Metastatic dissemination is the major cause of death from breast-cancer (BC). Fusobacterium nucleatum (F.n) is widely enriched in BC and has recently been identified as one of the high-risk factors for promoting BC metastasis. Here, with an experimental model, we demonstrated that intratumoral F.n induced BC aggressiveness by transcriptionally activating Epithelial-mesenchymal transition-associated genes. Therefore, the F.n may be a potential target to prevent metastasis. Given the fact that cancer-associated fibroblasts (CAFs) are abundant in BC and located near blood vessels, we report an optogenetic system that drives CAF to in situ produce human antibacterial peptide LL37, with the characteristics of biosafety and freely intercellular trafficking, for depleting intratumoral F.n, leading to a 72.1% reduction in lung metastatic nodules number without affecting the balance of the systemic flora. Notably, mild photothermal treatment was found that could normalize CAF, contributing to synergistically inhibiting BC metastasis. In addition, the system can also simultaneously encode a gene of TNF-related apoptosis-inducing ligand to suppress the primary tumor. Together, our study highlights the potential of local elimination of tumor pathogenic bacteria to prevent BC metastasis.

OBJECTIVE To investigate the effects of calcitriol on sepsis-induced immunosuppression and its potential mechanism. METHODS A sepsis-induced immunosuppression mice model was established using cecal ligation and puncture （CLP）. The 7-day survival rate， serum levels of tumor necrosis factor- α （TNF- α）， interleukin-6 （IL-6）， and IL-1β were determined in sham operation group， CLP group and calcitriol group （1 μg/kg）； the morphological changes of lung tissue in mice were observed. Lipopolysaccharide （LPS） tolerance macrophage models （representing sepsis-induced immunosuppression） were established using mice macrophage cell line RAW264.7 cells. The levels of TNF-α and IL-6 in cell supernatants as well as mRNA expressions of IL-1β， nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3 （NLRP3）， IL-18 and caspase-1 were assessed in culture medium group， LPS group， LPS tolerance group， and calcitriol （5 μmol/L） group. The following parameters were measured： propidium iodide （PI）-positive cell ratio， caspase-1 activity， lactate dehydrogenase （LDH） release， and Ca2+ levels. RESULTS Compared with CLP group， 7-day survival rate and serum levels of TNF-α， IL-6 and IL-1β were increased significantly in calcitriol group （P＜0.05）. Additionally， pulmonary tissue damage was markedly attenuated in calcitriol group. Compared with LPS tolerance group， the levels of TNF-α and IL-6 in cell supernatants， mRNA expressions of IL- 1β， NLRP3， IL-18 and caspase-1， PI-positive cell ratio， caspase-1 activity， LDH release， and Ca2+ levels were all increased significantly in calcitriol group （P＜0.05）. CONCLUSIONS Calcitriol can reverse sepsis-induced immunosuppression， and the mechanism of action may be E-mail：yarfwy@163.com achieved by the binding of calcitriol to vitamin D receptor，which promotes the release of Ca2+ from the endoplasmic reticulum， thereby driving the NLRP3/caspase-1-mediated pyroptosis pathway.

ObjectiveTo investigate the significance of different non-treatment thresholds or upper limits of normal （ULN） of alanine aminotransferase （ALT） in evaluating significant liver pathological injury in patients with chronic hepatitis B virus （HBV） infection， and to provide guidance for clinical diagnosis and treatment. MethodsThis study was conducted among 733 patients with chronic HBV infection who were hospitalized in Ningbo No. 2 Hospital from January 2015 to December 2023 and underwent liver biopsy and histopathological examination， and all patients had a persistent ALT level of ≤40 U/L and positive HBV DNA （>30 IU/mL）. According to the treatment threshold or ULN of ALT， the patients were divided into group 1 with 575 patients （≤35 U/L for male patients， ≤25 U/L for female patients）， group 2 with 430 patients （≤30 U/L for male patients， ≤19 U/L for female patients）， group 3 with 443 patients （≤27 U/L for male patients， ≤24 U/L for female patients）， group 4 with 446 patients （≤25 U/L）， group 5 with 158 patients （>35 U/L for male patients， >25 U/L for female patients）， and group 6 with 145 patients （>30 — ≤35 U/L for male patients， >19 — ≤25 U/L for female patients）. Groups 2， 5， and 6 were compared to analyze the severity of liver pathological injury in patients with different ALT levels and the constituent ratio of patients with significant liver pathological injury， and groups 1， 2， 3， and 4 were compared to investigate the value of different ULN or non-treatment thresholds of ALT in determining liver inflammation grade （G）， liver fibrosis stage （S）， and the treatment indication based on liver pathology. The independent-samples t test was used for comparison of normally distributed continuous data between two groups； a one-way analysis of variance was used for comparison between multiple groups， and the least significant difference t-test or the Tambane’s test was used for further comparison between two groups； the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups， and the Kruskal-Wallis H test was used for comparison between multiple groups and further comparison between two groups； the chi-square test or the Fisher’s exact test was used for comparison of categorical data between groups； a Ridit analysis was used for comparison of ranked data. A multivariate Logistic regression analysis （forward stepwise） was performed with whether liver pathology met the treatment indication （≥G2 and/or ≥S2） as the dependent variable and related factors with a significant impact on the dependent variable （P <0.05） as the independent variable. The receiver operating characteristic （ROC） curve was plotted， and the area under the ROC curve （AUC）， as well as sensitivity， specificity， positive predictive value， negative predictive value， positive likelihood ratio， and negative likelihood ratio， was used to assess the diagnostic value of different non-treatment thresholds of ALT. ResultsAmong the 733 patients， 259 （35.33%） had ≥G2 liver inflammation， 211 （28.79%） had ≥S2 liver fibrosis， and 306 （41.75%） had treatment indication （≥G2 and/or ≥S2）. There was a significant difference in liver inflammation grade （G0 — G4） between groups 2， 5， and 6 （χ²=22.869， P <0.001）， and there were also significant differences in the constituent ratios of patients with ≥G2 or ≥G3 liver inflammation between the three groups （χ²=21.742 and 14.921， P<0.001 and P=0.001）. There was a significant difference in liver fibrosis stage （S0 — S4） between groups 2， 5， and 6 （χ²=16.565， P<0.001）， and there were also significant differences in the constituent ratios of patients with ≥S2， ≥S3 or S4 liver fibrosis between the three groups （χ²=13.264， 13.050， and 6.260， P=0.001， 0.001， and 0.044）. There were significant differences between groups 2， 5， and 6 in the constituent ratios of patients with or without treatment indication based on liver pathology （χ²=20.728， P<0.001）. There were significant differences between groups 2， 5， and 6 in the constituent ratio of male patients （χ²=24.836， P<0.05）， age （F=5.710， P<0.05）， ALT （F=473.193， P<0.05）， aspartate aminotransferase （AST） （F=107.774， P<0.05）， ALT/AST ratio （F=40.167， P<0.05）， γ-glutamyl transpeptidase （GGT） （H=15.463， P<0.05）， aspartate aminotransferase-to-platelet ratio index （APRI） （H=63.024， P<0.05）， and LIF-5 （5 indicators for liver inflammation and fibrosis） （H=46.397， P<0.05）. In groups 1 — 4， compared with the patients without treatment indication， the patients with treatment indication had a significantly lower constituent ratio of patients with positive HBeAg， significantly lower levels of platelet count （PLT） and HBV DNA， and significantly higher age， ALT， AST， GGT， APRI， FIB-4， and LIF-5 （all P<0.05）. The Logistic regression analysis showed that age （odds ratio ［OR］=1.044， 95% confidence interval ［CI］： 1.025 — 1.063， P<0.001）， GGT （OR=1.022， 95%CI： 1.007 — 1.038， P=0.003）， and HBV DNA （OR=0.839， 95%CI： 0.765 — 0.919， P<0.001） were influencing factors for treatment indication based on liver pathology in group 1； HBeAg （OR=1.978， 95%CI： 1.269 — 3.082， P=0.003）， age （OR=1.048， 95%CI： 1.025 — 1.071， P<0.001）， GGT （OR=1.016， 95%CI： 1.001 — 1.031， P=0.041）， and PLT （OR=0.995， 95%CI： 0.991 — 1.000， P=0.049） were influencing factors in group 2； age （OR=1.040， 95%CI： 1.014 — 1.066， P=0.002）， ALT （OR=1.047， 95%CI： 1.005 — 1.092， P=0.029）， HBV DNA （OR=0.817， 95%CI： 0.736 — 0.907， P<0.001）， and LIF-5 （OR=7.382， 95%CI： 1.151 — 47.330， P=0.035） were influencing factors in group 3； age （OR=1.054， 95%CI： 1.031 — 1.077， P<0.001）， ALT （OR=1.061， 95%CI： 1.016 — 1.107， P=0.008）， and HBV DNA （OR=0.825， 95%CI： 0.743 — 0.917， P<0.001） were influencing factors in group 4. The diagnostic performance for identifying ≥G2 liver inflammation， ≥S2 liver fibrosis， and treatment indication in groups 1 — 4 had an AUC of >0.7； group 1 showed the lowest sensitivity （28.76%） and the highest specificity， positive predictive value， positive likelihood ratio， and negative likelihood ratio in judging treatment indication； group 2 had the highest sensitivity and negative predictive value and the lowest negative likelihood ratio； groups 3 and 4 had similar diagnostic indicators. ConclusionIn patients with chronic HBV infection and a persistently low ALT level， the severity of liver histopathological injury and the constituent ratio of significant liver histopathological injury decrease with the reduction in ALT level. A higher non-treatment threshold or ULN of ALT can help to identify the patients requiring treatment （with a higher specificity）， while a lower non-treatment threshold or ULN of ALT can help to identify the patients who do not require treatment （with a higher sensitivity）.

Objective To investigate the analgesic effects of different doses of dexmedetomidine(Dex)in regulating the brain-derived neurotrophic factor(BDNF)/protein kinase B(AKT)/cyclica-denosine monophosphate response element binding protein(CREB)signaling pathway in elderly rats with spinal fractures.Methods Sixty rats were randomly divided into control group(skin incision only),model group(spinal fracture without any drug treatment),positive drug group(spinal fracture+0.2 μg/kg sufentanil),low-dose Dex group(spinal fracture+0.4 μg/kg Dex),medium-dose Dex group(spinal fracture+0.6 μg/kg Dex)and high-dose Dex group(spinal fracture+0.8 μg/kg Dex),with ten rats in each group.Mechanical pain threshold and thermal pain threshold were used to assess pain and sedation effects in elderly rats with spinal fractures.Modified neurological severity score(mNSS)was employed to evaluate the degree of neurological dysfunction.Enzyme-linked im-munosorbent assay(ELISA)was performed to detect serotonin(5-HT),substance P(SP),calci-tonin gene-related peptide(CGRP)neurotransmitter levels,tumor necrosis factor-α(TNF-α)and interleukin-1 β(IL-1 β)inflammatory factor levels.Colorimetric assays were used to measure malon-dialdehyde(MDA)oxidative stress expression levels;kits were applied to determine superoxide dis-mutase(SOD)and catalase(CAT)oxidative stress indicator levels.Western blotting(WB)analy-sis was conducted to examine BDNF,phosphorylated(p)-AKT and p-CREB protein expression lev-els in the spinal dorsal horn tissues of elderly rats with spinal fractures.Results Compared with the control group,the model group showed significantly increased mNSS scores,5-HT,SP,CGRP,TNF-α,IL-1 β and MDA expression levels,and significantly decreased mechanical pain thresholds,thermal pain thresholds,SOD,CAT,as well as BDNF,p-AKT and p-CREB protein expression lev-els(P＜0.05).Compared with the model group,the positive drug group and the medium-and high-dose Dex groups exhibited significantly lower mNSS scores,5-HT,SP,CGRP,TNF-α,IL-1βand MDA expression levels,and significantly higher mechanical pain thresholds,thermal pain thresholds,SOD,CAT,as well as BDNF,p-AKT and p-CREB protein expression levels(P＜0.05).Compared with the positive drug group,the low-dose Dex group had significantly higher mNSS scores,5-HT,SP,CGRP,TNF-α,IL-1 β and MDA expression levels,and significantly low-er mechanical pain thresholds,thermal pain thresholds,as well as BDNF,p-AKT andp-CREB pro-tein expression levels(P＜0.05);the high-dose Dex group showed significantly lower mNSS scores,5-HT,SP,CGRP,TNF-α,IL-1 β and MDA expression levels,and significantly higher me-chanical pain thresholds,thermal pain thresholds,as well as BDNF,p-AKT and p-CREB protein expression levels(P＜0.05).Compared with the low-dose Dex group,the medium-and high-dose Dex groups demonstrated significantly lower mNSS scores,5-HT,SP,CGRP,TNF-α,IL-1 β and MDA expression levels,and significantly higher mechanical pain thresholds,thermal pain thresh-olds,SOD,CAT,as well as BDNF,p-AKT and p-CREB protein expression levels(P＜0.05),in-dicating dose-dependent effect.Conclusion Dex may alleviate pain and reduce its impact on neu-rological function caused by spinal fractures in elderly rats through activation of the BDNF/AKT/CREB signaling pathway.

Objective To explore the influencing factors of liver fibrosis in patients with metabolic dysfunction-associated fatty liver disease(MAFLD)complicated with chronic hepatitis B(CHB),and to find clinically convenient predictive parameters for assessing liver fibrosis risk.Methods A retrospective analysis was conducted on 221 cases of MAFLD with CHB diagnosed and treated at the Second Hospital of Lanzhou University between January 2015 and August 2022.Patients were divided into low-risk(FIB-4<1.30,n=84),medium-risk(1.30≤FIB-4≤2.67,n=94)and high-risk(FIB-4>2.67,n=43)liver fibrosis groups based on the Fibrosis-4(FIB-4)index.General clinical data,laboratory indicators and composite indicators were compared among the three groups.Variables were screened using forward stepwise regression,and binary logistic regression analysis was performed to determine independent predictors of liver fibrosis.A prediction model was constructed and evaluated using receiver operating characteristic(ROC)curve analysis.Results Age,AST and Triglyceride-glucose index(TyG)were independent risk factors for liver fibrosis in patients with MAFLD combined with CHB,while platelet-to-lymphocyte ratio(PLR)was an independent protective factor(all P<0.05).ROC curve analysis showed that the area under the curve(AUC)for age,AST,TyG,PLR,age-AST and AST-TyG in predicting liver fibrosis were 0.668,0.764,0.680,0.738,0.856 and 0.805,respectively.At the optimal cut-off values,the sensitivities were 86.0%,67.4%,93.0%,62.8%,86.0%and 79.1%,and the specificities were 43.3%,82.0%,51.7%,86.0%,71.3%and 70.2%.Conclusion Age,AST,TyG and PLR are influencing factors of liver fibrosis in MAFLD combined with CHB patients.The parameters established based on these factors may predict the risk of liver fibrosis,and combined prediction can improve predictive efficacy.

Objective To screen antidepressant-active compounds from Polygonati Rhizoma and explore their effects and possible mechanisms against depression induced by simulated weightlessness.Methods A systems pharmacology approach was used to screen potential antidepressant-active compounds and their targets from Polygonati Rhizoma.The hindlimb unloading(HLU)rat model was employed for the study.Twenty-four healthy male Sprague-Dawley rats were randomly divided into three groups:control group(administered 0.5%carboxymethylcellulose by gavage),HLU group(hindlimb unloading),and HLU+treatment group(hindlimb unloading+active compound gavage),with 8 rats in each group.After 28 days of hindlimb unloading,depressive-like behaviors in rats were evaluated using the forced swimming test and tail suspension test.Hippocampal morphology was examined with H&E staining,and GO and KEGG enrichment analyses were conducted on the targets of active compounds.Results A total of 38 active compounds were screened from Polygonati Rhizoma,among which apigenin had an oral bioavailability of 23.06%and a drug-likeness score of 0.21.Compound-target network analysis indicated that apigenin had the highest degree and betweenness centrality values,suggesting it might be the key active component with antidepressant potential in Polygonati Rhizoma.In the forced swimming and tail suspension tests,rats in the HLU group showed a significant increase in immobility time compared to the control group,indicating successful establishment of the depression model.However,compared to the HLU group,rats in the HLU plus apigenin group exhibited significantly reduced immobility time.The H&E staining results of hippocampal tissue showed a significant reduction in the number of hippocampal neurons,along with numerous shrunken neurons and small vacuoles in nerve fibers in the HLU group.In contrast,the treatment group exhibited an increased number of hippocampal neurons,with improved cellular morphology.Target enrichment analysis indicated that apigenin targets were mainly involved in the regulation of apoptosis and cancer-related signaling pathways.Conclusion Apigenin significantly improved depressive-like behaviors in rats subjected to hindlimb unloading,and it has a protective effect on hippocampal tissue.It may provide a new natural active compound for the treatment of depression caused by spaceflight-induced weightlessness.

To explore the diagnostic value of detachable string magnetically controlled capsule gastroscope (ds-MCE) for esophageal diseases in plateau area, clinical data of 45 patients who underwent ds-MCE at Qinghai Special Hospital of Cardio-Cerebrovascular Diseases from January 2024 to June 2024 were retrospectively analyzed to explore the application characteristics and advantages of ds-MCE. The results showed that ds-MCE examination was successfully completed in all 45 patients. Diagnosis was confirmed in 30 cases (66.67%, 30/45) including 28 cases (93.33%) of esophagitis, 8 cases (26.67%) of esophageal ulcer, 8 cases (26.67%) of esophageal varices, 5 cases (16.67%) of hiatal herniawere, 3 cases (10.00%) of esophageal polyp, 1 case (3.33%) of achalasia, 1 case (3.33%) of esophageal papilloma, and 1 case (3.33%) of lower esophageal and cardiac carcinoma. Compared with traditional endoscopy and capsule endoscopy, ds-MCE has the advantages of no need for anesthesia and high safety, which provides a new and important diagnostic option for esophageal diseases in plateau area.

[Summary]Early-onset DM and suboptimal glycemic control leads to irreversible damage to nerves,blood vessels,and other target organs.Vitamin D is an important calcium and phosphorus regulator in the body,and its receptor is present in various cells throughout the body,playing an integral role in many biological effects.Previous studies have identified an inverse or independent relationship between vitamin D levels and the prevalence of microangiopathic complications in patients with type 2 diabetes mellitus(T2DM).However,it remains to be investigated whether serum vitamin D levels have a contributory role in the development of microvascular complications in patients with early-onset T2DM,and whether supplementation with vitamin D has a beneficial impact on the risk of microvascular complications in early-onset T2DM.In this article,we will review the advances in the relationship between vitamin D and early-onset T2DM combined with microangiopathy.

Objective:To explore the effect of esketamine on lung ischemia-reperfusion oxidative stress markers and pulmonary complications in patients undergoing radical surgery for lung cancer.Methods:A prospective randomized-controlled study was conducted. A total of 60 patients undergoing radical lung cancer surgery in Cangzhou People's Hospital from October 2023 to April 2024 were selected as the research objects. The patients were randomly divided into group E (30 cases) and group C (30 cases) according to the envelope drawing method. The patients in group E received an intravenous injection of esketamine at 0.5 mg/kg before skin incision, followed by continuous intravenous infusion until 30 minutes before the end of surgery. The patients in group C was administered an equivalent dose of 0.9% NaCl solution. The lung function, inflammatory factors, oxidative stress markers, and the incidence of complications were compared between the 2 groups at different time intervals [after anesthesia induction (T 1), 60 minutes after single-lung ventilation (T 2), 30 minutes after resuming bilateral lung ventilation (T 3), and 60 minutes after resuming bilateral lung ventilation (T 4)]. Results:The age of patients in both groups was (62±8) years. At T 2, T 3, and T 4, the oxygenation index (OI) of group E [(413±57), (387±52), (364±48) mmHg (1 mmHg = 0.133 kPa), respectively] was higher than that of group C [(377±52), (359±47), (333±42) mmHg, respectively]. The intrapulmonary shunt rate of group E [(26.9±3.3)%, (24.6±3.1)%, (13.3±2.2)%, respectively] was lower than that of group C[(33.5±4.3)%, (28.4±3.7)%, (16.2±2.7)%, respectively], and the differences were statistically significant ( t = 2.56, 2.16, 2.66, 6.29, 4.34, 4.32, respectively); the differences in the above indictors at T 1 between the 2 groups were not statistically significant (all P > 0.05), and there were statistically significant differences in the above indictors at T 1, T 2, T 3, T 4 between the 2 groups (all P < 0.001). At T 4, the levels of serum tumor necrosis factor-alpha, interleukin-6, and interleukin-8 in group E [(93±11) ng/ml, (14.9±1.7) pg/ml, (11.4±2.2) pg/ml, respectively] were lower than those in group C [(136±15) ng/ml, (19.9±2.8) pg/ml, (15.6±4.6) pg/ml, respectively], and the differences were statistically significant ( t = 12.89, 8.40, 4.61, all P < 0.001). At T 1, the differences in the levels of inflammatory factors of both groups were not statistically significant (all P > 0.05); and the levels of inflammatory factors at T 4 were lower than those at T 1 of both groups, and the differences were statistically significantly (all P < 0.001). At T 4, the level of superoxide dismutase in group E [(66±6) U/ml] was higher than that in group C [(56±5) U/ml]. The levels of myeloperoxidase, malondialdehyde and catalase in group E [(3.0±0.4) U/g, (4.01±0.26) mmol/ml, (44±5) U/ml, respectively] were lower than those in group C [(5.7±0.7) U/g, (4.91±0.52) mmol/ml, (56±6) U/ml, respectively],and the differences were statistically significant ( t = 6.43, 18.83, 8.48, 8.74, all P < 0.001). There were no statistically significant differences in the levels of oxidative stress indicators between the 2 groups at T 1, while there were statistically significant differences in the levels of oxidative stress indicators between the 2 groups at T 1 and T 4 (all P < 0.001). The incidence of complications in group E [6.7% (2/30)] was lower than that in group C [26.7% (8/30)], and the differences were statistically significant ( χ2 = 4.32, P = 0.038). Conclusions:Esketamine can alleviate lung ischemia-reperfusion injury, improve postoperative oxygenation function, and reduce the incidence of complications.

Hepatitis B virus(HBV)infection is the main risk factor for the development and progres-sion of hepatocellular carcinoma(HCC).Through re-peated inflammatory stimulation,liver cells regen-eration,fibrosis,and scar formation,it may eventu-ally progress to HCC.Antiviral treatment reduces the incidence of HBV-related HCC and the risk of postoperative recurrence by reducing HBV DNA lev-el,thereby improving prognosis.Many recent stud-ies have found that different kinds of nucleos(t)ide analogues(NAs)may have differential improve-ments in the prevention of HBV-related HCC occur-rence and postoperative recurrence.This article re-views the differential improvement of different cat-egories of NAs in HBV-related HCC and the possible mechanisms.