Background:Optimal length of proximal resection margin (PRM) for locally advanced Siewert type II adenocarcinoma of esophagogastric junction (AEG) remained undetermined. Especially, the relationship between PRM length after neoadjuvant chemotherapy (NAC) and survival were seldom reported. Methods:A total of 108 consecutive locally advanced Siewert type II AEG patients were enrolled. The clinicopathological characteristics, PRM length and survival outcomes were collected. Cox proportional hazard model was used to compare the hazard rates of survival and recurrence between patients with length above and below the cut-off value. Univariable and multivariable analyses were performed to analysis association between PRM length and prognosis. Results:The mean PRM length was 13mm (range: 1-45 mm). PRM status was independent factor for recurrence-free survival (RFS) (HR 3.177, 95%CI 1.098-9.193, p = 0.033). 4 patients (3.7%) had positive PRM on histological pathology, and they suffered shorter RFS than patients with negative PRM (16.0 ± 4.3 months vs 60.1 ± 3.9 months, p = 0.002). In 104 patients with negative PRM, NAC was administered to 53 patients (51.0%). The length of PRM was not associated with survival outcomes in NAC group and surgery alone (SA) group, respectively. The hazard rates of survival and recurrence did not differ between the patients with length of PRM above and below the cut-off value (p>0.05). No statistically significant differences in survival outcomes were observed between patients with different PRM lengths in either the NAC group or the SA group. Similarly, no statistically significant differences in survival outcomes were found across different PRM lengths, no matter which treatment strategy was chosen. Conclusions:A positive status of PRM appears to be associated with adverse survival outcomes of patients with locally advanced Siewert type II AEG after surgery. However, for patients with negative status, the length of the PRM does not influence survival, regardless of whether they undergo surgical resection alone or NAC followed by surgery.

Background Primary percutaneous coronary intervention (PPCI) is the preferred treatment for ST-segment elevation myocardial infarction (STEMI). Treatment delay significantly affects the prognosis of STEMI patients. Objectives The aim of this study was to investigate the treatment delay and its influencing factors for STEMI in Beijing. Methods STEMI patients undergoing PPCI at 65 hospitals between 2018 and 2022 were enrolled. Treatment delays were collected and analyzed using mixed-effects models to assess the impact of admission time, arrival mode, and hospital level. Results Among 13,445 individuals, median total ischemic time (TIT), symptom onset-to-door time (S2D), and door-to-balloon time (D2B) were 188 minutes (Q1-Q3: 133-288 minutes), 116 minutes (Q1-Q3: 60-200 minutes), and 72 minutes (Q1-Q3: 58-89 minutes), respectively. Compared with off-hours admissions, S2D was longer and D2B was shorter for on-hours admissions (P < 0.001 for both). Median TIT, S2D, and D2B were longer for self-transported patients than for ambulance-transported patients (P < 0.001 for all). Median TIT and S2D were shorter and D2B was longer at nontertiary hospitals than at tertiary hospitals (P < 0.001 for all). According to linear mixed-effects models adjusting for confounders, off-hours admission was linked to 6.6% shorter S2D but 11.6% longer D2B. Ambulance transport was independently associated with 9.0% shorter S2D and 10.3% shorter D2B. Treatment at tertiary hospitals was associated with 19.0% longer S2D. Conclusions Despite advances in STEMI management, prehospital delay remains the dominant component of TIT in Beijing. Future strategies should focus on improving hospital preparedness, increasing ambulance use, and minimizing interhospital disparities to reduce treatment delay.

BACKGROUND:Inherited cardiomyopathy (ICM) is a genetic disorder characterized by abnormal myocardial structure and function, often progressing to heart failure. FHOD3, a member of the Formin gene family, plays a crucial role in cardiomyocyte cytoskeletal organization. Mutations in FHOD3 have been associated with various cardiomyopathies, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and left ventricular noncompaction (LVNC). However, the molecular mechanisms underlying FHOD3 deficiency-induced cardiomyopathy remain elusive. METHODS:A FHOD3 knockout (FHOD3-/-) human embryonic stem cell (hESC) line was generated using the CRISPR/Cas9 system and subsequently differentiated into cardiomyocytes (hESC-CMs). Sarcomere structure, calcium handling, mitochondrial function, and contractility were evaluated via immunofluorescence, electron microscopy, Seahorse metabolic analysis, and high-definition video analysis, respectively. Transcriptomic sequencing was performed to identify differentially expressed genes and enriched pathways. RESULTS:FHOD3-deficient hESC-CMs exhibited marked sarcomere disorganization and degradation, impaired calcium handling and compromised mitochondrial function, ultimately leading to reduced contractility. Transcriptomic analysis revealed significant downregulation of sarcomere-related genes and calcium-handling genes, with enrichment in pathways associated with cardiomyopathy and calcium signaling. Furthermore, FHOD3 deficiency triggered the phosphorylation of CaMKII (Thr286), a key regulator of cardiac hypertrophy and remodeling, contributing to the progression of heart failure. Treatment with the myosin activator Omecamtiv mecarbil (OM) partially restored contractility without affecting calcium handling, highlighting its potential as a therapeutic strategy. CONCLUSIONS:Our study establishes a valuable human-derived model for investigating the molecular mechanisms of FHOD3 deficiency-induced cardiomyopathy. This model allows for extensive investigation into the phenotypes caused by FHOD3 deficiency and identifies CaMKII activation as a crucial factor contributing to the HF phenotype. Additionally, this model serves as an important tool for discovering novel therapeutic agents, and we demonstrate that OM can partially improve myocardial function in FHOD3 KO hESC-CMs.

Mitochondrial dysfunction is pivotal in the pathogenesis of cardiac ischemia/reperfusion (I/R) injury. Restoring mitochondrial function represents a promising strategy for mitigating I/R-induced cardiac injury. Mitochondrial fission regulator 1-like protein (MTFR1L), a recently identified mitochondrial dynamics protein, is abundantly expressed in the cardiac tissues. However, its functional role in I/R injury remains undefined. Here, Mtfr1l-knockout mice and human embryonic-stem-cell-derived cardiomyocytes are utilized to investigate the role of MTFR1L in myocardial I/R injury and elucidate its contribution to mitochondrial integrity and function. MTFR1L deficiency markedly worsened I/R-induced cardiac injury and mitochondrial dysfunction. These phenotypes were partially reversed by mitochondria-anchored apoptosis-inducing factor (AIF) overexpression. Mechanistically, MTFR1L protects the heart via 2 interconnected pathways. First, MTFR1L sustains AIF dimerization and stabilizes the AIF-CHCHD4 (coiled-coil-helix-coiled-coil-helix domain containing 4) complex, thereby preserving mitochondrial contact site and cristae organizing system integrity and cristae architecture to facilitate electron transport chain supercomplex assembly, sustain mitochondrial respiration, and limit reactive oxygen species production. Second, by physically interacting with AIF, MTFR1L prevents its mitochondrial release and nuclear translocation, thereby suppressing intrinsic apoptosis. Overall, these findings identify MTFR1L as a cardioprotective protein against myocardial I/R injury through a dual mechanism, providing new insights into the functional repertoire of MTFR1L beyond its previously recognized role in mitochondrial dynamics. Targeting MTFR1L or its interactors may offer novel therapeutic strategies for alleviating mitochondrial dysfunction and myocardial injury.

Mitochondrial damage is a pivotal driver of myocardial ischemia-reperfusion (MIR) injury. While PRKN (parkin RBR E3 ubiquitin protein ligase), a key E3 ubiquitin ligase in the PINK1 (PTEN induced kinase 1)-PRKN mitophagy pathway, has been extensively studied, its role and mechanisms in acute MIR injury remain incompletely understood. Here, we demonstrated that PRKN exacerbates MIR injury by promoting cardiomyocyte ferroptosis under hypoxia-reoxygenation (H/R) conditions. Mechanistically, PRKN interacts with and mediates the ubiquitination and proteasomal degradation of IMMT/MIC60 (inner membrane mitochondrial protein), a core mitochondrial inner membrane protein essential for cristae architecture and mitochondrial integrity. This disruption of IMMT facilitates lysosomal degradation of GPX4 (glutathione peroxidase 4), a major ferroptosis suppressor, thereby triggering ferroptosis. Consistent with these findings, cardiac-specific immt knockout mice displayed increased susceptibility to MIR injury in vivo. Our findings establish PRKN-driven IMMT degradation as a key pathological mechanism in MIR injury and identify the PRKN-IMMT axis as a potential therapeutic target for cardioprotection.Abbreviations: ATG5, autophagy related 5; ATP, adenosine triphosphate; CCCP, carbonyl cyanide m-chlorophenylhydrazone; CHX, cycloheximide; cKO, cardiomyocyte-specific knockout; CQ, chloroquine; CRISPR, clustered regularly interspaced short palindromic repeats; EF, ejection fraction; Fer-1, ferrostatin-1; FS, fractional shortening; GO, Gene Ontology; GPX4, glutathione peroxidase 4; GST, glutathione S-transferase; gRNA, guide RNA; hiPSC-CMs, human induced pluripotent stem cell-derived cardiomyocytes; H/R, hypoxia-reoxygenation; IF, immunofluorescence; IHC, immunohistochemistry; IMMT/MIC60, inner membrane mitochondrial protein; IP, immunoprecipitation; LoxP, locus of X-overP1; KO, knockout; KR, lysine residues mutated to arginine; MDA, malondialdehyde; MFN2, mitofusin 2; MIR, myocardial ischemia reperfusion; MMP, mitochondrial membrane potential; mPTP, mitochondrial permeability transition pore; mtROS, mitochondrial reactive oxygen species; NAC, N-acetylcysteine; OMM, outer mitochondrial membrane; PRKN, parkin RBR E3 ubiquitin protein ligase; RAB7, RAB7, member RAS oncogene family; RNA-seq, RNA sequencing; UB, ubiquitin; WB, western blot; WT, wild-type.

Objective:The aim of this study was to investigate the quantitative flow ratio (QFR) outcomes in the left circumflex artery (LCX) following the placement of a crossover stent from the left main coronary artery (LM) to the left anterior descending artery (LAD) in LM bifurcation lesions. In addition, we sought to assess the relationship between these QFR results and clinical prognoses. Background:The treatment approach for LM bifurcation lesions remains a topic of debate, with the LM-LAD single-stent technique being one possible option. QFR, a fractional flow reserve calculation method derived from angiography that does not require pressure guide wires, could serve as an alternative functional assessment of the LCX. This study aims to evaluate the clinical outcomes of postoperative LCX by utilizing QFR measurements, addressing a current gap in the relevant literature on this topic. Methods:This study was a retrospective, single-center analysis of patients with LM bifurcation lesions who underwent percutaneous coronary intervention (PCI) guided by intravascular ultrasound. QFR values were derived from angiographies. The primary endpoint was the 1-year rate of major adverse cardiac events, defined as a composite of cardiovascular death, target bifurcation-related myocardial infarction (MI), or target bifurcation revascularization. The secondary clinical endpoint was defined as the persistence or recurrence of angina pectoris after PCI. Results:We analyzed 91 patients from a total of 180 who were screened for LM bifurcation lesions. All patients completed the 1-year follow-up. The pre- and post-PCI QFR values were 0.89 ± 0.09 and 0.86 ± 0.11, respectively. Subgroup analysis showed that 74 patients were in the postoperative QFR ≥0.80 group, whereas 17 patients were in the QFR <0.80 group. In addition, 32 patients had a ΔQFR ≥0, and 58 patients had a ΔQFR <0. Nine patients (9.9%) achieved the primary endpoint, including one patient with non-ST elevation myocardial infarction who received revascularization in both the LM-LAD and LCX arteries. In addition, nine patients (9.9%) reported no substantial improvement in their chest pain symptoms. Post-LCX-QFR <0.8 was associated with a higher 1-year incidence of cardiovascular death or MI (P = 0.036). ΔQFR proved to be a robust predictor of the 1-year incidence of the primary endpoint, with an incidence of 15.3% in the ΔQFR ≥0 group compared to 0% in the ΔQFR <0 group (area under the curve: 0.822; 95% CI: 0.728-0.895, P < 0.001), especially when ΔQFR ≤-0.03. Conclusions:After the LM-LAD single-stent strategy for LM bifurcation lesions, a ΔQFR of LCX ≤-0.03 was associated with a higher risk of 1-year main adverse cardiac events, indicating the superior prognostic value of the post-PCI physiological assessment.

Limited research has been conducted on the short-term outcomes comparing laparoscopic pancreaticoduodenectomy (LPD) and robotic pancreaticoduodenectomy (RPD), particularly in the post-learning curve stage. This study aims to investigate surgical efficacy and provide clinical practices for selecting suitable techniques between LPD and RPD. A retrospective study was conducted on consecutive patients who underwent RPD and LPD between April 2016 and December 2023. Baseline characteristics, pathological information, and perioperative data were analyzed. Propensity score matching (PSM) analysis was performed to ensure the comparability of important factors between the groups. A total of 277 patients were enrolled in the study, of which 145 underwent RPD. Following PSM, 116 patients were included in each group and baseline characteristics were well matched. The RPD group demonstrated a lower conversion rate to laparotomy (5.2

Stereotactic body radiotherapy (SBRT) is superior to conventional radiotherapy for the treatment of lung tumors but can lead to radiation-induced heart damage (RIHD). Its risk factors have not been clarified. The purpose of our study was to determine the risk factors for early RIHD in patients undergoing pulmonary SBRT. We prospectively included patients who planned to receive pulmonary SBRT at our center from January 2020 to May 2021. Two-dimensional speckle tracking echocardiography was performed within 2 months after radiotherapy. The diagnostic criterion for early RIHD was a decrease in global longitudinal strain by ≥ 15

This is the first stage of the phase 1b/2 trial evaluating the effectiveness and safety of toripalimab, irinotecan, and bevacizumab in patients with rectal cancer refusing up-front surgery or radiation therapy (rectum cohort) and patients with T4NanyM0 colon cancer (colon cohort) with deficiency of mismatch repair (dMMR) or microsatellite instability (MSI). This trial allows a doctor-patient shared decision-making process to determine whether to omit irinotecan or bevacizumab and the optimal surgery timing. The primary endpoint pathological complete response (pCR) rates in the full analysis set (FAS) and per-protocol set (PPS) are 57.1% (95% confidence interval [CI] 28.9-82.3) and 66.7% (34.9-90.1), respectively, in the colon cohort (n = 14) and 75.0% (35.6-95.5) and 100% (51.7-100.0), respectively, in the rectum cohort (n = 8). No disease recurrence occurs in PPS. No grade 4-5 drug-related adverse events are observed. Toripalimab with or without irinotecan and bevacizumab shows promising efficacy and manageable toxicity in dMMR/MSI T4NanyM0 colon cancer and locally advanced rectal cancer (ClinicalTrials.gov: NCT04988191).

Anastomotic leakage (AL) is a serious complication that may occur following the double stapling technique (DST). The study aims to investigate the efficacy of anastomotic reinforcement using barbed sutures in preventing AL after laparoscopic low anterior resection (LAR) for rectal cancer. During the period from November 1, 2018 to November 1, 2023, a total of 725 consecutive patients who had underwent laparoscopic LAR for rectal cancer were enrolled in this study. The patients were divided into two groups: the continuous barbed suture reinforcement group (N = 296) and the control group (N = 429). Inter-group comparisons were used the chi-squared test, Fisher’s exact test, and nonparametric tests. Independent risk or protective factors for AL were analyzed using the multivariate logistic regression. Among the 725 patients enrolled in this study, 24 patients (3.3

Background:Acute ST-segment elevation myocardial infarction (STEMI) is characterized by a rapid inflammatory response, with mast cells (MCs) playing a significant role. However, the relationship between MC activation and the adverse outcomes remains unclear. This study investigated the association between the MC activation biomarker, tryptase, and major adverse cardiovascular events (MACE). Methods:This prospective study included patients with STEMI who underwent primary percutaneous coronary intervention (PPCI) at Peking University Third Hospital between July 2020 and July 2023. Tryptase levels were detected from plasma samples collected 6 hours post-PPCI and using ELISA method. All patients were followed up every 6 months, with MACE as the primary endpoint. Results:The study enrolled 514 patients with STEMI who underwent PPCI (mean age: 59.27 ± 13.26 years, 16.93% female). The median follow-up time was 13.28 (10.47-37.61) months, during which 85 patients (16.54%) experienced MACE. Patients in the higher tryptase group had a higher risk of MACE (HR 2.60 [1.68-4.01], P < 0.001). Tryptase was an independent risk factor of MACE (HR 1.56 [1.29-1.88] per 1-unit increase, P < 0.001). Subgroup analysis revealed the prognostic value of tryptase among different age groups, left ventricular ejection levels, and patients with hypertension, hyperlipidemia, smoking and diabetes. The addition of tryptase to the basic model had an incremental effect on the predictive value for MACE (AUC: 0.763 vs 0.702, P = 0.002). Conclusion:In this study, elevated tryptase levels, a biomarker of MC activation, were identified as a significant predictor of MACE in STEMI patients undergoing PPCI. Trial Registration:(ClinicalTrials.gov NCT05802667).

BackgroundPrevious studies have shown that pro-inflammatory diets increase the risk of coronary heart disease (CHD) and all-cause mortality. The dietary inflammatory index (DII) is a quantitative measure of dietary inflammation, and its accuracy has been validated by several studies.MethodsThis study included 43,842 participants aged ≥18 years from the National Health and Nutrition Examination Survey (NHANES) 1999–2018. The data of CHD was obtained through a questionnaire survey, and the DII was calculated using 24-h dietary recall data. Generalized linear models and logistic regression were used to determine the mediation factors, and subgroup analyses were conducted to evaluate the interaction between DII and CHD. Mean decrease in Gini (MDG) was used to determine the importance of individual dietary components.ResultsThe age of the participants was 49.81 ± 18.10 years, with 20,793 (47.4%) being male. A total of 1,892 (4.3%) participants were diagnosed with CHD, and the median DII score was 1.33 (0.11, 2.40). After adjusting for potential confounders, logistic regression analysis revealed that DII independently associated with CHD [OR: 1.049 (1.012–1.087), p = 0.008]. Triglyceride-glucose index, visceral adiposity index, body mass index, waist-to-height ratio, high-density lipoprotein, and glomerular filtration rate (all p < 0.05) may mediate the relationship between DII and CHD. Subgroup analyses showed that DII was more sensitive in participants aged <75 years (p < 0.001), females (p = 0.028), those with low cholesterol levels (p = 0.004), and individuals with low Framingham risk scores (p = 0.005). MDG analysis indicated that carbohydrate, vitamin C and iron intake have the greatest impact on CHD.ConclusionThis study suggests that various metabolic and lipid indicators play a mediating role in the relationship between DII and CHD. DII may have a greater adverse impact on traditional low-risk CHD populations.

Background The assessment of coronary function and microcirculation in patients with ST-segment elevation myocardial infarction (STEMI) may be useful to guide long-term prognosis, but the research is limited. This study aimed to investigate the value of angio-based fraction flow reserve (AccuFFR) and an index of microcirculatory resistance (AccuIMR) after percutaneous coronary intervention (PCI) for evaluating the long-term prognosis of STEMI patients. Methods Data of patients with STEMI who underwent PCI at Peking University Third Hospital between January 2017 and March 2022 were retrospectively analyzed. AccuFFR and AccuIMR were analyzed immediately after primary PCI. According to AccuFFR and AccuIMR, patients were classified into four groups: normal coronary function, macrovascular disorder, microvascular disorder, and mixed disorder. Results A total of 1297 patients were enrolled. The median follow-up time was 35 (24, 58) months. The risks of major adverse cardiovascular events (MACE), all-cause death, cardiovascular death and readmission for heart failure in the mixed disorder group were significantly higher than those in the other three groups (all P < 0.001). Both AccuFFR (hazard ratio [HR]: 0.948 per 0.01 increase, 95%CI: 0.914-0.983, P=0.004) and AccuIMR (HR: 1.018, 95%CI: 1.009-1.027, P<0.001) were independent predictors of MACE. A nomogram model was established to predict MACE after PCI in patients with STEMI at 1, 3, and 5 years. The ROC curve, C-index, and calibration curve showed that the model had high discrimination. Conclusion Coronary function and microcirculation assessment immediately after primary PCI are important in evaluating the prognosis of patients with STEMI. (Trial registration: NCT06435728)

Globally, totally laparoscopic total gastrectomy is increasingly being accepted by surgeons for the treatment of gastric cancer. Overlap anastomosis and π-shaped anastomosis are the two most commonly used anastomosis methods in total laparoscopic surgery; however, their safety and suitability for the population are still unclear. A total of 162 consecutive patients with gastric cancer who underwent total laparoscopic total gastrectomy with overlap or π-shaped anastomosis were retrospectively analyzed. The intraoperative conditions and postoperative complications were compared. A significant difference in the tumor location was found between the two groups (p < 0.05). No significant difference was found in the operation time, intraoperative blood loss, and postoperative hospital stay between the two anastomosis methods (p > 0.05); however, the π-shaped anastomosis group had more postoperative anastomotic leakage (p < 0.05). Overlap anastomosis is recommended as the preferred anastomosis for totally laparoscopic total gastrectomy, and π-shaped anastomosis can be applied to non-gastroesophageal junction cancer with lower tumor location.

BACKGROUND:The multicentre RESOLVE trial examined the efficacy of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in gastric or gastro-oesophageal junction cancer. Initial analyses did not encompass overall survival owing to the immature data. This paper provides an updated analysis of the survival data from the RESOLVE trial. METHODS:In this randomised, open-label, phase 3 study, participants aged 18 years or older with cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma who were feasible for D2 lymphadenectomy and had a Karnofsky performance score of 70 or higher were enrolled. Participants were randomly assigned in a 1:1:1 ratio via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day 1 of each 21-day cycle plus oral capecitabine 1000 mg/m2 twice a day on days 1-14, adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day 1 of each 21-day cycle plus oral S-1 40-60 mg twice a day on days 1-14), or perioperative SOX (intravenous oxaliplatin 130 mg/m2 on day 1 of each 21-day cycle plus oral S-1 40-60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy. The primary endpoint, assessed in the modified intention-to-treat population, was 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-CapOx and the non-inferiority (hazard ratio [HR] non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx, and has been reported previously. This final report focuses on the secondary endpoint of 5-year overall survival, also assessed in the modified intention-to-treat population. Other secondary endpoints-R0 resection rate and safety-were not updated in this analysis. The study is registered at ClinicalTrials.gov, NCT01534546, and is complete. FINDINGS:Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were enrolled and randomly assigned, of whom 1022 participants were included in the modified intention-to-treat population: 345 (259 male, 86 female) in the adjuvant-CapOx group, 340 (238 male, 102 female) in the adjuvant-SOX group, and 337 (271 male, 66 female) in the perioperative-SOX group. As of April 7, 2022, the median duration of follow-up was 62·8 months (IQR 52·0-75·1). The 5-year overall survival rates were 52·1% (95% CI 46·3-57·5) for the adjuvant-CapOx group, 61·0% (55·3-66·2) for the adjuvant-SOX group, and 60·0% (54·2-65·3), for the perioperative-SOX group. Overall survival was significantly prolonged with perioperative-SOX (HR 0·79; 95% CI 0·62-1·00, p=0·049) and adjuvant-SOX (HR 0·77, 0·61-0·98, p=0·033), compared with adjuvant-CapOx. INTERPRETATION:Consistent with the initial analysis of 3-year disease-free survival, the extended 5-year overall survival analysis from the RESOLVE trial confirmed the survival advantage of perioperative-SOX and adjuvant-SOX compared with the standard adjuvant-CapOx regimen. The SOX regimen, given perioperatively or as an adjuvant treatment, emerges as a potential standard treatment modality for locally advanced gastric or gastro-oesophageal junction cancer management in Asian patients. FUNDING:The National Key Research and Development Program of China, the National Natural Science Foundation of China, the Capital's Funds for Health Improvement and Research, the Beijing Natural Science Foundation, National Natural Science Foundation of China, the Beijing Natural Science Foundation, Taiho, Hengrui Pharmaceutical and Sanofi-Aventis. TRANSLATION:For the Chinese translation of the abstract see Supplementary Materials section.

BACKGROUND:Dilated cardiomyopathy (DCM) constitutes a major cause of heart failure, characterized by high mortality rates and a limited availability of effective therapeutic options. A substantial body of evidence indicates that mutations in the Nexilin (NEXN) gene are significant pathogenic contributors to DCM, but the pathogenic mechanism for dilated cardiomyopathy is unclear. METHODS:A human NEXN homozygous knockout cardiomyocyte model was established by combining CRISPR/Cas9 gene editing technology and human induced pluripotent stem cells (hiPSCs)-directed differentiation technology. Cell model phenotypic assays were done to characterize the pathological features of the resulting NEXN-deficient cardiomyocytes. RESULTS:NEXN gene knockout did not affect the pluripotency and differentiation efficiency of hiPSCs. NEXN-deficient cardiomyocytes showed disordered junctional membrane complexes, abnormal excitation-contraction coupling, increased oxidative stress and decreased energy metabolism level. Moreover, levo-carnitine and sarcoplasmic reticulum calcium ATPase (SERCA2a) Activator 1 were identified as promising therapeutic agents for the treatment of DCM. CONCLUSION:We demonstrated that NEXN was one of the important components in maintaining the structure and function of cardiomyocyte junctional membrane complexes (JMCs), excitation-contraction coupling and energy metabolism of cardiomyocytes, while the loss of its function would lead to DCM. This model represents an important tool to gain insight into the mechanism of DCM, elucidate the gene-phenotype relationship of NEXN deficiency and facilitate drug screening.

Background Laparoscopic surgery is increasingly used for rectal cancer, but the long-term oncological outcomes for low rectal cancer have not been fully established. We aimed to evaluate the 3-year survival outcomes of laparoscopic surgery versus open surgery in the treatment of low rectal cancer. Methods This multicentre, randomised, controlled, non-inferiority trial was conducted at 22 tertiary hospitals in China. Individuals aged 18-75 years with histologically confirmed cT1-2N0, cT3-4aN0, or cT1-4aN1-2 rectal adenocarcinoma within 5 cm from the dentate line were eligible for inclusion. Participants were randomly assigned (2:1) to undergo laparoscopic surgery or open surgery. Central randomisation was conducted using a web response system, and was stratified by clinical stage, age, sex, BMI, and American Society of Anesthesiologists classification. Investigators, patients and statisticians were not masked to group allocation. The primary outcome was 3-year disease-free survival, defined as the time from the date of surgery to the date of locoregional recurrence, distant metastasis, or death from any cause, whichever occurred first. Non-inferiority was defined as a lower limit of onesided 975% CI for group difference (laparoscopic surgery group minus open surgery group) of greater than -10%. The primary analyses were performed in the modified intention-to-treat population, which excluded patients with distant metastasis discovered during surgery and those who did not undergo surgery or underwent local resection only. The trial is registered with ClinicalTrials.gov, NCT01899547, and has been completed. Findings Between Nov 12, 2013, and June 6, 2018, 1070 patients were enrolled and randomly assigned to treatment. 1039 patients (685 in the laparoscopic surgery group and 354 in the open surgery group; median age 57 years, IQR 50 to 64; 620 [60%] male and 419 [40%] women) were included in the modified intention-to-treat analysis. 3-year disease-free survival was 814% (95% CI 782 to 841) in the laparoscopic surgery group and 798% (752 to 836) in the open surgery group (hazard ratio [HR] 092, 95% CI 069 to 123; p=056). The difference between groups was 160% (one-sided 975% CI -334 to infinity, p<00001 for non-inferiority). 3-year overall survival was 917% (95% CI 893 to 935) in the laparoscopic surgery group and 937% (906 to 958) in the open surgery group (HR 134, 95% CI 082 to 219; p=024). 3-year locoregional recurrence was 37% (95% CI 25 to 53) and 23% (11 to 43), respectively (HR 164, 95% CI 074 to 363; p=022). 5-year overall survival was 846% (95% CI 815 to 871) and 866% (825 to 898) in the open group (HR 116, 95% CI 082 to 164; p=041). Interpretation Laparoscopic surgery performed by experienced surgeons is non-inferior to open surgery for 3-year disease-free survival among patients with low rectal cancer. These results support the use of laparoscopic surgery for low rectal cancer. Funding The Key Clinical Specialty Discipline Construction Program of the National Health and Family Planning Commission of China; Minimally Invasive Medical Center Construction Program, Fujian Province, China; and Joint Funds for the Innovation of Science and Technology, Fujian Province, China. Copyright (c) 2024 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Radiation-induced heart damage (RIHD) has become an important factor affecting the long-term prognosis of cancer patients, and there are still no effective prevention or treatment measures. The purpose of this study was to evaluate the prevention and treatment effect of trimetazidine (TMZ) on early subclinical cardiac damage. We conducted a prospective, single-centre, randomized controlled study in the Department of Radiation Oncology of Peking University Third Hospital from May 2021 to April 2022. Patients who planned to receive pulmonary stereotactic body radiotherapy (SBRT) were randomly divided into a TMZ group and a control group. The TMZ group was treated with TMZ 2 weeks before SBRT (20 mg/time, 3 times a day, for 12 weeks). The control group received SBRT 2 weeks after admission. The primary outcomes were myocardial strain indices. Safety was analysed in all treated patients. We enrolled 73 patients, of whom 36 were assigned to the TMZ group and 37 to the control group. One patient in each of the two groups was lost to follow-up. The main outcome index, global longitudinal strain (GLS), was better in the TMZ group than the control group (-11.8 ± 3.7% vs. -10.1 ± 3.4%, P=0.042). There was no significant difference between the two groups in any secondary outcome indicators, including cardiac injury markers, cardiac structure, left ventricular ejection fraction and diastolic function indices. No drug-related adverse reactions occurred. In patients who plan to undergo pulmonary SBRT, TMZ can improve the myocardial strain parameter GLS after pulmonary SBRT, suggesting that TMZ has preventive and therapeutic effects on RIHD. Trial registration: ClinicalTrials.gov: NCT04939857 (25/06/2021).

Purpose To investigate whether the mixed approach is a safe and advantageous way to operate laparoscopic right hemicolectomy. Methods A retrospective study was performed on 316 patients who underwent laparoscopic right hemicolectomy in our center. They were assigned to the middle approach group (n = 158) and the mixed approach group (n = 158) according to the surgical approaches. The baseline data like gender,age and body mass index as well as the intraoperative and postoperative conditions including operation time, blood loss, postoperative hospital stay and complications were analyzed. Results There were no significant differences in age, sex, BMI, ASA grade and tumor characteristics between the two groups. Compared with the middle approach group, the mixed approach group was significantly lower in terms of operation time (217.61 min vs 154.31 min, p < 0.001), intraoperative blood loss (73.8 ml vs 37.97 ml, p < 0.001) and postoperative drainage volume. There was no significant difference in the postoperative complications like postoperative anastomotic leakage, postoperative infection and postoperative intestinal obstruction. Conclusions Compared with the middle approach, the mixed approach is a safe and advantageous way that can significantly shorten the operation time, reduce intraoperative bleeding and postoperative drainage volume, and does not prolong the length of hospital stay or increase the morbidity postoperative complications.