Photodynamic immunotherapy is a promising strategy for cancer treatment. However, the dysfunctional tumor vasculature results in tumor hypoxia and the low efficiency of drug delivery, which in turn restricts the anticancer effect of photodynamic immunotherapy. In this study, we designed photosensitive lipid nanoparticles. The synthesized PFBT@Rox Lip nanoparticles could produce type I/II reactive oxygen species (ROS) by electron or energy transfer through PFBT under light irradiation. Moreover, this nanosystem could alleviate tumor hypoxia and promote vascular normalization through Roxadustat. Upon irradiation with white light, the ROS produced by PFBT@Rox Lip nanoparticles in situ dysregulated calcium homeostasis and triggered endoplasmic reticulum stress, which further promoted the release of damage-associated molecular patterns, enhanced antigen presentation, and stimulated an effective adaptive immune response, ultimately priming the tumor microenvironment (TME) together with the hypoxia alleviation and vessel normalization by Roxadustat. Indeed, in vivo results indicated that PFBT@Rox Lip nanoparticles promoted M1 polarization of tumor-associated macrophages, recruited more natural killer cells, and augmented infiltration of T cells, thereby leading to efficient photodynamic immunotherapy and potentiating the anti-primary and metastatic tumor efficacy of PD-1 antibody. Collectively, photodynamic immunotherapy with PFBT@Rox Lip nanoparticles efficiently program TME through the induction of immunogenicity and oxygenation, and effectively suppress tumor growth through immunogenic cell death and enhanced anti-tumor immunity.

Alzheimer's disease (AD) is regarded as a neurodegenerative disease, and it has been proposed that AD may be a systemic disease. Studies have reported associations between non-neurological diseases and AD. The correlations between AD pathology and systemic (non-neurological) pathological changes are intricate, and the mechanisms underlying these correlations and their causality are unclear. In this article, we review the association between AD and disorders of other systems. In addition, we summarize the possible mechanisms associated with AD and disorders of other systems, mainly from the perspective of AD pathology. Regarding the relationship between AD and systemic pathological changes, we aim to provide a new outlook on the early warning signs and treatment of AD, such as establishing a diagnostic and screening system based on more accessible peripheral samples.
Alzheimer Disease/therapy* ; Humans ; Brain/pathology*

Objective To analyze the structural and phylogenetic characteristics of the mitochondrial genome from Bulinus globosus, so as to provide a theoretical basis for classification and identification of species within the Bulinus genus, and to provide insights into understanding of Bulinus-schistosomes interactions and the mechanisms of parasite transmission. Methods B. globosus samples were collected from the Ruya River basin in Zimbabwe. Mitochondrial DNA was extracted from B. globosus samples and the corresponding libraries were constructed for high-throughput sequencing on the Illumina NovaSeq 6000 platform. After raw sequencing data were subjected to quality control using the fastp software, genome assembly was performed using the A5-miseq and SPAdes tools, and genome annotation was conducted using the MITOS online server. Circular maps and sequence plots of the mitochondrial genome were generated using the CGView and OGDRAW software, and the protein conservation motifs and structures were analyzed using the TBtools software. Base composition and codon usage bias were analyzed and visualized using the software MEGA X and the ggplot2 package in the R software. In addition, a phylogenetic tree was created in the software MEGA X after sequence alignment with the software MAFFT 7, and visualized using the software iTOL. Results The mitochondrial genome of B. globosus was a 13 730 bp double-stranded circular molecule, containing 2 ribosomal RNA (rRNA) genes, 22 transfer RNA (tRNA) genes, and 13 protein-coding genes, with a marked AT preference. The mitochondrial genome composition of B. globosus was similar to that of other species within the Bulinus genus. Phylogenetic analysis revealed that the complete mitochondrial genome sequence of B. globosus was clustered with B. truncatus, B. nasutus, and B. ugandae into the same evolutionary clade, and gene superfamily analysis showed that the metabolism-related proteins of B. globosus were highly conserved, notably the cytochrome c oxidase family, which showed a significant consistency. Conclusions This is the first whole mitochondrial genome sequencing to decode the compositional features of the mitochondrial genome of B. globosus from Zimbabwe and its evolutionary relationship within the Bulinus genus, which provides important insights for further understanding of the phylogeny and mitochondrial genome characteristics of the Bulinus genus.

Objective:To evaluate the efficacy of an etoposide (Vp16) -intensified conditioning regimen in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for the treatment of relapsed/refractory acute myeloid leukemia (AML).Method:A retrospective analysis was conducted on the clinical data of 27 recipients with relapsed/refractory AML who underwent allo-HSCT using a Vp16-intensified conditioning regimen at Aerospace Center Hospital from January 2019 to January 2022. Transplantation-related complications and treatment outcomes were observed. Kaplan-Meier survival analysis was used to assess the overall survival (OS) and disease-free survival (DFS) rates.Result:Among the 27 recipients, there were 14 males and 13 females, with a median age of 41 years (range: 12~55 years). Except for one recipient who experienced primary graft failure, the remaining 26 recipients achieved hematopoietic reconstitution. The median neutrophil and platelet engraftment times were 13 days (range: 9~20 days) and 13.5 days (range: 11~33 days), respectively. Regimen-related toxicity (RRT) was mainly gastrointestinal toxicity and oral mucositis, and no deaths were attributed to RRT. A total of 12 recipients (44.44%) developed acute graft-versus-host disease (aGVHD), of whom 3 cases (11.11%) had grade III~IV aGVHD. Chronic GVHD (cGVHD) occurred in 13 recipients (48.15%), including 8 cases (29.63%) of extensive cGVHD. The median follow-up time after transplantation was 17 months (range: 1~48 months). Fifteen recipients (55.56%) survived without disease, while 12 recipients (44.44%) died— 9 due to relapse and 3 due to transplant-related complications. The 1-year overall survival and DFS rates were 74.07% and 59.26%, respectively; the 2-year overall survival and DFS rates were 59.26% and 55.56%, respectively. The 2-year relapse rate and transplant-related mortality (TRM) were 33.33% and 11.11%, respectively.Conclusion:The Vp16-intensified conditioning regimen in allo-HSCT appears to be a viable treatment option for patients with relapsed/refractory AML, offering favorable efficacy and manageable safety.

Objective:To explore the effects of Xiaoyao Conger Decoction pretreatment on model rats of tinnitus with syndrome of liver-qi stagnation and spleen deficiency (TLSSD) and its preliminary mechanisms.Methods:The rats were divided into four groups: a blank group, a model group, a positive group, and Xiaoyao Conger high- and low-dosage groups, with 7 rats in each group according to random number table method. Except for the blank group, the TLSSD model was prepared by the composite etiological method in all groups of rats. The positive group received a gavage of carbamazepine at 15 mg/kg, while Xiaoyao Conger high- and low-dosage groups were given 30 g/kg and 15 g/kg of Xiaoyao Conger Decoction, respectively. The blank and model groups were administered an equal volume of saline once daily for 4 weeks. The frequency of conditioned avoidance response behaviors in rats was recorded before and at 2 and 4 weeks post-drug administration; TCM syndrome scores were documented before and after treatment; auditory brainstem response (ABR) thresholds were monitored at frequencies of 4, 12, 20, and 28 kHz; IL-1β mRNA expression in the inferior colliculus and cochlea was detected by RT-qPCR; and the levels of γ-aminobutyric acid (GABA) and glutamic acid (Glu) in hippocampal tissues were determined by LC-MS/MS.Results:The model group exhibited symptoms of liver depression, including irritability, yellow fur, and a dark red tongue, along with signs of spleen deficiency such as lethargy, decreased activity, and loose stools. Compared to the model group, rats in the Xiaoyao Conger high- and low-dosage groups demonstrated a reduction in conditioned avoidance response behaviors ( P<0.05 or P<0.01), a decrease in TCM syndrome scores ( P<0.05 or P<0.01), lower ABR thresholds at 12, 20, and 28 kHz ( P<0.01), reduced levels of IL-1β mRNA in the inferior colliculus and cochlea ( P<0.05 or P<0.01), and decreased hippocampal Glu levels ( P<0.01). Conclusion:The therapeutic effect of Xiaoyao Conger Decoction pretreatment on TLSSD rats may be related to its ability to improve the mood disorders and stress, reduce the neuroinflammatory response, regulate the CNS neurotransmitter balance, and correct the overexcitability of the auditory centre, etc.

Objective To investigate the prognostic value of optic nerve sheath diameter(ONSD)measured by critical care ultrasound combined with serum biomarkers[S100 calcium-binding protein β(S100β)and neuron-specific enolase(NSE)]in patients with severe traumatic brain injury.Methods A total of 103 adult severe traumatic brain injury patients admitted to the intensive care unit of this hospital from A-pril 1,2023,to April 1,2024 were enrolled.All patients underwent invasive intracranial pressure monitoring after admission,alongside bedside critical care ultrasound measurement of ONSD at 3 mm behind the globe and serum biomarker testing.Baseline data and Glasgow outcome scale(GOS)scores at 90 days after dis-charge were recorded.Patients were divided into the survival and the non-survival groups based on GOS scores.Receiver operating characteristic(ROC)curve analysis and area under the curve(AUC)were used to evaluate the predictive performance of ONSD and serum biomarkers for poor prognosis in severe traumatic brain injury patients.Results Ninety-six patients were ultimately included,with 52(54.1％)in the survival group and 44(45.9％)in the non-survival group.Significant differences were observed in blood glucose,Glas-gow coma scale(GCS)score,acute physiology and chronic health evaluation Ⅱ(APACHE Ⅱ)score,ONSD,NSE,and S100β levels(P＜0.05)between the two groups.Multivariate analysis identified ONSD(OR=4.962,95％CI:3.473-6.254),NSE(OR=2.704,95％CI:1.987-3.033),S100β(OR=2.983,95％CI:1.843-4.571),and APACHE Ⅱ score(OR=3.726,95％CI:2.837-4.592)as independent predictors of mortality in severe traumatic brain injury patients(P＜0.05).The combination of ONSD,NSE,and S100β yielded an AUC of 0.840 for predicting poor prognosis,with a specificity of 88.3％and sensitivity of 98.6％.Conclusion ONSD and serum brain injury biomarkers(NSE,S100β)are associated with in-hospital prognosis in severe traumatic brain injury patients.Their combined detection can effectively predict a poor outcome.

OBJECTIVE To provide direction and reference for the adjustment of the discount rate （DR） in China’s pharmacoeconomic guidelines. METHODS Search was conducted on the official websites of the International Society for Pharmacoeconomics and Outcomes Research， health technology assessment agencies in various countries/regions， as well as relevant websites of other upper-middle-income or high-income countries/regions. The recommended DR， adjustment trends， and setting rationales in pharmacoeconomic evaluation guidelines across different countries/regions were then summarized and compared. Based on theoretical derivation and literature analysis， the effects of different DR on the incremental cost-effectiveness ratio （ICER） were examined. RESULTS & CONCLUSIONS Among the 40 included guidelines， the base-case DR ranged from 1.5% to 5%， with 5% being the most common value； the range for sensitivity analysis was 0 to 12%. Thirty-six countries/regions applied the same DR to both costs and health outcomes， while in the Netherlands， Belgium， Poland and Czech Republic， DR for costs was higher than for health outcomes. In recent years， Korea， France and Ireland had lowered their DR in response to economic changes， whereas the Netherlands and Czech Republic had raised their DR for cost. The setting of the DR was primarily based on the public project investment interest rate or referred to recommendations from internationally authoritative institutions and other relevant guidelines. The direction and magnitude of the impact of different DR on the ICER largely depended on the distribution of costs and health outcomes between the intervention and reference measure. The setting and adjustment of DR were closely associated with the economic environment. Based on international experience, the DR in China can be lowered by 0.5% to 1.5%， and localized empirical research can be conducted using internationally common estimation methods.

Objective:To compare the efficacy of closed reduction and internal fixation combined with percutaneous kyphoplasty (PKP) and non-operative treatment for intertrochanteric fracture combined with osteoporotic vertebral compression fracture (OVCF) in the elderly.Methods:A retrospective cohort study was conducted to analyze the clinical data of 59 patients with intertrochanteric fracture combined with OVCF admitted to Tianjin Hospital from June 2020 to June 2023, including 16 males and 43 females, aged 66-91 years [(80.2±6.8)years]. The injured vertebral segments included T 10 in 3 patients, T 11 in 9, T 12 in 18, L 1 in 17, L 2 in 8, and L 3 in 4. According to the Genant semi-quantitative classification of vertebral fracture, 42 patients were scaled into grade 1 and 17 into grade 2. Based on the AO classification of intertrochanteric fracture, 33 patients were classified as type A1, 21 type A2, and 5 type A3. All the patients underwent closed reduction and internal fixation for intertrochanteric fractures, among whom 26 patients received PKP after the internal fixation of OVCF (PKP group) and 33 patients received non-surgical treatment after the internal fixation of OVCF (non-surgical group). The healing of the hip incision at 2 weeks after internal fixation and the healing of intertrochanteric fractures at 6 months after surgery were observed in both groups. The visual analogue scale (VAS) for low back pain was compared between the two groups before PKP, immediately after PKP, at 3 months after PKP, and at the last follow-up. The Oswestry disability index (ODI), anterior vertebral height ratio, and Cobb angle of the injured vertebrae were compared between the two groups before PKP, at 3 months after PKP, and at the last follow-up. The Harris hip function score was compared between the two groups at 3 months after internal fixation and at the last follow-up. Cement leakage was observed. The incidence of deep vein thrombosis (DVT) in the lower extremities after internal fixation were compared between the two groups. Results:All the patients were followed up for 10-46 months [(25.5±9.9)months]. The hip incisions of both groups all healed by first intention at 2 weeks after internal fixation, and the intertrochanteric fracture in both groups had bony union at 6 months after surgery. There were no significant differences between the two groups in VAS or ODI before PKP ( P>0.05). Immediately after PKP, at 3 months after PKP, and at the last follow-up, the VAS scores for low back pain were (2.6±0.6)points, (2.4±0.9)points, and (1.5±0.5)points in the PKP group, which were lower than those in the non-surgical group [(8.2±0.8)points, (3.7±1.2)points, and (3.3±0.6)points] ( P<0.01). At 3 months after PKP and at the last follow-up, the ODI values were (21.4±6.9)% and (16.2±6.3)% in the PKP group, which were lower than (38.6±11.6)% and (32.7±12.0)% in the non-surgical group ( P<0.01). The VAS for low back pain and ODI in both groups were gradually improved at each time point after PKP compared with those before PKP ( P<0.05 or 0.01). There were no significant differences in the anterior vertebral height ratio or Cobb angle of the injured vertebrae in the two groups before PKP ( P>0.05). At 3 months after PKP and at the last follow-up, the anterior vertebral height ratio was (79.8±9.6)% and (79.3±9.4)% in the PKP group, which were higher than (73.4±9.3)% and (62.0±10.4)% in the non-surgical group ( P<0.05 or 0.01); the values of the Cobb angle of the injured vertebrae were (12.6±3.6)° and (12.0±3.3)°in the PKP group, which were lower than (15.5±2.6)° and (20.4±4.9)° in the non-surgical group ( P<0.01). There were no significant differences in the anterior vertebral height ratio and Cobb angle of the injured vertebrae in the PKP group before PKP and at each time point after PKP ( P>0.05) while in the non-surgical group, the anterior vertebral height ratio at each time point after PKP was lower than that before PKP and the Cobb angle of the injured vertebrae was increased compared with that before PKP ( P<0.01). At 3 months after internal fixation and at the last follow-up, the Harris hip function scores in the PKP group were (76.4±3.4)points and (87.7±4.5)points, which were higher than (57.0±6.8)points and (76.3±8.9)points in the non-surgical group ( P<0.01). The Harris hip function scores in both groups were improved at the last follow-up, compared with those at 3 months after internal fixation. Five patients had cement leakage in the PKP group, all of which were lateral leakage.There was no occurrence of radiating pain in the lower extremities. The incidence of DVT at 1 month after internal fixation was 19.2% (5/26) in the PKP group, which was lower than 57.6% (19/33) in the non-surgical group ( P<0.01). Conclusion:Compared with non-operative treatment after the closed reduction and internal fixation, PKP after internal fixation can significantly relieve low back pain in the early stage, improve the functional restoration of the vertebral column, maintain vertebral height, prevent kyphosis, promote the recovery of the hip joint function, and reduce the occurrence of DVT in the lower extremities in the treatment of intertrochanteric fracture combined with OVCF.

Objective:To evaluate the effects and underlying mechanisms of metabolites derived from the kidney-reinforcing, blood circulation-activating, and collateral dredging decoction on the proliferation of multiple myeloma (MM) KM3 cells.Methods:MM KM3 cells in the logarithmic growth phase were treated with 3%, 6%, 9%, or 12% metabolites of kidney-reinforcing, blood circulation-activating, and collateral dredging decoction. Cell viability was assessed using the CCK-8 assay. Apoptosis and necrosis were evaluated using flow cytometry and TUNEL staining. Mitochondrial and cellular ultrastructural changes were examined using transmission electron microscopy. mRNA and protein expression levels of dynamin-related protein 1 (Drp1), mitochondrial fission protein 1 (Fis1), mitochondrial fission factor (MFF), PTEN-induced kinase 1 (Pink1), and E3 ubiquitin ligase (Parkin) were determined through quantitative real-time PCR and western blotting. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) combined with network pharmacology, was utilized for reverse verification of the pharmacodynamic mechanisms and therapeutic targets underlying the anti-MM activity of this decoction.Results:The metabolites of the kidney-reinforcing, blood circulation-activating, and collateral dredging decoction inhibited KM3 cell proliferation and induced apoptosis in a dose-dependent manner. Transmission electron microscopy revealed increased mitochondrial fission and autophagic structures, with effects intensifying at higher metabolite concentrations. mRNA and protein expression of Drp1, Fis1, MFF, Pink1, and Parkin were significantly upregulated in treatment groups compared to controls ( P<0.05), with the most pronounced effects observed in the 12% metabolite group ( P<0.01). HPLC-MS/MS identified 121 bioactive compounds in BHTF, which shared 474 overlapping targets with MM. Enrichment analysis suggested that BHTF exerts antitumor effects primarily through apigenin, palmatine, and other key components by modulating TNF, NF-κB, and mitophagy pathways. Conclusion:The kidney-reinforcing and blood circulation-activating and collateral dredging decoction suppresses the proliferation of MM KM3 cells, potentially through mechanisms involving the regulation of mitochondrial dynamics and induction of autophagy.

Objective To investigate the characteristics of macrophage depletion by clodronate liposomes(CL)in a carbon tetrachloride(CCl4)-induced liver fibrosis mouse model,and to analyze the transcriptomic features.Methods Thirty-two C57BL/6 mice were divided randomly into plain control liposomes for clophosome(PL)and clodronate liposome(CL)groups(n=16 mice per group),and administered intraperitoneal injections of PL and CL,respectively.On day 5,each group was further divided into normal(N)and model(M)subgroups(n=8 mice per subgroup).Mice in group M received 10％CCl4 intraperitoneally to induce liver fibrosis,while mice in group N received an equal volume of olive oil.After 4 weeks,serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)levels were measured,and hepatic inflammation and collagen deposition were evaluated by hematoxylin/eosin and Sirius red staining,respectively.Total RNA was extracted from liver tissues for transcriptomic sequencing and subsequent differential gene expression analysis.Results Serum ALT and AST levels were significantly elevated in the PL-M group(P＜0.01),with fibrosis staging primarily at S3,compared with S1 in the CL-M group.Totals of 1462 and 2119 differentially expressed genes(|log fold change|＞2 and P＜0.05)were identified in the PL and CL groups,respectively.Gene Ontology analysis revealed enrichment in multiple biological processes,cellular components,and molecular functions in both models,and Kyoto Encyclopedia of Genes and Genomes analysis identified 29 significantly enriched pathways(P＜0.05).The upregulation of genes including Lgals7 and Timp1 and the downregulation of Mup-ps16 and Mup15 were validated by reverse transcription-quantitative polymerase chain reaction,consistent with transcriptomic trends(P＜0.05).Conclusions This study highlights the characteristics and transcriptomic features of macrophage depletion in the CCl4-induced liver fibrosis model,providing a theoretical reference for research on the immune mechanisms of liver fibrosis.