Recent data suggest that vascular endothelial growth factor receptor inhibitor (VEGFRi) can enhance the anti-tumor activity of the anti-programmed cell death-1 (anti-PD-1) antibody in colorectal cancer (CRC) with microsatellite stability (MSS). However, the comparison between this combination and standard third-line VEGFRi treatment is not performed, and reliable biomarkers are still lacking. We retrospectively enrolled MSS CRC patients receiving anti-PD-1 antibody plus VEGFRi (combination group, n=54) or VEGFRi alone (VEGFRi group, n=32), and their efficacy and safety were evaluated. We additionally examined the immune characteristics of the MSS CRC tumor microenvironment (TME) through single-cell and spatial transcriptomic data, and an MSS CRC immune cell-related signature (MCICRS) that can be used to predict the clinical outcomes of MSS CRC patients receiving immunotherapy was developed and validated in our in-house cohort. Compared with VEGFRi alone, the combination of anti-PD-1 antibody and VEGFRi exhibited a prolonged survival benefit (median progression-free survival: 4.4 vs. 2.0 months, P=0.0024; median overall survival: 10.2 vs. 5.2 months, P=0.0038) and a similar adverse event incidence. Through single-cell and spatial transcriptomic analysis, we determined ten MSS CRC-enriched immune cell types and their spatial distribution, including naive CD4⁺ T, regulatory CD4⁺ T, CD4⁺ Th17, exhausted CD8⁺ T, cytotoxic CD8⁺ T, proliferated CD8⁺ T, natural killer (NK) cells, plasma, and classical and intermediate monocytes. Based on a systemic meta-analysis and ten machine learning algorithms, we obtained MCICRS, an independent risk factor for the prognosis of MSS CRC patients. Further analyses demonstrated that the low-MCICRS group presented a higher immune cell infiltration and immune-related pathway activation, and hence a significant relation with the superior efficacy of pan-cancer immunotherapy. More importantly, the predictive value of MCICRS in MSS CRC patients receiving immunotherapy was also validated with an in-house cohort. Anti-PD-1 antibody combined with VEGFRi presented an improved clinical benefit in MSS CRC with manageable toxicity. MCICRS could serve as a robust and promising tool to predict clinical outcomes for individual MSS CRC patients receiving immunotherapy.
Humans ; Colorectal Neoplasms/drug therapy* ; Male ; Female ; Immunotherapy ; Middle Aged ; Aged ; Tumor Microenvironment/immunology* ; Retrospective Studies ; Microsatellite Instability ; Transcriptome ; Single-Cell Analysis ; Programmed Cell Death 1 Receptor/immunology* ; Gene Expression Profiling ; Immune Checkpoint Inhibitors/therapeutic use* ; Adult ; Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors*

Objective To explore the neuroprotective effects of osteocalcin(OCN)on an Alzheimer's disease(AD)cell model and its potential mechanisms,providing a scientific basis for new therapeutic targets for AD.Methods Human neuroblastoma cell line SH-SY5Y was treated with 40 nmol/L okadaic acid(OA)for 24 h to establish an AD cell model.The cells were divided into a normal group(untreated SH-SY5Y cells),a model group(40 nmol/L OA intervention),and an OCN intervention group(intervention with various concentrations of OCN in the AD cell model),and AKT knockout/overexpression groups(AKT-KO group and AKT-OE group),and AKT-KO OCN group and AKT-OE OCN group.CCK-8 assay was used to detect the changes in cell viability.Wright's staining was employed to observe the morphological changes of AD cells.Western blotting was utilized to detect the protein levels of Tau,p-Tau,Bax,Bcl-2,Caspase-3 and their lytic types,as well as the expression of Tau,p-Tau,mTOR,AKT and p-AKT in each group after AKT knockout/overexpression.TUNEL staining and flow cytometry were applied to detect the changes in early and late apoptotic cells and the apoptotic rate in the OCN-treated AD cell model.Results ①Compared to the normal group,the model group exhibited a significant decrease in cell viability,noticeable morphological and structural damage,upregulation of p-Tau and Caspase-3,increased early and late apoptosis,and a significantly higher apoptotic rate(P<0.05).②After treatment of different concentrations of OCN for 24 h,cell viability was increased to varying degrees compared to the AD model group,with the 100 pg/mL OCN group showing a significant increase in cell viability(P<0.01)and marked improvement in cell number and morphology(P<0.01).③ Compared to the AD cell model group,the p-Tau/Tau ratio was decreased in all OCN treatment groups,particularly in the 100 pg/mL OCN intervention group,where the p-Tau/Tau ratio was significantly lower than that of the model group(P<0.01).④ Compared to the model group,a significant concentration-dependent decrease in the Cleaved Caspase-3/Caspase-3 ratio was observed when OCN concentrations ranged from 1 to 100 pg/mL,with a significant reduction in the Bax/Bcl-2 ratio in the 100 pg/mL group(P<0.000 1).⑤ The results of TUNEL staining and flow cytometry showed that,compared to the model group,all concentrations of OCN effectively inhibited the apoptosis in the AD model cells,with a significant reduction in early and late apoptotic cells and apoptotic rate in the 100 pg/mL OCN group.⑥ Compared with the control group and the model group,the P-AKT was significantly increased in the AKT-OE group after AKT overexpression(P<0.05).The expression level of AKT protein was decreased in the AKT-KO group after AKT knockout(P<0.05).When the AKT pathway was inhibited,the expression level of p-Tau was higher in the AKT-KO group than the control group(P<0.05),and when the AKT was overexpressed,the expression level was significantly inhibited(P<0.05).Conclusion OCN may inhibit cell apoptosis and reduce p-tau protein level by regulating the ratio of Caspase-3/Caspase-3 and Bax/Bcl-2,and thereby improve the morphology of AD model cells and effectively protect nerve cells,which may be related to the regulation of the AKT/mTOR pathway.

Objective:Postoperative neurosurgical bacterial meningitis (PNBM) has been frequently reported, but fewer studies have focused on the contemporaneous comparison of clinical features of PNBM caused by different pathogenic bacteria. This study aimed to simultaneously investigate the clinical characteristics and outcomes of PNBM by Gram-positive bacterial(GPB) or Gram-negative bacterial (GNB) infection.Methods:Inpatients with PNBM at our institution were recruited between February 2013 and October 2023. These PNBM patients were categorized into two groups: GPB infection and GNB infection. Data from electronic medical records were collected and analyzed.Results:A total of 401 patients with PNBM were finally included, with 78 (19.5%) having GPB infections and 323 (80.5%)having GNB infection. The average age of the patients was 56 years, and 55.1% were male. Compared to the GPB group, PNBM patients with GNB infection had significantly higher SOFA and APACHE Ⅱ scores, higher proportions of hyperthermia (body temperature>39°C) and altered consciousness, increased ratios of postoperative cerebral hemorrhage or intracranial aneurysm, as well as greater needs for ICU treatment and mechanical ventilation (all P <0.05). The proportions of inflammatory indicators such as blood CRP and PCT≥2 ng/mL, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) were significantly higher in the GNB group (all P<0.05). In contrast, The concentrations of hemoglobin and albumin were substantially lower in this group(both P <0.05). Additionally, the cerebrospinal fluid in the GNB group showed significantly higher nucleated cell counts, protein concentration, and adenosine deaminase concentration, and but lower glucose level (all P <0.001). A total of 426 bacterial strains were isolated, with 343 strains (80.5%) being GNB and 83 strains (19.5%) being GPB. Among these, 25 (6.2%) patients had 2 or more gram-positive or gram-negative bacterial infections. The proportions of multidrug-resistant (MDR) bacteria and intrathecal treatment were higher in the GNB group (80.5% vs. 68.7%, 36.5% vs. 2.6%, respectively), while the ratio of correct empirical antibiotic treatment was significantly lower (30.3% vs. 80.0%) (all P <0.05). In terms of outcomes, the length of stay in the ICU was significantly longer in the GNB group [(median (interquartile range, IQR): 11.5 (5.25,22.75) vs. 17.0 (9.0,30.0), P <0.01)], and the rate of septic shock (9.3% vs. 2.6%), poor prognosis (GCS≤8 at discharge) (65.9% vs. 32.1%), and 28-day hospital mortality rate (34.4% vs. 10.3%) were significantly higher compared to the GPB group (all P <0.05). However, there were no differences in 7-day hospital mortality and total hospitalization time. Conclusions:Gram-negative bacterial infections are more prevalent than Gram-positive bacterial infections in PNBM, and they are also associated with more severe symptoms, abnormal cerebrospinal fluid findings, higher severity, and more treatment difficulty. Despite comparable short-term (7-day) mortality rates between Gram-positive and Gram-negative bacterial infections, Gram-negative bacterial infections result in higher medium- to long-term (14-day and 28-day) case-fatality rates among patients with post-neurosurgical bacterial meningitis and are associated with overall poorer prognosis, warranting greater attention from clinicians.

Lung cancer is characterized by high incidence and mortality rates and invasiveness, and its occurrence and development are influenced by various factors. Mitochondria, as ubiquitous organelles in the human body, regulate cellular processes, such as metabolism, signal transduction, oxidative stress, and genomic instability, thereby affecting the initiation and progression of lung cancer. This article summarizes the recent research progress on mitochondrial-targeted drugs, mitochondrial transfer, and mitochondrial gene therapy for lung cancer treatment. This work also discusses the principles and prospects of mitochondrial therapy to provide new insights for lung cancer treatment.

Objective It analyzes the equity of pharmacists'allocation in China's healthcare organizations from 2012 to 2021,in order to provide reference for improving the service accessibility of pharmacists.Methods Based on the degree of agglomeration,analyzing the current situation and changing trend of pharmacists'allocation in healthcare organizations among different areas and provinces.Results The current allocation of pharmacists in China's healthcare organizations has not met the requirements.The situation in the eastern economically developed areas is better than that in other areas of the country either by geography or by population.While the western areas are large and sparsely populated,so the accessibility of pharmacist service is poor based on geographical allocation,but the equity is good based on population allocation.In the central area,the accessibility of pharmacist service is better when the allocation is based on geographical,but the equity is worse when the allocation is based on population.Conclusion China should further enrich the team of pharmacists in healthcare organizations to promote the coordinated development of different provinces.Furthermore,it also helps to promote the equity of pharmacists'allocation in China's healthcare organizations.

Objective It analyzes the equity of pharmacists'allocation in China's healthcare organizations from 2012 to 2021,in order to provide reference for improving the service accessibility of pharmacists.Methods Based on the degree of agglomeration,analyzing the current situation and changing trend of pharmacists'allocation in healthcare organizations among different areas and provinces.Results The current allocation of pharmacists in China's healthcare organizations has not met the requirements.The situation in the eastern economically developed areas is better than that in other areas of the country either by geography or by population.While the western areas are large and sparsely populated,so the accessibility of pharmacist service is poor based on geographical allocation,but the equity is good based on population allocation.In the central area,the accessibility of pharmacist service is better when the allocation is based on geographical,but the equity is worse when the allocation is based on population.Conclusion China should further enrich the team of pharmacists in healthcare organizations to promote the coordinated development of different provinces.Furthermore,it also helps to promote the equity of pharmacists'allocation in China's healthcare organizations.

Objective It analyzes the equity of pharmacists'allocation in China's healthcare organizations from 2012 to 2021,in order to provide reference for improving the service accessibility of pharmacists.Methods Based on the degree of agglomeration,analyzing the current situation and changing trend of pharmacists'allocation in healthcare organizations among different areas and provinces.Results The current allocation of pharmacists in China's healthcare organizations has not met the requirements.The situation in the eastern economically developed areas is better than that in other areas of the country either by geography or by population.While the western areas are large and sparsely populated,so the accessibility of pharmacist service is poor based on geographical allocation,but the equity is good based on population allocation.In the central area,the accessibility of pharmacist service is better when the allocation is based on geographical,but the equity is worse when the allocation is based on population.Conclusion China should further enrich the team of pharmacists in healthcare organizations to promote the coordinated development of different provinces.Furthermore,it also helps to promote the equity of pharmacists'allocation in China's healthcare organizations.

Objective It analyzes the equity of pharmacists'allocation in China's healthcare organizations from 2012 to 2021,in order to provide reference for improving the service accessibility of pharmacists.Methods Based on the degree of agglomeration,analyzing the current situation and changing trend of pharmacists'allocation in healthcare organizations among different areas and provinces.Results The current allocation of pharmacists in China's healthcare organizations has not met the requirements.The situation in the eastern economically developed areas is better than that in other areas of the country either by geography or by population.While the western areas are large and sparsely populated,so the accessibility of pharmacist service is poor based on geographical allocation,but the equity is good based on population allocation.In the central area,the accessibility of pharmacist service is better when the allocation is based on geographical,but the equity is worse when the allocation is based on population.Conclusion China should further enrich the team of pharmacists in healthcare organizations to promote the coordinated development of different provinces.Furthermore,it also helps to promote the equity of pharmacists'allocation in China's healthcare organizations.

Objective It analyzes the equity of pharmacists'allocation in China's healthcare organizations from 2012 to 2021,in order to provide reference for improving the service accessibility of pharmacists.Methods Based on the degree of agglomeration,analyzing the current situation and changing trend of pharmacists'allocation in healthcare organizations among different areas and provinces.Results The current allocation of pharmacists in China's healthcare organizations has not met the requirements.The situation in the eastern economically developed areas is better than that in other areas of the country either by geography or by population.While the western areas are large and sparsely populated,so the accessibility of pharmacist service is poor based on geographical allocation,but the equity is good based on population allocation.In the central area,the accessibility of pharmacist service is better when the allocation is based on geographical,but the equity is worse when the allocation is based on population.Conclusion China should further enrich the team of pharmacists in healthcare organizations to promote the coordinated development of different provinces.Furthermore,it also helps to promote the equity of pharmacists'allocation in China's healthcare organizations.

Objective It analyzes the equity of pharmacists'allocation in China's healthcare organizations from 2012 to 2021,in order to provide reference for improving the service accessibility of pharmacists.Methods Based on the degree of agglomeration,analyzing the current situation and changing trend of pharmacists'allocation in healthcare organizations among different areas and provinces.Results The current allocation of pharmacists in China's healthcare organizations has not met the requirements.The situation in the eastern economically developed areas is better than that in other areas of the country either by geography or by population.While the western areas are large and sparsely populated,so the accessibility of pharmacist service is poor based on geographical allocation,but the equity is good based on population allocation.In the central area,the accessibility of pharmacist service is better when the allocation is based on geographical,but the equity is worse when the allocation is based on population.Conclusion China should further enrich the team of pharmacists in healthcare organizations to promote the coordinated development of different provinces.Furthermore,it also helps to promote the equity of pharmacists'allocation in China's healthcare organizations.