ObjectiveTo investigate the functional role and underlying molecular mechanisms of fumarylacetoacetate hydrolase （FAH） in the progression of glioblastoma （GBM）. MethodsDifferential expression analysis was performed on the TCGA-GBM， GSE4290， and GSE116520 datasets. Weighted gene co-expression network analysis （WGCNA） was used to identify key modules， and Cox regression and risk modeling were used to screen prognostic genes. Immune infiltration analysis of prognostic genes was carried out by using single-cell RNA sequencing panels. The clinical expression signature of FAH in GBM was analyzed in the TCGA and HPA databases. The functional role of FAH was validated by in vitro and in vivo experiments， and pathway analysis was performed to explore the underlying mechanisms. ResultsA total of 152 overlapping genes were identified across the three GBM datasets （P<0.05）. WGCNA revealed that the turquoise module was most strongly associated with tumor purity， stromal score， immune score， and ESTIMATE score （P<0.001）. Compared with normal tissues， three prognostic genes （CTSD， FAH， and THBD） were upregulated in GBM and correlated with immune infiltration （P<0.05）. FAH mRNA and protein levels were elevated in GBM tissues relative to normal tissues， and its expression was significantly associated with age stratification and TP53 mutation （P<0.05）. CCK-8 assay results showed that， compared with the shNC group， the proliferative activity of GBM cells in the shFAH group was reduced （P<0.001）. Transwell migration and invasion assays demonstrated that， relative to the shNC group， the numbers of migrated and invaded cells in the shFAH group decreased （P<0.05）. Western blot analysis revealed that the protein expression levels of PI3K， p-AKT， and p-mTOR in the shFAH group decreased compared with those in the shNC group （P<0.05）. In vivo subcutaneous xenograft experiments further confirmed that tumor volume and weight significantly decreased in the shFAH group compared with the shNC group （P<0.001）. ConclusionFAH promotes GBM progression by activating the PI3K/AKT/mTOR signaling pathway and may serve as a potential therapeutic target for GBM.

Objective:To investigate the clinical efficacy of 3D-printed metal augment or integrated acetabular prostheses for reconstruction of bone defects in hip revision.Methods:A total of 11 patients who underwent total hip revision in Zhengzhou Orthopaedic Hospital from June 2021 to July 2023 were retrospectively analysed. There were 5 males and 6 females, age 64.8±10.7 years (range, 58-75 years), and body mass index 23.3±4.8 kg/m 2 (range, 21-27 kg/m 2). Paprosky classification of acetabular bone defects: 3 cases of type IIA, 4 cases of type IIB, 3 cases of type IIIA, 1 case of type IIIB. Reasons for revision: 8 cases of aseptic loosening, 3 cases after infection exclusion procedure. A 3D-printed metal augment was used in 9 cases (8 cases of aseptic loosening and 1 case of infected exclusion procedure) and a 3D-printed integrated acetabulum was used in 2 cases (infected exclusion procedure). The time from primary total hip arthroplasty to revision was 11.8±5.6 years (range, 5-17 years). Harris hip score and visual analogue scale (VAS) were used to evaluate the improvement of hip function and pain recovery. The leg length discrepancy, vertical height and horizontal position of the hip rotation center were measured on pelvic anteroposterior X-ray films. Results:All patients successfully completed the operation. The operation time was 145.9±35.5 min (range, 110-159 min), and the intraoperative blood loss was 950.5±310.8 ml (range, 680-1,450 ml). The postoperative Harris hip function score was significantly higher than that before operation ( F=554.085, P<0.001). One year after operation, the Harris hip function score was 74.36±5.16, which was higher than that before operation 32.18±4.07, and the difference was statistically significant ( P<0.05). The VAS scores of all patients decreased after operation, and the difference was statistically significant compared with that before operation ( F=177.717, P<0.001). The VAS score at 1 year after operation was 1.27±0.65, which was lower than that before operation 6.18±1.17, and the difference was statistically significant ( P<0.05). The preoperative leg length discrepancy was 1.97±0.71 cm, which was greater than 0.69±0.52 cm at the last follow-up, and the difference was statistically significant ( t=4.824, P<0.001). The vertical height of the hip rotation center was 1.88±0.46 cm on the affected side and 1.67±0.35 cm on the healthy side, showing no significant difference ( t=1.205, P=0.242). The postoperative horizontal position of the hip rotation center was 3.48±0.55 cm on the affected side and 3.54±0.32 cm on the healthy side, and the difference was no statistically significant ( t=-0.313, P=0.758). One case had an intraoperative greater trochanteric fracture that healed 3 months after reduction and internal fixation. All patients were followed up for 21.3±9.5 months (range, 15-31 months). All incisions healed in one stage, and all patients were fully weight-bearing at 3 months after operation. At the last follow-up, there was no case of loosening, dislocation or infection of the prosthesis; 4 cases had mild claudication, 1 case had heterotopic ossification, and the patients had good hip flexion and extension functions, which did not affect daily life without further treatment. Conclusion:The clinical efficacy of 3D-printed metal augment or integrated acetabular prosthesis for reconstruction of acetabular bone defects is satisfactory, which can restore the normal center of rotation of the hip joint and has a low incidence of postoperative complications.

Objective:To explore the safety and efficacy of intraosseous regional administration (IORA) of vancomycin for preventing infection in primary total knee arthroplasty (TKA).Methods:A total of 124 patients with knee osteoarthritis undergoing TKA between February 2024 and May 2024 at nine hospitals were enrolled. Preoperative infection prophylaxis involved either IORA (0.5 g vancomycin administered via intraosseous regional infusion before incision) or intravenous infusion (1 g vancomycin via peripheral vein). The IORA group included 15 males and 47 females with a median age of 66.5 years (range, 60.0-70.0 years), while the intravenous group included 14 males and 48 females with a median age of 66.0 years (range, 61.8-70.3 years) years. Intraoperative samples were collected including fat and synovium tissues after incision, before prosthesis placement, and after tourniquet release; distal femoral cancellous bone during femoral osteotomy; proximal tibial cancellous bone during tibial osteotomy; proximal intercondylar cancellous bone before prosthesis placement; and peripheral blood from non-infused arms at surgery initiation and after tourniquet release. Vancomycin concentrations were measured using liquid chromatography-tandem mass spectrometry. Vital sign changes were recorded from admission to 5~10 minutes post-IORA (IORA group) or post-incision (intravenous group). Follow-ups were conducted on postoperative day 1 and 3, and at 1 and 3 months, to document complications including IORA-related adverse events, periprosthetic joint infections, surgical site infections, red man syndrome, acute kidney injury, deep vein thrombosis and so on.Results:Vancomycin concentrations in bone, fat, and synovial tissue samples were significantly higher in the IORA group than in the intravenous group ( P<0.05), while vancomycin concentrations in blood samples were significantly lower in the IORA group than in the intravenous group ( P<0.05). Only 7.3%(41/558) of tissue samples in the IORA group had vancomycin concentrations below 2.0 μg/g (the minimum inhibitory concentration of vancomycin against coagulase-negative staphylococcus), compared to 59.3%(331/558) in the intravenous group (χ 2=11.285, P<0.001). In the intravenous group, 16.9%(21/124) of blood samples had vancomycin concentrations exceeding 15.0 mg/L (the threshold associated with a significantly increased risk of nephrotoxicity), while all concentrations in the IORA group were below this threshold, the difference was statistically significant (χ 2=22.943, P<0.001). There were no statistically significant difference ( P>0.05) in vital signs changes before and after vancomycin administration between the two groups. Two patients in the intravenous group experienced incision exudate, while no other related complications occurred in either group. Conclusions:Compared to the traditional intravenous infusion of 1 g vancomycin, intraosseous injection of a low dose (0.5 g) of vancomycin achieves higher local tissue concentrations in the knee joint with a lower incidence of adverse reactions and is safe for infection prophylaxis. Despite guidelines not recommending the routine use of vancomycin for preventing infection after primary TKA, intraosseous injection of 0.5 g vancomycin may be considered intraoperatively for primary TKA in the following scenarios: patients in medical institutions with a high prevalence of methicillin-resistant staphylococcus aureus (MRSA) infections, patients with potential preoperative MRSA colonization, or patients with cephalosporin allergy.

One of the basic questions in the aging field is whether there is a fundamental difference between the aging of lower invertebrates and mammals. A major difference between the lower invertebrates and mammals is the abundancy of noncoding RNAs, most of which are not conserved. We have previously identified a noncoding RNA Terc-53 that is derived from the RNA component of telomerase Terc. To study its physiological functions, we generated two transgenic mouse models overexpressing the RNA in wild-type and early-aging Terc-/- backgrounds. Terc-53 mice showed age-related cognition decline and shortened life span, even though no developmental defects or physiological abnormality at an early age was observed, indicating its involvement in normal aging of mammals. Subsequent mechanistic study identified hyaluronan-mediated motility receptor (Hmmr) as the main effector of Terc-53. Terc-53 mediates the degradation of Hmmr, leading to an increase of inflammation in the affected tissues, accelerating organismal aging. adeno-associated virus delivered supplementation of Hmmr in the hippocampus reversed the cognition decline in Terc-53 transgenic mice. Neither Terc-53 nor Hmmr has homologs in C. elegans. Neither do arthropods express hyaluronan. These findings demonstrate the complexity of aging in mammals and open new paths for exploring noncoding RNA and Hmmr as means of treating age-related physical debilities and improving healthspan.
Animals ; Mice ; RNA, Untranslated/metabolism* ; Aging/genetics* ; Mice, Transgenic ; Telomerase/metabolism* ; RNA/genetics* ; Hippocampus/metabolism* ; Humans ; Mice, Inbred C57BL

Given the increasing concern regarding antibacterial resistance, the antimicrobial properties of naphthoquinones have recently attracted significant attention. While 1,4-naphthoquinone and its derivatives have been extensively studied, the antibacterial properties of 5,8-dihydroxy-1,4-naphthoquinone derivatives remain relatively unexplored. This study presents a comprehensive in vitro and in vivo analysis of the antibacterial activity of 35 naturally sourced and chemically synthesized derivatives of 5,8-dihydroxy-1,4-naphthoquinone. Kirby-Bauer antibiotic testing identified three compounds with activity against methicillin-resistant Staphylococcus aureus (MRSA), with one compound (PNP-02) demonstrating activity comparable to vancomycin in minimum inhibitory concentration, minimum bactericidal concentration (MBC), and time-kill assays. Microscopic and biochemical analyses revealed that PNP-02 adversely affects the cell wall and cell membrane of MRSA. Mechanistic investigations, including proteomic sequencing analyses, Western blotting, and RT-qPCR assays, indicated that PNP-02 compromises cell membrane integrity by inhibiting arginine biosynthesis and pyrimidine metabolism pathways, thereby increasing membrane permeability and inducing bacterial death. In an in vivo mouse model of skin wound healing, PNP-02 exhibited antibacterial efficacy similar to vancomycin. The compound demonstrated low toxicity to cultured human cells and in hemolysis assays and remained stable during serum incubation. These findings suggest that PNP-02 possesses promising bioactivity against MRSA and represents a potential novel antibacterial agent.
Methicillin-Resistant Staphylococcus aureus/genetics* ; Anti-Bacterial Agents/chemistry* ; Naphthoquinones/administration & dosage* ; Animals ; Microbial Sensitivity Tests ; Mice ; Humans ; Staphylococcal Infections/microbiology* ; Molecular Structure

Objective To evaluate the efficacy of immunotherapy combined with local treatment in elderly patients with advanced non-small cell lung cancer(NSCLC).Methods A total of 164 elderly patients with advanced NSCLC admitted in Chinese PLA General Hospital from January 2018 to October 2022 were selected as subjects.According to whether they have received immunotherapy combined with local treatment,they were divided into local treatment group(n=82)and non-local treatment group(n=82).The primary endpoint was overall survival(OS),while secondary endpoints included progression-free survival(PFS),objective response rate(ORR),and disease control rate(DCR).Cox proportional hazard models were applied to assess prognostic factors.Results The median OS in local treatment group was superior to non-local treatment group.Multivariate analysis confirmed that Eastern Cooperative Oncology Group performance status score ≥ 2 points,bone metastasis,and pleural effusion were independent poor prognostic factors.Conclusion The combination of immunotherapy and local treatment may provide OS of elderly patients with advanced NSCLC.

Objective:To investigate the clinical efficacy of 3D-printed metal augment or integrated acetabular prostheses for reconstruction of bone defects in hip revision.Methods:A total of 11 patients who underwent total hip revision in Zhengzhou Orthopaedic Hospital from June 2021 to July 2023 were retrospectively analysed. There were 5 males and 6 females, age 64.8±10.7 years (range, 58-75 years), and body mass index 23.3±4.8 kg/m 2 (range, 21-27 kg/m 2). Paprosky classification of acetabular bone defects: 3 cases of type IIA, 4 cases of type IIB, 3 cases of type IIIA, 1 case of type IIIB. Reasons for revision: 8 cases of aseptic loosening, 3 cases after infection exclusion procedure. A 3D-printed metal augment was used in 9 cases (8 cases of aseptic loosening and 1 case of infected exclusion procedure) and a 3D-printed integrated acetabulum was used in 2 cases (infected exclusion procedure). The time from primary total hip arthroplasty to revision was 11.8±5.6 years (range, 5-17 years). Harris hip score and visual analogue scale (VAS) were used to evaluate the improvement of hip function and pain recovery. The leg length discrepancy, vertical height and horizontal position of the hip rotation center were measured on pelvic anteroposterior X-ray films. Results:All patients successfully completed the operation. The operation time was 145.9±35.5 min (range, 110-159 min), and the intraoperative blood loss was 950.5±310.8 ml (range, 680-1,450 ml). The postoperative Harris hip function score was significantly higher than that before operation ( F=554.085, P<0.001). One year after operation, the Harris hip function score was 74.36±5.16, which was higher than that before operation 32.18±4.07, and the difference was statistically significant ( P<0.05). The VAS scores of all patients decreased after operation, and the difference was statistically significant compared with that before operation ( F=177.717, P<0.001). The VAS score at 1 year after operation was 1.27±0.65, which was lower than that before operation 6.18±1.17, and the difference was statistically significant ( P<0.05). The preoperative leg length discrepancy was 1.97±0.71 cm, which was greater than 0.69±0.52 cm at the last follow-up, and the difference was statistically significant ( t=4.824, P<0.001). The vertical height of the hip rotation center was 1.88±0.46 cm on the affected side and 1.67±0.35 cm on the healthy side, showing no significant difference ( t=1.205, P=0.242). The postoperative horizontal position of the hip rotation center was 3.48±0.55 cm on the affected side and 3.54±0.32 cm on the healthy side, and the difference was no statistically significant ( t=-0.313, P=0.758). One case had an intraoperative greater trochanteric fracture that healed 3 months after reduction and internal fixation. All patients were followed up for 21.3±9.5 months (range, 15-31 months). All incisions healed in one stage, and all patients were fully weight-bearing at 3 months after operation. At the last follow-up, there was no case of loosening, dislocation or infection of the prosthesis; 4 cases had mild claudication, 1 case had heterotopic ossification, and the patients had good hip flexion and extension functions, which did not affect daily life without further treatment. Conclusion:The clinical efficacy of 3D-printed metal augment or integrated acetabular prosthesis for reconstruction of acetabular bone defects is satisfactory, which can restore the normal center of rotation of the hip joint and has a low incidence of postoperative complications.

Objective:To compare the efficacy of hip hemiarthroplasty via the fracture line approach versus modified Harding approach in the treatment of unstable intertrochanteric fractures in the elderly.Methods:A retrospective cohort study was conducted to analyze the clinical data of 79 elderly patients with unstable intertrochanteric fractures who were admitted to Zhengzhou Orthopaedic Hospital between July 2018 and February 2024, including 17 males and 62 females, aged 80-96 years [(84.0±9.6)years]. According to the AO classification, the fractures were classified as type A2 in 61 patients and type A3 in 18. All the patients underwent hip hemiarthroplasty, 33 of whom were treated via the fracture line approach (fracture line approach group) and 46 via the modified Harding approach (modified Harding approach group). The incision length, operation duration, intraoperative blood loss, blood transfusion volume, and weight-bearing time were documented. At 1 month, 3 months after surgery and at the last follow-up, hip function and pain were assessed using the Harris hip score and visual analogue scale (VAS). Postoperative dislocation rate, fracture nonunion rate, incidence of other complications (vascular injury, neurologic impairment, prosthesis loosening, lower extremity venous thrombosis, and surgical site infection) and 12-month mortality rate were recorded.Results:All the patients were followed up for 12-36 months [(18.0±5.1)months]. The operation duration and intraoperative blood loss were (68.2±8.4)minutes and (286.6±63.7)ml in the fracture line approach group, which were significantly shorter or less than (72.4±6.7)minutes and (321.3±76.2)ml in the modified Harding approach group ( P<0.05). However, there were no statistically significant differences in the incision length, blood transfusion volume or weight-bearing time between the two groups ( P>0.05). Harris hip scores and VAS scores at 1 month, 3 months, and at the last follow-up showed no significant differences between the two groups ( P>0.05). The dislocation rate was 0 in the fracture line approach group, superior to 13% in the modified Harding approach group ( P<0.05). There were no statistically significant differences in the fracture nonunion rate, incidence of other complications, or 12-month mortality rate between the two groups ( P>0.05). Conclusion:Compared with the modified Harding approach, hip hemiarthroplasty via the fracture line approach in the treatment of unstable intertrochanteric fractures in the elderly can shorten the operation time, reduce intraoperative blood loss, and lower the postoperative dislocation rate.

Objective:To explore the safety and efficacy of intraosseous regional administration (IORA) of vancomycin for preventing infection in primary total knee arthroplasty (TKA).Methods:A total of 124 patients with knee osteoarthritis undergoing TKA between February 2024 and May 2024 at nine hospitals were enrolled. Preoperative infection prophylaxis involved either IORA (0.5 g vancomycin administered via intraosseous regional infusion before incision) or intravenous infusion (1 g vancomycin via peripheral vein). The IORA group included 15 males and 47 females with a median age of 66.5 years (range, 60.0-70.0 years), while the intravenous group included 14 males and 48 females with a median age of 66.0 years (range, 61.8-70.3 years) years. Intraoperative samples were collected including fat and synovium tissues after incision, before prosthesis placement, and after tourniquet release; distal femoral cancellous bone during femoral osteotomy; proximal tibial cancellous bone during tibial osteotomy; proximal intercondylar cancellous bone before prosthesis placement; and peripheral blood from non-infused arms at surgery initiation and after tourniquet release. Vancomycin concentrations were measured using liquid chromatography-tandem mass spectrometry. Vital sign changes were recorded from admission to 5~10 minutes post-IORA (IORA group) or post-incision (intravenous group). Follow-ups were conducted on postoperative day 1 and 3, and at 1 and 3 months, to document complications including IORA-related adverse events, periprosthetic joint infections, surgical site infections, red man syndrome, acute kidney injury, deep vein thrombosis and so on.Results:Vancomycin concentrations in bone, fat, and synovial tissue samples were significantly higher in the IORA group than in the intravenous group ( P<0.05), while vancomycin concentrations in blood samples were significantly lower in the IORA group than in the intravenous group ( P<0.05). Only 7.3%(41/558) of tissue samples in the IORA group had vancomycin concentrations below 2.0 μg/g (the minimum inhibitory concentration of vancomycin against coagulase-negative staphylococcus), compared to 59.3%(331/558) in the intravenous group (χ 2=11.285, P<0.001). In the intravenous group, 16.9%(21/124) of blood samples had vancomycin concentrations exceeding 15.0 mg/L (the threshold associated with a significantly increased risk of nephrotoxicity), while all concentrations in the IORA group were below this threshold, the difference was statistically significant (χ 2=22.943, P<0.001). There were no statistically significant difference ( P>0.05) in vital signs changes before and after vancomycin administration between the two groups. Two patients in the intravenous group experienced incision exudate, while no other related complications occurred in either group. Conclusions:Compared to the traditional intravenous infusion of 1 g vancomycin, intraosseous injection of a low dose (0.5 g) of vancomycin achieves higher local tissue concentrations in the knee joint with a lower incidence of adverse reactions and is safe for infection prophylaxis. Despite guidelines not recommending the routine use of vancomycin for preventing infection after primary TKA, intraosseous injection of 0.5 g vancomycin may be considered intraoperatively for primary TKA in the following scenarios: patients in medical institutions with a high prevalence of methicillin-resistant staphylococcus aureus (MRSA) infections, patients with potential preoperative MRSA colonization, or patients with cephalosporin allergy.

Objective:To compare the efficacy of hip hemiarthroplasty via the fracture line approach versus modified Harding approach in the treatment of unstable intertrochanteric fractures in the elderly.Methods:A retrospective cohort study was conducted to analyze the clinical data of 79 elderly patients with unstable intertrochanteric fractures who were admitted to Zhengzhou Orthopaedic Hospital between July 2018 and February 2024, including 17 males and 62 females, aged 80-96 years [(84.0±9.6)years]. According to the AO classification, the fractures were classified as type A2 in 61 patients and type A3 in 18. All the patients underwent hip hemiarthroplasty, 33 of whom were treated via the fracture line approach (fracture line approach group) and 46 via the modified Harding approach (modified Harding approach group). The incision length, operation duration, intraoperative blood loss, blood transfusion volume, and weight-bearing time were documented. At 1 month, 3 months after surgery and at the last follow-up, hip function and pain were assessed using the Harris hip score and visual analogue scale (VAS). Postoperative dislocation rate, fracture nonunion rate, incidence of other complications (vascular injury, neurologic impairment, prosthesis loosening, lower extremity venous thrombosis, and surgical site infection) and 12-month mortality rate were recorded.Results:All the patients were followed up for 12-36 months [(18.0±5.1)months]. The operation duration and intraoperative blood loss were (68.2±8.4)minutes and (286.6±63.7)ml in the fracture line approach group, which were significantly shorter or less than (72.4±6.7)minutes and (321.3±76.2)ml in the modified Harding approach group ( P<0.05). However, there were no statistically significant differences in the incision length, blood transfusion volume or weight-bearing time between the two groups ( P>0.05). Harris hip scores and VAS scores at 1 month, 3 months, and at the last follow-up showed no significant differences between the two groups ( P>0.05). The dislocation rate was 0 in the fracture line approach group, superior to 13% in the modified Harding approach group ( P<0.05). There were no statistically significant differences in the fracture nonunion rate, incidence of other complications, or 12-month mortality rate between the two groups ( P>0.05). Conclusion:Compared with the modified Harding approach, hip hemiarthroplasty via the fracture line approach in the treatment of unstable intertrochanteric fractures in the elderly can shorten the operation time, reduce intraoperative blood loss, and lower the postoperative dislocation rate.