Reactive oxygen species (ROS) are major contributors to radiation therapy-induced side effects in cancer patients. A fusion antioxidant enzyme comprising glutathione S-transferase (GST), superoxide dismutase 1 (SOD1), and a transmembrane peptide has been shown to effectively mitigate ROS-induced damage. To enhance its targeting capability, the fusion protein was further modified by incorporating a matrix metalloproteinase-2/9 substrate peptide (X) and the transmembrane peptide R9, yielding the antioxidant enzyme GST-SOD1-X-R9 (GS1XR). This modification reduced its transmembrane ability in tumor cells, thereby selectively protecting normal cells from oxidative stress. However, the use of non-human GST poses potential immunogenicity risks. In this study, we employed seamless cloning technology to construct an expression vector containing the human GST gene to replace the non-human GST gene, and then expressed and purified novel fusion antioxidant enzymes GS1R and GS1XR. The protective effects of newly constructed GS1R and GS1XR against hydrogen peroxide (H₂O₂)-induced oxidative damage in L-02 cells were then evaluated using GS1 as a control. Enzymatic activity assays revealed that the specific activity of GST in GS1XR remained unchanged compared to the unmodified protein, while SOD activity was enhanced. Exposure to 200 μmol/L H₂O₂ transiently activated the nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway; however, this activation diminished after 24 h, reducing cell viability to 48.4%. Both GS1R and GS1XR effectively scavenged intracellular ROS, directly counteracting oxidative stress and promoting Nrf2 nuclear translocation, thereby activating antioxidant pathways and restoring cell viability to normal levels. The two enzymes showed comparable efficacy. In contrast, GS1, lacking transmembrane capability, was restricted to scavenging extracellular ROS and provided only limited protection. In conclusion, both novel fusion antioxidant enzymes demonstrated significant potential in safeguarding normal cells from ROS-mediated oxidative damage. The findings provide a foundation for further investigation in related field.
Humans ; Oxidative Stress/drug effects* ; Hydrogen Peroxide ; Antioxidants/metabolism* ; Glutathione Transferase/metabolism* ; Recombinant Fusion Proteins/pharmacology* ; Superoxide Dismutase-1 ; Reactive Oxygen Species/metabolism* ; Superoxide Dismutase/biosynthesis*

Fragile X syndrome(FXS)is caused by abnormal duplication and amplification of the FMR1 gene CGG.This article reports a pair of brothers diagnosed with FXS by genetic testing.Two patients,aged 15 and 14 years old respectively,both had clinical manifestations such as language disorders,intellectual disabilities,attention deficit disorder,autism spectrum disorder,and FXS's characteristic facial features.The proband had a rare late-onset epileptic seizure,which was well treated with levetiracetam,while his younger brother had no electroencephalogram abnormalities after repeated follow-up.This pair of cases suggests that the clinical phenotype of FXS has diversity and heterogeneity.

The purpose of this study was to investigate the damage mechanism of pathogenic E.coli on mouse brain microvascular endothelial cells(BMEC cells)and mouse alveolar macrophages(MH-S cells),as well as the lung and brain of healthy mice.In this study,BMEC cells and MH-S cells were infected with pathogenic E.coli strains,and cell morphological changes were observed.Plate counting method was used to detect the adhesion and invasion ability of the strains to cells and the number of bacteria in the lungs and brains of mice.RT-qPCR was used to detect the ex-pression of TNF-α,IL-1β and IL-6 genes in cells and mouse organs at different time periods.West-ern blot was used to detect the expression of p-NF-κB,p-JAK2 and p-STAT3 proteins related to inflammation in cells and mouse organs after infection.The results showed that the cell culture medium of the infection group was turbid,the cell vision became dark and blurred,some cells shrank and died,and more fragments were produced.The adhesion rate and invasion rate of BMEC cells at 3 h were significantly lower than those at 6 h(P＜0.050),and the adhesion rate and inva-sion rate of MH-S cells at 3 h were significantly higher than those at 6 h(P＜0.010).Infected mice had a large area of swelling and bleeding in the brain,and the lungs had different degrees of swell-ing and bleeding.The bacterial load in the brain and lung was the highest at 12 h.Compared with the control group,the mRNA expression levels of IL-1β,IL-6 and TNF-α in the infection group were significantly increased at 3 h and 6 h(P＜0.050),and the mRNA expression levels of inflam-matory factors in BMEC cells and MH-S cells were the highest at 6 and 3 h,respectively.The mR-NA expression of inflammatory factors in the brain and lung of infected mice showed a trend of in-creasing first and then decreasing with time,with the highest expression at 12 h after infection.The expression levels of p-NF-κB protein in BMEC cells,MH-S cells,lung and brain tissues of mice in the infection group were significantly higher than those in the control group(P＜0.001),and the expression levels of p-JAK2 protein and p-STAT3 protein were significantly lower than those in the control group(P＜0.050).The above results showed that pathogenic E.coli could adhere and invade BMEC cells and MH-S cells,colonize in lung and brain tissues of mice,promote the expres-sion of NF-κB protein in cells and tissues,inhibit the expression of JAK2 protein and STAT3 pro-tein,and then stimulate cells and tissues to produce inflammatory response.

Objective: In the global phase 3 Study 309/KEYNOTE-775 (NCT03517449) at the first interim analysis, lenvatinib+pembrolizumab significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) versus treatment of physician’s choice chemotherapy (TPC) in patients with previously treated advanced/recurrent endometrial cancer (EC). This exploratory analysis evaluated outcomes in patients enrolled in East Asia at the time of prespecified final analysis. Methods: Women ≥18 years with histologically confirmed advanced, recurrent, or metastatic EC with progressive disease after 1 platinum-based chemotherapy (2 if 1 given in neoadjuvant/ adjuvant setting) were enrolled. Patients were randomized 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks (≤35 cycles) or TPC (doxorubicin or paclitaxel). Primary endpoints were PFS per RECIST v1.1 by blinded independent central review and OS. No alpha was assigned for this subgroup analysis. Results: Among 155 East Asian patients (lenvatinib+pembrolizumab, n=77; TPC, n=78), median follow-up time (data cutoff: March 1, 2022) was 34.3 (range, 25.1–43.0) months.Hazard ratios (HRs) with 95% confidence intervals (CIs) for PFS (lenvatinib+pembrolizumab vs. TPC) were 0.74 (0.49–1.10) and 0.64 (0.44–0.94) in the mismatch repair proficient (pMMR) and all-comer populations, respectively. HRs (95% CI) for OS were 0.68 (0.45–1.02) and 0.61 (0.41–0.90), respectively. ORRs were 36% with lenvatinib+pembrolizumab and 22% with TPC (pMMR) and 39% and 21%, respectively (all-comers). Treatment-related adverse events occurred in 97% and 96% (grade 3–5, 74% and 72%), respectively. Conclusion Lenvatinib+pembrolizumab provided clinically meaningful benefit with manageable safety compared with TPC, supporting its use in East Asian patients with previously treated advanced/recurrent EC.

Objective: In the global phase 3 Study 309/KEYNOTE-775 (NCT03517449) at the first interim analysis, lenvatinib+pembrolizumab significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) versus treatment of physician’s choice chemotherapy (TPC) in patients with previously treated advanced/recurrent endometrial cancer (EC). This exploratory analysis evaluated outcomes in patients enrolled in East Asia at the time of prespecified final analysis. Methods: Women ≥18 years with histologically confirmed advanced, recurrent, or metastatic EC with progressive disease after 1 platinum-based chemotherapy (2 if 1 given in neoadjuvant/ adjuvant setting) were enrolled. Patients were randomized 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks (≤35 cycles) or TPC (doxorubicin or paclitaxel). Primary endpoints were PFS per RECIST v1.1 by blinded independent central review and OS. No alpha was assigned for this subgroup analysis. Results: Among 155 East Asian patients (lenvatinib+pembrolizumab, n=77; TPC, n=78), median follow-up time (data cutoff: March 1, 2022) was 34.3 (range, 25.1–43.0) months.Hazard ratios (HRs) with 95% confidence intervals (CIs) for PFS (lenvatinib+pembrolizumab vs. TPC) were 0.74 (0.49–1.10) and 0.64 (0.44–0.94) in the mismatch repair proficient (pMMR) and all-comer populations, respectively. HRs (95% CI) for OS were 0.68 (0.45–1.02) and 0.61 (0.41–0.90), respectively. ORRs were 36% with lenvatinib+pembrolizumab and 22% with TPC (pMMR) and 39% and 21%, respectively (all-comers). Treatment-related adverse events occurred in 97% and 96% (grade 3–5, 74% and 72%), respectively. Conclusion Lenvatinib+pembrolizumab provided clinically meaningful benefit with manageable safety compared with TPC, supporting its use in East Asian patients with previously treated advanced/recurrent EC.

Objective: In the global phase 3 Study 309/KEYNOTE-775 (NCT03517449) at the first interim analysis, lenvatinib+pembrolizumab significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) versus treatment of physician’s choice chemotherapy (TPC) in patients with previously treated advanced/recurrent endometrial cancer (EC). This exploratory analysis evaluated outcomes in patients enrolled in East Asia at the time of prespecified final analysis. Methods: Women ≥18 years with histologically confirmed advanced, recurrent, or metastatic EC with progressive disease after 1 platinum-based chemotherapy (2 if 1 given in neoadjuvant/ adjuvant setting) were enrolled. Patients were randomized 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks (≤35 cycles) or TPC (doxorubicin or paclitaxel). Primary endpoints were PFS per RECIST v1.1 by blinded independent central review and OS. No alpha was assigned for this subgroup analysis. Results: Among 155 East Asian patients (lenvatinib+pembrolizumab, n=77; TPC, n=78), median follow-up time (data cutoff: March 1, 2022) was 34.3 (range, 25.1–43.0) months.Hazard ratios (HRs) with 95% confidence intervals (CIs) for PFS (lenvatinib+pembrolizumab vs. TPC) were 0.74 (0.49–1.10) and 0.64 (0.44–0.94) in the mismatch repair proficient (pMMR) and all-comer populations, respectively. HRs (95% CI) for OS were 0.68 (0.45–1.02) and 0.61 (0.41–0.90), respectively. ORRs were 36% with lenvatinib+pembrolizumab and 22% with TPC (pMMR) and 39% and 21%, respectively (all-comers). Treatment-related adverse events occurred in 97% and 96% (grade 3–5, 74% and 72%), respectively. Conclusion Lenvatinib+pembrolizumab provided clinically meaningful benefit with manageable safety compared with TPC, supporting its use in East Asian patients with previously treated advanced/recurrent EC.

OBJECTIVETo investigate the feasibility and short-term efficacy of laparoscopic resection of primary local gastric and intestinal gastrointestinal stromal tumors(GIST).

METHODSClinicopathological data of 26 patients with GIST, 20 located at the stomach and 6 at the intestine, undergoing laparoscopic complete resection from October 2010 to April 2013 were retrospectively analyzed.

RESULTSHand-assisted laparoscopic surgery was performed in 3 patients with gastric GIST, while the other 23 underwent regular laparoscopic surgery. All the procedures were performed successfully without conversion to open operation. According to tumor location and growth types, gastric local resection was performed in 18 cases, distal gastrectomy in 2 cases and intestinal segmental resection in all 6 cases of intestinal GIST. The mean diameter of tumor was (4.5±1.6) cm. The mean operational time was(96.2±28.2) min, with a mean blood loss of (49.6±38.6) ml. Postoperative bowel function recovery time was (2.3±0.7) d and the length of postoperative hospital stay was (6.8±1.9) d. Bleeding from gastrointestinal tract developed in 1 patient after resection of intestinal GIST. Postoperative pathology indicated very low risk of GIST in 1(3.8%), low risk in 13(50.0%), intermediate in 9(34.6%) and high risk in 3(11.5%) patients, respectively. After a follow-up ranging form 3 to 32 months, no recurrence or death was found.

CONCLUSIONLaparoscopic surgery of primary local GISTs from stomach or intestine is safe and feasible in selected patients, with less invasiveness, rapid recovery, and favorable short-term outcomes.

Gastrectomy ; Gastrointestinal Stromal Tumors ; surgery ; Hand-Assisted Laparoscopy ; Humans ; Intestinal Neoplasms ; surgery ; Laparoscopy ; Length of Stay ; Neoplasm Recurrence, Local ; Operative Time ; Retrospective Studies ; Stomach Neoplasms ; surgery ; Treatment Outcome

Objective To investigate the feasibility and short-term efficacy of laparoscopic resection of primary local gastric and intestinal gastrointestinal stromal tumors (GIST). Methods Clinicopathological data of 26 patients with GIST, 20 located at the stomach and 6 at the intestine, undergoing laparoscopic complete resection from October 2010 to April 2013 were retrospectively analyzed. Results Hand-assisted laparoscopic surgery was performed in 3 patients with gastric GIST , while the other 23 underwent regular laparoscopic surgery. All the procedures were performed successfully without conversion to open operation. According to tumor location and growth types , gastric local resection was performed in 18 cases , distal gastrectomy in 2 cases and intestinal segmental resection in all 6 cases of intestinal GIST. The mean diameter of tumor was (4.5±1.6) cm. The mean operational time was (96.2 ±28.2) min, with a mean blood loss of (49.6 ±38.6) ml. Postoperative bowel function recovery time was(2.3±0.7) d and the length of postoperative hospital stay was (6.8± 1.9) d. Bleeding from gastrointestinal tract developed in 1 patient after resection of intestinal GIST. Postoperative pathology indicated very low risk of GIST in 1 (3.8%), low risk in 13 (50.0%), intermediate in 9 (34.6%) and high risk in 3 (11.5%) patients, respectively. After a follow-up ranging form 3 to 32 months, no recurrence or death was found. Conclusion Laparoscopic surgery of primary local GISTs from stomach or intestine is safe and feasible in selected patients, with less invasiveness, rapid recovery, and favorable short-term outcomes.

Objective To investigate the feasibility and short-term efficacy of laparoscopic resection of primary local gastric and intestinal gastrointestinal stromal tumors (GIST). Methods Clinicopathological data of 26 patients with GIST, 20 located at the stomach and 6 at the intestine, undergoing laparoscopic complete resection from October 2010 to April 2013 were retrospectively analyzed. Results Hand-assisted laparoscopic surgery was performed in 3 patients with gastric GIST , while the other 23 underwent regular laparoscopic surgery. All the procedures were performed successfully without conversion to open operation. According to tumor location and growth types , gastric local resection was performed in 18 cases , distal gastrectomy in 2 cases and intestinal segmental resection in all 6 cases of intestinal GIST. The mean diameter of tumor was (4.5±1.6) cm. The mean operational time was (96.2 ±28.2) min, with a mean blood loss of (49.6 ±38.6) ml. Postoperative bowel function recovery time was(2.3±0.7) d and the length of postoperative hospital stay was (6.8± 1.9) d. Bleeding from gastrointestinal tract developed in 1 patient after resection of intestinal GIST. Postoperative pathology indicated very low risk of GIST in 1 (3.8%), low risk in 13 (50.0%), intermediate in 9 (34.6%) and high risk in 3 (11.5%) patients, respectively. After a follow-up ranging form 3 to 32 months, no recurrence or death was found. Conclusion Laparoscopic surgery of primary local GISTs from stomach or intestine is safe and feasible in selected patients, with less invasiveness, rapid recovery, and favorable short-term outcomes.

Objective To investigate the efficacy of sunitinib in the treatment of patients with imatinibresistant advanced gastrointestinal stromal tumor (GIST).Methods The clinical data of 45 patients with imatinib-resistant advanced GIST who received the treatment of sunitinib (37.5 mg/d) at the First Affiliated Hospital of Sun Yat-Sen University from March 2008 to June 2012 were retrospectively analyzed.The mutation of c-kit and platelet-derived growth factor receptor α (PDGFRα) was detected,and the efficacy of imatinib was assessed after the treatment for 3 months,and factors influencing the survival were analysed.The survival rate was calculated using the Kaplan-Meier method,survival analysis was done using the one-way analysis of variance,and multivariate analysis was done using the COX regression model.Results The median time of treatment with sunitinib for the 45 patients was 11.0 months (range,4-37 months).The complete remission rate,partial response rate,rate of stabilized condition and disease progression rate were 15.6％ (7/45),8.9％ (4/45),46.7％ (21/45) and 28.9％ (13/45) after the treatment with sunitinib for 3 months.All the patients with clinical (imaging) complete remission received surgery for metastatic lesions or B-ultrasound guided ablation for single liver metastasis before the treatment with sunitinib.The most common grade 3 or 4 adverse reactions of sunitinib were hand-foot syndrome and anemia.C-kit and PDGFRα mutational analysis were carried out.C-kit exon 9 mutation was detected in 9 patients,c-kit exon 11 mutation in 21 patients,and no mutation was detected in 12 patients.The median progression-free survival time was 8.0 months (range,4.1-11.9 months),and the median overall survival time was 25.0 months (range,13.4-36.6 months).The results of univariate analysis showed that the primary lesion sites and mutational status of primary lesions were factors influencing the progression-free survival and overall survival (x2=5.967,6.622 ; 7.965,8.765,P ＜ 0.05).The results of multivariate analysis showed that only the mutational status of c-kit of primary lesions was the independent factor influencing the progression-free survival and overall survival (Wald =6.540,7.205,P ＜ 0.05).The progression-free survival and overall survival of patients with c-kit exon 9 mutation and patients with no gene mutation were significantly longer than patients with c-kit exon 11 mutation (x2 =7.965,8.765,P ＜ 0.05).Conclusion Sunitinib with a dosage of 37.5 mg/d could effectively treat patients with imatinib-resistant advanced GIST.A better survival is observed in patients with c-kit exon 9 mutation or with no gene mutation when compared with patients with c-kit exon 11 mutation.