BACKGROUND: Neoadjuvant therapy enhances the possibility of achieving radical resection and improves the prognosis for locally advanced gastric cancer (GC). However, there is a lack of evidence regarding the optimal extent of resection for locally advanced proximal GC after neoadjuvant therapy. METHODS: In this study, 330 patients underwent resection in Peking University Cancer Hospital, with curative intent after neoadjuvant therapy for histologically confirmed proximal GC from January 2009 to December 2022. RESULTS: In this study, 45 patients underwent proximal gastrectomy (PG), while 285 underwent total gastrectomy (TG). After propensity-score matching, 110 patients (71 TG and 39 PG) were included in the analysis. No significant differences between PG and TG regarding short-term outcomes and long-term prognosis were found. Specifically, PG demonstrated comparable overall survival to TG ( P = 0.47). Subgroup analysis revealed that although not statistically significant, PG showed a potential advantage over TG in overall survival for patients with tumor-long diameters less than 4 cm ( P  = 0.31). However, for those with a long diameter larger than 4 cm, TG had a better survival probability ( P  = 0.81). No substantial differences were observed in baseline characteristics, surgical safety, postoperative recovery, and postoperative complications. CONCLUSION For locally advanced proximal GC with objective response to neoadjuvant therapy (long diameter <4 cm), PG is an alternative surgical procedure.
Humans ; Stomach Neoplasms/drug therapy* ; Gastrectomy/methods* ; Neoadjuvant Therapy/methods* ; Male ; Female ; Middle Aged ; Propensity Score ; Aged ; Adult ; Retrospective Studies

Objective:To analyze the target signaling pathway of histone H3K27 methylation-induced podocyte injury, verify the regulatory effect of histone H3K27 methylation on podocyte injury in focal segmental glomerulosclerosis (FSGS) mice through target signaling pathway, and explore the mechanism of abnormal methylation of histone H3K27-induced podocyte injury in FSGS mice.Methods:(1) Cell experiments: primary cultured immortalized mouse podocytes MPC5 were cultured in vitro, and divided into control group, adriamycin (ADR) group, ADR+GSK-J4 (histone demethylase, KDM6B inhibitor) group, ADR+coumarin A1 (C-A1, JAK2 agonist) group and ADR+GSK-J4+C-A1 group. The transmission electron microscope was used to observe ultrastructure of podocytes. Immunofluorescence was used to detect the protein expression of H3K27me3 and nephrin in podocytes. The whole genome sequence of podocytes was obtained, the differentially expressed genes were screened, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used for enrichment analysis. Real time-quantitative PCR and Western blotting were used to detect the gene and protein expression of JAK2-STAT3 signaling pathway in podocytes respectively. Enzyme-linked immunosorbent assay was used to detect interleukin 6 (IL-6), monocyte chemotactic protein 1 (MCP-1), α-smooth muscle actin (α-SMA) and transforming growth factor β1 (TGF-β1). (2) Animal experiments: EZH2 gene knock out ( EZH2podKo)-FSGS (tail vein injection of ADR) mouse models were established, and divided into EZH2ctrl+control group ( n=20), EZH2ctrl+FSGS ( n=20), EZH2podKo+control group ( n=30) and EZH2podKo+FSGS group ( n=30). HE staining was used to observe the morphology of kidney tissues. Immunohistochemistry was used to detect the H3K27me3 protein expression in podocytes. Real time-quantitative PCR and Western blotting were used to verify the gene and protein expression of JAK2-STAT3 signaling pathway respectively. Enzyme-linked immunosorbent assay was used to detect IL-6, MCP-1, α-SMA and TGF-β1 of kidney tissues. Results:(1) Cell experiments: Compared with control group, the nucleus shrank and ruptured, the cytoplasm showed vacuole, and mitochondria and endoplasmic reticulum swelled in ADR group, which verified that the podocyte injury model of ADR nephropathy was successfully established. Compared with control group, the protein expression level of H3K27me3 in ADR group was significantly lower ( P<0.05). Compared with ADR group, the protein expression level of H3K27me3 in podocytes in ADR+GSK-J4 group was significantly higher ( P<0.05), and there were 502 increased genes and 443 decreased genes. GO enrichment analysis showed that the differentially enriched peaks were mainly in ribonucleoprotein complex biogenesis, ribosome biogenesis, establishment of protein localization to organelle, and involved in regulation of receptor signaling pathway via JAK-STAT and receptor signaling pathway via JAK-STAT. Differential expressed genes were Irf1, Tnfrsf1a, S ocs1, Notch1, Gadd45a, Hes1 and Socs3, involving in the regulation of JAK-STAT signaling pathway. KEGG enrichment analysis showed that the differentially enriched peaks were mainly in amyotrophic lateral sclerosis, and the target genes were Mcl1, Egfr, Socs1, Cdkn1a, Pdgfa and Socs3, involving in the regulation of JAK-STAT signaling pathway. Compared with ADR group, the mRNA and protein expression levels of JAK2 and STAT3 in the ADR+GSK-J4 group were significantly lower, and the downstream inflammatory factors of IL-6, MCP-1 and α-SMA were significantly higher (all P<0.05). Compared with ADR group, the protein expression level of nephrin in ADR+GSK-J4 group was higher ( P<0.05), and the protein expression level of nephrin in ADR+C-A1 group was lower ( P<0.05). Compared with ADR+GSK-J4 group, the protein expression level of nephrin in ADR+GSK-J4+C-A1 group was lower ( P<0.05). (2) Animal experiments: Compared with EZH2ctrl+FSGS group, EZH2podKo+FSGS group showed obvious renal tissue damage, matrix hyperplasia in mesangial area with massive homogeneous substance deposition, apoptosis and necrosis of renal tubular epithelial cells, obvious thickening and extensive fusion of glomerular epithelial cells, basement membrane collapse, and compression and narrowing of capillary structure. Compared with EZH2ctrl+FSGS group, the protein expression level of H3K27me3 in EZH2podKo+FSGS group was significantly lower, and the mRNA and protein expression levels of JAK2 and STAT3, and the levels of IL-6, MCP-1, α-SMA and TGF-β1 were higher (all P<0.05). Conclusions:Abnormal methylation modification of H3K27 leads to change of target gene expression, activation of JAK2-STAT3 signaling pathway, podocyte injury, glomerulosclerosis and renal tubular injury, participating in the development of FSGS.

Objective:This study aims to analyze the economic impact of postoperative complications after colorectal cancer surgery.Methods:A retrospective cohort study was conducted. Patients with a preoperative pathological diagnosis of colorectal cancer who met surgical indications and underwent surgical treatment were included, while those with incomplete hospitalization cost data were excluded. From March 2017 to March 2022, three hundred and ninety-two colorectal cancer patients treated at Peking University Cancer Hospital and Institute Gastrointestinal Cancer Center I, were enrolled. Descriptive statistics were performed on the incidence of complications, hospitalization costs, and postoperative length of stay. A cohort was established based on the presence of postoperative complications (POC) and absence of postoperative complications (non-POC) to study economic differences. Propensity score matching analysis was employed to reduce potential confounding factors.Results:Among 392 colorectal cancer patients, 90 (23.0%) developed POC (POC group), while 302 were in the non-POC group. Significant statistical differences were found between the two groups in terms of operation duration, extent of resection, and stoma creation (all P < 0.05); other baseline indicators showed no significant differences (all P>0.05). The median hospitalization cost for patients with postoperative anastomotic leakage was 115 973 yuan, an increase of 38 941 yuan (50.5%) over the non-POC group's 77 059 yuan; the median hospitalization cost for patients with mechanical obstruction was 111 477 yuan, an increase of 34 418 yuan (44.7%) over the non-POC group; and the median hospitalization cost for patients with wound infection was 95 860 yuan, an increase of 18 801 yuan (24.4%) over the non-POC group. The median postoperative length of stay for patients with anastomotic leakage, mechanical obstruction, and wound infection was 22.0 days, 22.0 days, and 18.5 days, respectively, compared to 9.0 days in the non-POC group, extending by 13.0 days, 13.0 days, and 9.5 days. After propensity score matching, each group had 68 patients, and there were no statistically significant differences in preoperative and intraoperative observations between the two groups (all P>0.05); compared to the non-POC group, the hospitali- zation costs in the POC group significantly increased (89 165 yuan vs. 75 437 yuan, P<0.001), and the postoperative length of stay also significantly extended (14.0 days vs. 8.0 days, P<0.001). Conclusions:The occurrence of POC after colorectal cancer surgery significantly increases hospitalization costs and length of stay. This study provides specific and accurate reference data for subsequent health economic decision-making. This is the first detailed economic impact analysis of postoperative complications of colorectal cancer with a large sample size, which includes an economic impact analysis for each POC and subgroup.

Objective:This study aims to analyze the economic impact of postoperative complications after colorectal cancer surgery.Methods:A retrospective cohort study was conducted. Patients with a preoperative pathological diagnosis of colorectal cancer who met surgical indications and underwent surgical treatment were included, while those with incomplete hospitalization cost data were excluded. From March 2017 to March 2022, three hundred and ninety-two colorectal cancer patients treated at Peking University Cancer Hospital and Institute Gastrointestinal Cancer Center I, were enrolled. Descriptive statistics were performed on the incidence of complications, hospitalization costs, and postoperative length of stay. A cohort was established based on the presence of postoperative complications (POC) and absence of postoperative complications (non-POC) to study economic differences. Propensity score matching analysis was employed to reduce potential confounding factors.Results:Among 392 colorectal cancer patients, 90 (23.0%) developed POC (POC group), while 302 were in the non-POC group. Significant statistical differences were found between the two groups in terms of operation duration, extent of resection, and stoma creation (all P < 0.05); other baseline indicators showed no significant differences (all P>0.05). The median hospitalization cost for patients with postoperative anastomotic leakage was 115 973 yuan, an increase of 38 941 yuan (50.5%) over the non-POC group's 77 059 yuan; the median hospitalization cost for patients with mechanical obstruction was 111 477 yuan, an increase of 34 418 yuan (44.7%) over the non-POC group; and the median hospitalization cost for patients with wound infection was 95 860 yuan, an increase of 18 801 yuan (24.4%) over the non-POC group. The median postoperative length of stay for patients with anastomotic leakage, mechanical obstruction, and wound infection was 22.0 days, 22.0 days, and 18.5 days, respectively, compared to 9.0 days in the non-POC group, extending by 13.0 days, 13.0 days, and 9.5 days. After propensity score matching, each group had 68 patients, and there were no statistically significant differences in preoperative and intraoperative observations between the two groups (all P>0.05); compared to the non-POC group, the hospitali- zation costs in the POC group significantly increased (89 165 yuan vs. 75 437 yuan, P<0.001), and the postoperative length of stay also significantly extended (14.0 days vs. 8.0 days, P<0.001). Conclusions:The occurrence of POC after colorectal cancer surgery significantly increases hospitalization costs and length of stay. This study provides specific and accurate reference data for subsequent health economic decision-making. This is the first detailed economic impact analysis of postoperative complications of colorectal cancer with a large sample size, which includes an economic impact analysis for each POC and subgroup.

Objective:To analyze the target signaling pathway of histone H3K27 methylation-induced podocyte injury, verify the regulatory effect of histone H3K27 methylation on podocyte injury in focal segmental glomerulosclerosis (FSGS) mice through target signaling pathway, and explore the mechanism of abnormal methylation of histone H3K27-induced podocyte injury in FSGS mice.Methods:(1) Cell experiments: primary cultured immortalized mouse podocytes MPC5 were cultured in vitro, and divided into control group, adriamycin (ADR) group, ADR+GSK-J4 (histone demethylase, KDM6B inhibitor) group, ADR+coumarin A1 (C-A1, JAK2 agonist) group and ADR+GSK-J4+C-A1 group. The transmission electron microscope was used to observe ultrastructure of podocytes. Immunofluorescence was used to detect the protein expression of H3K27me3 and nephrin in podocytes. The whole genome sequence of podocytes was obtained, the differentially expressed genes were screened, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used for enrichment analysis. Real time-quantitative PCR and Western blotting were used to detect the gene and protein expression of JAK2-STAT3 signaling pathway in podocytes respectively. Enzyme-linked immunosorbent assay was used to detect interleukin 6 (IL-6), monocyte chemotactic protein 1 (MCP-1), α-smooth muscle actin (α-SMA) and transforming growth factor β1 (TGF-β1). (2) Animal experiments: EZH2 gene knock out ( EZH2podKo)-FSGS (tail vein injection of ADR) mouse models were established, and divided into EZH2ctrl+control group ( n=20), EZH2ctrl+FSGS ( n=20), EZH2podKo+control group ( n=30) and EZH2podKo+FSGS group ( n=30). HE staining was used to observe the morphology of kidney tissues. Immunohistochemistry was used to detect the H3K27me3 protein expression in podocytes. Real time-quantitative PCR and Western blotting were used to verify the gene and protein expression of JAK2-STAT3 signaling pathway respectively. Enzyme-linked immunosorbent assay was used to detect IL-6, MCP-1, α-SMA and TGF-β1 of kidney tissues. Results:(1) Cell experiments: Compared with control group, the nucleus shrank and ruptured, the cytoplasm showed vacuole, and mitochondria and endoplasmic reticulum swelled in ADR group, which verified that the podocyte injury model of ADR nephropathy was successfully established. Compared with control group, the protein expression level of H3K27me3 in ADR group was significantly lower ( P<0.05). Compared with ADR group, the protein expression level of H3K27me3 in podocytes in ADR+GSK-J4 group was significantly higher ( P<0.05), and there were 502 increased genes and 443 decreased genes. GO enrichment analysis showed that the differentially enriched peaks were mainly in ribonucleoprotein complex biogenesis, ribosome biogenesis, establishment of protein localization to organelle, and involved in regulation of receptor signaling pathway via JAK-STAT and receptor signaling pathway via JAK-STAT. Differential expressed genes were Irf1, Tnfrsf1a, S ocs1, Notch1, Gadd45a, Hes1 and Socs3, involving in the regulation of JAK-STAT signaling pathway. KEGG enrichment analysis showed that the differentially enriched peaks were mainly in amyotrophic lateral sclerosis, and the target genes were Mcl1, Egfr, Socs1, Cdkn1a, Pdgfa and Socs3, involving in the regulation of JAK-STAT signaling pathway. Compared with ADR group, the mRNA and protein expression levels of JAK2 and STAT3 in the ADR+GSK-J4 group were significantly lower, and the downstream inflammatory factors of IL-6, MCP-1 and α-SMA were significantly higher (all P<0.05). Compared with ADR group, the protein expression level of nephrin in ADR+GSK-J4 group was higher ( P<0.05), and the protein expression level of nephrin in ADR+C-A1 group was lower ( P<0.05). Compared with ADR+GSK-J4 group, the protein expression level of nephrin in ADR+GSK-J4+C-A1 group was lower ( P<0.05). (2) Animal experiments: Compared with EZH2ctrl+FSGS group, EZH2podKo+FSGS group showed obvious renal tissue damage, matrix hyperplasia in mesangial area with massive homogeneous substance deposition, apoptosis and necrosis of renal tubular epithelial cells, obvious thickening and extensive fusion of glomerular epithelial cells, basement membrane collapse, and compression and narrowing of capillary structure. Compared with EZH2ctrl+FSGS group, the protein expression level of H3K27me3 in EZH2podKo+FSGS group was significantly lower, and the mRNA and protein expression levels of JAK2 and STAT3, and the levels of IL-6, MCP-1, α-SMA and TGF-β1 were higher (all P<0.05). Conclusions:Abnormal methylation modification of H3K27 leads to change of target gene expression, activation of JAK2-STAT3 signaling pathway, podocyte injury, glomerulosclerosis and renal tubular injury, participating in the development of FSGS.

Objective:To investigate the effects and underlying mechanisms of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/NF-κB signaling pathway in human kidney-2(HK-2) cells of hyperuricemic nephropathy.Methods:HK-2 cells were cultured in vitro and randomly divided into control group and experimental group. The experimental group was induced by high uric acid (720 μmol/L) immersion for 48 h to establish a cell model of hyperuricemic nephropathy in vitro and subsequently divided into hyperuricemic group, overexpressed protease activated receptor 2 (PAR2) and knockdown PAR2 group. The expressions of PAR2, PI3K, AKT, NF-κB mRNA were measured by real-time PCR. The expressions of PAR2, PI3K, AKT and NF-κB protein were measured by Western blotting. The expressions of tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), pro-interleukin-1β (pro-IL-1β), interleukin-1β (IL-1β) and transforming growth factor-β1 (TGF-β1) were detected by enzyme linked immunosorbent assay (ELISA). Results:(1) Compared with the control group, the expressions of PAR2, PI3K, AKT and NF-κB mRNA and protein in hyperuricemic group were significantly increased (all P<0.05), the expressions of TNF-α, MCP-1, IL-6, pro-IL-1β, IL-1β and TGF-β1 in the supernatant in hyperuricemic group were significantly increased (all P<0.01). (2) Compared with the hyperuricemic group, the expressions of PAR2, PI3K, AKT and NF-κB mRNA and protein in overexpressed PAR2 group were significantly increased (all P<0.05), the expressions of TNF-α, MCP-1, IL-6, IL-1β and TGF-β1 in the supernatant were significantly increased (all P<0.05). (3) Compared with the hyperuricemic group, the expression of PAR2, PI3K, AKT and NF-κB mRNA and protein in knockdown PAR2 group were significantly decreased (all P<0.05), the expressions of IL-6, pro-IL-1β, IL-1β and TGF-β1 in the supernatant were significantly decreased (all P<0.05). Conclusions:In the process of uric acid-induced HK-2 cell damage, uric acid significantly up-regulates the expression of PI3K/AKT/NF-κB signaling pathway by activating PAR2, leading to a marked increase in inflammatory damage. Knocking down PAR2 inhibits the expression of PI3K/AKT/NF-κB signaling pathway, which can effectively reduce the inflammatory damage of HK-2 cells.

Objective To observe the level of CD4+CD25+ regulatory T cells (CD4+CD25+ Treg cells) with positive fork head transcription factor 3 (Foxp3) and changes of T-box transcription factor TBX1 (TBX1) and myocyte specific enhancer 2D (MEF2D) expression in peripheral blood of rats with acute rejection after renal transplantation,and to investigate its regulatory mechanisms by combined with renal function,plasma interleukin-10 (IL-10),interferon-γ (IFN-γ) and renal histopathological changes.Methods Rat renal transplantation model was established and divided into two groups:acute rejection group (AR group) and non-acute rejection group (non-AR group).Their renal function including serum creatinine (Scr) and blood urea nitrogen (BUN) in plasma was measured.The renal histopathology was observed by HE staining.Levels of IL-10 and IFN-γ in plasma were detected by ELISA.The proportion of CD4+CD25+ Treg cells was measured by flow cytometry.The mRNA expressions of Foxp3,TBX1 and MEF2D in CD4+CD4+Treg cells were detected by real-time PCR,and their protein expressions were tested by Western blotting.Results Compared with these in the non-AR group,the levels of BUN,Scr and IFN-γ significantly increased in AR group (all P ＜ 0.05),while IL-10 decreased (P ＜ 0.05).Renal histopathology in the acute rejection group showed glomerular hypertrophy and mesangial cell proliferation,capillary proliferation and neutrophil infiltration;renal interstitial edema and tubular necrosis,accompanied by lymphocytes,plasma cells and neutrophils infiltration.Compared with that in the non-AR group,the percentage of CD4+CD25+ Treg cells in peripheral blood was notably lowered in AR group (4.50％±0.50％ vs 5.74％±1.96％,P ＜ 0.05).The mRNA and protein expressions of Foxp3 and MEF2D were lower in AR group than those in non-AR group,while the expressions of TBX1 was elevated (all P ＜ 0.05).Conclusions In rats with acute renal allograft rejection,the percentage of CD4+CD25+ Treg cells and expressions of Foxp3,MEF2D and IL-10 decrease,while the expressions of TBX1 and IFN-γ enhance.These participate in the development of acute rejection after renal transplantation,and aggravate the renal damage.