Uveal melanoma(UM)is the most common primary intraocular malignancy in adults, characterized by high invasiveness and unique metastatic biological features. Although local treatments(such as proton beam therapy and brachytherapy)can effectively control the primary lesion, approximately 50% of patients eventually develop distant metastasis, with the liver being the primary target organ(occurring in 90% of cases). This highlights a paradigm shift in treatment focus from mere local control to systemic prevention and management. For metastatic UM(mUM), current treatment strategies encompass biomarker-guided molecular targeted therapy, immunotherapy(including Tebentafusp, vaccines, and oncolytic virus therapy), and liver-directed therapy. Focusing on the synergy between local and systemic prevention and control, this article systematically elaborates on the precision local treatment for primary UM, the decision-making pathway for systemic treatment of metastatic UM based on molecular subtyping, the integration of local and systemic therapies for liver metastases, and the translational value of nanomedicine in addressing therapeutic bottlenecks. It provides insights for optimizing clinical management of mUM and developing novel therapeutic strategies.

Objective To explore the characteristics and correlation between perivascular spaces (PVS) and diffusion tensor image analysis along perivascular spaces (DTI-ALPS) index in patients with amnestic mild cognitive impairment (aMCI). Methods A retrospective study was conducted on a total of 118 participants, including cognitive normal (CN) healthy controls and aMCI patients, recruited from the Department of Neurology, Zhongshan Hospital, Fudan University from September 2020 to September 2022. All participants underwent structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). An automatic segmentation algorithm was used to quantify PVS metrics in the brain, and DTI-ALPS index was calculated based on DTI. Differences in DTI-ALPS index and PVS metrics between the CN and aMCI groups were compared. Multivariate logistic regression was used to identify independent factors influencing aMCI. Correlation analysis was performed to assess relationships among DTI-ALPS index, PVS metrics, and cognitive scores. Results A total of 80 CN healthy controls and 38 aMCI patients were included. The DTI-ALPS index was significantly lower in the aMCI group compared with the CN group (1.28±0.18 vs 1.37±0.21, P＝0.018), while differences in PVS metrics between groups were not statistically significant. Multivariate logistic regression analysis indicated that DTI-ALPS index was an independent factor affecting aMCI (OR＝0.097, 95%CI 0.011–0.833, P＝0.033). Correlation analysis revealed a positive relationship between DTI-ALPS index and MMSE score (r＝0.210, P＝0.023) as well as PVS length in the centrum semiovale (r＝0.216, P＝0.019). Conclusions The DTI-ALPS index may serve as an imaging biomarker for identifying early cognitive impairment, and patients with aMCI exhibit abnormal DTI-ALPS indices, suggesting that brain glymphatic system dysfunction may occur prior to morphological changes.

ObjectiveTo investigate whether intestinal deficiency of lanosterol synthase （LSS）， a key enzyme in cholesterol synthesis， influences the progression of metabolic dysfunction-associated steatotic liver disease （MASLD） by regulating intestinal cholesterol absorption and immune response. MethodsLSS heterozygous knockout （LSS^+/-） mice and wild-type （WT） controls were generated using CRISPR/Cas9 technology and fed either a high-fat diet （HFD） or regular chow （CHOW）. The model was validated by genotyping. Hepatic steatosis was assessed by HE and oil red O staining. Immunohistochemistry was used to detect the localization and expression of NPC1L1 and CD36 proteins in the intestine. Western blot analysis was performed to measure JNK phosphorylation and TLR4 protein levels in intestinal tissues. Real-time quantitative polymerase chain reaction （qPCR） was employed to examine the mRNA expression of TLR4 and IL-6. ResultsLSS^+/- mice were successfully validated by genotyping and reduced intestinal LSS protein expression. HE and oil red O staining of liver sections showed that， compared with WT mice fed a CHOW diet， WT mice fed a HFD exhibited a marked increase in hepatic lipid vacuoles. In contrast， compared with HFD-fed WT mice， HFD-fed LSS^+/- mice displayed significantly attenuated hepatic lipid deposition and reduced serum ALT levels （P<0.05）. Immunohistochemical analysis revealed that， compared with WT mice， the expression of the cholesterol absorption protein NPC1L1 in the intestinal villi of LSS^+/- mice was downregulated under both CHOW and HFD conditions （P_HFD<0.001）. Conversely， the expression of the fatty acid transporter CD36 was upregulated in the intestines of LSS^+/- mice （P_CHOW<0.05， P_HFD<0.01）. Western blot analysis demonstrated that， compared with WT mice， TLR4 protein expression in the intestines of LSS^+/- mice significantly increased under both CHOW and HFD conditions （both P<0.05）. JNK phosphorylation level was significantly elevated in LSS^+/- mice under CHOW condition （both P<0.05）. Under HFD condition， total JNK protein expression increased， but its phosphorylation level showed no significant change. qPCR analysis showed that， compared with WT mice， the mRNA levels of TLR4 （P_CHOW<0.01， P_HFD<0.000 1） and IL-6 （P_CHOW<0.001， P_HFD<0.01） were significantly upregulated in the intestines of LSS^+/-mice. ConclusionLSS deficiency counteracts hepatic lipid deposition by orchestrating a synergistic reprogramming involving restricted intestinal cholesterol absorption， enhanced fatty acid utilization， and activation of immune pathways， suggesting intestinal LSS as a potential therapeutic target of MASLD.

ObjectiveTo investigate the effect of hypoxia on pemetrexed （PE）-mediated apoptosis in non-small cell lung cancer cells. MethodsA549 cells were cultured under 21% O₂ （normoxia） or 1% O₂ （hypoxia）， and treated with 8 μmol/L PE for 48 h. The cells were divided into normoxic control group， normoxic vehicle group， normoxic drug-treated group， hypoxic control group， hypoxic vehicle group and hypoxic drug-treated group. Trypan blue staining was used to observe cell death after PE intervention under normoxia and hypoxia. Flow cytometry was adopted to detect cell apoptosis rate. Wound healing assay was used to assess cell migration. Western blot was performed to detect the protein levels of MRP-1， Cleaved Caspase-3， E-Cadherin and N-Cadherin. ResultsTrypan blue staining results showed that the cell death rate was reduced in PE-treated cells under hypoxia compared with the normoxic PE group （P<0.001）. Flow cytometry results indicated that PE induced cell apoptosis under both normoxic and hypoxic conditions.However， the apoptosis rate of the normoxic PE group was significantly higher than that of the hypoxic PE group （P<0.000 1）. Wound healing assay showed that the migration distance of A549 cells decreased after PE treatment for 24 h and 48 h under normoxia and hypoxia when compared with the control group （P<0.05）， while no significant difference was found between the normoxic PE group and the hypoxic PE group. Western blot results revealed that MRP-1 expression was markedly higher in hypoxic PE-treated cells than in normoxic PE-treated cells （P<0.000 1）. Compared with the control group， Cleaved Caspase-3 expression was upregulated in A549 cells following PE intervention under normoxia （P<0.05）， whereas no obvious alteration in Cleaved Caspase-3 expression was detected in hypoxic PE-treated cells. Under both normoxic and hypoxic conditions， PE treatment downregulated the expression of E-Cadherin （P<0.000 1，P<0.001） and N-Cadherin （P<0.05，P<0.000 1）. In addition， the expression levels of E-Cadherin and N-Cadherin in the hypoxic PE group were significantly lower than those in the normoxic PE group （all P<0.000 1）. ConclusionHypoxia significantly attenuates the pro-apoptotic effect of PE on A549 cells and blocks Cleaved Caspase-3 activation. This mechanism may be related to hypoxia-induced MRP-1 overexpression and reduced drug accumulation. Interfering with MRP-1 or restoring the activity of the apoptosis pathway may serve as a novel strategy to overcome hypoxia-induced drug resistance.

Objective To investigate the effects of hyaluronic acid and proteoglycan-linked protein 1 (HAPLN1) secreted by synovial fibroblasts (FLS) on the polarization of macrophages (Mϕ) in rheumatoid arthritis (RA). Methods Human monocytic leukemia cells (THP-1) were differentiated into Mϕ, which were subsequently exposed to recombinant HAPLN1 (rHAPLN1). RA-FLS were transfected separately with HAPLN1 overexpression plasmid (HAPLN1^OE) or small interfering RNA targeting HAPLN1 (si-HAPLN1), and then co-cultured with Mϕ to establish a co-culture model. The viability of Mϕ was assessed using the CCK-8 assay, and the proportions of pro-inflammatory M1-type and anti-inflammatory M2-type Mϕ were analyzed by flow cytometry. Additionally, the expression levels of inflammatory markers, including interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), and inducible nitric oxide synthase (iNOS), were quantified using quantitative real-time PCR and Western blot analysis. Results The viability of Mϕ was increased in the rHAPLN1 group compared to the control group. Furthermore, both the M1/Mϕ ratio and inflammatory factor levels were elevated in the rHAPLN1 and HAPLN1^OE groups. In contrast, the si-HAPLN1 group exhibited a decrease in the M1/Mϕ ratio and inflammatory factor expression. Notably, the introduction of rHAPLN1 in rescue experiments further promoted Mϕ polarization towards the M1 phenotype. Conclusion HAPLN1, secreted by RA fibroblast-like synoviocytes (RA-FLS), enhances Mϕ polarization towards the M1 phenotype.
Humans ; Arthritis, Rheumatoid/genetics* ; Macrophages/immunology* ; Fibroblasts/metabolism* ; Phenotype ; Extracellular Matrix Proteins/genetics* ; Proteoglycans/genetics* ; Synovial Membrane/cytology* ; Tumor Necrosis Factor-alpha/genetics* ; Interleukin-1beta/genetics* ; Nitric Oxide Synthase Type II/genetics* ; Cell Differentiation ; Coculture Techniques ; THP-1 Cells

HDAC7, a member of class IIa HDACs, plays a pivotal regulatory role in tumor, immune, fibrosis, and angiogenesis, rendering it a potential therapeutic target. Nevertheless, due to the high similarity in the enzyme active sites of class IIa HDACs, inhibitors encounter challenges in discerning differences among them. Furthermore, the substitution of key residue in the active pocket of class IIa HDACs renders them pseudo-enzymes, leading to a limited impact of enzymatic inhibitors on their function. In this study, proteolysis targeting chimera (PROTAC) technology was employed to develop HDAC7 drugs. We developed an exceedingly selective HDAC7 PROTAC degrader B14 which showcased superior inhibitory effects on cell proliferation compared to TMP269 in various diffuse large B cell lymphoma (DLBCL) and acute myeloid leukemia (AML) cells. Subsequent investigations unveiled that B14 disrupts BCL6 forming a transcriptional inhibition complex by degrading HDAC7, thereby exerting proliferative inhibition in DLBCL. Our study broadened the understanding of the non-enzymatic functions of HDAC7 and underscored the importance of HDAC7 in the treatment of hematologic malignancies, particularly in DLBCL and AML.

OBJECTIVE Aimd to investigate the prevalence of olfactory dysfunction among healthy elderly individuals in China using a large sample size and to explore its correlations with demographic and other factors.METHODS A total of 5 258 participants who aged 60 and above underwent the T&T olfactometer test and completed questionnaires.The prevalence of olfactory dysfunction was reported,and logistic regression analyses were performed to assess the associations between olfactory dysfunction and other factors.RESULTS The overall prevalence of olfactory dysfunction in the study was 26.5%.Independent risk factors for olfactory dysfunction included advanced age,rural residence(OR=1.88,95%CI:1.60-2.22,P<0.01),current smoking(OR=1.45,95%CI:1.15-1.83,P<0.01),and self-reported olfactory dysfunction(OR=10.12,95%CI:8.44-12.14,P<0.01).In contrast,female gender(OR=0.70,95%CI:0.58-0.85,P<0.01)and high educational attainment were independently associated with a lower prevalence of olfactory dysfunction.CONCLUSION The prevalence of olfactory dysfunction among individuals aged 60 and above increased with age.Male gender,rural residence,low educational attainment,current smoking,and self-reported decline in olfactory function were independently associated with olfactory dysfunction.

Objective To explore the potential cross-sectional categories of health promotion behaviors in patients after PCI and analyze their influencing factors,so as to provide a reference for formulating targeted interventions to improve health promotion behaviors in patients after PCI.Methods A total of 242 patients who underwent PCI surgery in the Department of Cardiovascular Medicine of a tertiary hospital in Sichuan Province from February to May 2024 were selected by convenience sampling method.The general information questionnaire,the health promotion lifestyle scale,the health literacy scale for patients with chronic diseases,and the perceived social support scale were used to conduct the survey.The potential profile analysis of health promotion behaviors in patients after PCI was carried out,and the influencing factors were explored by univariate analysis and multiple logistic regression analysis.Results A total of 230 patients after PCI completed the study.The results of potential profile analysis showed that the health promotion behaviors of patients after PCI could be divided into three potential profiles:"low health promotion-poor behavior group"(n=71,30.9%),"medium health promotion behavior group"(n=53,23.0%),and"high health promotion-positive behavior group"(n=106,46.1%).Logistic regression analysis showed that medical payment methods,the number of chronic diseases,whether they had received chronic disease-related knowledge guidance,health literacy,and social support were the influencing factors of the potential profile of health promotion behaviors of patients after PCI(all P<0.05).Conclusion The health promotion behaviors of patients after PCI have obvious categorical characteristics.Nursing staff should formulate personalized intervention strategies according to the characteristics and influencing factors of each category,improve the health literacy and comprehension of social support of patients after PCI,and then improve their health promotion behaviors.

Cancer-associated venous thromboembolism(CAT)refers to the presence of venous thromboem-bolism including deep vein thrombosis and pulmonary embolism in patients with malignant cancer.Studies have indicated that CAT has become the second leading cause of death among cancer patients.Similar to other methods used to prevent and treat venous thromboembolism,anticoagulation remains to be the primary approach for CAT.However,the occurrence of CAT is influenced by various factors such as tumor type,staging,complications,treat-ment,and prognosis.This complexity makes the prevention and management of CAT more difficult and challeng-ing.This article reviews the classification of commonly used anticoagulant drugs in clinical practice,emphasizing the current status and advancements in their application for the prevention and treatment of cancer-related venous thromboembolism in order to provide valuable reference for clinical medication.

ObjectiveTo explore the establishment of performance assessment indicators for the classification and grading of public health staff in district-level Centers for Disease Control and Prevention (CDCs), and to provide a basis for such evaluations. MethodsThrough literature review and group interviews, performance evaluation indicators were developed based on competency evaluation. Experts were invited to evaluate the weight of performance evaluation indicators for public health staff from different categories, with the average value used to represent the weight of each indicator. ResultsTwenty-nine experts from universities in Shanghai, municipal CDCs, and district CDCs participated, yielding an expert authority coefficient of 0.86. The performance evaluation indicators for department managers were categorized into three levels, with 4 indicators at the primary level, 16 indicators at the secondary level, and 42 indicators at the tertiary level, while those for general staff included 4 primary indicators, 15 secondary indicators, and 36 tertiary indicators. Significant differences were observed in the weight coefficients of the primary indicators (internal operations, professional work, and learning and growth) between department managers and general staff. The top three secondary indicators for department managers were department management, monitoring and prevention, and level of expertise. For mid-level and senior staff, the top three secondary indicators were monitoring and prevention, level of expertise, and research work. The top three secondary indicators for junior staff were monitoring and prevention, professional expertise, and professional attitude. No significant statistical differences were found among tertiary indicators. ConclusionThe developed performance evaluation indicators are reliable. Staff at different levels and classifications should be evaluated using different performance evaluation standards to accurately reflect individual performance and contributions.