Alcoholic liver disease （ALD） poses a serious threat to the health of drinkers worldwide， and establishing appropriate animal models of ALD is an important foundation for conducting disease-related research. Due to the physiological and pathophysiological differences between rodents and humans， alcohol feeding alone is difficult to induce a model that closely matches the disease manifestations in humans， and therefore， the “two-hit” hypothesis （ combining alcohol with another liver injury factor to induce the expected state of liver injury） has been widely used. This article classifies the more commonly used and effective “two-hit” regimens into three major categories of special diets， chemical substances， and genetic engineering， which are divided into high-fat diet， high-iron diet， carbon tetrachloride， lipopolysaccharide， and genetic engineering for further analysis. Although these five “two-hit” models have their own advantages and disadvantages， they can nearly cover the disease spectrum of ALD. In the future， the development of ALD animal models can focus on narrowing the pathophysiological differences in alcohol-induced liver injury between animals and humans and simulating more complex drinking patterns in humans.

Background and Aims:Microsatellite-stable(MSS)colorectal cancer(CRC)generally exhibits poor responsiveness to immune checkpoint inhibitors(ICIs),and effective immunotherapy strategies remain lacking.Anti-angiogenic agents such as bevacizumab(BEV)can improve the tumor immune microenvironment and act synergistically with ICIs.This multicenter real-world study compared the efficacy of different immunotherapy-based combination regimens in patients with MSS/MSI-L/pMMR advanced CRC,aiming to identify the optimal treatment strategy.Methods:A total of 100 patients with MSS/MSI-L/pMMR advanced CRC who received systemic treatment between November 2019 and February 2025 at four tertiary hospitals in Hunan,China,were retrospectively enrolled.Patients were classified into six treatment groups:chemotherapy alone,chemotherapy+targeted therapy,immunotherapy alone,immunotherapy+chemotherapy,immunotherapy+targeted therapy,and immunotherapy+chemotherapy+targeted therapy.The primary endpoints were overall survival(OS)and progression-free survival(PFS),while secondary endpoints were objective response rate(ORR)and disease control rate(DCR).Additionally,among patients receiving immunotherapy,subgroup analysis was performed according to BEV administration.Results:Among all 100 patients,the immunotherapy+chemotherapy+targeted therapy group achieved the highest ORR(32.0%)and DCR(76.0%)and was the only regimen yielding a complete response(CR).Compared with chemotherapy or immunotherapy alone,the triplet regimen significantly improved OS(P<0.05);although PFS improvement did not reach statistical significance,a clear late-stage separation of survival curves was observed.In the immunotherapy subgroup,BEV-containing regimens achieved markedly better outcomes than non-BEV regimens,with DCR of 75.0%vs.48.8%,median OS of 18.9 vs.11.5 months,and median PFS of 13.8 vs.7.2 months(all P<0.001).Cox regression analysis showed that compared with chemotherapy alone,the triplet regimen significantly reduced the risk of death(HR=0.11)and disease progression(HR=0.25)(both P=0.002).Vascular invasion was identified as an adverse prognostic factor for PFS(HR=3.0,P=0.007).Conclusion:This multicenter real-world study demonstrated that combining immunotherapy with chemotherapy and targeted therapy significantly improves DCR and survival outcomes in patients with MSS/MSI-L/pMMR advanced CRC,with BEV-containing triplet regimens providing the most pronounced benefit.BEV may enhance immune responsiveness by modulating the tumor microenvironment and promoting effector T-cell infiltration,offering a promising therapeutic direction for"immune-cold"CRC.Prospective randomized studies are warranted to further validate its clinical value and define appropriate patient populations.

Objective:To analyze the research hotspots and trends in the stigmatization of adolescents living with HIV/AIDS.Methods:Relevant literature was retrieved from the Web of Science Core Collection database, with the search covering from database inception to May 1, 2024. CiteSpace software was used to conduct bibliometric analysis, including the distribution of countries, institutions, authors, keywords, and cited references. Knowledge maps were generated to visualize the findings.Results:A total of 414 articles were included in the analysis. The number of publications has shown an overall upward trend. The United States had the highest number of publications (244 articles), the most productive institution was University of Cape Town (31 articles), and the most productive author was Linda-Gail Bekker (9 articles). Research hotspots mainly focused on stigmatization, behavioral patterns, mental health, treatment adherence, social support, and intervention models.Conclusions:Research on the stigmatization of adolescents living with HIV/AIDS is currently at a critical stage. Future studies should continue to explore the multidimensional impact of stigma and focus on the development of region-specific and individualized intervention models, while actively constructing a comprehensive support system within the field of public health.

Background and Aims:Microsatellite-stable(MSS)colorectal cancer(CRC)generally exhibits poor responsiveness to immune checkpoint inhibitors(ICIs),and effective immunotherapy strategies remain lacking.Anti-angiogenic agents such as bevacizumab(BEV)can improve the tumor immune microenvironment and act synergistically with ICIs.This multicenter real-world study compared the efficacy of different immunotherapy-based combination regimens in patients with MSS/MSI-L/pMMR advanced CRC,aiming to identify the optimal treatment strategy.Methods:A total of 100 patients with MSS/MSI-L/pMMR advanced CRC who received systemic treatment between November 2019 and February 2025 at four tertiary hospitals in Hunan,China,were retrospectively enrolled.Patients were classified into six treatment groups:chemotherapy alone,chemotherapy+targeted therapy,immunotherapy alone,immunotherapy+chemotherapy,immunotherapy+targeted therapy,and immunotherapy+chemotherapy+targeted therapy.The primary endpoints were overall survival(OS)and progression-free survival(PFS),while secondary endpoints were objective response rate(ORR)and disease control rate(DCR).Additionally,among patients receiving immunotherapy,subgroup analysis was performed according to BEV administration.Results:Among all 100 patients,the immunotherapy+chemotherapy+targeted therapy group achieved the highest ORR(32.0%)and DCR(76.0%)and was the only regimen yielding a complete response(CR).Compared with chemotherapy or immunotherapy alone,the triplet regimen significantly improved OS(P<0.05);although PFS improvement did not reach statistical significance,a clear late-stage separation of survival curves was observed.In the immunotherapy subgroup,BEV-containing regimens achieved markedly better outcomes than non-BEV regimens,with DCR of 75.0%vs.48.8%,median OS of 18.9 vs.11.5 months,and median PFS of 13.8 vs.7.2 months(all P<0.001).Cox regression analysis showed that compared with chemotherapy alone,the triplet regimen significantly reduced the risk of death(HR=0.11)and disease progression(HR=0.25)(both P=0.002).Vascular invasion was identified as an adverse prognostic factor for PFS(HR=3.0,P=0.007).Conclusion:This multicenter real-world study demonstrated that combining immunotherapy with chemotherapy and targeted therapy significantly improves DCR and survival outcomes in patients with MSS/MSI-L/pMMR advanced CRC,with BEV-containing triplet regimens providing the most pronounced benefit.BEV may enhance immune responsiveness by modulating the tumor microenvironment and promoting effector T-cell infiltration,offering a promising therapeutic direction for"immune-cold"CRC.Prospective randomized studies are warranted to further validate its clinical value and define appropriate patient populations.

Objective:To analyze the research hotspots and trends in the stigmatization of adolescents living with HIV/AIDS.Methods:Relevant literature was retrieved from the Web of Science Core Collection database, with the search covering from database inception to May 1, 2024. CiteSpace software was used to conduct bibliometric analysis, including the distribution of countries, institutions, authors, keywords, and cited references. Knowledge maps were generated to visualize the findings.Results:A total of 414 articles were included in the analysis. The number of publications has shown an overall upward trend. The United States had the highest number of publications (244 articles), the most productive institution was University of Cape Town (31 articles), and the most productive author was Linda-Gail Bekker (9 articles). Research hotspots mainly focused on stigmatization, behavioral patterns, mental health, treatment adherence, social support, and intervention models.Conclusions:Research on the stigmatization of adolescents living with HIV/AIDS is currently at a critical stage. Future studies should continue to explore the multidimensional impact of stigma and focus on the development of region-specific and individualized intervention models, while actively constructing a comprehensive support system within the field of public health.

[Objective] To investigate the functional differences and potential effects of chromatin spatial structure in patients with normal karyotype and complex karyotype multiple myeloma. [Methods] High-throughput chromosome conformational capture (Hi-C) analysis was performed on plasma cells of 1 case with 1q21 complex karyotype and 1 case with normal karyotype multiple myeloma, and the differences in three-dimensional genome structure between the two patients were analyzed, and the transcriptome characteristics of plasma cells were combined to investigate the differential features through gene functional enrichment. [Results] A/B switch occurred in 36% of the chromatin compartments in two cases, and 1 041 genes in patient with complex karyotype had B/A switch. About 3 500 topological association domains (TADs) were identified in each sample, and there was no significant difference. The number of loops identified in complex karyotype sample was 1 069, which was 1/6 of the normal sample, and there were significant differences in the number of three different types of loops, which to some extent reflected the loss of genome stability. Transcriptome analysis showed significant differences in expression profiles between the two patients, and a total of 6 150 differentially expressed genes (3 303 up-regulated genes and 2 847 down-regulated genes) were identified. [Conclusion] Compared with patient with normal karyotype, patient with 1q21 complex karyotype multiple myeloma exhibit significant changes in the spatial structure of plasma cell chromatin at different levels, which leads to changes in gene expression and activation of pathways related to cancer progression.

Objective To investigate the safety and efficacy of flow-directed devices(flow diverter,FD)in the treatment of intracranial anterior cerebral artery aneurysms(ACAA).Methods The clinical data of 21 patients with ACAA,who were admitted to the Department of Neurointerventional Medicine of the First Affiliated Hospital of Zhengzhou University of China to receive FD treatment between February 2019 and August 2022,were retrospectively analyzed.After the treatment,O'Kelly Marotta(OKM)grading criteria was used to determine the degree of occlusion of the aneurysm,and the modified Rankin Scale(mRS)score was adopted to assess the clinical prognosis(0-2 points being defined as a good prognosis,and 3-5 points being defined as a poor prognosis).Results A total of 24 FD stents were implanted in 24 patients(24 aneurysms in total),and the technical success rate of stent implantation was 100％.During the perioperative period,complications occurred in 2 patients(8.3％),including hemorrhagic event(n=l)and ischemic event(n=l).The mRS score in all the 24 patients was ≤2 points.Follow-up imaging examination showed that OKM grade B was seen in 2 patients(8.3％),grade C in 6 patients(25％),and grade D(complete healing)in 16 patients(66.7％).Conclusion For the treatment of ACAA,the FD stent implantation is a safe and effective method.During the postoperative and the long-term follow-up period,neither serious ischemic or hemorrhagic complications nor neurological complications are observed.

Objective We aimed to investigate the effects of Biejiajian Pills on MHCC-97H hepatoma cells and whether Biejiajian Pills regulate the epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway through miR-885-5p.Methods SPF SD rats (n = 10) were randomly divided into the blank group and the Biejiajian Pills (1.1 g/kg) group to prepare blank and Biejiajian Pills-containing serum. MHCC-97H cells in the logarithmic growth phase were divided into the model group, blank serum groups with different concentrations (5％, 10％, 15％, and 20％), the serum containing Biejiajian Pills group, and the blank group without cells. Cell proliferation was detected by the CCK-8 assay, and the optimal intervention time and concentration of drug-containing serum were screened. MHCC-97H cells were divided into the blank control group (no intervention), the Biejiajian Pills-containing serum group (20％ Biejiajian Pills-containing serum), the miR-885-5p mimics group (transfected with miR-885-5p mimics), the miR-NC group (transfected with miR-885-5p NC), and the Biejiajian Pills-containing serum + miR-885-5p mimics group (treated with 20％ Biejiajian Pills-containing serum and transfected with miR-885-5p mimics). Cells in each group were cultured for 72 hours. A dual luciferase reporter assay was conducted to verify the targeting relationship between miR-885-5p and EGFR. Cell proliferation was detected by the CCK-8 assay, cell migration and invasion abilities were detected by the cell scratch assay and the Transwell invasion assay. Annexin V-APC/PI double staining was performed to detect the apoptosis level, and real-time fluorescence quantitative PCR (RT-qPCR) analysis was conducted to determine the mRNA expression levels of miR-885-5p, EGFR, MEK, and ERK1/2. The expression levels of EGFR, p-EGFR, MEK, p-MEK, ERK1/2, p-ERK1/2, matrix metalloproteinase 1 (MMP1), and CyclinD1 were determined by Western blotting analysis. The subcutaneous tumor model of MHCC-97H hepatoma cells in nude mice was established by subcutaneous injection to observe the inhibitory effect of Biejiajian Pills of different doses(0.55,1.1,2.2 g/kg).Results The optimal concentration and intervention time of Biejiajian Pills-containing serum were 20％ and 72 hours, respectively. Meanwhile, the dual luciferase reporter assay showed that miR-885-5p could directly target EGFR. No statistical significances between the blank control group and the miR-NC group were observed (P>0.05). Compared with the blank control group, the proliferation rates of MHCC-97H hepatoma cells in the Biejiajian Pills-containing serum group, the miR-885-5p mimics group, and the Biejiajian Pills-containing serum + miR-885-5p mimics group were significantly decreased (P<0.01), and their migration and invasion abilities were significantly decreased (P<0.05, P<0.01). At the same time, the protein expression levels of CyclinD1 and MMP1, which are closely related to cell proliferation and invasion, were significantly downregulated (P<0.05, P<0.01). The proportions of late apoptotic cells and the proportion of total apoptotic cells were significantly increased (P<0.01). In the Biejiajian Pills-containing serum group, the miR-885-5p mimics group, and the Biejiajian Pills-containing serum + miR-885-5p mimics group, miR-885-5p mRNA was significantly upregulated (P<0.01) and EGFR, MEK, and ERK1/2 were significantly downregulated at the mRNA level (P<0.05, P<0.01). EGFR, MEK, and ERK1/2 phosphorylation was inhibited (P<0.01), and the Biejiajian Pills-containing serum + miR-885-5p mimics group showed the best effect (P<0.05, P<0.01). The subcutaneous liver tumor model in nude mice verified that Biejiajian Pills can inhibit tumor growth in a dose-dependent manner. Conclusion Biejiajian Pills can promote apoptosis of MHCC-97H hepatoma cells and inhibit their proliferation, invasion, and migration. The mechanism may be related to the targeted regulation of the EGFR/MAPK/ERK signaling pathway by miR-885-5p.

Objective:To analyze clinical characteristics of acromegaly patients who have discordant growth hormone(GH) or insulin-like growth factor-1(IGF-1) levels and evaluate impact of different GH cut-offs on discordance rate.Methods:A retrospective analysis was conducted on data from 66 acromegaly patients treated at Nanjing Drum Tower Hospital from November 2017 to March 2023. Patients were categorized based on the nadir GH(GHn) and IGF-1 levels at the last follow-up into four groups: controlled, high GH, high IGF-1, and active. Clinical and metabolic parameters were compared across these groups, and impact of different GHn and fasting growth hormone(GHf) cut-offs on discordance rate was evaluated.Results:No statistically significant differences were observed among groups in age, duration of follow-up, imaging characteristics(all P>0.05). High IGF-1 group had higher fasting insulin and homeostasis model assessment for β cell function compared to controlled and high GH group(all P<0.05), while these parameters did not differ between high GH and controlled group. High IGF-1 group had higher carboxy-terminal cross-linked telopeptide of type 1 collagen, osteocalcin and procollagen type 1 N-terminal propeptide compared to controlled and high GH group, but differences were not statistically significant(all P>0.05). These parameters also did not differ between high GH and controlled group. Discordance rate was not significantly different when GHn cut-offs was 1.0 μg/L or 0.4 μg/L(30.3% vs 21.3%, P=0.146). Compared to 2.5 μg/L, discordance rate was lower when GHf cut-off was 1.0 μg/L(39.4% vs 24.3%, P=0.041). Conclusion:The discordance rate in treated acromegaly patients during follow-up is approximately 30%. Different GH measurement timings and cut-offs significantly impact discordance rate. Patients with normal GH and elevated IGF-1 levels are at potential risk of active disease, and require closer follow-up. This study provides a valuable reference for treatment of patients with discordant GH and IGF-1 levels.

Objective:To identify the clinical and pathological characteristics of adrenocortical carcinoma(ACC) with hypercortisolism and analyze the prognostic factors.Methods:Clinical data of ACC patients between January 2003 and December 2022 from Nanjing Drum Tower Hospital were collected retrospectively. Clinical and pathological characteristics were compared between ACC patients with hypercortisolism and nonfunctional ACCs. Kaplan-Meier method was used for survival analyses and Cox regression models were performed to analyze prognostic factors for ACC patients.Results:In 61 cases of ACC patients, the average age was (49.33±16.32) years. After a median follow-up of 77 months(95% CI 47.49-106.51 months), median overall survival and progression-free survival were 50 months(95% CI 20.44-79.56 months) and 29 months(95% CI 22.87-35.13 months), respectively. Among 36 patients with complete endocrinologic evaluations, 19(52.77%) were diagnosed with hypercortisolism. Compared with nonfunctional ACC, patients with hypercortisolism had more hypokalemia(42.11% vs 6.25%, P=0.022), capsular invasion(68.42% vs 25.00%, P=0.018), and distant metastases(73.68% vs 25.00%, P=0.007). Median overall survival and progression-free survival were significantly shorter than nonfunctional ACC(overall survival: 39 months vs 67 months, P=0.009; progression-free survival: 30 months vs 51 months, P=0.040) as well. Multivariate Cox regression analyses indicated that Ki67 index( HR=1.078, P=0.024) was an independent risk factor for overall survival. Hypercortisolism( HR=71.112, P=0.006), Ki67 index( HR=1.345, P=0.003), adjuvant therapy( HR=176.652, P=0.012), and operation( HR=0.020, P=0.003), were associated with disease progression. Conclusion:ACC accompanied by hypercortisolism is more prone to invasion and distant metastasis, resulting in shorter survival. Hypercortisolism is an independent prognostic factor for ACC patients.