In Vivo Base Editing of Scn5a Rescues Type 3 Long QT Syndrome in Mice.

BACKGROUND: Pathogenic variants in SCN5A can result in long QT syndrome type 3, a life-threatening genetic disease. Adenine base editors can convert targeted A T base pairs to G C base pairs, offering a promising tool to correct pathogenic variants. METHODS: We generated a long QT syndrome type 3 mouse model by introducing the T1307M pathogenic variant into the Scn5a gene. The adenine base editor was split into 2 smaller parts and delivered into the heart by adeno-associated virus serotype 9 (AAV9-ABEmax) to correct the T1307M pathogenic variant. RESULTS: Both homozygous and heterozygous T1307M mice showed significant QT prolongation. Carbachol administration induced Torsades de Pointes or ventricular tachycardia for homozygous T1307M mice (20%) but not for heterozygous or wild-type mice. A single intraperitoneal injection of AAV9-ABEmax at postnatal day 14 resulted in up to 99.20% Scn5a transcripts corrected in T1307M mice. Scn5a mRNA correction rate >60% eliminated QT prolongation; Scn5a mRNA correction rate <60% alleviated QT prolongation. Partial Scn5a correction resulted in cardiomyocytes heterogeneity, which did not induce severe arrhythmias. We did not detect off-target DNA or RNA editing events in ABEmax-treated mouse hearts. CONCLUSIONS: These findings show that in vivo AAV9-ABEmax editing can correct the variant Scn5a allele, effectively ameliorating arrhythmia phenotypes. Our results offer a proof of concept for the treatment of hereditary arrhythmias.

UBXN11 Predicts as a Poor Index for Colorectal Cancer and Contributes to the Tumorigenesis by Activating NF-κB Signaling.

BACKGROUND: The complex mechanisms of colorectal cancer (CRC) pathogenesis and progression remain poorly understood. This study endeavors to unravel the role of UBXN11within the context of CRC. METHODS: UBXN11 expression level in CRC, stomach adenocarcinoma and esophageal carcinoma, and the overall survival in corresponding cancers were analyzed using UALCAN database. Human CRC cell lines and xenograft mouse model with UBXN11 overexpression were established to investigate the pathological role of UBXN11 in CRC progression. Luciferase assay, qPCR, and Western blot were performed to dissect the interaction between UBXN11 and NF-κB signaling. RESULTS: Heightened UBXN11 expression was observed in various digestive tract tumors, which was positively correlated with the reduced overall survival rates in CRC patients. Overexpression of UBXN11 significantly enhanced CRC cell proliferation in vitro and promoted tumor growth in vivo. Mechanistically, UBXN11 promoted CRC tumorigenesis through increasing the activation of NF-κB signaling pathway. CONCLUSIONS: This study underscores the pivotal role of UBXN11 in CRC progression and paves the way for novel therapeutic strategies for CRC treatment.

Trends and projections of ovarian cancer incidence in Hong Kong: A population-based study.

INTRODUCTION: This study analyzed the incidence of ovarian cancer in Hong Kong and its association with age, calendar period and birth cohort, made projections through 2030, and attributed differences in new cancer cases to demographic and epidemiologic changes. MATERIAL AND METHODS: Incidence data for ovarian cancer were obtained from the Hong Kong Cancer Registry. We employed the age-period-cohort modeling approach to investigate the association between ovarian cancer incidence and age in Hong Kong women, with particular emphasis on examining the changing trends of period and cohort effects on incidence. We projected the incidence of ovarian cancer in Hong Kong between 2018 and 2030 and attributed the rise in new cancer cases to epidemiologic and demographic shifts. RESULTS: Between 1990 and 2017, a total of 11 182 women were diagnosed with ovarian cancer in Hong Kong. Crude and age-standardized rates increased from 8.2 and 7.8 per 100 000 person-years to 16.3 and 11.5 per 100 000 person-years, respectively. New cases of ovarian cancer rose from 225 in 1990 to 645 in 2017. We observed an increased risk of ovarian cancer throughout the study period and in the post-1940 birth cohort. The projected incidence rate and new cases of ovarian cancer are expected to continue growing due to demographic and epidemiologic changes such as fertility patterns and lifestyle factors, with an estimated 981 cases in 2030. CONCLUSIONS: The period risk and cohort risk of ovarian cancer among Hong Kong women is increasing. Demographic and epidemiologic changes may continue to increase ovarian cancer incidence and new cases in Hong Kong.

ß-Aminoisobutyric acid supplementation attenuated salt-sensitive hypertension in Dahl salt-sensitive rats through prevention of insufficient fumarase.

The human Dietary Approaches to Stop Hypertension-Sodium Trial has shown that ß-aminoisobutyric acid (BAIBA) may prevent the development of salt-sensitive hypertension (SSHT). However, the specific antihypertensive mechanism remains unclear in the renal tissues of salt-sensitive (SS) rats. In this study, BAIBA (100 mg/kg/day) significantly attenuated SSHT via increased nitric oxide (NO) content in the renal medulla, and it induced a significant increase in NO synthesis substrates (L-arginine and malic acid) in the renal medulla. BAIBA enhanced the activity levels of total NO synthase (NOS), inducible NOS, and constitutive NOS. BAIBA resulted in increased fumarase activity and decreased fumaric acid content in the renal medulla. The high-salt diet (HSD) decreased fumarase expression in the renal cortex, and BAIBA increased fumarase expression in the renal medulla and renal cortex. Furthermore, in the renal medulla, BAIBA increased the levels of ATP, ADP, AMP, and ADP/ATP ratio, thus further activating AMPK phosphorylation. BAIBA prevented the decrease in renal medullary antioxidative defenses induced by the HSD. In conclusion, BAIBA's antihypertensive effect was underlined by the phosphorylation of AMPK, the prevention of fumarase's activity reduction caused by the HSD, and the enhancement of NO content, which in concert attenuated SSHT in SS rats.

Global burden attributable to high sodium intake from 1990 to 2019.

BACKGROUND AND AIMS: High sodium intake is associated with a higher risk of a wide range of diseases. We aimed to estimate the pattern and trend of the global disease burden associated with high sodium intake from 1990 to 2019. METHODS AND RESULTS: We obtained numbers and rates of death and disability-adjusted life year (DALY) attributable to high sodium intake by sex, socio-demographic index, and country from the Global Burden of Disease Study 2019. We calculated the estimated annual percentage change to evaluate the age-standardized rate (ASR) of the burden attributable to high sodium intake between 1990 and 2019. We further calculated the contribution of population growth, population aging, and age-specific rates of death and DALY to the net change in the total number of deaths and DALYs attributable to high sodium intake. From 1990 to 2019, global age-standardized rates of death and DALY attributable to high sodium intake substantially decreased for both sexes. However, there were significant increases in the total numbers of deaths and DALYs attributable to high sodium intake, which were driven by population growth and population aging. The attribution of population growth and population aging varied widely across countries, with a higher contribution of population growth in most developing countries and a higher contribution of population aging in countries with slow population growth. CONCLUSIONS: Although the global burden attributable to high sodium intake in terms of age-standardized rate declined from 1990 to 2019, the absolute burden increased significantly, which was driven by population growth and population aging.

Short-term outcomes of double versus single pyloromyotomy at peroral endoscopic pyloromyotomy in the treatment of gastroparesis (with video).

BACKGROUND AND AIMS: The prevalence of gastroparesis (Gp), a chronic debilitating disorder, and resulting hospitalizations are increasing. Gastric peroral endoscopic pyloromyotomy (POP or GPOEM) is a novel technique in the treatment of refractory Gp. Despite the initial promising results of GPOEM, one-third of patients do not exhibit any clinical response. Furthermore, loss of clinical response was reported in several studies. No response or loss of response after GPOEM may be related to inadequate myotomy. The aim of our study is to examine whether double pyloromyotomy at GPOEM is superior to single pyloromyotomy. METHOD: A retrospective case-controlled study of patients who underwent GPOEM for refractory Gp at our tertiary care institution between June 2015 and March 2018 was performed. Because the follow-up time for the single myotomy group was much longer than that of the double myotomy group, we matched the length of follow-up for the single myotomy group to that of the double myotomy group. The outcomes were measured by the changes in the Gastroparesis Cardinal Symptom Index (GCSI) before and 3 to 6 months after the procedure. Adverse events and other procedural and clinical parameters were also compared. RESULTS: Ninety patients underwent GPOEM (55 single and 35 double pyloromyotomy). The mean age was 47 ± 14 years, and the mean duration of symptoms was 5.3 ± 4.4 years. The average GCSI score was 3.8 before the GPOEM, and the average GCSI score 6 months after procedure was 1.8. Thirty-seven of 55 (67%) patients who underwent single pyloromyotomy achieved clinical response compared with 30 of 35 (86%) patients who underwent double pyloromyotomy. There were no significant differences for procedure time, postoperative pain, or length of hospital stay between the 2 groups. There was no difference in adverse events in the 2 pyloromyotomy groups. CONCLUSION: Double pyloromyotomy is a safe and feasible technique during GPOEM. Clinical success was higher in patients undergoing double pyloromyotomy compared with single pyloromyotomy in this nonrandomized, short-term follow-up study. Long-term studies are needed to further confirm our results.

[Neurological complications of posterior vertebral column resection for severe rigid congenital spinal deformities].

OBJECTIVE: To analyze the risk factors of neurological complications of posterior vertebral column resection in the treatment of severe rigid congenital spinal deformities. METHODS: The clinical data of 88 patients with severe rigid congenital spinal deformities who underwent PVCR in Department Of Orthopaedics, Xijing Hospital, Fourth Military Medical University from June 2007 to November 2012 were collected. There were 39 males and 49 females at the average age of 16.9 years (range 6-46 years). To measure the Cobb angle and balance at preoperative, postoperative and follow up, and to record the operation report, neurological complications and at follow up. The relevant factors of neurological complications were analyzed by one-way analysis, including: age, Cobb angle, operation time, body mass index, pulmonary function, blood volume loss, resection level, number of vertebrae fixed, number of vertebrae resected, usage of cage or titanium mesh, preoperative neurologic function, the type of deformity and combination of spinal canal deformity, and further analyzed by multiariable Logistic regression analysis. RESULTS: The average follow up was 42 months (range 19 to 83 months). The number of resected vertebrae average 1.3 (range 1 to 3), operative time average 502.4 min (range 165.0 to 880.0 min), estimate blood loss average 2,238 ml (range 100 to 11,500 ml) for an average 69.3% blood volume loss (range 9% to 299%). The average preoperative major coronal curve of 93.6° corrected to 22.2°, at the final follow-up, the coronal curve was 22.2° with a correction of 76.8%. The average preoperative coronal imbalance (absolute value) was 2.5 cm decreasing to 1.3 cm at the final follow-up. The average preoperative major sagittal curve of 88.2° corrected to 28.7°, at the final follow-up, the sagittal curve was 29.2°, average decrease in kyphosis of 59.0°. The average preoperative sagittal imbalance (absolute value) was 3.1 cm decreasing to 1.2 cm at the final follow-up. There were 12 patients (13.6%) developed a neurological complications. High rate of neurological complications was occurred in patients with operative time greater than 480 min, pulmonary dysfunction, blood volume loss greater than 50%, T7-T99 osteotomy and preoperative neurologic compromise (P=0.046, 0.000, 0.000, 0.033, 0.043). CONCLUSIONS: Posterior vertebral column resection can achieve satisfactory efficacy in treatment of severe spinal deformities. Pulmonary dysfunction and blood volume loss greater than 50% were significant risk factors of neurological complications.

The coumarin component isofraxidin targets the G-protein-coupled receptor S1PR1 to modulate IL-17 signaling and alleviate ulcerative colitis.

OBJECTIVE: The increasing global prevalence of ulcerative colitis (UC) underscores the imperative to explore novel therapeutic approaches. Traditional Chinese medicine has historically shown potential in addressing this ailment. The current study aimed to elucidate the functional attributes and underlying mechanisms of isofraxidin, a coumarin derivative from Acanthopanax, in the context of UC. METHODS: A murine model of dextran sodium sulfate (DSS)-induced UC was established, and we conducted a comprehensive assessment of the influence of isofraxidin on UC symptomatology, colonic histopathological manifestations, the inflammatory response, and apoptosis. The potential receptor of isofraxidin was initially identified through the Target database and molecular docking analysis. Subsequent in vivo and in vitro experiments were conducted to determine the effects of isofraxidin on the identified receptor and associated signaling pathways. Transfection was used to examine the receptor's role in the regulatory mechanism of isofraxidin. RESULTS: Isofraxidin reduced UC symptoms and colonic histopathological impairments. Furthermore, isofraxidin ameliorated the DSS-induced inflammatory response and apoptosis in tissues. S1PR1 was identified as a target of isofraxidin and effectively suppressed activation of the IL-17 signaling pathway. Intriguingly, cellular experiments indicated that overexpression of S1PR1 counteracted the protective effect of isofraxidin. DISCUSSION: In summary, our investigation revealed that isofraxidin could modulate S1PR1 and regulate the IL-17 signaling pathway, thus ameliorating DSS-induced UC. These findings establish a robust foundation for considering isofraxidin as a prospective therapeutic intervention to treat UC.

Constructing models for Crohn's disease diagnosis and prediction of infliximab non-response based on angiogenesis-related genes.

Background: Angiogenesis response plays a crucial role in the occurrence and development of Crohn's disease (CD) and may involve the mechanism of infliximab non-response. However, the role of angiogenesis-related genes in Crohn's disease has not been comprehensively studied. This study aimed to explore the expression profiles of angiogenesis-related genes in CD patients and construct models for disease diagnosis and prediction of infliximab non-response. Methods: CD-related microarray datasets were collected from the GEO database. Unsupervised consensus clustering analysis was performed based on differentially expressed angiogenesis-related genes to divide CD samples into two distinct clusters. Weighted gene co-expression network analysis (WGCNA) was conducted on the clusters to identify angiogenesis-related module. Based on the differentially expressed genes in the module, machine learning algorithms were employed to further identify hub genes and construct a disease diagnostic model. Subsequently, treatment outcome-related genes were extracted from these hub genes, and a predictive model for infliximab non-response in CD patients was ultimately built. Results: Based on angiogenesis-related genes, we identified two distinct CD clusters (C1 and C2). Compared to C1, the metabolic pathways in C2 were significantly upregulated, and there was a higher abundance of cell clusters such as M1 macrophages and plasma cells. Additionally, C2 showed a poorer response to infliximab. Furthermore, a predictive model for infliximab non-response in CD patients was constructed based on the hub genes, and it was successfully validated using an external dataset. Conclusion: Comprehensive analysis of angiogenesis-related genes revealed different clusters of CD, which exhibited differential response rates to infliximab. The construction of models provides a reference for disease diagnosis and drug selection, aiding in clinical decision-making.

Metabolomics reveals the defense mechanism of histidine supplementation on high-salt exposure-induced hepatic oxidative stress.

AIMS: This study mainly evaluated the protective mechanism of histidine against the hepatic oxidative stress after high-salt exposure (HSE) through combined analysis of non-targeted metabolomics and biological metabolic networks. MATERIALS AND METHODS: Dahl salt-sensitive (SS) rats were fed with normal-salt diet or HSE ± histidine in addition to drinking water for 14 days. Gas chromatography-mass spectrometry was used to analyze the hepatic metabolites. The metabolic profile was analyzed by SIMCA-14.1, the metabolic correlation network was performed using Gephi-0.9.2, and pathway enrichment was analyzed using MetaboAnalyst 5.0 online website. KEY FINDINGS: Results indicated that HSE disturbed the hepatic metabolic profile, generated abnormal liver metabolism and exacerbated oxidative stress. Histidine supplementation significantly reversed the hepatic metabolic profile. Of note, 14 differential metabolic pathways were enriched after histidine supplementation, most of which played an important role in ameliorating redox and nitric oxide (NO) metabolism. Histidine administration decreased the levels of hydroperoxide and malondialdehyde, and increased the activities of antioxidant enzymes (Catalase, Superoxide Dismutase, Glutathione S-transferase and Glutathione reductases). Histidine effectively enhanced the endogenous synthesis of glutathione by increasing the levels of glutamate and cysteine, thereby enhancing the antioxidant capacity of the glutathione system. After histidine administration, lysine, glutamate, and hypotaurine owned a higher metabolic centrality in the correlation network. In addition, histidine could also effectively increase the endogenous synthesis of NO by enhancing the L-arginine/NO pathway. SIGNIFICANCE: This study offers new insights into the metabolic mechanisms underlying the antioxidant protective effect of histidine on the liver.