Left Ventricular Vertical Run-Length Nonuniformity MRI Adds Prognostic Value to MACE in Patients with End-Stage Renal Disease.

BACKGROUND: Vertical run-length nonuniformity (VRLN) is a texture feature representing heterogeneity within native T1 images and reflects the extent of cardiac fibrosis. In uremic cardiomyopathy, interstitial fibrosis was the major histological alteration. The prognostic value of VRLN in patients with end-stage renal disease (ESRD) remains unclear. PURPOSE: To evaluate the prognostic value of VRLN MRI in patients with ESRD. STUDY TYPE: Prospective. POPULATION: A total of 127 ESRD patients (30 participants in the major adverse cardiac events, MACE group). FIELD STRENGTH/SEQUENCE: 3.0 T/steady-state free precession sequence, modified Look-Locker imaging. ASSESSMENT: MRI image qualities were assessed by three independent radiologists. VRLN values were measured in the myocardium on the mid-ventricular short-axis slice of T1 mapping. Left ventricular (LV) mass, LV end-diastolic and end-systolic volume, as well as LV global strain cardiac parameters were measured. STATISTICAL TESTS: The primary endpoint was the incident of MACE from enrollment time to January 2023. MACE is a composite endpoint consisting of all-cause mortality, acute myocardial infarction, stroke, heart failure hospitalization, and life-threatening arrhythmia. Cox proportional-hazards regression was performed to test whether VRLN independently correlated with MACE. The intraclass correlation coefficients of VRLN were calculated to evaluate intraobserver and interobserver reproducibility. The C-index was computed to examine the prognostic value of VRLN. P-value <0.05 were considered statistically significant. RESULTS: Participants were followed for a median of 26 months. VRLN, age, LV end-systolic volume index, and global longitudinal strain remained significantly associated with MACE in the multivariable model. Adding VRLN to a baseline model containing clinical and conventional cardiac MRI parameters significantly improved the accuracy of the predictive model (C-index of the baseline model: 0.781 vs. the model added VRLN: 0.814). DATA CONCLUSION: VRLN is a novel marker for risk stratification toward MACE in patients with ESRD, superior to native T1 mapping and LV ejection fraction. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY STAGE: 2.

Prognostic significance of non-infarcted myocardium correlated with microvascular impairment evaluated dynamically by native T1 mapping.

OBJECTIVES: This study aimed to investigate the influence of microvascular impairment on myocardial characteristic alterations in remote myocardium at multiple time points, and its prognostic significance after acute ST-segment elevation myocardial infarction (STEMI). METHODS: Patients were enrolled prospectively and performed CMR at baseline, 30 days, and 6 months. The primary endpoint was major adverse cardiac events (MACE): death, myocardial reinfarction, malignant arrhythmia, and hospitalization for heart failure. Cox proportional hazards regression modeling was analyzed to estimate the correlation between T1 mapping of remote myocardium and MACE in patients with and without microvascular obstruction (MVO). RESULTS: A total of 135 patients (mean age 60.72 years; 12.70% female, median follow-up 510 days) were included, of whom 86 (63.70%) had MVO and 26 (19.26%) with MACE occurred in patients. Native T1 values of remote myocardium changed dynamically. At 1 week and 30 days, T1 values of remote myocardium in the group with MVO were higher than those without MVO (p = 0.030 and p = 0.001, respectively). In multivariable cox regression analysis of 135 patients, native1w T1 (HR 1.03, 95%CI 1.01-1.04, p = 0.002), native30D T1 (HR 1.05, 95%CI 1.03-1.07, p < 0.001) and LGE (HR 1.10, 95%CI 1.05-1.15, p < 0.001) were joint independent predictors of MACE. In multivariable cox regression analysis of 86 patients with MVO, native30D T1 (HR 1.05, 95%CI 1.04-1.07, p < 0.001) and LGE (HR 1.10, 95%CI 1.05-1.15, p < 0.001) were joint independent predictors of MACE. CONCLUSIONS: The evolution of native T1 in remote myocardium was associated with the extent of microvascular impairment after reperfusion injury. In patients with MVO, native30D T1 and LGE were joint independent predictors of MACE.

Efficacy and safety of anastomotic leak testing in gastric cancer: a randomized controlled trial.

BACKGROUND: Anastomosis-related complications such as bleeding, leakage, and strictures, continue to be serious complications of gastric cancer surgery. Presently, these complications have yet to be reliably prevented. Here we design a comprehensive leak testing procedure which combines gastroscopy, air, and methylene blue (GAM) leak testing. We aimed to evaluated the efficacy and safety of the GAM procedure in patients with gastric cancer. METHODS: Patients aged 18-85 years without an unresectable factor as confirmed via CT were enrolled in a prospective randomized clinical trial at a tertiary referral teaching hospital and were randomly assigned to two groups: intraoperative leak testing group (IOLT) and no intraoperative leak testing group (NIOLT). The primary endpoint was the incidence of postoperative anastomosis-related complications in the two groups. RESULTS: 148 patients were initially randomly assigned to the IOLT group (n = 74) and to the NIOLT group (n = 74) between September 2018 and September 2022. After exclusions, 70 remained in the IOLT group and 68 in the NIOLT group. In the IOLT group, 5 patients (7.1%) were found to have anastomotic defects intraoperatively, which included anastomotic discontinuity, bleeding, and strictures. The NIOLT group had a higher incidence of postoperative anastomotic leakage compared to the IOLT group: 4 patients (5.8%) vs 0 patients (0%), respectively. No GAM-related complications were observed. CONCLUSION: The GAM procedure is an intraoperative leak test that can be performed safely and efficiently after a laparoscopic total gastrectomy. GAM anastomotic leak testing may effectively prevent technical defect-related anastomotic complications in patients with gastric cancer who undergo a gastrectomy. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT04292496.

Using Multi-model Diffusion Weighted Imaging to Study Acute Kidney Injury in Patients with Acute Pancreatitis.

OBJECTIVE: To explore the diagnostic value and severity of acute kidney injury (AKI) in patients with acute pancreatitis (AP) using intravoxel incoherent motion imaging (IVIM), diffusion tensor imaging (DTI), and diffusion kurtosis imaging (DKI). METHODS: 224 AP patients, categorized into either the AKI group or the non-AKI group, were retrospectively analyzed in this study. MRI sequences included routine abdominal, IVIM, DTI, and DKI scans, and the main MRI parameters of kidney imaging and clinical characteristics were measured. The diagnostic performance of AKI was compared, and the relationships among these indices, glomerular filtration rate (eGFR), and AKI staging were analyzed. Finally, all parameters were analyzed by single and multi-parameter regression. RESULTS: Compared with the non-AKI group, the fast apparent diffusion coefficient (ADC) value and perfusion fraction (Ff ADC) value of the renal medulla in the AKI group were significantly lower than those in the non-AKI group. The fractional anisotropy (FA) value in the renal cortex was significantly lower than that in the medulla and significantly lower than in the non-AKI group. Lastly, the renal medulla mean kurtosis (MK) value was also significantly lower in the AKI group compared to the non- AKI group and exhibited the best diagnostic value for AKI in AP patients. The renal medulla MK value positively correlated with AKI staging and negatively correlated with eGFR. The MK value was an independent risk factor for AKI, as evidenced by multi-parameter logistic regression analysis. CONCLUSION: The measurement of renal DKI parameters is practical for diagnosing and predicting the severity of acute kidney injury in AP patients.

Inhibition of the HEG1-KRIT1 interaction increases KLF4 and KLF2 expression in endothelial cells.

The transmembrane protein heart of glass1 (HEG1) directly binds to and recruits Krev interaction trapped protein 1 (KRIT1) to endothelial junctions to form the HEG1-KRIT1 protein complex that establishes and maintains junctional integrity. Genetic inactivation or knockdown of endothelial HEG1 or KRIT1 leads to the upregulation of transcription factors Krüppel-like factors 4 and 2 (KLF4 and KLF2), which are implicated in endothelial vascular homeostasis; however, the effect of acute inhibition of the HEG1-KRIT1 interaction remains incompletely understood. Here, we report a high-throughput screening assay and molecular design of a small-molecule HEG1-KRIT1 inhibitor to uncover acute changes in signaling pathways downstream of the HEG1-KRIT1 protein complex disruption. The small-molecule HEG1-KRIT1 inhibitor 2 (HKi2) was demonstrated to be a bona fide inhibitor of the interaction between HEG1 and KRIT1 proteins, by competing orthosterically with HEG1 through covalent reversible interactions with the FERM (4.1, ezrin, radixin, and moesin) domain of KRIT1. The crystal structure of HKi2 bound to KRIT1 FERM revealed that it occupies the same binding pocket on KRIT1 as the HEG1 cytoplasmic tail. In human endothelial cells (ECs), acute inhibition of the HEG1-KRIT1 interaction by HKi2 increased KLF4 and KLF2 mRNA and protein levels, whereas a structurally similar inactive compound failed to do so. In zebrafish, HKi2 induced expression of klf2a in arterial and venous endothelium. Furthermore, genome-wide RNA transcriptome analysis of HKi2-treated ECs under static conditions revealed that, in addition to elevating KLF4 and KLF2 expression, inhibition of the HEG1-KRIT1 interaction mimics many of the transcriptional effects of laminar blood flow. Furthermore, HKi2-treated ECs also triggered Akt signaling in a phosphoinositide 3-kinase (PI3K)-dependent manner, as blocking PI3K activity blunted the Akt phosphorylation induced by HKi2. Finally, using an in vitro colocalization assay, we show that HKi6, an improved derivative of HKi2 with higher affinity for KRIT1, significantly impedes recruitment of KRIT1 to mitochondria-localized HEG1 in CHO cells, indicating a direct inhibition of the HEG1-KRIT1 interaction. Thus, our results demonstrate that early events of the acute inhibition of HEG1-KRIT1 interaction with HKi small-molecule inhibitors lead to: (i) elevated KLF4 and KLF2 gene expression; and (ii) increased Akt phosphorylation. Thus, HKi's provide new pharmacologic tools to study acute inhibition of the HEG1-KRIT1 protein complex and may provide insights to dissect early signaling events that regulate vascular homeostasis.

Fangchinoline exerts anticancer effects on colorectal cancer by inducing autophagy via regulation AMPK/mTOR/ULK1 pathway.

Autophagy has become a promising target for cancer therapy. Fangchinoline (Fan) has been shown to exert anticancer effects in some types of cancers. However, the anticancer effects on colorectal cancer (CRC) and the underlying mechanisms have never been elucidated. More specifically, regulation of autophagy in CRC by Fan has never been reported before. In the present study, Fan was found to induce apoptosis and autophagic flux in the CRC cell lines HT29 and HCT116, which was reflected by the enhanced levels of LC3-II protein and p62 degradation, and the increased formation of autophagosomes and puncta formation by LC3-II. Meanwhile, combination with the early-stage autophagy inhibitor 3-methyladenine (3-MA) but not the late-stage autophagy inhibitor chloroquine (CQ) further increased Fan-induced cell death, which suggested the cytoprotective function of autophagy induced by Fan in both HT29 and HCT116 cells. Moreover, Fan treatment demonstrated a dose- and time-dependently increase in the phosphorylation of AMPK and decrease in the phosphorylation of mammalian target of rapamycin (mTOR) and ULK1, leading to the activation of the AMPK/mTOR/ULK1 signaling pathway. Furthermore, in the HT29 xenograft model, Fan inhibited tumor growth in vivo. These results indicate that Fan inhibited CRC cell growth both in vitro and in vivo and revealed a new molecular mechanism involved in the anticancer effect of Fan on CRC, suggesting that Fan is a potent autophagy inducer and might be a promising anticancer agent.