ObjectiveHepatocellular carcinoma (HCC) represents 90% of all primary liver cancers. The main risk factors associated with HCC include viral hepatitis (B and/or C), alcohol abuse, and metabolic dysfunction-associated steatotic liver disease (MASLD), which progressively advance to liver fibrosis, cirrhosis, and ultimately evolve into HCC. Surgical resection represents the most effective treatment for HCC, while recent advances in immunotherapy, including immune checkpoint inhibitors and adoptive cell therapies, have provided improved treatment prospects for patients with unresectable HCC. However, the complex metabolic heterogeneity of HCC limits the therapeutic efficacy. Metabolic intermediates acyl-CoA not only provide energy and substrates for numerous biochemical reactions but also serve as donors for protein lysine acylation, a major class of post-translational modification (PTM). Therefore, a deeper understanding of the molecular mechanisms underlying protein lysine acylation and hepatocarcinogenesis is urgently needed. MethodsThe levels of protein lysine acylation and silence information regulator 5 (SIRT5) expression levels in clinical HCC samples were analyzed by Western blot. Quantitative malonylome and succinylome of HCC samples were analyzed by antibody-based affinity enrichment coupled with tandem mass spectrometry. The proliferation of HCC cells was analyzed with Cell Counting Kit-8 (CCK-8) assays, the apoptosis was quantified by Annexin V-FITC/propidium iodide (PI) staining coupled with flow cytometry, and the ability of cells to migrate was assayed by Transwell assays. The enzymatic activity of glutathione S-transferase Mu 1 (GSTM1) was quantified. Transgenic mice with hepatic overexpression of SIRT5 were constructed using CRISPR-Cas9, and primary hepatocarcinogenesis was induced by administration of diethylnitrosamine. ResultsWestern blot analysis indicated that the expression level of SIRT5 was elevated in clinical samples from HCC patients, and the levels of lysine malonylation, glutarylation, and succinylation were significantly reduced in HCC tissues. Knockout of SIRT5 in MHCC-97H and MHCC-97L hepatoma cells suppressed cell proliferation, and increased the percentage of apoptotic cells significantly. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the differentially malonylome and succinylome of HCC samples revealed significant enrichment in two major classes of biological processes: core energy metabolism (e.g., glycolysis/gluconeogenesis, tricarboxylic acid metabolic process, fatty acid beta oxidation) and detoxification and oxidative stress response (e.g., response to toxic substance, chemical carcinogenesis, reactive oxygen species (ROS)). SIRT5 removes malonylation from lysine residues in GSTM1 and restores its detoxification activity, which is crucial for the survival of hepatocytes under stressed conditions. More importantly, in vivo experiment indicated that hepatic-specific overexpression of SIRT5 in mice accelerated diethylnitrosamine-induced liver fibrosis and hepatocarcinogenesis, indicating the critical role of SIRT5 in HCC progression. ConclusionThis study highlights the previously unrecognized SIRT5-GSTM1 axis as a key regulator in hepatocarcinogenesis, and suggests a potential target for the treatment of patients with HCC.

Objective To investigate the post-discharge exercise behavior and factors influencing moderate to vigorous intensity physical activity (MVPA) in patients undergoing lung surgery. Methods A total of 2874 patients from the large prospective, observational perioperative lung symptom study cohort (CN-PRO-Lung 3) in the Department of Thoracic Surgery at Sichuan Cancer Hospital between April 7, 2021, and January 31, 2024, were selected as the survey subjects. A survey was conducted using the Investigation of Exercise Behavior after Lung Surgery questionnaire and the International Physical Activity Questionnaire-Short Form (IPAQ-SF) among patients who underwent lung surgery. Binary logistic regression was used to analyze the factors influencing patients’ engagement in MVPA. Results A total of 702 patients were surveyed, including 252 males and 450 females, with an average age of (52.4±10.2) years. Patients with lung cancer accounted for 85.9%. Only 36.0% of the patients had regular exercise habits, while 42.3% did not engage in any physical activity. The three main barriers for postoperative exercise were physical discomfort (pain, coughing, shortness of breath, etc, 54.7%), lack of professional guidance (41.7%), and concerns about the surgical wound (28.9%). The proportions of patients engaging in vigorous, moderate, and low-intensity physical activity were 5.7%, 28.2%, and 66.1%, respectively. Multivariate analysis showed that patients with a personal annual income ≥50000 yuan (OR=1.52, 95%CI 1.01-2.29, P=0.044), high school education or above (OR=1.92, 95%CI 1.33-2.76, P<0.001), and lobectomy (OR=1.44, 95%CI 1.02-2.03, P=0.037) engaged in more MVPA. Conclusion Patients undergoing lung surgery have inadequate physical activity after discharge, particularly lacking in MVPA. Patients with higher income, higher educational levels, and lobectomy are more frequently engaged in MVPA. Measures such as symptom control, providing exercise guidance, and enhancing education on wound care may potentially improve the inadequate physical activity in lung surgery patients after discharge.

Objectives:To investigate the enhancement of tumor penetration and photodynamic therapy (PDT) efficacy in triple-negative breast cancer by hyaluronidase (HAase) using a novel pH-responsive IR780-loaded photosensitive micelle.Methods:The pH-responsive IR780-loaded photosensitive micelles were prepared using the nanoprecipitation method, and their morphology, size, and encapsulation efficiency were characterized. The in vitro stability and pH-responsive drug release of the micelles were also evaluated. The cytotoxicity of the micelles on triple-negative breast cancer cells (MDA-MB-231) was assessed using a cell counting kit. A nude mouse breast cancer model was established, and HAase was injected intratumorally 24 hours before intravenous injection of the photosensitive micelles. The effect of HAase on the biodistribution and tumor uptake of the micelles was detected using small animal in vivo imaging. CD31 and HIF-1α immunofluorescence staining were performed to investigate the mechanism of HAase-enhanced tumor penetration. The body weight and tumor volume of the mice were measured, and necrosis and apoptosis of tumor tissues were assessed using HE staining and TUNEL staining, respectively. Results:Transmission electron microscopy showed that the micelles had a uniform particle size of approximately 60-70 nm, with a hydrated particle size of (98.03±0.22) nm. The IR780 encapsulation efficiency was 74.15%, with a drug loading content of 2.07%. After 7 days at 4 ℃, there was no significant change in hydrated particle size ( P=0.062). The 24-hour release rates of the micelles in PBS at pH 7.4 and 6.5 were (2.41±0.21)% and (43.69±2.09)%, respectively, showing a significant difference ( P＜0.000 1). The cytotoxicity assay revealed that the cell viability in the micelles group without light exposure was significantly higer than that in the micelles group under light exposure [(97.00±5.38)% vs. (53.27±9.00)%, P=0.000 2]. The micelles were able to target and accumulate in the tumor tissue, and this accumulation increased significantly with HAase treatment. CD31 and HIF-1α immunofluorescence staining indicated that the CD31 signal was enhanced [(0.27±0.05)% vs. (4.57±0.27)%, P＜0.000 1] and the HIF-1α signal was reduced [(5.14±0.38)% vs. (0.08±0.04)%, P＜0.000 1] in the HAase-treated group compared to that in the micelle-only group. After 11 days of treatment with HAase combined with photosensitive micelles, there was no statistically significant difference in mouse body weight ( P＞0.05). However, the tumor volume inhibition rate in the HAase-micelle-mediated PDT group was significantly higher than that in the micelle-mediated PDT group [(87.66±6.37)% vs. (25.34±12.63)%, P=0.002]. Histological staining showed a significant increase in tumor cell necrosis and apoptosis in the HAase-micelle-mediated PDT group. Conclusion:HAase enhances the deep tumor penetration and targeted accumulation of pH-responsive IR780-loaded photosensitive micelles, significantly improves the efficacy of photodynamic therapy in triple-negative breast cancer.

The aim of this updated guideline is to provide comprehensive recommendations for the management of gout in patients with common comorbidities, such as chronic kidney disease(CKD), cardiovascular disease(CVD), diabetes, osteoarthritis(OA), and gastrointestinal disorders. This guideline was developed by a multidisciplinary expert panel consisting of specialists in endocrinology, rheumatology, nephrology, cardiology, gastroenterology, and methodology. The development process adhered to standard methodologies, including PICO(population, intervention, comparator, and outcomes) question deconstruction, systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation(GRADE) for evidence and recommendation evaluation, Delphi voting, and expert consensus. The guideline presents 26 evidence-based recommendations addressing 7 clinical questions for patients with hyperuricemia and gout in the context of comorbidities. Key recommendations include the maintenance of strict serum urate targets, particularly for patients with CKD stage≥3, chronic gouty arthritis, and OA, in order to prevent disease progression. In patients with CVD or diabetes, intra-articular triamcinolone is preferred over systemic glucocorticoids. Prioritized anti-inflammatory treatments for patients with CKD, gastrointestinal diseases and OA are recommended. The guideline also introduces emerging therapies, such as interleukin-1 inhibitors and selective urate transport inhibitors, as potential treatment options for refractory cases. The update offers a comprehensive, patient-centered approach to managing gout, particularly in individuals with associated comorbidities. Multidisciplinary collaboration and emerging new treatments and evidence ensure the optimization of the recommendations.

Objective:To explore the pathogenesis,clinical features,treatment strategies,and prognosis of pediatric lymphoepithelioma-like carcinoma(LELC).Methods:A retrospective analysis was conducted on the clinical data of patients with LELC aged<18 years,treated at Sun Yat-sen University Cancer Center from March 2008 to June 2023.Results:A total of 19 children and adolescents were included in the analys-is,comprising 10 males(52.6%)and 9 females(47.4%),with a median age of 12.9(4.3-17.0)years.Fourteen patients(73.7%)lived in Guangdong province,with the remainder scattered across other regions.Primary LELC sites were the mediastinum(11 cases,57.9%),parot-id glands(4 cases,21%),neck(1 case,5.3%),lungs(1 case,5.3%),salivary glands(1 case,5.3%),and submandibular glands(1 case,5.3%).Among these,15 patients(78.9%)had at least one distant metastasis at initial diagnosis,with common metastasis sites being cervical lymph nodes.Multivariate Cox regression analysis identified tumor volume≥801 cm3 as an independent adverse prognostic factor of poor overall survival(OS)(P<0.01).The 2-year OS and progression-free survival(PFS)rates were 84.2%and 57.9%,respectively.The 2-year OS for pa-tients who underwent surgery,chemotherapy,and radiotherapy was 100%,compared with 25%for those who received only partial treat-ment(P=0.007).The 2-year PFS rate was significantly higher in patients receiving first-line combination therapy with programmed death-1(PD-1)antibodies(100%)compared with those not treated with PD-1 antibodies(38.5%)(P=0.020).For patients with tumor volume≥801 cm3,the 2-year OS was 40.0%,whereas for those with a tumor volume<801 cm3,the 2-year OS was 100%(P<0.001).The 2-year OS for pa-tients who underwent radiotherapy was 100%,while it was 0 for those who did not receive radiotherapy(P<0.001).Conclusions:Pediatric LELC exhibits a relatively favorable prognosis with multidisciplinary treatment,including surgery,chemotherapy,and radiotherapy.The com-bined use of PD-1 antibodies at the time of initial diagnosis could offer potential benefits and warrants further exploration.

Objective To investigate the in vitro antiviral effects of Blumea balsamifera(L.)DC.extract against Coxsackievirus B5(CVB5).Methods A series of dilutions of Coxsackievirus were prepared and co-cultured with RD cells to determine the TCID50 value.Subsequently,different concentrations of the extract were added to a 96-well plate containing RD cells to evaluate their impact on cell viability.The ability of Blumea balsamifera extract to inhibit Coxsackievirus was further observed in the 96-well plate containing RD cells and the extract.Results The TCID50 value of Coxsackie virus solution was 10-7.67.The inhibition rate of Blumea balsamifera extract against Coxsackievirus increased with concentration,with an IC50 value of 7.26 mg/L.At a concen-tration of 50 mg/L,the extract caused a decrease in RD cell viability(P＜0.05),but within the concentration range of 6.25 to 50 mg/L,it increased the viability of virus-infected RD cells(P＜0.05),with a selectivity index(SI)exceeding 6.89.Conclusion Blumea balsamifera(L.)DC.extract exhibits in vitro activity against Coxsackievirus.

The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/Akt/mTOR)signaling pathway plays a crucial role in the regulation of renal fibrosis by participating in inflammatory response,oxidative stress and autophagy.Paeoniflorin exhibits remarkable efficacy in treating myocardial and liver fibrosis.This article provides a comprehensive review on the research progress of paeoniflora in preventing and treating renal fibrosis through modulation of the PI3K/Akt/mTOR signaling pathway,offering novel insights for traditional Chinese medicine-based approaches to prevent and treat renal fibrosis.

Aim To study the effect of anti-PD-L1 monoclonal antibody on high-fat diet-induced athero-sclerosis in ApoE-/-mice.Methods Twenty-four ApoE-/-mice were randomly divided into the normal group,high-fat group,and high-fat+anti-PD-L1 mAb group.After 70 days,the blood samples were harves-ted.Blood vessels(aortic root to abdominal aorta)and liver from each groups were stained with Oil Red O.Hematoxylin-eosin staining(HE)was employed to vis-ualize structural changes in liver.Enzyme-linked im-munosorbent assay(ELISA)was applied to detect the serum levels of total cholesterol(CHO),triglyceride(TG),high-density lipoprotein(HDL-c),low-density lipoprotein(LDL-c)and inflammatory factors(IFN-γ,TNF-α,IL-1 β).Flow cytometry was used to detect the proportion of lymphocytes(CD4 and CD8).RT-PCR was utilized to assess the expressions of IFN-γ,TNF-α,IL-1 β,CD4 and CD8 in liver.Results Compared with the high-fat group,the treatment with anti-PD-L1 monoclonal antibody promoted vascular wall and liver lipid accumulation,and also up-regulated serum and liver content of cholesterol(CHO),triglyceride(TG)and high-density lipoprotein(HDL-c).Treatment with anti-PD-L1 monoclonal antibody up-regulated the con-tent of alanine aminotransferase(GPT)and aspartate aminotransferase(GOT)in serum and liver,but not al-kaline phosphatase(AKP).ELISA test indicated that treatment with anti-PD-L1 monoclonal antibody stimu-lated the serum level of IFN-γ,TNF-α and IL-1 β.Fur-thermore,the mRNA level of IFN-γ,TNF-α and IL-1 βin liver was also up-regulated after treatment with anti-PD-L1 monoclonal antibody.With flow cytometry,we observed that treatment with anti-PD-L1 monoclonal antibody promoted hepatic CD8+T and CD8+IFN-γ+T cell activation,but had no effect on CD4+IFN-γ+T cell activation under high-fat feeding conditions.Con-clusions Anti-PD-L1 monoclonal antibody adminis-tered under high-fat feeding conditions can damage liv-er function and aggravate atherosclerosis by activating liver CD8+IFN-γ+T cells.

Objectives:To investigate the enhancement of tumor penetration and photodynamic therapy (PDT) efficacy in triple-negative breast cancer by hyaluronidase (HAase) using a novel pH-responsive IR780-loaded photosensitive micelle.Methods:The pH-responsive IR780-loaded photosensitive micelles were prepared using the nanoprecipitation method, and their morphology, size, and encapsulation efficiency were characterized. The in vitro stability and pH-responsive drug release of the micelles were also evaluated. The cytotoxicity of the micelles on triple-negative breast cancer cells (MDA-MB-231) was assessed using a cell counting kit. A nude mouse breast cancer model was established, and HAase was injected intratumorally 24 hours before intravenous injection of the photosensitive micelles. The effect of HAase on the biodistribution and tumor uptake of the micelles was detected using small animal in vivo imaging. CD31 and HIF-1α immunofluorescence staining were performed to investigate the mechanism of HAase-enhanced tumor penetration. The body weight and tumor volume of the mice were measured, and necrosis and apoptosis of tumor tissues were assessed using HE staining and TUNEL staining, respectively. Results:Transmission electron microscopy showed that the micelles had a uniform particle size of approximately 60-70 nm, with a hydrated particle size of (98.03±0.22) nm. The IR780 encapsulation efficiency was 74.15%, with a drug loading content of 2.07%. After 7 days at 4 ℃, there was no significant change in hydrated particle size ( P=0.062). The 24-hour release rates of the micelles in PBS at pH 7.4 and 6.5 were (2.41±0.21)% and (43.69±2.09)%, respectively, showing a significant difference ( P＜0.000 1). The cytotoxicity assay revealed that the cell viability in the micelles group without light exposure was significantly higer than that in the micelles group under light exposure [(97.00±5.38)% vs. (53.27±9.00)%, P=0.000 2]. The micelles were able to target and accumulate in the tumor tissue, and this accumulation increased significantly with HAase treatment. CD31 and HIF-1α immunofluorescence staining indicated that the CD31 signal was enhanced [(0.27±0.05)% vs. (4.57±0.27)%, P＜0.000 1] and the HIF-1α signal was reduced [(5.14±0.38)% vs. (0.08±0.04)%, P＜0.000 1] in the HAase-treated group compared to that in the micelle-only group. After 11 days of treatment with HAase combined with photosensitive micelles, there was no statistically significant difference in mouse body weight ( P＞0.05). However, the tumor volume inhibition rate in the HAase-micelle-mediated PDT group was significantly higher than that in the micelle-mediated PDT group [(87.66±6.37)% vs. (25.34±12.63)%, P=0.002]. Histological staining showed a significant increase in tumor cell necrosis and apoptosis in the HAase-micelle-mediated PDT group. Conclusion:HAase enhances the deep tumor penetration and targeted accumulation of pH-responsive IR780-loaded photosensitive micelles, significantly improves the efficacy of photodynamic therapy in triple-negative breast cancer.

Objective:To investigate the differences in clinical outcomes of septic children with varying serum zinc levels,and to analyze the relationship between reduced serum zinc levels and organ dysfunction as well as 28-day mortality in septic children.Methods:This study conducted a retrospective analysis of clinical data from pediatric patients diagnosed with sepsis or septic shock in the Department of critical care medicine of the children's Hospital of Soochow University between January 2017 and December 2022.Clinical characteristics,organ dysfunction,and prognosis were compared between two groups:children with low serum zinc levels and those with normal zinc levels.Results:The serum zinc level of septic children within 24 hours of admission was 9.60(5.52,13.80)μmol/L,with 50.54%(94/186)of the children exhibiting low serum zinc levels(<10.07 μmol/L).Compared to the normal serum zinc group,the low serum zinc group had a significantly lower Pediatric Critical Illness Score(PCIS)[(78.71±9.35)vs.(85.12±8.51),P=0.005]and higher 28-day mortality(46.80%vs.14.13%,P<0.001).The low serum zinc group also had a higher proportion of invasive mechanical ventilation(64.89%vs.47.82%,P=0.019),renal replacement therapy(15.59%vs.3.26%,P=0.003),and use of vasoactive drugs(56.38%vs.30.43%,P<0.001).The rate of underlying conditions in the low serum zinc group was significantly higher than that in the normal serum zinc group(57.44%vs.36.95%,P=0.005).Additionally,the low serum zinc group had a higher incidence of disseminated intravascular coagulation(DIC),respiratory failure,acute kidney injury,shock,and multiple organ dysfunction syndrome(MODS)compared to the normal serum zinc group(P<0.05).Serum zinc levels had predictive value for 28-day mortality in septic children(AUC=0.813;95%CI:0.725～0.902;P<0.001).A serum zinc level of less than 6.950 μmol/L predicted the death of septic children with a sensitivity of 0.618 and a specificity of 0.902.Conclusion:Sepsis in children is commonly associated with low serum zinc levels,especially in those with underlying conditions such as hematologic and oncologic disorders.Sepsis patients hypozincemia with a higher incidence of DIC,respiratory failure,acute kidney injury,shock,and MODS.A serum zinc level below 6.95 μmol/L serves as a significant predictor of 28-day mortality in children with severe sepsis.