Lipid-Lowering Efficacy of Combination Therapy With ModerateIntensity Statin and Ezetimibe Versus High-Intensity Statin Monotherapy:A Randomized, Open-Label, NonInferiority Trial From Korea

Objective@#This phase IV, multicenter, randomized controlled, open-label, and parallel clinical trial aimed to compare the efficacy and safety of ezetimibe and moderate intensity rosuvastatin combination therapy to that of high intensity rosuvastatin monotherapy in patients with atherosclerotic cardiovascular disease (ASCVD). @*Methods@#This study enrolled patients with ASCVD and after a four-week screening period, patients were randomly assigned to receive either rosuvastatin and ezetimibe (RE 10/10 group) or high-intensity rosuvastatin (R20 group) only in a 1:1 ratio. The primary outcome was the difference in the percent change in the mean low-density lipoprotein cholesterol (LDL-C) level from baseline to 12 weeks between two groups after treatment. @*Results@#The study found that after 12 and 24 weeks of treatment, the RE10/10 group had a greater reduction in LDL-C level compared to the R20 group (−22.9±2.6% vs. −15.6 ± 2.5% [p=0.041] and −24.2±2.5% vs. −12.9±2.4% [p=0.001] at 12 and 24 weeks, respectively). Moreover, a greater number of patients achieved the target LDL-C level of ≤70 mg/dL after the treatment period in the combination group (74.6% vs. 59.9% [p=0.012] and 76.2% vs. 50.8% [p<0.001] at 12 and 24 weeks, respectively). Importantly, there were no significant differences in the occurrence of overall adverse events and adverse drug reactions between two groups. @*Conclusion@#Moderate-intensity rosuvastatin and ezetimibe combination therapy had better efficacy in lowering LDL-C levels without increasing adverse effects in patients with ASCVD than high-intensity rosuvastatin monotherapy.

Exposure to Hazardous Substances and Their Health Effects Among Residents Living Near Three Industrial Waste Incinerators in Korea

Background@#This study aimed to evaluate exposure to various hazardous substances emitted by incineration facilities and their likely effect on the health for residents of Bugi-myeon, Cheongju, Korea, which has three incineration facilities. @*Methods@#Heavy metals, polycyclic aromatic hydrocarbons (PAHs), and dioxin concentrations in the air and soil of exposed and control areas were measured. Moreover, the exposure levels to harmful substances and its effects on health were investigated in 1,124 exposed and 232 control adults. @*Results@#PAHs and dioxin concentrations in the air in the exposed area were significantly higher than in the control area. Urinary cadmium and PAHs metabolite concentrations were significantly higher in the exposed group than in the control group. The exposure group also had a higher prevalence of depression and self-reported allergic symptoms than the control group. @*Conclusion@#The possibility of residents in Bugi-myeon being exposed to hazardous substances at incineration facilities cannot be ruled out. To prevent them from further exposure to hazardous substances, it is necessary to prohibit the expansion of additional incineration facilities in this area and to implement continuous monitoring projects for residents

Predicting the Response of Neoadjuvant Chemotherapy in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer With Axillary Lymph Node Metastasis by Multigene Assay / 한국유방암학회지

Purpose@#The GenesWell™ breast cancer test (BCT) is a recently developed multigene assay that predicts the risk of distant recurrence in patients with hormone receptor-positive (HR+) and human epidermal growth factor-2 negative (HER2−) early breast cancer (BC). The ability of this assay to predict the response to neoadjuvant chemotherapy (NACT) has not been established to date. @*Methods@#Biopsy specimens from HR+/HER2− BC patients with axillary lymph node (LN) metastasis who underwent NACT were analyzed using the BCT score. The modified BCT score was developed and patients classified into high-and low-response groups. A total of 88 patients were available for the BCT score among the 108 eligible patients. The median followup duration was 35.9 (7.8–128.5) months. @*Results@#Among them, 61 (65.1%) had cN1 and 53 (60.2%) had cT1 or cT2 disease. The BCT score was low in 25 (28.4%) patients and high in 63 (71.6%). Among the 50 patients with pathologic complete response or partial response, 41 (82.0%) were in the high BCT score group and 9 (18.0%) were in the low BCT score group. Among the 38 patients with stable or progressive disease, 22 (57.9%) were in the high BCT score group and 16 (42.1%) were in the low BCT score group (p = 0.025). Ki-67 before NACT was a significant factor for predicting tumor response (p = 0.006; 3.81 [1.50–10.16]). The BCT score showed a significant response to NACT (p = 0.016; 4.18 [1.34–14.28]). Distant metastasis-free survival was significantly different between the high- and low-response groups (p = 0.004). @*Conclusion@#We demonstrated that the BCT score predicts NACT responsiveness in HR+/ HER2− BC with LN metastasis and might help determine whether NACT should be performed. Further studies are required to validate these results.

Relationship Between Breast and Axillary Pathologic Complete Response According to Clinical Nodal Stage: A Nationwide Study From Korean Breast Cancer Society / 한국유방암학회지

Purpose@#We evaluated the relationship between breast pathologic complete response (BpCR) and axillary pathologic complete response (ApCR) after neoadjuvant chemotherapy (NACT) according to nodal burden at presentation. As the indications for NACT have expanded, clinicians have started clinical trials for the omission of surgery from the treatment plan in patients with excellent responses to NACT. However, the appropriate indications for axillary surgery omission after excellent NACT response remain unclear. @*Methods@#Data were collected from patients in the Korean Breast Cancer Society Registry who underwent NACT followed by surgery between 2010 and 2020. We analyzed pathologic axillary nodal positivity after NACT according to BpCR stratified by tumor subtype in patients with cT1-3/N0-2 disease at diagnosis. @*Results@#A total of 6,597 patients were identified. Regarding cT stage, 528 (9.5%), 3,778 (67.8%), and 1,268 (22.7%) patients had cT1, cT2, and cT3 disease, respectively. Regarding cN stage, 1,539 (27.7%), 2,976 (53.6%), and 1,036 (18.7%) patients had cN0, cN1, and cN2 disease, respectively. BpCR occurred in 21.6% (n = 1,427) of patients, while ApCR and pathologic complete response (ypCR) occurred in 59.7% (n = 3,929) and ypCR 19.4% (n = 1,285) of patients, respectively. The distribution of biologic subtypes included 2,329 (39.3%) patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative disease, 1,122 (18.9%) with HR-positive/HER2-positive disease, 405 (6.8%) with HR-negative/HER2-positive disease, and 2,072 (35.0%) with triple-negative breast cancer . Among the patients with BpCR, 89.6% (1,122/1,252) had ApCR. Of those with cN0 disease, most (99.0%, 301/304) showed ApCR. Among patients with cN1-2 disease, 86.6% (821/948) had ApCR. @*Conclusion@#BpCR was highly correlated with ApCR after NACT. In patients with cN0 and BpCR, the risk of missing axillary nodal metastasis was low after NACT. Further research on axillary surgery omission in patients with cN0 disease is needed.

Osstem Cardiotec Centum Stent Versus Xience Alpine Stent for De Novo Coronary Artery Lesion: A Multicenter, Randomized, Parallel-Designed, Single Blind Test

Background and objectives@#To compare the safety and efficacy of a new everolimus-eluting stent with an abluminal-coated biodegradable polymer (Osstem Cardiotec Centum) with those of the Xience Alpine stent (Xience). @*Methods@#This randomized, prospective, multicenter, parallel-designed, single-blind trial was conducted among patients with myocardial ischemia undergoing percutaneous coronary intervention (PCI) from 21st September 2018 until 3rd July 2020. The primary efficacy endpoint was in-segment late lumen loss (LLL) at 270 days after the procedure and the primary safety endpoints were major adverse cardiac events (MACE), composite of cardiac death, myocardial infarction, and target lesion revascularization. @*Results@#We enrolled 121 patients and analyzed 113 patients who finished 270 days of followup for the primary efficacy endpoint. The mean age of the participants was 66.8 years. As for the primary efficacy endpoint, LLL of the Osstem Cardiotec Centum group was 0.09±0.13 mm and that of the Xience group was 0.12±0.14 mm (upper limit of 1-sided 95% confidence interval, 0.02; p for non-inferiority, 0.0084). This result demonstrates the non-inferiority of the Osstem Cardiotec Centum. As for the primary safety endpoint, MACE occurred in one patient (1.59% of the Xience group). Meanwhile, no MACE occurred in the Osstem Cardiotec Centum group. @*Conclusions@#The Osstem Cardiotec Centum is non-inferior to the Xience Alpine ® stent and is confirmed to be safe. It could be safely and effectively applied to patients with coronary artery disease undergoing PCI.

Characteristics of dog-bite injuries and factors affecting hospitalization in a single-center emergency department setting in Korea

Objective@#We conducted this study to examine the characteristics of dog-bite injuries and to analyze the factors affecting hospitalization in a single-center emergency department (ED) setting in Korea. @*Methods@#The current single-center, retrospective, cohort study was conducted on 202 patients with dog-bite injuries who visited our medical institution between 2011 and 2019 through a retrospective analysis of their medical records. @*Results@#The Pearson’s chi-square test indicated that outpatient treatment had a significant positive correlation with the location of the bite. Also, hospitalization had a significant positive correlation with age and the depth of the bite wounds (P=0.002, P=0.031, and P=0.034, respectively). On multiple regression analysis, it was observed that hospitalization had a significant positive correlation with age (odds ratio [OR], 1.421; 95% confidence interval [CI], 1.047-1.529; P=0.011) and the depth of the bite wounds (OR, 1.077; 95% CI, 1.013-1.139; P=0.014). @*Conclusion@#In conclusion, our results indicate that older patients and those with deeper bite wounds are vulnerable to hospitalization. This would be helpful in an ED setting for dispensing treatment to those with dog-bite injuries.

Changes in Korean National Healthcare Insurance Policy and Breast Cancer Surgery Trend in Korea

Background@#Since April 2015, the Korean National Health Insurance (NHI) has reimbursed breast cancer patients, approximately 50% of the cost of the breast reconstruction (BR) procedure. We aimed to investigate NHI reimbursement policy influence on the rate of immediate BR (IBR) following total mastectomy (TM). @*Methods@#We retrospectively analyzed breast cancer data between April 2011 and June 2016. We divided patients who underwent IBR following TM for primary breast cancer into “uninsured” and “insured” groups using their NHI statuses at the time of surgery. Univariate analyses determined the insurance influence on the decision to undergo IBR. @*Results@#Of 2,897 breast cancer patients, fewer uninsured patients (n = 625) underwent IBR compared with those insured (n = 325) (30.0% vs. 39.8%, P < 0.001). Uninsured patients were younger than those insured (median age [range], 43 [38–48] vs. 45 [40–50] years; P < 0.001).Pathologic breast cancer stage did not differ between the groups (P = 0.383). More insured patients underwent neoadjuvant chemotherapy (P = 0.011), adjuvant radiotherapy (P < 0.001), and IBR with tissue expander insertion (P = 0.005) compared with those uninsured. @*Conclusion@#IBR rate in patients undergoing TM increased after NHI reimbursement.

External validation and comparison of the Pediatric Emergency Care Applied Research Network and Canadian Assessment of Tomography for Childhood Head Injury 2 clinical decision rules in children with minor blunt head trauma

Objective@#Among the pediatric population with minor head trauma, it is difficult to determine an indication for the usage of brain computerized tomography (CT). Our study aims to compare the efficiency of the most commonly used clinical decision rules: the Pediatric Emergency Care Applied Research Network (PECARN) and Canadian Assessment of Tomography for Childhood Head Injury 2 (CATCH2). @*Methods@#This retrospective study investigated whether the PECARN and CATCH2 rules were applicable to Korean children with minor head trauma for reducing the use of brain CT imaging, while detecting intracranial pathology. @*Results@#Overall, 251 patients (0–5 years old) admitted to emergency rooms within 24 hours of injury were included between August 2015 to August 2018. The performance results are as follows: the PECARN and CATCH2 rules had a sensitivity of 80.00% (51.91%–95.67%) and 100% (78.20%–100.00%) with a specificity of 28.39% (22.73%–34.60%) and 15.25% (10.92%–20.49%), respectively; the negative predictive values were 98.58% and 100%, respectively. Overall, the CATCH2 rule was more successful than the PECARN rule in detecting intracranial pathology; however, there was no significant difference between them. Furthermore, the PECARN and CATCH2 rules lowered the rate of head CT imaging in our study group. @*Conclusion@#Both the rules significantly lowered the rate of indicated brain CT. However, since the CATCH2 rule had higher sensitivity and negative predictive value than the PECARN rule, it is more appropriate to be used in emergency rooms for detecting intracranial pathology in children with minor head trauma.

Changes in Korean National Healthcare Insurance Policy and Breast Cancer Surgery Trend in Korea

Background@#Since April 2015, the Korean National Health Insurance (NHI) has reimbursed breast cancer patients, approximately 50% of the cost of the breast reconstruction (BR) procedure. We aimed to investigate NHI reimbursement policy influence on the rate of immediate BR (IBR) following total mastectomy (TM). @*Methods@#We retrospectively analyzed breast cancer data between April 2011 and June 2016. We divided patients who underwent IBR following TM for primary breast cancer into “uninsured” and “insured” groups using their NHI statuses at the time of surgery. Univariate analyses determined the insurance influence on the decision to undergo IBR. @*Results@#Of 2,897 breast cancer patients, fewer uninsured patients (n = 625) underwent IBR compared with those insured (n = 325) (30.0% vs. 39.8%, P < 0.001). Uninsured patients were younger than those insured (median age [range], 43 [38–48] vs. 45 [40–50] years; P < 0.001).Pathologic breast cancer stage did not differ between the groups (P = 0.383). More insured patients underwent neoadjuvant chemotherapy (P = 0.011), adjuvant radiotherapy (P < 0.001), and IBR with tissue expander insertion (P = 0.005) compared with those uninsured. @*Conclusion@#IBR rate in patients undergoing TM increased after NHI reimbursement.

External validation and comparison of the Pediatric Emergency Care Applied Research Network and Canadian Assessment of Tomography for Childhood Head Injury 2 clinical decision rules in children with minor blunt head trauma

Objective@#Among the pediatric population with minor head trauma, it is difficult to determine an indication for the usage of brain computerized tomography (CT). Our study aims to compare the efficiency of the most commonly used clinical decision rules: the Pediatric Emergency Care Applied Research Network (PECARN) and Canadian Assessment of Tomography for Childhood Head Injury 2 (CATCH2). @*Methods@#This retrospective study investigated whether the PECARN and CATCH2 rules were applicable to Korean children with minor head trauma for reducing the use of brain CT imaging, while detecting intracranial pathology. @*Results@#Overall, 251 patients (0–5 years old) admitted to emergency rooms within 24 hours of injury were included between August 2015 to August 2018. The performance results are as follows: the PECARN and CATCH2 rules had a sensitivity of 80.00% (51.91%–95.67%) and 100% (78.20%–100.00%) with a specificity of 28.39% (22.73%–34.60%) and 15.25% (10.92%–20.49%), respectively; the negative predictive values were 98.58% and 100%, respectively. Overall, the CATCH2 rule was more successful than the PECARN rule in detecting intracranial pathology; however, there was no significant difference between them. Furthermore, the PECARN and CATCH2 rules lowered the rate of head CT imaging in our study group. @*Conclusion@#Both the rules significantly lowered the rate of indicated brain CT. However, since the CATCH2 rule had higher sensitivity and negative predictive value than the PECARN rule, it is more appropriate to be used in emergency rooms for detecting intracranial pathology in children with minor head trauma.

Neurological outcomes and survival rate of out-of-hospital cardiac arrest patients with return of spontaneous circulation after percutaneous coronary intervention across age groups: a cross-sectional study

Objective@#Little is known about percutaneous coronary intervention (PCI) and its benefits in elderly patients with out-of-hospital cardiac arrest (OHCA). This study compared the survival to discharge and the neurological outcomes across the age groups of patients with OHCA. @*Methods@#Using the national cardiac arrest registry, OHCA patients with a return of spontaneous circulation from 2013 to 2017 were included in this study. The PCI history of the patients was obtained from their medical records. The outcomes were cerebral performance category (CPC) 1 and 2 and survival to discharge. Multivariable logistic regression analysis was performed, and an interaction term was evaluated to compare the effects of PCI across the age groups. @*Results@#This study included 22,320 patients. In the interaction term, the adjusted odds ratio (AOR) (95% confidence interval [CI]) for a good CPC was 2.84 (2.43-3.32) for the age group of 18-64 years, 3.26 (2.53-4.21) for the age group of 65-74 years, 3.37 (2.33-4.88) for the age group of 75-84 years, and 2.54 (0.92-7.01) for the age group of 85-106 years. The AOR (95% CI) for survival to hospital discharge was 3.31 (2.82-3.88) for the age group of 18-64 years, 2.65 (2.09-3.35) for the age group of 65-74 years, 2.20 (1.61-3.02) for the age group of 75-84 years, and 1.64 (0.73-3.67) for the age group of 85-106 years. @*Conclusion@#In the OHCA patients, the PCI group had more good outcomes (good CPC, survival to discharge) than the non-PCI group, but this benefit was not shown in those aged over 85 years. On the other hand, it could not explain why PCI should not be performed in the elderly, suggesting that age alone should not be used to make decisions regarding early invasive strategies.

Impact of Hospital Volume of Percutaneous Coronary Intervention (PCI) on In-Hospital Outcomes in Patients with Acute Myocardial Infarction: Based on the 2014 Cohort of the Korean Percutaneous Coronary Intervention (K-PCI) Registry

Background and Objectives@#The relationship between the hospital percutaneous coronary intervention (PCI) volumes and the in-hospital clinical outcomes of patients with acute myocardial infarction (AMI) remains the subject of debate. This study aimed to determine whether the in-hospital clinical outcomes of patients with AMI in Korea are significantly associated with hospital PCI volumes. @*Methods@#We selected and analyzed 17,121 cases of AMI, that is, 8,839 cases of non-ST-segment elevation myocardial infarction and 8,282 cases of ST-segment elevation myocardial infarction, enrolled in the 2014 Korean percutaneous coronary intervention (K-PCI) registry. Patients were divided into 2 groups according to hospital annual PCI volume, that is, to a high-volume group (≥400/year) or a low-volume group (<400/year). Major adverse cardiovascular and cerebrovascular events (MACCEs) were defined as composites of death, cardiac death, non-fatal myocardial infarction (MI), stent thrombosis, stroke, and need for urgent PCI during index admission after PCI. @*Results@#Rates of MACCE and non-fatal MI were higher in the low-volume group than in the high-volume group (MACCE: 10.9% vs. 8.6%, p=0.001; non-fatal MI: 4.8% vs. 2.6%, p=0.001, respectively). Multivariate regression analysis showed PCI volume did not independently predict MACCE. @*Conclusions@#Hospital PCI volume was not found to be an independent predictor of in-hospital clinical outcomes in patients with AMI included in the 2014 K-PCI registry.

Melatonin-Induced PGC-1α Improves Angiogenic Potential of Mesenchymal Stem Cells in Hindlimb Ischemia

Despite the therapeutic effect of mesenchymal stem cells (MSCs) in ischemic diseases, pathophysiological conditions, including hypoxia, limited nutrient availability, and oxidative stress restrict their potential. To address this issue, we investigated the effect of melatonin on the bioactivities of MSCs. Treatment of MSCs with melatonin increased the expression of peroxisome proliferatoractivated receptor gamma coactivator-1 alpha (PGC-1α). Melatonin treatment enhanced mitochondrial oxidative phosphorylation in MSCs in a PGC-1α-dependent manner. Melatonin-mediated PGC-1α expression enhanced the proliferative potential of MSCs through regulation of cell cycle-associated protein activity. In addition, melatonin promoted the angiogenic ability of MSCs, including migration and invasion abilities and secretion of angiogenic cytokines by increasing PGC-1α expression. In a murine hindlimb ischemia model, the survival of transplanted melatonin-treated MSCs was significantly increased in the ischemic tissues, resulting in improvement of functional recovery, such as blood perfusion, limb salvage, neovascularization, and protection against necrosis and fibrosis. These findings indicate that the therapeutic effect of melatonin-treated MSCs in ischemic diseases is mediated via regulation of PGC-1α level. This study suggests that melatonin-induced PGC-1α might serve as a novel target for MSC-based therapy of ischemic diseases, and melatonin-treated MSCs could be used as an effective cell-based therapeutic option for patients with ischemic diseases.

Social Stigmata of Electroconvulsive Therapy and Their Reduction Strategies

Modified electroconvulsive therapy (ECT) which started in 1950s is a safe and efficacious treatment for several mental disorders including mood disorders and psychotic disorders. However, its usage in present days is still limited by misconceptions and stigmata of ECT. This paper overviews the background from which the stigmata of ECT stemmed and the current status of stigmata surrounding ECT among the public and medical professionals. In addition, a few potential strategies for reducing stigmata of ECT are provided in this review.

Social Stigmata of Electroconvulsive Therapy and Their Reduction Strategies

Modified electroconvulsive therapy (ECT) which started in 1950s is a safe and efficacious treatment for several mental disorders including mood disorders and psychotic disorders. However, its usage in present days is still limited by misconceptions and stigmata of ECT. This paper overviews the background from which the stigmata of ECT stemmed and the current status of stigmata surrounding ECT among the public and medical professionals. In addition, a few potential strategies for reducing stigmata of ECT are provided in this review.

A Giant Pseudo-Aneurysm on the Anastomosis Site for a Redo Bentall Operation due to Behçet Disease Treated by Thoracic Endovascular Aortic Aneurysm Repair with a Custom-Made Stent Graft

A 34-year-old man who had undergone aortic valve replacement 8 years ago underwent an additional Bentall operation due to mechanical valve dehiscence 2 years later. Subsequently, he was diagnosed with Behçet disease and Batter syndrome. A week after being hospitalized again due to chest pain and dyspnea, a large pseudo-aneurysm was detected on computed tomography. Because of the excessively large size of the pseudo-aneurysm, surgical treatment seemed very risky. Therefore, we planned to perform thoracic endovascular aortic repair (TEVAR) and treated him successfully. However, the patient experienced recurrence of the same symptoms 4 months later, and was found to have type IV endoleak.He received a TEVAR procedure again, and it was successful.

Left Hemitruncus Treated Along with Ventricular Septal Defect in a Neonate

Hemitruncus arteriosus is a rare cardiovascular malformation in which one of the pulmonary arteries anomalously originates from the aorta. Left hemitruncus arteriosus, defined as the origination of the left pulmonary artery from the aorta, is less common than right hemitruncus arteriosus. In this study, we report the case of a neonate diagnosed with left hemitruncus arteriosus, ventricular septal defect, and atrial septal defect who underwent successful surgical treatment.

Effects of cholesterol levels on outcomes of out-of-hospital cardiac arrest: a cross-sectional study

OBJECTIVE: High cholesterol level is a risk factor for coronary artery disease, and coronary artery disease is a major risk factor for out-of-hospital cardiac arrest (OHCA). However, the effect of cholesterol level on outcomes of OHCA has been poorly studied. This study aimed to determine the effect of cholesterol level on outcomes of OHCA.METHODS: This cross-sectional study used the CAPTURES (Cardiac Arrest Pursuit Trial with Unique Registration and Epidemiologic Surveillance) project database in Korea. Multivariable conditional logistic regression analysis was performed to estimate the effect of cholesterol level on outcomes in OHCA.RESULTS: In all, 584 cases of OHCA were analyzed; those with cholesterol levels <120 mg/dL were classified as having low total cholesterol (TC) (n=197), those with levels ranging from 120–199 mg/dL as middle TC (n=322), and those with ≥200 mg/dL as high TC (n=65). Compared to low TC, more patients with middle TC and high TC survived to discharge (9.1% vs. 22.0% and 26.2%, respectively, P=0.001). The good cerebral performance category also increased in that order (4.1 % vs. 14.6% and 23.1%, respectively, P≤0.001). Comparing middle TC and high TC with low TC, adjusted odds ratios (95% confidence intervals) were 1.97 (1.06 to 3.64) and 2.53 (1.08 to 5.92) for survival to discharge, respectively, and 2.53 (1.07 to 5.98) and 4.73 (1.63 to 13.71) for good neurological recovery, respectively.CONCLUSION: Higher cholesterol is associated with better outcomes in OHCA; cholesterol level is a good predictor of outcomes of OHCA.

Cripto Enhances Proliferation and Survival of Mesenchymal Stem Cells by Up-Regulating JAK2/STAT3 Pathway in a GRP78-Dependent Manner

Cripto is a small glycosylphosphatidylinositol-anchored signaling protein that can detach from the anchored membrane and stimulate proliferation, migration, differentiation, vascularization, and angiogenesis. In the present study, we demonstrated that Cripto positively affected proliferation and survival of mesenchymal stem cells (MSCs) without affecting multipotency. Cripto also increased expression of phosphorylated janus kinase 2 (p-JAK2), phosphorylated signal transducer and activator of transcription 3 (p-STAT3), 78 kDa glucose-regulated protein (GRP78), c-Myc, and cyclin D1. Notably, treatment with an anti-GRP78 antibody blocked these effects. In addition, pretreatment with STAT3 short interfering RNA (siRNA) inhibited the increase in p-JAK2, c-Myc, cyclin D1, and BCL3 levels caused by Cripto and attenuated the pro-survival action of Cripto on MSCs. We also found that incubation with Cripto protected MSCs from apoptosis caused by hypoxia or H₂O₂ exposure, and the level of caspase-3 decreased by the Cripto-induced expression of B-cell lymphoma 3-encoded protein (BCL3). These effects were sensitive to down-regulation of BCL3 expression by BCL3 siRNA. Finally, we showed that Cripto enhanced expression levels of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and hepatocyte growth factor (HGF). In summary, our results demonstrated that Cripto activated a novel biochemical cascade that potentiated MSC proliferation and survival. This cascade relied on phosphorylation of JAK2 and STAT3 and was regulated by GRP78. Our findings may facilitate clinical applications of MSCs, as these cells may benefit from positive effects of Cripto on their survival and biological properties.

Melatonin Rescues Mesenchymal Stem Cells from Senescence Induced by the Uremic Toxin p-Cresol via Inhibiting mTOR-Dependent Autophagy

p-Cresol, found at high concentrations in the serum of chronic kidney failure patients, is known to cause cell senescence and other complications in different parts of the body. p-Cresol is thought to mediate cytotoxic effects through the induction of autophagy response. However, toxic effects of p-cresol on mesenchymal stem cells have not been elucidated. Thus, we aimed to investigate whether p-cresol induces senescence of mesenchymal stem cells, and whether melatonin can ameliorate abnormal autophagy response caused by p-cresol. We found that p-cresol concentration-dependently reduced proliferation of mesenchymal stem cells. Pretreatment with melatonin prevented pro-senescence effects of p-cresol on mesenchymal stem cells. We found that by inducing phosphorylation of Akt and activating the Akt signaling pathway, melatonin enhanced catalase activity and thereby inhibited the accumulation of reactive oxygen species induced by p-cresol in mesenchymal stem cells, ultimately preventing abnormal activation of autophagy. Furthermore, preincubation with melatonin counteracted other pro-senescence changes caused by p-cresol, such as the increase in total 5′-AMP-activated protein kinase expression and decrease in the level of phosphorylated mechanistic target of rapamycin. Ultimately, we discovered that melatonin restored the expression of senescence marker protein 30, which is normally suppressed because of the induction of the autophagy pathway in chronic kidney failure patients by p-cresol. Our findings suggest that stem cell senescence in patients with chronic kidney failure could be potentially rescued by the administration of melatonin, which grants this hormone a novel therapeutic role.