USP29 activation mediated by FUBP1 promotes AURKB stability and oncogenic functions in gastric cancer.

BACKGROUND: Gastric cancer is a highly prevalent cancer type and the underlying molecular mechanisms are not fully understood. Ubiquitin-specific peptidase (USP) 29 has been suggested to regulate cell fate in several types of cancer, but its potential role in gastric carcinogenesis remains unclear. METHODS: The expression of USP29 in normal and gastric cancer tissues was analyzed by bioinformatics analysis, immunohistochemistry and immunoblot. Gene overexpression, CRISPR-Cas9 technology, RNAi, and Usp29 knockout mice were used to investigate the roles of USP29 in cell culture, xenograft, and benzo[a]pyrene (BaP)-induced gastric carcinogenesis models. We then delineated the underlying mechanisms using mass spectrometry, co-immunoprecipitation (Co-IP), immunoblot, ubiquitination assay, chromatin immunoprecipitation (ChIP), quantitative real-time PCR (qRT-PCR), and luciferase assays. RESULTS: In this study, we found that USP29 expression was significantly upregulated in gastric cancers and associated with poor patient survival. Ectopic expression of USP29 promoted, while depletion suppressed the tumor growth in vitro and in vivo mouse model. Mechanistically, transcription factor far upstream element binding protein 1 (FUBP1) directly activates USP29 gene transcription, which then interacts with and stabilizes aurora kinase B (AURKB) by suppressing K48-linked polyubiquitination, constituting a FUBP1-USP29-AURKB regulatory axis that medicates the oncogenic role of USP29. Importantly, systemic knockout of Usp29 in mice not only significantly decreased the BaP-induced carcinogenesis but also suppressed the Aurkb level in forestomach tissues. CONCLUSIONS: These findings uncovered a novel FUBP1-USP29-AURKB regulatory axis that may play important roles in gastric carcinogenesis and tumor progression, and suggested that USP29 may become a promising drug target for cancer therapy.

Novel Sprayable Antioxidative Dressing Based on Fullerene and Curdlan for Accelerating Chronic Wound Healing.

The effective treatment of chronic wounds represents a critical global medical challenge demanding urgent attention. Persistent inflammation, driven by an excess of reactive oxygen radicals, sets in motion a detrimental cycle leading to chronic wounds and impeding the natural healing process. This study develops a sprayable wound dressing by covalently grafting amino fullerene to carboxymethylated curdlan (CMC-C). This novel dressing exhibits excellent biocompatibility, antioxidant, and reactive oxygen species scavenging properties. Furthermore, it demonstrates a targeted affinity for HEK-a cells, efficiently reducing the inflammatory response while promoting cell proliferation and migration in vitro. Moreover, the animal experiment investigations reveal that CMC-C significantly accelerates chronic wounds healing by regulating the inflammatory process, promoting collagen deposition, and improving vascularization. These results demonstrate the potential of the sprayable dressing (CMC-C) in curing the healing of chronic wounds through the modulation of the inflammatory microenvironment. Overall, the sprayable hydrogel dressing based on water-soluble derivative of fullerene and curdlan emerges as a potential approach for clinical applications in the treatment of chronic wounds.

A brain-wide genome-wide association study of candidate quantitative trait loci associated with structural and functional phenotypes of pain sensitivity.

Individual pain sensitivity is modulated by the brain's structural and functional features, but its heritability remains unclear. This paper conducted a brain-wide genome-wide association study (GWAS) to explore the genetic bases of neuroimage phenotypes of pain sensitivity. In total, 432 normal participants were divided into high and low pain sensitivity groups according to the laser quantitative test threshold. Then, the brain's gray matter density (GMD) features correlated with pain sensitivity were identified. Next, GWAS was performed on each GMD phenotype using quality-controlled genotypes. Based on the heatmap and hierarchical clustering results, the right insula was identified for further refined analysis in terms of subregions GMD and resting-state functional connectivity (rs-FC) phenotypes. The results indicate that the right insula GMD in the high sensitivity group is significantly lower than that in the low sensitivity group. Also, the TT/TC group at locus rs187974 has lower right insula GMD than the CC group. Further, loci at gene CYP2D6 may lead to a variation of rs-FC between the right insula and left putamen. In conclusion, our study suggests that the right insula and multiple candidate loci may be importantly involved in pain sensitivity modulation, which may guide the future development of precision pain therapeutics.

Clinical Features and Outcomes of Long-Term Lead Performance by Left Bundle Branch Pacing.

Left bundle branch pacing (LBBP) is an emerging physiological pacing technique that expanded in recent reports. The long-term safety and feasibility of LBBP lack adequate evaluation.The study aimed to evaluate the long-term lead performance and clinical outcomes of LBBP.We retrospectively enrolled 123 consecutive patients scheduled for LBBP implantation from January to December 2018. The pacing parameters, electrocardiograms, echocardiographic measurements, and complications associated with LBBP were tracked at implant and follow-up.LBBP was successfully performed in 110 of 123 (89.4%) patients. Left ventricular end-diastolic dimension (LVEDd) and left ventricular ejection fraction (LVEF) improved from baseline in patients with reduced LVEF (n = 29; LVEDd, 55.6 ± 8.1 mm versus 63.4 ± 4.9 mm, P < 0.001; LVEF, 51.6% ± 13.6% versus 33.7% ± 5.5%, P < 0.001) while no significant change was found in patients with preserved LVEF (n = 81; LVEDd, 49.6 ± 12.0 mm versus 51.2 ± 6.0 mm, P = 0.38; LVEF, 65.8% ± 7.9% versus 65.8% ± 7.3%, P = 0.99). In seven patients, LBBP lead protuberance into the LV cavity was observed, with a mean distance between the screw tip and the LV septum of 3.0 ± 0.8 mm (range from 1.8 to 3.9 mm). The LBBP parameters remained stable.LBBP is a novel physiological, safe, and effective pacing technique for patients with atrioventricular block. Lower BMI, diabetes and thinner interventricular septum (IVS) thickness are associated with mechanical complications.

Metabolomic and transcriptomic studies of improvements in myocardial infarction due to Pycr1 deletion.

Myocardial infarction (MI) remains a major challenge to cardiovascular health worldwide, with poor healing leaving a direct impact on patients' quality of life and survival. Metabolic abnormalities after MI are receiving increasing attention. Our previous studies showed that enhancing proline catabolism ameliorates hypoxic damage to myocardial cells; therefore, we sought to determine whether reducing the synthesis of endogenous proline also affects MI. We analysed GEO datasets associated with MI and western blot of mouse heart tissue in an MI model to demonstrate pyrroline-5-carboxylate reductase 1 (Pycr1) expression level after MI. We constructed Pycr1 KO mice by CRISPR/Cas9 technology to explore the effect of Pycr1 gene KO after MI using transcriptomic and metabolomic techniques. In this study, we found reduced mRNA and protein expression levels of Pycr1 in the hearts of mice after MI. We observed that Pycr1 gene KO has a protective effect against MI, reducing the area of MI and improving heart function. Using transcriptomics approaches, we found 215 upregulated genes and 247 downregulated genes after KO of the Pycr1 gene, indicating that unsaturated fatty acid metabolism was affected at the transcriptional level. Metabolomics results revealed elevated content for 141 metabolites and decreased content for 90 metabolites, among which the levels of fatty acids, glycerol phospholipids, bile acids, and other metabolites increased significantly. The changes in these metabolites may be related to the protective effect of Pycr1 KO on the heart after MI. Pycr1 gene KO has a protective effect against MI and our research will lay a solid foundation for the development of future Pycr1-related drug targets.

Neglected immunoregulation: M2 polarization of macrophages triggered by low-dose irradiation plays an important role in bone regeneration.

Current studies have found that low-dose irradiation (IR) can promote bone regeneration. However, mechanism studies of IR-triggered bone regeneration mainly focus on the effects of osteoblasts, neglecting the role of the surrounding immune microenvironment. Here in this study, in vitro proliferation experiments showed that low-dose IR ≤2 Gy could promote the proliferation of bone marrow mesenchymal stem cells (BMSCs), and qRT-PCR assay showed that low-dose IR ≤2 Gy could exert the M2 polarization of Raw264.7 cells, while IR >2 Gy inhibited BMSC proliferation and triggered M1 polarization in Raw264.7 cells. The ALP and mineralized nodules staining showed that low-dose IR ≤2 Gy not only promoted osteoblast mineralization through IR-triggered osteoblast proliferation but also through M2 polarization of Raw264.7 cells, while high-dose IR >2 Gy had the opposite effect. The co-incubation of BMSC with low-dose IR irradiated Raw264.7 cell supernatants increased the mRNA expression of BMP-2 and Osx. The rat cranial defects model revealed that low-dose IR ≤2 Gy gradually promoted bone regeneration, while high-dose IR >2 Gy inhibited bone regeneration. Detection of macrophage polarity in peripheral blood samples showed that low-dose IR ≤2 Gy increased the expression of CD206 and CD163, but decreased the expression of CD86 and CD80 in macrophages, which indicated M2 polarization of macrophages in vivo, while high-dose IR had the opposite effect. Our finding innovatively revealed that low-dose IR ≤2 Gy promotes bone regeneration not only by directly promoting the proliferation of osteoblasts but also by triggering M2 polarization of macrophages, which provided a new perspective for immune mechanism study in the treatment of bone defects with low-dose IR.

Current Opinions on New-Onset Left Bundle Branch Block after Transcatheter Aortic Valve Replacement and the Search for Physiological Pacing.

Transcatheter aortic valve replacement possesses a high validity for patients with aortic stenosis who are considered high risk for aortic valve replacement surgery, nowadays it is also considered for patients with intermediate risk or even lower risk in certain situations. The incidence of new conduction abnormalities remains to be a tough problem, in particular, left bundle branch block. New-onset left bundle branch block is a major concern despite improvements in valve technology, and it may affect postoperative prognosis. Understanding the anatomical relationship between the conduction system and the aortic root, clarify factors related to the procedure, devices, and patients, might help to reduce the conduction abnormalities. Physiological pacing has emerged as a reasonable pacing strategy for patients with cardiac insufficiency post-valve replacement, especially combined with left bundle branch block. The purpose of this review is to summarize the current opinion on the incidence of new-onset left bundle branch block associated with transcatheter aortic valve replacement, to offer insights into its anatomical and procedural causes, clinical consequences, and more importantly, the prospect of applying physiological pacing as a therapeutic method for these patients.

Timing matters: there are significant differences in short-term outcomes between two time points of status epilepticus.

BACKGROUND: In 2015, the International League Against Epilepsy proposed a new conceptual definition of status epilepticus (SE) with two operational dimensions (t1 and t2) to guide emergency treatment. The purpose of this study was to compare clinical characteristics and prognoses of patients at these two different time points. METHODS: We conducted a prospective observational cohort study of consecutive adults diagnosed with SE. In case of convulsive SE, t1 is 5 min and t2 is 30 min, whereas in case of focal SE with impaired consciousness, t1 is 10 min, t2 is 60 min. Data on clinical characteristics, including age, gender, history of prior seizures, neuroimaging, semiology, duration, and etiology of SE, were collected. The primary outcome was mortality, with seizure recurrence as a secondary measure, and functional status as tertiary outcome of enrolled patients at 3 months after SE onset. RESULTS: We screened one hundred patients with SE, with a median age of 66 years and 61% were male. Fifty-six (56.0%) patients reached t1 of SE, while 44 (44.0%) reached t2 of SE. Convulsive SE (52.0%, n = 52) was more common than focal SE with impaired consciousness (48.0%, n = 48). Status epilepticus secondary to an acute symptomatic process was the most common (50%, n = 50). Patients meeting t2 of SE demonstrated a remarkably increased risk of mortality (unadjusted analysis-RR 3.606, 95%CI 1.552-8.376, p = 0.003; adjusted analysis-RR 2.924, 95%CI 1.221-7.003, p = 0.016) and unfavorable functional status (unadjusted analysis-RR 1.803, 95%CI 1.280-2.539, p = 0.001; adjusted analysis-RR 1.664, 95%CI 1.184-2.340, p = 0.003) at 3 months compared to those who only reached t1 of SE. Patients reaching t2 of SE were more likely to experience seizure recurrence, however, there was no significant difference between the two cohorts. CONCLUSIONS: Our study provides strong support for the new definition of SE. Patients meeting t2 of SE tend to have a remarkably increased risk of mortality and unfavorable functional outcomes compared to those who only reached t1 of SE. Furthermore, patients were likely to experience seizure recurrence after undergoing an episode of SE. Physicians must be educated about prompt recognition and appropriate management of SE.

Preliminary experience of permanent left bundle branch area pacing using stylet-directed pacing lead without delivery sheath.

BACKGROUND: Left bundle branch area pacing (LBBAP) aims to capture the cardiac conduction system in area of the left bundle branch. Currently, LBBAP is mainly performed using lumen-less pacing leads (LLLs) with preshaped sheath. However, the data on LBBAP with stylet-driven leads (SDLs) without sheath is limited. OBJECTIVE: This study presents the feasibility, safety, and pacing characteristics of LBBAP using SDLs without the support of sheath. METHODS: A total of 25 patients with bradycardia indications who received LBBAP implantation with an attempt of SDL (FINELINE II 4471 lead, Boston Scientific, MA, US) between August 2020 and April 2021 at Sir Run Run Shaw Hospital were included in this retrospective cohort study. Twenty of them finally were paced with SDL in priority (SDL-LBBAP group). Twenty propensity score matching patients who underwent LBBAP with LLL (Select Secure 3830 lead, Medtronic, MN, US) and 20 right ventricular septal pacing (RVSP) with regular active fixation lead respectively in the same period (the LLL-LBBAP group and RVSP group) were compared using ECG characteristics, pacing parameters and complications during 6-month follow-up. RESULTS: LBBAP was successful with SDL in 23 of 25 patients (92%) and 20 of them were paced with SDL first. In the SDL-LBBAP group, the average age was 70.4 ± 8.2 years, and 55% of patients were male. Paced QRS duration and the stimulus to peak left ventricular activation time (Sti-LVAT) in SDL-LBBAP group were similar with those in LLL-LBBAP group and significantly shorter than those in RVSP group (126.1±14.1 ms vs. 124.8±10.9 ms, p = 1.00; 77.7 ± 11.2 ms vs. 73.5 ± 9.3 ms, P = .75; 126.1 ± 14.1 ms vs. 147.7 ± 22.5 ms, P<.001; 77.7 ± 11.2 ms vs. 97.0 ± 13.2 ms, P<.001). The pacing threshold and R-wave amplitude of SDL-LBBAP group were 0.53 ± 0.18V and 11.53 ± 3.63 mV at baseline respectively, which were comparable with the other two groups. During the 6-month follow-up, the pacing parameters remained stable and no lead-related complications were recorded. CONCLUSION: It is feasible and safe to use stylet-directed pacing lead for permanent LBBAP without a delivery sheath. Similar to LLL, LBBAP using SDL showed stable parameters and narrower paced QRS duration compared with RVSP, which could be an alternative to LLL in LBBAP.

Comparison of synchronization between left bundle branch and his bundle pacing in atrial fibrillation patients: An intra-patient-controlled study.

BACKGROUND: His bundle pacing (HBP) is a physiological pacing strategy to preserve the electrical synchrony of ventricular conduction and left ventricular (LV) function. Left bundle branch pacing (LBBP) has emerged as an alternative physiological pacing technique. OBJECTIVE: To evaluate cardiac electrical and mechanical synchrony comparing LBBP and HBP in patients with permanent atrial fibrillation (AF). METHODS: Consecutive patients with symptomatic bradycardia and AF were enrolled from January to June of 2019. The cardiac electrical and mechanical synchrony in different pacing mode were evaluated at baseline and after implantation. RESULTS: Both HBP and LBBP were performed in 20 patients. LBBP significantly widened the QRS duration compared with the intrinsic conduction (113.2 ± 14.5  vs. 96.5 ± 16.2 ms; p = .01), while HBP did not (104.5 ± 22.3  vs. 96.5 ± 16.2 ms; p = .12). Both LBBP and HBP patients had similar LV myocardial strain measurements for the mechanical synchrony evaluation without significant change compared with baseline. There was no significant difference in right ventricular synchrony measurement between LBBP and HBP. Compared to HBP, LBBP had less interventricular synchrony (IMVD, 14.7 ± 9.2  vs. 3.1 ± 12.7 ms, p < .01; Ts-LV-RV, 37.9 ± 10.7  vs. 18.5 ± 10.8 ms, p < .001). CONCLUSIONS: Although LBBP's a physiological pacing mode can achieve a similar cardiac electrical and mechanical synchronization when compared to HBP, LBBP results in modest delay in RV activation, and the clinical implication remains to be studied.