Background/Aims: Transmembrane 4 L six family member 1 (TM4SF1) is highly expressed and contributes to the progression of various malignancies. However, how it modulates hepatocellular carcinoma (HCC) progression and senescence remains to be elucidated. Methods: TM4SF1 expression in HCC samples was evaluated using immunohistochemistry and flow cytometry. Cellular senescence was assessed through SA-β-gal activity assays and Western blot analysis. TM4SF1-related protein interactions were investigated using immunoprecipitation-mass spectrometry, co-immunoprecipitation, bimolecular fluorescence complementation, and immunofluorescence. Tumor-infiltrating immune cells were analyzed by flow cytometry. The HCC mouse model was established via hydrodynamic tail vein injection. Results: TM4SF1 was highly expressed in human HCC samples and murine models. Knockdown of TM4SF1 suppressed HCC proliferation both in vitro and in vivo, inducing non-secretory senescence through upregulation of p16 and p21. TM4SF1 enhanced the interaction between AKT1 and PDPK1, thereby promoting AKT phosphorylation, which subsequently downregulated p16 and p21. Meanwhile, TM4SF1-mediated AKT phosphorylation enhanced PD-L1 expression while reducing major histocompatibility complex class I level on tumor cells, leading to impaired cytotoxic function of CD8+ T cells and an increased proportion of exhausted CD8+ T cells. In clinical HCC samples, elevated TM4SF1 expression was associated with resistance to anti-PD-1 immunotherapy. Targeting TM4SF1 via adeno-associated virus induced tumor senescence, reduced tumor burden and synergistically enhanced the efficacy of anti-PD-1 therapy. Conclusions Our results revealed that TM4SF1 regulated tumor cell senescence and immune evasion through the AKT pathway, highlighting its potential as a therapeutic target in HCC, particularly in combination with first-line immunotherapy.

Background/Aims: Transmembrane 4 L six family member 1 (TM4SF1) is highly expressed and contributes to the progression of various malignancies. However, how it modulates hepatocellular carcinoma (HCC) progression and senescence remains to be elucidated. Methods: TM4SF1 expression in HCC samples was evaluated using immunohistochemistry and flow cytometry. Cellular senescence was assessed through SA-β-gal activity assays and Western blot analysis. TM4SF1-related protein interactions were investigated using immunoprecipitation-mass spectrometry, co-immunoprecipitation, bimolecular fluorescence complementation, and immunofluorescence. Tumor-infiltrating immune cells were analyzed by flow cytometry. The HCC mouse model was established via hydrodynamic tail vein injection. Results: TM4SF1 was highly expressed in human HCC samples and murine models. Knockdown of TM4SF1 suppressed HCC proliferation both in vitro and in vivo, inducing non-secretory senescence through upregulation of p16 and p21. TM4SF1 enhanced the interaction between AKT1 and PDPK1, thereby promoting AKT phosphorylation, which subsequently downregulated p16 and p21. Meanwhile, TM4SF1-mediated AKT phosphorylation enhanced PD-L1 expression while reducing major histocompatibility complex class I level on tumor cells, leading to impaired cytotoxic function of CD8+ T cells and an increased proportion of exhausted CD8+ T cells. In clinical HCC samples, elevated TM4SF1 expression was associated with resistance to anti-PD-1 immunotherapy. Targeting TM4SF1 via adeno-associated virus induced tumor senescence, reduced tumor burden and synergistically enhanced the efficacy of anti-PD-1 therapy. Conclusions Our results revealed that TM4SF1 regulated tumor cell senescence and immune evasion through the AKT pathway, highlighting its potential as a therapeutic target in HCC, particularly in combination with first-line immunotherapy.

Background/Aims: Transmembrane 4 L six family member 1 (TM4SF1) is highly expressed and contributes to the progression of various malignancies. However, how it modulates hepatocellular carcinoma (HCC) progression and senescence remains to be elucidated. Methods: TM4SF1 expression in HCC samples was evaluated using immunohistochemistry and flow cytometry. Cellular senescence was assessed through SA-β-gal activity assays and Western blot analysis. TM4SF1-related protein interactions were investigated using immunoprecipitation-mass spectrometry, co-immunoprecipitation, bimolecular fluorescence complementation, and immunofluorescence. Tumor-infiltrating immune cells were analyzed by flow cytometry. The HCC mouse model was established via hydrodynamic tail vein injection. Results: TM4SF1 was highly expressed in human HCC samples and murine models. Knockdown of TM4SF1 suppressed HCC proliferation both in vitro and in vivo, inducing non-secretory senescence through upregulation of p16 and p21. TM4SF1 enhanced the interaction between AKT1 and PDPK1, thereby promoting AKT phosphorylation, which subsequently downregulated p16 and p21. Meanwhile, TM4SF1-mediated AKT phosphorylation enhanced PD-L1 expression while reducing major histocompatibility complex class I level on tumor cells, leading to impaired cytotoxic function of CD8+ T cells and an increased proportion of exhausted CD8+ T cells. In clinical HCC samples, elevated TM4SF1 expression was associated with resistance to anti-PD-1 immunotherapy. Targeting TM4SF1 via adeno-associated virus induced tumor senescence, reduced tumor burden and synergistically enhanced the efficacy of anti-PD-1 therapy. Conclusions Our results revealed that TM4SF1 regulated tumor cell senescence and immune evasion through the AKT pathway, highlighting its potential as a therapeutic target in HCC, particularly in combination with first-line immunotherapy.

AIM: To investigate the efficacy of small-incision horizontal space nuclear splitting surgery and phacoemulsification combined with regional refractive multifocal intraocular lens(MIOL)implantation in the treatment of hard nuclear cataract.METHODS:A retrospective analysis was performed for 288 patients(288 eyes)with hard nuclear cataract who admitted to our hospital from January 2022 to December 2023, and they were divided into control group(144 eyes treated with phacoemulsification and regional refractive MIOL)and observation group(144 eyes treated with small-incision horizontal space nuclear splitting surgery and regional refractive MIOL)according to different treatment methods. The operation time, pre- and post-operative best corrected visual acuity, astigmatism, central corneal thickness, corneal endothelial density, tear film function, and complications were compared between the two groups.RESULTS:There was no difference in operation time between the two groups(P>0.05). There was no difference in the preoperative and 3 mo postoperative best corrected visual acuity(all P>0.05), and the best corrected visual acuity of the two groups at 3 mo postoperatively was improved compared with the preoperative level(all P<0.05). There were differences in central corneal thickness, corneal endothelial density and astigmatism between the two groups at 1 wk and 3 mo after surgery(all P<0.05). There were differences in breakup time(BUT)and ocular surface disease index(OSDI)scores between the two groups at 1 wk after surgery(all P<0.001), and the incidence of complications in the observation group(4.2%)was significantly lower than that in the control group(18.1%; P<0.001).CONCLUSION:Both surgical methods can effectively treat patients with hard nuclear cataracts, and small-incision horizontal space nuclear splitting surgery combined with regional refractive MIOL implantation has less corneal damage and fewer complications.

[Abstract] Objective: To investigate the effects of salidroside on the proliferation, invasion and apoptosis of cervical squamous cell carcinoma C33A cells and explore its possible mechanism. Methods: C33A cells were divided into 4 groups: control group, low-dose group (salidroside 50 μg/mL), high-dose group (salidroside 150 μg/mL), and AG490 group (inhibitor of JAK2/STAT3 signaling pathway, 50 μmol/L). Effects of salidroside and AG490 on the proliferation, invasion and apoptosis of C33A cells were detected by MTT method, EdU labeling experiment, Transwell assay, Rh123 staining and Flow cytometry, respectively. Western blotting was used to detect the effects of salidroside and AG490 on the expressions of JAK2/STAT3 pathway-related proteins (p-JAK2, p-STAT3) and apoptosis-related proteins (Bax, Bcl-2, caspase-3) in C33A cells. Result: Compared with the control group, the proliferation and DNA synthesis as well as the invasion of C33Acells in the low-dose group were significantly inhibited (all P<0.05), while the apoptosis was significantly enhanced (P<0.05); in the meanwhile, the fluorescence intensity of Rh123 was significantly reduced (all P<0.05) and the membrane structure of C33A cells were destroyed; moreover, the expressions of p-JAK2, p-STAT3 and Bcl-2 were significantly decreased while the expressions of Bax and caspase-3 were significantly increased (all P<0.05). Compared with the low-dose group, the effects of high-dose salidroside and AG490 on the proliferation, invasion, apoptosis and related protein expressions in C33A cells were more significant (all P<0.05), but there was no difference between the high-dose group and the AG490 group. Conclusion: Salidroside can inhibit the proliferation and invasion of C33A cells and promote cell apoptosis. Its mechanism may be related to inhibition of JAK2/ STAT3 signaling pathway.

AIM: To compare the effects of different nucleus chopping methods on the central corneal thickness, corneal endothelial cell(CEC)count and tear inflammatory indicators in patients with hard nucleus cataract.METHODS: Retrospective study. Totally 89 patients(89 eyes)with hard nucleus cataract who treated in our hospital were included from January 2020 to December 2022. According to different intraoperative nucleus chopping methods, the patients were divided into reverse prechop group(46 eyes)and phaco-chop group(43 eyes). The total effective rate of surgery and visual acuity recovery were compared between the two groups. Corneal related indicators(central corneal thickness, CEC count, CEC area), tear inflammatory indicators and tear film function [tear film break-up time(BUT), Chinese Dry Eye Questionnaire(CDEQ), Schirmer Ⅰ test(SⅠt)] were observed before and after surgery in both groups, and the degree of corneal edema was evaluated.RESULTS: The effective phaco time, phaco energy and cumulative complex energy parameters in the phaco-chop group were longer or higher than those in the reverse prechop group(P<0.05). The macular retinal thickness in the reverse prechop group at 7 d and 1 mo after surgery was thinner than that in the phaco-chop group, the central corneal thickness at 3 and 7 d after surgery was also thinner than that in the phaco-chop group, the CEC count at 3 mo after surgery was more than that in the phaco-chop group, the CEC loss rate was lower than that in the phaco-chop group, and the CEC area at 3 mo after surgery was smaller than that in the phaco-chop group(P<0.05). The levels of tear TNF-α and IL-6 at 7 d and 1 mo after surgery in the reverse prechop group were lower than those in the phaco-chop group(P<0.05). The BUT at 1 and 3 mo after surgery was longer in the reverse prechop group than that in the phaco-chop group(P<0.05). The CDEQ score in the reverse prechop group was lower than that in the phaco-chop group at 1 and 3 mo after surgery(P<0.05). The SⅠt at 1 and 3 mo after surgery was higher in the reverse prechop group compared with that in the phaco-chop group(P<0.05). The degree of corneal edema at 1 d after surgery was milder in the reverse prechop group than that in the phaco-chop group(P<0.05). CONCLUSION: Compared with phaco-chop, the application of reverse-chopper prechop combined with phacoemulsification can better reduce the ultrasonic energy in the treatment of hard nuclear cataract, and it is more conducive to reducing the postoperative inflammatory degree, improving the tear film function and relieving the corneal edema degree.