Idiopathic pulmonary fibrosis (IPF), a chronic interstitial lung disease, is characterized by aberrant wound healing, excessive scarring and the formation of myofibroblastic foci. Although the role of alternative splicing (AS) in the pathogenesis of organ fibrosis has garnered increasing attention, its specific contribution to pulmonary fibrosis remains incompletely understood. In this study, we identified an up-regulation of serine/arginine-rich splicing factor 7 (SRSF7) in lung fibroblasts derived from IPF patients and a bleomycin (BLM)-induced mouse model, and further characterized its functional role in both human fetal lung fibroblasts and mice. We demonstrated that enhanced expression of Srsf7 in mice spontaneously induced alveolar collagen accumulation. Mechanistically, we investigated alternative splicing events and revealed that SRSF7 modulates the alternative splicing of pyruvate kinase (PKM), leading to metabolic dysregulation and fibroblast activation. In vivo studies showed that fibroblast-specific knockout of Srsf7 in conditional knockout mice conferred resistance to bleomycin-induced pulmonary fibrosis. Importantly, through drug screening, we identified lomitapide as a novel modulator of SRSF7, which effectively mitigated experimental pulmonary fibrosis. Collectively, our findings elucidate a molecular pathway by which SRSF7 drives fibroblast metabolic dysregulation and propose a potential therapeutic strategy for pulmonary fibrosis.

Objective:To evaluate the relationship between postoperative changes in femoral head coverage (FHC) after S 2-Alar-Iliac (S 2AI) screw fixation and the development of sagittal imbalance during follow-up in patients with adult spinal deformity (ASD), providing insights for clinical assessment and treatment strategies. Methods:A consecutive cohort of 98 ASD patients who underwent S2AI fixation between September 2019 and September 2021 was retrospectively analyzed. Patients were divided into two groups based on changes in femoral head coverage (ΔFHC): the FHC-C group (upper quartile ΔFHC, 25 cases) and the FHC-NC group (lower quartile ΔFHC, 24 cases). Additionally, patients were classified into proximal junctional kyphosis (PJK) and non-PJK groups based on their clinical outcomes at the last follow-up. Standing full-spine anteroposterior and lateral X-rays were taken preoperatively, postoperatively, and at the two-year follow-up to measure and document the following spinal parameters: Cobb angle, proximal lumbar lordosis (PLL), distal lumbar lordosis (DLL), lumbar lordosis (LL), lordosis distribution index (LDI), sagittal vertical axis (SVA), coronal balance distance (CBD), thoracic kyphosis (TK), T 1 pelvic angle (T 1PA), pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), PI-LL, and proximal junctional angle (PJA). Parameters related to hip joint coverage included: femoral head coverage (FHC), lateral center-edge angle (LCE angle), acetabular index (AI), Sharp angle, and extrusion index (EI). Comparisons of radiographic indicators between the two groups were performed at preoperative, postoperative, and final follow-up assessments. The visual analogue scale (VAS) was used to evaluate the hip pain and back pain. Results:At final follow-up, the incidence of PJK was significantly higher in the FHC-NC group [37.5% (9/24)] compared to the FHC-C group [16.0% (4/25)] (χ 2=3.952, P=0.042). Moreover, the increase in sagittal vertical axis (ΔSVA) was significantly greater in the FHC-NC group (35.9±44.7 mm vs. 14.6±31.8 mm, t=2.216, P=0.031). Patients with PJK had significantly higher preoperative T 1PA (36.8°±10.8° vs. 31.9°±18.4°, t=2.150, P=0.034) and lower immediate postoperative ΔFHC (1.7%±1.5% vs. 3.3%±2.5%, t=2.987, P=0.004), as well as lower changes in lateral center-edge angle during follow-up (0.3°±3.0° vs. 1.1°±8.9°, t=2.334, P=0.022). Pearson correlation analysis revealed significant negative correlations between postoperative ΔFHC and both ΔSVA ( r=-0.374, P=0.008) and proximal junctional angle changes (ΔPJA, r=-0.429, P=0.006). Additionally, increases in VAS leg pain scores correlated negatively with immediate postoperative FHC ( r=-0.314, P=0.025) and ΔFHC ( r=-0.298, P=0.031). Logistic regression indicated that immediate postoperative ΔFHC was a protective factor against PJK [ OR=0.722, 95% CI (0.541, 0.963), P=0.009), with a ROC-determined optimal ΔFHC cut-off of 3.90% (AUC=0.723, Youden index=0.847). Conclusions:Postoperative evaluation of femoral head coverage is clinically important for ASD patients undergoing S2AI screw fixation. A pre-to-post ΔFHC below 3.90% may indicate reduced hip compensation capacity, increasing risks for hip pain, sagittal imbalance progression, and PJK postoperatively.

Objective To compare regression models for age estimation constructed based on the Pulp Dentinal Index(PDI)of the first permanent molars and explore a more accurate and applicable novel method.Methods A total of 900 Cone Beam Computed Tomography(CBCT)image datasets from adult Han Chinese individuals(455 males and 445 females)residing in Sichuan province,China,were collected from the Affiliated Hospital of North Sichuan Medical College.The PDI of the first permanent molars were measured using Mimics software.Regression analysis was performed with age as the dependent variable and PDI as the independent variable to establish and validate the optimal mathematical model for age estimation.Results Strong correlations were observed between the PDI of all four first permanent molars and age,with the correlation being stronger for maxillary teeth compared to mandibular teeth,and the highest correlation found in the left maxillary first molar among females(r=0.881).Significant differences in PDI were identified between maxillary and mandibular positions as well as between genders(P＜0.05),but not between left and right positions(P＞0.05).Among the 11 mathematical models constructed,the cubic regression model outperformed others,with the left maxillary first molar model demonstrating the best performance(Age=73.93-70.79x-68.75x2+94.33x3),yielding a mean absolute error(MAE)of 4.88 years.Conclusion Among the 11 regression models constructed in this study based on CBCT-measured PDI values of the first permanent molars,the cubic regression model exhibited the highest accuracy,with an MAE of 4.88 years.

Objective:To investigate the role and mechanism of leucine-rich α-2-glycoprotein 1 (LRG1) in the fibrosis of human pterygium fibroblasts (HPFs).Methods:A total of 30 nasal primary pterygium tissues from patients who underwent pterygium excision surgery and 30 nasal normal conjunctival tissues from patients who underwent strabismus correction surgery were collected from the First Affiliated Hospital of Harbin Medical University between January 2022 and March 2023, serving as the pterygium group and normal control group, respectively.LRG1 protein expression in both groups was detected by immunofluorescence staining.The mRNA and protein levels of LRG1 and transforming growth factor-β1 (TGF-β1) were evaluated by quantitative real-time PCR (qRT-PCR) and Western blot.Primary HPFs were cultured from excised pterygium tissues using tissue block adhesion method, and cell morphology was observed.Vmentin and cytokeratin were identified by immunofluorescence staining.HPFs were divided into recombinant human LRG1 (rhLRG1) group and blank control group treated with or without 10 μg/ml rhLRG1 for 24 hours, respectively, and cell migration was evaluated via scratch assay.Additionally, HPFs were divided into blank control group, LRG1 overexpression group and LRG1 knockdown group.HPFs in LRG1 overexpression group and LRG1 knockdown group were transfected with LRG1 overexpression plasmids and small interfering RNA for 24 hours, respectively.TGF-β1 mRNA level was evaluated by qRT-PCR and expression of TGF-β1, fibronectin (FN), type Ⅲ collagen (COL3), and α-smooth muscle actin (α-SMA) proteins were evaluated by Western blot.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Harbin Medical University (No.2022IIT026).Written informed consent was obtained from each subject.Results:HPFs were successfully isolated, exhibiting spindle-shaped morphology with whorled arrangement, positive identification for vimentin, and negative immunofluorescence staining for cytokeratin.The migration rate of the rhLRG1 group was (83.01±2.56)%, significantly higher than (50.32±4.97)% of the blank control group ( t=9.59, P<0.001).Immunofluorescence staining results showed that compared with normal conjunctival tissue, LRG1 protein was significantly higher expressed in pterygium tissue and was widely distributed in fibrous connective tissue and epithelial layer.Both mRNA and protein levels of LRG1 and TGF-β1 were significantly higher in the pterygium group than in the normal control group (mRNA: t=10.18, 6.15, both P<0.05.protein: t=6.83, 8.79, both P<0.05).In the LRG1 overexpression group, mRNA level of TGF-β1, and protein levels of FN, COL3 and α-SMA were significantly increased compared with the blank control and LRG1 knockdown groups (all P<0.05). Conclusions:LRG1 promotes fibrosis and enhances the migration ability in HPFs, and its mechanism may be associated with the upregulation of the TGF-β1 signaling pathway.

Objective:To investigate the role and mechanism of leucine-rich α-2-glycoprotein 1 (LRG1) in the fibrosis of human pterygium fibroblasts (HPFs).Methods:A total of 30 nasal primary pterygium tissues from patients who underwent pterygium excision surgery and 30 nasal normal conjunctival tissues from patients who underwent strabismus correction surgery were collected from the First Affiliated Hospital of Harbin Medical University between January 2022 and March 2023, serving as the pterygium group and normal control group, respectively.LRG1 protein expression in both groups was detected by immunofluorescence staining.The mRNA and protein levels of LRG1 and transforming growth factor-β1 (TGF-β1) were evaluated by quantitative real-time PCR (qRT-PCR) and Western blot.Primary HPFs were cultured from excised pterygium tissues using tissue block adhesion method, and cell morphology was observed.Vmentin and cytokeratin were identified by immunofluorescence staining.HPFs were divided into recombinant human LRG1 (rhLRG1) group and blank control group treated with or without 10 μg/ml rhLRG1 for 24 hours, respectively, and cell migration was evaluated via scratch assay.Additionally, HPFs were divided into blank control group, LRG1 overexpression group and LRG1 knockdown group.HPFs in LRG1 overexpression group and LRG1 knockdown group were transfected with LRG1 overexpression plasmids and small interfering RNA for 24 hours, respectively.TGF-β1 mRNA level was evaluated by qRT-PCR and expression of TGF-β1, fibronectin (FN), type Ⅲ collagen (COL3), and α-smooth muscle actin (α-SMA) proteins were evaluated by Western blot.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Harbin Medical University (No.2022IIT026).Written informed consent was obtained from each subject.Results:HPFs were successfully isolated, exhibiting spindle-shaped morphology with whorled arrangement, positive identification for vimentin, and negative immunofluorescence staining for cytokeratin.The migration rate of the rhLRG1 group was (83.01±2.56)%, significantly higher than (50.32±4.97)% of the blank control group ( t=9.59, P<0.001).Immunofluorescence staining results showed that compared with normal conjunctival tissue, LRG1 protein was significantly higher expressed in pterygium tissue and was widely distributed in fibrous connective tissue and epithelial layer.Both mRNA and protein levels of LRG1 and TGF-β1 were significantly higher in the pterygium group than in the normal control group (mRNA: t=10.18, 6.15, both P<0.05.protein: t=6.83, 8.79, both P<0.05).In the LRG1 overexpression group, mRNA level of TGF-β1, and protein levels of FN, COL3 and α-SMA were significantly increased compared with the blank control and LRG1 knockdown groups (all P<0.05). Conclusions:LRG1 promotes fibrosis and enhances the migration ability in HPFs, and its mechanism may be associated with the upregulation of the TGF-β1 signaling pathway.

Objective:To evaluate the relationship between postoperative changes in femoral head coverage (FHC) after S 2-Alar-Iliac (S 2AI) screw fixation and the development of sagittal imbalance during follow-up in patients with adult spinal deformity (ASD), providing insights for clinical assessment and treatment strategies. Methods:A consecutive cohort of 98 ASD patients who underwent S2AI fixation between September 2019 and September 2021 was retrospectively analyzed. Patients were divided into two groups based on changes in femoral head coverage (ΔFHC): the FHC-C group (upper quartile ΔFHC, 25 cases) and the FHC-NC group (lower quartile ΔFHC, 24 cases). Additionally, patients were classified into proximal junctional kyphosis (PJK) and non-PJK groups based on their clinical outcomes at the last follow-up. Standing full-spine anteroposterior and lateral X-rays were taken preoperatively, postoperatively, and at the two-year follow-up to measure and document the following spinal parameters: Cobb angle, proximal lumbar lordosis (PLL), distal lumbar lordosis (DLL), lumbar lordosis (LL), lordosis distribution index (LDI), sagittal vertical axis (SVA), coronal balance distance (CBD), thoracic kyphosis (TK), T 1 pelvic angle (T 1PA), pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), PI-LL, and proximal junctional angle (PJA). Parameters related to hip joint coverage included: femoral head coverage (FHC), lateral center-edge angle (LCE angle), acetabular index (AI), Sharp angle, and extrusion index (EI). Comparisons of radiographic indicators between the two groups were performed at preoperative, postoperative, and final follow-up assessments. The visual analogue scale (VAS) was used to evaluate the hip pain and back pain. Results:At final follow-up, the incidence of PJK was significantly higher in the FHC-NC group [37.5% (9/24)] compared to the FHC-C group [16.0% (4/25)] (χ 2=3.952, P=0.042). Moreover, the increase in sagittal vertical axis (ΔSVA) was significantly greater in the FHC-NC group (35.9±44.7 mm vs. 14.6±31.8 mm, t=2.216, P=0.031). Patients with PJK had significantly higher preoperative T 1PA (36.8°±10.8° vs. 31.9°±18.4°, t=2.150, P=0.034) and lower immediate postoperative ΔFHC (1.7%±1.5% vs. 3.3%±2.5%, t=2.987, P=0.004), as well as lower changes in lateral center-edge angle during follow-up (0.3°±3.0° vs. 1.1°±8.9°, t=2.334, P=0.022). Pearson correlation analysis revealed significant negative correlations between postoperative ΔFHC and both ΔSVA ( r=-0.374, P=0.008) and proximal junctional angle changes (ΔPJA, r=-0.429, P=0.006). Additionally, increases in VAS leg pain scores correlated negatively with immediate postoperative FHC ( r=-0.314, P=0.025) and ΔFHC ( r=-0.298, P=0.031). Logistic regression indicated that immediate postoperative ΔFHC was a protective factor against PJK [ OR=0.722, 95% CI (0.541, 0.963), P=0.009), with a ROC-determined optimal ΔFHC cut-off of 3.90% (AUC=0.723, Youden index=0.847). Conclusions:Postoperative evaluation of femoral head coverage is clinically important for ASD patients undergoing S2AI screw fixation. A pre-to-post ΔFHC below 3.90% may indicate reduced hip compensation capacity, increasing risks for hip pain, sagittal imbalance progression, and PJK postoperatively.

Objective To compare regression models for age estimation constructed based on the Pulp Dentinal Index(PDI)of the first permanent molars and explore a more accurate and applicable novel method.Methods A total of 900 Cone Beam Computed Tomography(CBCT)image datasets from adult Han Chinese individuals(455 males and 445 females)residing in Sichuan province,China,were collected from the Affiliated Hospital of North Sichuan Medical College.The PDI of the first permanent molars were measured using Mimics software.Regression analysis was performed with age as the dependent variable and PDI as the independent variable to establish and validate the optimal mathematical model for age estimation.Results Strong correlations were observed between the PDI of all four first permanent molars and age,with the correlation being stronger for maxillary teeth compared to mandibular teeth,and the highest correlation found in the left maxillary first molar among females(r=0.881).Significant differences in PDI were identified between maxillary and mandibular positions as well as between genders(P＜0.05),but not between left and right positions(P＞0.05).Among the 11 mathematical models constructed,the cubic regression model outperformed others,with the left maxillary first molar model demonstrating the best performance(Age=73.93-70.79x-68.75x2+94.33x3),yielding a mean absolute error(MAE)of 4.88 years.Conclusion Among the 11 regression models constructed in this study based on CBCT-measured PDI values of the first permanent molars,the cubic regression model exhibited the highest accuracy,with an MAE of 4.88 years.

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment landscape for chronic myeloid leukemia (CML). However, TKI resistance poses a significant challenge, leading to treatment failure and disease progression. Resistance mechanisms include both BCR::ABL1-dependent and BCR::ABL1-independent pathways. The mechanisms underlying BCR::ABL1 independence remain incompletely understood, with CML cells potentially activating alternative signaling pathways, including the AKT/mTOR and JAK2/STAT5 pathways, to compensate for the loss of BCR::ABL1 kinase activity. This study explored tumoral VISTA (encoded by VSIR) as a contributing factor to TKI resistance in CML patients and identified elevated tumoral VISTA levels as a marker of resistance and poor survival. Through in vitro and in vivo analyses, we demonstrated that VSIR knockdown and the application of NSC-622608, a novel VISTA inhibitor, significantly impeded CML cell proliferation and induced apoptosis by attenuating the AKT/ mTOR and JAK2/STAT5 pathways, which are crucial for CML cell survival independent of BCR::ABL1 kinase activity. Moreover, VSIR overexpression promoted TKI resistance in CML cells. Importantly, the synergistic effect of NSC-622608 with TKIs offers a potent therapeutic avenue against both imatinib-sensitive and imatinib-resistant CML cells, including those harboring the challenging T315I mutation. Our findings highlight the role of tumoral VISTA in mediating TKI resistance in CML, suggesting that inhibition of VISTA, particularly in combination with TKIs, is an innovative approach to enhancing treatment outcomes in CML patients, irrespective of BCR::ABL1 mutation status. This study not only identified a new pathway contributing to TKI resistance but also revealed the possibility of targeting tumoral VISTA as a means of overcoming this significant clinical challenge.

Objective:To investigate the efficacy of radiofrequency ablation combined with ozone therapy under CT guidance in the treatment of lumbar disc herniation.Methods:A total of 93 patients with lumbar disc herniation who were admitted to The First Hospital of Jiaxing from January 2019 to May 2022 were included in this study. They were randomly divided into an observation group ( n = 47) and a control group ( n = 46). The control group was treated with radiofrequency ablation and the observation group was treated with radiofrequency ablation combined with ozone therapy. Efficacy was compared between the two groups at 3 months after surgery. The pain was compared between the two groups before and 7 days and 3 months after surgery. Inflammatory factors were compared between the two groups before and 7 days after surgery. The lumbar spine function was compared between the two groups before and 3 months after surgery. Results:At 3 months after surgery, the excellent and good rate in the observation group was significantly higher than that in the control group [89.36% (42/47) vs. 71.74% (33/47), χ2 = 4.63, P < 0.05). At 7 days and 3 months after surgery, Visual Analogue Scale scores in the observation group were (2.91 ± 0.54) points and (1.32 ± 0.31) points, respectively, which were significantly lower than (3.76 ± 0.62) points and (2.08 ± 0.47) points in the control group ( t = 7.06, 9.22, both P < 0.001). At 7 days after surgery, serum interleukin-1β, interleukin-6, and tumor necrosis factor-α in the observation group were (0.24 ± 0.05) μg/L, (18.49 ± 3.47) ng/L, and (97.94 ± 17.43) ng/L, respectively, which were significantly lower than (0.37 ± 0.09) μg/L, (24.31 ± 4.12) ng/L, and (148.87 ± 20.13) ng/L, respectively in the control group ( t = 8.63, 7.37, 13.05, all P < 0.05). At 3 months after surgery, the Japanese Orthopedic Association score in the observation group was significantly higher than that in the control group [(25.68 ± 2.28) points vs. (21.17 ± 3.24) points, t = -7.78, P < 0.001], and the Oswestry Disability Index in the observation group was significantly lower than that in the control group [(9.84 ± 1.43) points vs. (13.46 ± 2.18) points, t = 9.49, P < 0.001]. Conclusion:Radiofrequency ablation combined with ozone therapy under CT guidance is highly effective on lumbar disc herniation. The combined therapy can reduce pain and inflammatory reactions in patients and improve lumbar function.

Objective:To investigate the regulatory role of defferentially expressed LOC107987438 in the pathogenesis of depressive disorder and provide a theoretical basis for its clinical application in depressive disorder.Methods:Differential expression of LOC107987438 was verified by quantitative real-time polymerase chain reaction(qRT-PCR)in peripheral blood monocular cells(PBMCs)of 60 patients with depressive disorder and 60 health controls. In addition, its diagnostic value was assessed by receiver operating characteristic(ROC)curves. Based on the ceRNA mechanism of lncRNA, the miRDB database was applied to predict the target miRNAs of LOC107987438, and the miRNAs with target score ≥ 80 among them were screened out.The screened miRNAs were then used to predict their potential target mRNAs through four databases which were TargetScan 8.0, miRTarBase, mirDIP and miRPathDB. Moreover, the predicted target mRNAs were annotated for gene ontology(GO)function annotation and tokoyo encyclopedia of genes and genomes(KEGG) pathway enrichment analysis via ClusterProfiler 4.0.5 package of R 4.1.1. Finally, a protein-protein interaction network was constructed using the STRING 11.5 platform to retrieve the interacting genes.Results:The qRT-PCR results showed that normalized expression of LOC107987438 in PBMCs of patients with depressive disorder was higher than that in health controls(depressive disorder: 2.084±1.357, health controls: 1.000±0.660, P<0.001). The ROC curve results showed that the area under curves(AUC)of LOC107987438 was 0.759(95% CI: 0.675-0.842, P<0.05), indicating its high potential diagnostic value. Bioinformatics analysis showed that hsa-miR-4670-3p, hsa-miR-619-3p, hsa-miR-6721-5p and hsa-miR-297 were the miRNAs with high bindings to LOC107987438. The results of KEGG signaling pathway enrichment revealed that hypoxia-inducible factor 1(HIF-1)signaling pathway, phosphatidylinositol 3-kinase-AKT(PI3K-Akt) signaling pathway and erythroblastic oncogene B(ErbB) signaling pathway were closely associated with depressive disorder. Among the top ten key genes screened by the protein-protein interaction network, kirsten rats arcomaviral oncogene homolog(KRAS), androgen receptor(AR), cyclic-AMP response binding protein1(CREB1), insulin-like growth factor 1(IGF1), cyclin-dependent kinase inhibitor 1B(CDKN1B) and calcium/calmodulin-dependent protein kinase type Ⅱ alpha(CAMK2A)were strongly associated with depressive disorder. Conclusion:The establishment of ceRNA regulatory network of LOC107987438 provides a theoretical basis for exploring the pathophysiology of depressive disorders.