated with the immune checkpoint regulators VTCN1(r=-0.393,P=0.018 3),LTA(r=-0.380,P=0.022 7),and PVR(r=-0.350,P=0.037 3).Conclusion High expression of MDK is associated with poor prognosis in CCA patients,and MDK has the potential of being used as a molecular marker for predicting the prognosis of CCA.MDK may promote the development and progression of CCA by regulating ubiquitin-mediated proteolysis and the infiltration of B cells and dendritic cells.