Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a de novo heterozygous mutation in TMEM63A (c.1894G>A; p. Ala632Thr) in a 7-year-old boy exhibiting hypomyelination. A Ca²⁺ influx assay suggested that this is a loss-of-function mutation. To explore how TMEM63A deficiency causes hypomyelination, we generated Tmem63a knockout mice. Genetic deletion of TMEM63A resulted in hypomyelination at postnatal day 14 (P14) arising from impaired differentiation of oligodendrocyte precursor cells (OPCs). Notably, the myelin dysplasia was transient, returning to normal levels by P28. Primary cultures of Tmem63a^-/- OPCs presented delayed differentiation. Lentivirus-based expression of TMEM63A but not TMEM63A_A632T rescued the differentiation of Tmem63a^-/- OPCs in vitro and myelination in Tmem63a^-/- mice. These data thus support the conclusion that the mutation in TMEM63A is the pathogenesis of the hypomyelination in the patient. Our study further demonstrated that TMEM63A-mediated Ca²⁺ influx plays critical roles in the early development of myelin and oligodendrocyte differentiation.
Animals ; Cell Differentiation/physiology* ; Oligodendroglia/metabolism* ; Mice, Knockout ; Mice ; Male ; Myelin Sheath/metabolism* ; Humans ; Child ; Cells, Cultured ; Oligodendrocyte Precursor Cells/metabolism*

Purpose: This study evaluates the prognostic significance of tumor size at disease progression (PD) and depth of response (DOR) in cancer patients. Materials and Methods: We performed post hoc analysis using data from six prospective clinical trials conducted by the Korean Cancer Study Group. Patients with tumor size at PD was categorized into ‘Mild PD’ and ‘Significant PD’ based on the cutoff values of relative change from baseline using maximally selected rank statistics. The overall survival (OS) and progression-free survival (PFS) were compared between PD and DOR categories. Results: Among the 194 evaluable patients, 130 experienced PD. A 35.48% decrease from baseline in tumor size at PD was chosen for the cutoff between mild and significant PD for OS (mild PD: tumor size from the baseline ≤ −35.48%; significant PD > −35.48%). The mild PD had superior OS compared to the significant PD (25.8 vs. 12.8 months; Hazard ratio [HR] 0.47, 95% CI 0.266-0.843, p=0.009). When using an exploratory cutoff based on whether the tumor size was below vs. exceeded from the baseline (mild PD: tumor size from the baseline ≤ 0%; significant PD > 0%), OS remained significantly longer in the mild PD (17.1 vs. 11.8 months; HR 0.60, 95% CI 0.392-0.932, p=0.021). The greatest DOR was associated with the longest OS and PFS (p<0.001 for both). Conclusion Tumor size at PD and DOR were significant prognostic factors for progressive disease. Maintaining a sufficiently reduced tumor size even during PD was associated with better survival outcomes.

Purpose: The Korean Cancer Study Group (KCSG) is a nationwide cancer clinical trial group dedicated to advancing investigator-initiated trials (IITs) by conducting and supporting clinical trials. This study aims to review IITs conducted by KCSG and quantitatively evaluate the survival and financial benefits of IITs for patients. Materials and Methods: We reviewed IITs conducted by KCSG from 1998 to 2023, analyzing progression-free survival (PFS) and overall survival (OS) gains for participants. PFS and OS benefits were calculated as the difference in median survival times between the intervention and control groups, multiplied by the number of patients in the intervention group. Financial benefits were assessed based on the cost of investigational products provided. Results: From 1998 to 2023, KCSG conducted 310 IITs, with 133 completed and published. Of these, 21 were included in the survival analysis. The analysis revealed that 1,951 patients in the intervention groups gained a total of 2,558.4 months (213.2 years) of PFS and 2,501.6 months (208.5 years) of OS, with median gains of 1.31 months in PFS and 1.58 months in OS per patient. When analyzing only statistically significant results, PFS and OS gain per patients was 1.69 months and 3.02 months, respectively. Investigational drug cost analysis from six available IITs indicated that investigational products provided to 252 patients were valued at 10,400,077,294 won (approximately 8,046,481 US dollars), averaging about 41,270,148 won (approximately 31,930 US dollars) per patient. Conclusion Our findings, based on analysis of published research, suggest that IITs conducted by KCSG led to survival benefits for participants and, in some studies, may have provided financial benefits by providing investment drugs.

Purpose: This study evaluates the prognostic significance of tumor size at disease progression (PD) and depth of response (DOR) in cancer patients. Materials and Methods: We performed post hoc analysis using data from six prospective clinical trials conducted by the Korean Cancer Study Group. Patients with tumor size at PD was categorized into ‘Mild PD’ and ‘Significant PD’ based on the cutoff values of relative change from baseline using maximally selected rank statistics. The overall survival (OS) and progression-free survival (PFS) were compared between PD and DOR categories. Results: Among the 194 evaluable patients, 130 experienced PD. A 35.48% decrease from baseline in tumor size at PD was chosen for the cutoff between mild and significant PD for OS (mild PD: tumor size from the baseline ≤ −35.48%; significant PD > −35.48%). The mild PD had superior OS compared to the significant PD (25.8 vs. 12.8 months; Hazard ratio [HR] 0.47, 95% CI 0.266-0.843, p=0.009). When using an exploratory cutoff based on whether the tumor size was below vs. exceeded from the baseline (mild PD: tumor size from the baseline ≤ 0%; significant PD > 0%), OS remained significantly longer in the mild PD (17.1 vs. 11.8 months; HR 0.60, 95% CI 0.392-0.932, p=0.021). The greatest DOR was associated with the longest OS and PFS (p<0.001 for both). Conclusion Tumor size at PD and DOR were significant prognostic factors for progressive disease. Maintaining a sufficiently reduced tumor size even during PD was associated with better survival outcomes.

Purpose: The Korean Cancer Study Group (KCSG) is a nationwide cancer clinical trial group dedicated to advancing investigator-initiated trials (IITs) by conducting and supporting clinical trials. This study aims to review IITs conducted by KCSG and quantitatively evaluate the survival and financial benefits of IITs for patients. Materials and Methods: We reviewed IITs conducted by KCSG from 1998 to 2023, analyzing progression-free survival (PFS) and overall survival (OS) gains for participants. PFS and OS benefits were calculated as the difference in median survival times between the intervention and control groups, multiplied by the number of patients in the intervention group. Financial benefits were assessed based on the cost of investigational products provided. Results: From 1998 to 2023, KCSG conducted 310 IITs, with 133 completed and published. Of these, 21 were included in the survival analysis. The analysis revealed that 1,951 patients in the intervention groups gained a total of 2,558.4 months (213.2 years) of PFS and 2,501.6 months (208.5 years) of OS, with median gains of 1.31 months in PFS and 1.58 months in OS per patient. When analyzing only statistically significant results, PFS and OS gain per patients was 1.69 months and 3.02 months, respectively. Investigational drug cost analysis from six available IITs indicated that investigational products provided to 252 patients were valued at 10,400,077,294 won (approximately 8,046,481 US dollars), averaging about 41,270,148 won (approximately 31,930 US dollars) per patient. Conclusion Our findings, based on analysis of published research, suggest that IITs conducted by KCSG led to survival benefits for participants and, in some studies, may have provided financial benefits by providing investment drugs.

Purpose: This study evaluates the prognostic significance of tumor size at disease progression (PD) and depth of response (DOR) in cancer patients. Materials and Methods: We performed post hoc analysis using data from six prospective clinical trials conducted by the Korean Cancer Study Group. Patients with tumor size at PD was categorized into ‘Mild PD’ and ‘Significant PD’ based on the cutoff values of relative change from baseline using maximally selected rank statistics. The overall survival (OS) and progression-free survival (PFS) were compared between PD and DOR categories. Results: Among the 194 evaluable patients, 130 experienced PD. A 35.48% decrease from baseline in tumor size at PD was chosen for the cutoff between mild and significant PD for OS (mild PD: tumor size from the baseline ≤ −35.48%; significant PD > −35.48%). The mild PD had superior OS compared to the significant PD (25.8 vs. 12.8 months; Hazard ratio [HR] 0.47, 95% CI 0.266-0.843, p=0.009). When using an exploratory cutoff based on whether the tumor size was below vs. exceeded from the baseline (mild PD: tumor size from the baseline ≤ 0%; significant PD > 0%), OS remained significantly longer in the mild PD (17.1 vs. 11.8 months; HR 0.60, 95% CI 0.392-0.932, p=0.021). The greatest DOR was associated with the longest OS and PFS (p<0.001 for both). Conclusion Tumor size at PD and DOR were significant prognostic factors for progressive disease. Maintaining a sufficiently reduced tumor size even during PD was associated with better survival outcomes.

Purpose: The Korean Cancer Study Group (KCSG) is a nationwide cancer clinical trial group dedicated to advancing investigator-initiated trials (IITs) by conducting and supporting clinical trials. This study aims to review IITs conducted by KCSG and quantitatively evaluate the survival and financial benefits of IITs for patients. Materials and Methods: We reviewed IITs conducted by KCSG from 1998 to 2023, analyzing progression-free survival (PFS) and overall survival (OS) gains for participants. PFS and OS benefits were calculated as the difference in median survival times between the intervention and control groups, multiplied by the number of patients in the intervention group. Financial benefits were assessed based on the cost of investigational products provided. Results: From 1998 to 2023, KCSG conducted 310 IITs, with 133 completed and published. Of these, 21 were included in the survival analysis. The analysis revealed that 1,951 patients in the intervention groups gained a total of 2,558.4 months (213.2 years) of PFS and 2,501.6 months (208.5 years) of OS, with median gains of 1.31 months in PFS and 1.58 months in OS per patient. When analyzing only statistically significant results, PFS and OS gain per patients was 1.69 months and 3.02 months, respectively. Investigational drug cost analysis from six available IITs indicated that investigational products provided to 252 patients were valued at 10,400,077,294 won (approximately 8,046,481 US dollars), averaging about 41,270,148 won (approximately 31,930 US dollars) per patient. Conclusion Our findings, based on analysis of published research, suggest that IITs conducted by KCSG led to survival benefits for participants and, in some studies, may have provided financial benefits by providing investment drugs.

Organophosphorus pesticides(OPs)are widely used in global agriculture,and pose a serious threat to ecological environment and human health due to their high environmental persistence and biological toxicity.Colorimetric sensing strategies based on the inhibition of acetylcholinesterase(AChE)have become an important method for detecting OPs because of their simplicity and high specificity.However,the sensitivity is limited by the insufficient catalytic efficiency of traditional nanozymes.In this study,a one-step solvothermal method was used to synthesize polyoxometalate nanoribbons(POM)loaded with gold nanoparticles(Au NPs),named Au-POM.Experimental results showed that Au-POM could catalyze the decomposition of H2O2 in an acidic environment(pH 4.0),demonstrating typical peroxidase-like activity.Based on this,an AChE,choline oxidase(ChOx)and Au-POM nano enzyme cascade catalytic system was constructed.In this system,AChE specifically catalyzed the hydrolysis of acetylcholine(ACh)to choline,and then ChOx mediated the oxidation of choline to produce H2O2.During this process,Au-POM acted as a peroxidase-like enzyme to catalyze the decomposition of H2O2 to generate reactive oxygen species,triggering a specific oxidation reaction of the chromogenic substrate 3,3',5,5'-tetramethylbenzidine(TMB)into oxidized form.When the OP pesticide ethoprophos(EP)was present,it inhibited the activity of AChE and blocked the generation of ACh and H2O2,indirectly inhibiting the oxidation of TMB.The color and absorbance of the solution changed in a concentration-dependent manner.The detection limit of this method for EP was 1.05 μmol/L,and the linear response range was 20-180 μmol/L(R2=0.998).This method was applied to detection of environmental water samples and coriander samples with satisfactory results,providing a reliable technical platform for monitoring of OPs in environment and food.

Objective:To explore the prognosis after radical resection for stage Ⅰ gastric cancer and the application value of adjuvant chemotherapy.Methods:The retrospective cohort study was conducted. The clinicopathological data of 3 353 patients with stage Ⅰ gastric cancer who were admitted to Fudan University Shanghai Cancer Center from January 2000 to December 2022 were collected. There were 2 369 males and 984 females, aged 60(range, 21-91) years. All patients underwent radical R 0 resection. Observation indicators: (1) clinicopathological characteristics of patients; (2) influencing factors for postoperative prognosis of patients; (3) prognostic analysis of patients; (4) construction and validation of a predictive model for the efficacy of postoperative adjuvant chemotherapy. Comparison of count data between groups was conducted using the chi-square test. Univariate and multivariate analyses were performed using the Cox proportional hazards regression model. The Kaplan-Meier method was used to calculate survival rates and draw survival curves, and the Log-rank test was used for survival analysis. Based on the multivariate analysis result, a nomogram prediction model was constructed to predict survival benefit. Results:(1) Clinicopatho-logical characteristics of patients. The highly, moderately, and poorly differentiated tumors were observed in 16, 234, 396 cases of 646 patients aged <50 years and 279, 1 617, 811 cases of 2 707 pati-ents aged ≥50 years, respectively, showing a significant difference in degree of tumor differentiation between them ( P<0.05). For 297 patients in stage T1N1M0, cases aged <50 years and ≥50 years were 71 and 226, cases of males and females were 184 and 113, cases with negative and positive vascular invasion were 37 and 260, cases with negative and positive nerve invasion were 275 and 22, cases without and with postoperative adjuvant chemotherapy were 222 and 75, respectively. The above indicators for 678 patients in stage T2N0M0 105, 573, 533, 145, 517, 161, 526, 152, 563, 115, respectively. There were significant differences in the above indicators between the two groups ( P<0.05). (2) Influencing factors for postoperative prognosis of patients. Results of multivariate analysis showed that age ≥50 years, stage T2, moderately differentiated tumor, the number of lymph nodes dissected <16, positive vascular invasion, carcinoembryonic antigen (CEA) ≥5 μg/L, and CA19-9 ≥37 U/mL were independent risk factors for disease-free survival (DFS) after surgery for stage Ⅰ gastric cancer ( hazard ratio=4.600, 1.555, 1.835, 1.362, 1.451, 1.571, 2.134, 95% confidence interval as 2.806-7.541, 1.205-2.006, 1.016-3.314, 1.059-1.753, 1.057-1.993, 1.100-2.243, 1.257-3.625, P<0.05). Age ≥50 years, stage T2, the number of lymph nodes dissected <16, positive vascular invasion, CEA ≥5 μg/L, and CA19-9 ≥37 U/mL were independent risk factors for overall survival (OS) after surgery for stage Ⅰ gastric cancer ( hazard ratio=5.208, 1.597, 1.373, 1.520, 1.464, 2.356, 95% confidence interval as 3.028-8.955, 1.231-2.072, 1.060-1.777, 1.099-2.104, 1.004-2.134, 1.385-4.009, P<0.05). Postoperative adjuvant chemotherapy was an independent protective factor for both DFS and OS after surgery for stage I gastric cancer ( hazard ratio=0.361 0.297, 95% confidence interval as 0.177-0.736, 0.131-0.674, P<0.05). (3) Prognostic analysis of patients. According to the results of multi-variate analysis, among 3 353 patients, there were significant differences in 5-year DFS rate and 10-year OS rate between patients aged <50 years and ≥50 years ( P<0.05). There were significant differences in 5-year DFS rate and 10-year OS rate among patients in TNM stage ⅠA and ⅠB ( P<0.05). There were significant differences in 5-year DFS rate and 10-year OS rate among patients in stage T1N0M0, T1N1M0, T2N0M0 ( P<0.05). There were significant differences in 5-year DFS rate and 10-year OS rate among patients with the highly, moderately, and poorly differentiated tumors ( P<0.05). There were significant differences in 5-year DFS rate and 10-year OS rate among patients with the number of lymph lodes dissected <16 and ≥16 ( P<0.05). There were significant differences in 5-year DFS rate and 10-year OS rate between patients with negative and positive vascular invasion ( P<0.05). There were significant differences in 5-year DFS rate and 10-year OS rate between patients with and without postoperative adjuvant chemotherapy ( P<0.05), among patients in stage T1N0M0, T1N1M0, T2N0M0 who received no postoperative adjuvant chemotherapy ( P<0.05). For patients in stage T1N1M0, there was no significant difference in 5-year DFS rate and 10-year OS rate between patients with and without postoperative adjuvant chemotherapy ( P>0.05).Results of stratified analysis showed that for patients aged ≥ 50 years, there were significant differences in 5-year DFS rate and 10-year OS rate between patients with and without postoperative adjuvant chemotherapy ( P<0.05). For patients in stage T2N0M0, there were significant differences in 5-year DFS rate and 10-year OS rate between patients with and without postoperative adjuvant chemotherapy ( P<0.05). For patients with positive vascular invasion, there were significant differences in 5-year DFS rate and 10-year OS rate between patients with and without postoperative adjuvant chemotherapy ( P<0.05). (4) Construction and validation of a predictive model for the efficacy of adjuvant chemotherapy. A nomogram predictive model was constructed based on the multivariate analysis results of OS and used for calculating net benefits and distribution. Among the 3 096 patients without postoperative adjuvant chemotherapy, 1 009 cases had a predicted net benefit of >5%-10%, and 250 patients had a predicted net benefit >10%. The predicted survival analysis further verified that the predicted benefit of adjuvant chemotherapy was consistent with the prognosis of patients. Conclusions:Patients with age ≥50 years, stage T2 tumors, moderately differentiated tumor, the number of lymph nodes dissected <16, positive vascular invasion have worse survival prognosis postoperative. Postoperative adjuvant chemotherapy provides better prognosis in high-risk patients. Patients in stage T1N1M0 have lower recurrence and survival risks, of whom with 1 metastatic lymph node is more suitable for follow-up rather than postoperative adjuvant chemotherapy.

Objective To comparatively analyze the clinical characteristics of primary bilateral macronodular adrenal hyperplasia(PBMAH)and adrenal cortisol-producing Adenoma(CPA),and enhance the understanding of two diseases.Methods The clinical data of 85 PBMAH patients(PBMAH group)and 195 CPA patients(CPA group)diagnosed at Department of Endocrinology,the First Medical Center of Chinese PLA General Hospital,from September 2014 to August 2024 were retrospectively analyzed.The demographic characteristics,comorbidities,biochemical indicators,adrenocorticotropic hormone-cortisol(ACTH-F)levels,and adrenal imaging features and treatment conditions were compared between the two groups.Results(1)General characteristics:Compared with CPA group,PBMAH group had older age at diagnosis and a higher proportion of male patients.(2)Clinical characteristics:Compared with CPA group,PBMAH group had a longer disease duration,a higher proportion of subclinical Cushing's syndrome(CS),and a higher proportion of hypertension,impaired glucose tolerance/diabetes,bone mass reduction or osteoporosis,with higher serum potassium levels,and the differences were statistically significant(P<0.01).(3)Hormone levels:Both PBMAH and CPA groups showed ACTH-F rhythm disorder,significantly increased cortisol levels and suppressed ACTH.Compared with PBMAH group,CPA group had stronger autonomous cortisol secretion ability,manifested by increased midnight serum cortisol(F0:00),16:00 serum cortisol(F16:00),24-hour urinary free cortisol(24 h UFC)levels and lower 8:00 serum ACTH(ACTH8:00)and 16:00 serum ACTH(ACTH16:00)(P<0.01).After low-dose dexamethasone suppression test(LDDST),CPA group showed lower suppression rates of ACTH and cortisol,and higher proportions of paradoxical elevation in serum cortisol and 24 h UFC compared with PBMAH(P<0.01).Conclusions PBMAH has a longer disease course and higher proportions of comorbid metabolic disorders than CPA,mostly manifested as subclinical Cushing's syndrome.CPA has stronger autonomous cortisol secretion ability,with cortisol less likely to be suppressed after LDDST and more obvious paradoxical elevation of cortisol and 24 h UFC.