Atrial-selective block of sodium channels by acehytisine in rabbit myocardium

AbstractAcehytisine, a multi-ion channel blocker, can markedly inhibit INa, ICa, IKur, If at various concentrations and effectively terminate and prevent atrial fibrillation (AF) in patients and animal models, but the molecular mechanism underlying its blockage remains elusive. In this study, we investigated the effects of acehytisine on action potentials and sodium channels of atrial and ventricular myocytes isolated from rabbit, using whole-cell recording system. We found that acehytisine exerted stronger blocking effects on sodium channels in atria than in ventricles, especially at depolarization (IC50: 48.48 ± 7.75 μmol/L in atria vs. 560.17 ± 63.98 μmol/L in ventricles). It also significantly shifted steady state inactivation curves toward negative potentials in atrial myocytes, without affecting the recovery kinetics from inactivation of sodium channels in the same cells. In addition, acehytisine inhibited INa in a use-dependent manner and regulated slow inactivation kinetics by different gating configurations. These findings indicate that acehytisine selectively blocks atrial sodium channels and possesses affinity to sodium channel in certain states, which provides additional evidence for the anti-AF of acehytisine

Identification and validation of a gap junction protein related signature for predicting the prognosis of renal clear cell carcinoma

BackgroundGap junction proteins (GJPs) are a class of channel proteins that are closely related to cell communication and tumor development. The objective of this study was to screen out GJPs related prognostic signatures (GRPS) associated with clear cell renal cell carcinoma (ccRCC).Materials and MethodsGJPs microarray data for ccRCC patients were obtained from The Gene Expression Omnibus (GEO) database, along with RNA sequencing data for tumor and paired normal tissues from The Cancer Genome Atlas (TCGA) database. In the TCGA database, least absolute shrinkage and selection Operator (LASSO) and Cox regression models were used to identify GJPs with independent prognostic effects as GRPS in ccRCC patients. According to the GRPS expression and regression coefficient from the multivariate Cox regression model, the risk score (RS) of each ccRCC patient was calculated, to construct the RS prognostic model to predict survival. Overall survival (OS) and progression-free survival (PFS) analyses; gene pan-cancer analysis; single gene survival analysis; gene joint effect analysis; functional enrichment analysis; tumor microenvironment (TME) analysis; tumor mutational burden (TMB) analysis; and drug sensitivity analysis were used to explore the biological function, mechanism of action and clinical significance of GRPS in ccRCC. Further verification of the genetic signature was performed with data from the GEO database. Finally, the cytofunctional experiments were used to verify the biological significance of GRPS associated GJPs in ccRCC cell lines.ResultsGJA5 and GJB1, which are GRPS markers of ccRCC patients, were identified through LASSO and Cox regression models. Low expression of GJA5 and GJB1 is associated with poor patient prognosis. Patients with high-RS had significantly shorter OS and PFS than patients with low-RS (p< 0.001). The risk of death for individuals with high-RS was 1.695 times greater than that for those with low-RS (HR = 1.695, 95%CI= 1.439-1.996, p< 0.001). Receiver Operating Characteristic (ROC) curve showed the great predictive power of the RS prognostic model for the survival rate of patients. The area under curve (AUC) values for predicting 1-year, 3-year and 5-year survival rates were 0.740, 0.781 and 0.771, respectively. The clinical column chart was also reliable for predicting the survival rate of patients, with AUC values of 0.859, 0.846 and 0.796 for predicting 1-year, 3-year and 5-year survival, respectively. The GRPS was associated with immune cell infiltration, the TME, the TMB, and sensitivity to chemotherapy drugs. Further in vitro experiments showed that knockdown of GJA5 or GJB1 could promote the proliferation, migration and epithelial-mesenchymal transition (EMT) and inhibit apoptosis of ccRCC cells.ConclusionGJA5 and GJB1 could be potential biological markers for predicting survival in patients with ccRCC

The clinical outcome of pembrolizumab for patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a single center, real world study in China

BackgroundThe KEYNOTE-048 and KEYNOTE-040 study have demonstrated the efficacy of pembrolizumab in recurrent or metastatic squamous cell carcinoma of the head and neck (R/M HNSCC), we conducted this real-world study to investigate the efficacy of pembrolizumab in patients with R/M HNSCC.MethodsThis is a single-center retrospective study conducted in the Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Shanghai, China). Between December 2020 and December 2022, a total of 77 patients with R/M HNSCC were included into analysis. The primary endpoint of the study was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), overall response rate (ORR)and toxicity.Efficacy was assessed according to RECIST version 1.1.SPSS 27.0 and GraphPad Prism 8.0 software were utilized to perform the statistical analysis.ResultsBy the cut-off date (February 28, 2023), the median OS,PFS and ORR were 15.97 months,8.53 months and 48.9% in patients treated with the pembrolizumab regimen in the first line therapy. Among these patients, 17 patients received pembrolizumab with cetuximab,and 18 received pembrolizumab with chemotherapy.We observed no significant differences between two groups neither in median OS (13.9 vs 19.4 months, P=0.3582) nor PFS (unreached vs 8.233 months, P= 0.2807). In the ≥2nd line therapy (n=30), the median OS, PFS and ORR were 5.7 months, 2.58 months and 20% respectively. Combined positive score (CPS) was eligible from 54 patients. For first line therapy, the median OS and PFS were 14.6 and 8.53 months in patients with CPS ≥1, and median OS and PFS were 14.6 and 12.33 months in patients with CPS ≥20. The immune-related adverse events (irAEs) were occurred in the 31 patients (31/77, 40.26%), and the most common potential irAEs were hypothyroidism (25.97%), and pneumonitis (7.79%).ConclusionOur real-world results indicated that pembrolizumab regimen is a promising treatment in patients with R/M HNSC

Advances of MnO2 nanomaterials as novel agonists for the development of cGAS-STING-mediated therapeutics

As an essential micronutrient, manganese plays an important role in the physiological process and immune process. In recent decades, cGAS-STING pathway, which can congenitally recognize exogenous and endogenous DNA for activation, has been widely reported to play critical roles in the innate immunity against some important diseases, such as infections and tumor. Manganese ion (Mn2+) has been recently proved to specifically bind with cGAS and activate cGAS-STING pathway as a potential cGAS agonist, however, is significantly restricted by the low stability of Mn2+ for further medical application. As one of the most stable forms of manganese, manganese dioxide (MnO2) nanomaterials have been reported to show multiple promising functions, such as drug delivery, anti-tumor and anti-infection activities. More importantly, MnO2 nanomaterials are also found to be a potential candidate as cGAS agonist by transforming into Mn2+, which indicates their potential for cGAS-STING regulations in different diseased conditions. In this review, we introduced the methods for the preparation of MnO2 nanomaterials as well as their biological activities. Moreover, we emphatically introduced the cGAS-STING pathway and discussed the detailed mechanisms of MnO2 nanomaterials for cGAS activation by converting into Mn2+. And we also discussed the application of MnO2 nanomaterials for disease treatment by regulating cGAS-STING pathway, which might benefit the future development of novel cGAS-STING targeted treatments based on MnO2 nanoplatforms

Expert Consensus on Microtransplant for Acute Myeloid Leukemia in Elderly Patients -Report From the International Microtransplant Interest Group

Recent studies have shown that microtransplant (MST) could improve outcome of patients with elderly acute myeloid leukemia (EAML). To further standardize the MST therapy and improve outcomes in EAML patients, based on analysis of the literature on MST, especially MST with EAML from January 1st, 2011 to November 30th, 2022, the International Microtransplant Interest Group provides recommendations and considerations for MST in the treatment of EAML. Four major issues related to MST for treating EAML were addressed: therapeutic principle of MST (1), candidates for MST (2), induction chemotherapy regimens (3), and post-remission therapy based on MST (4). Others included donor screening, infusion of donor cells, laboratory examinations, and complications of treatment

Unsupervised and Supervised Feature Selection for Incomplete Data via L_2,1-Norm and Reconstruction Error Minimization

Feature selection has been widely used in machine learning and data mining since it can alleviate the burden of the so-called curse of dimensionality of high-dimensional data. However, in previous works, researchers have designed feature selection methods with the assumption that all the information from a data set can be observed. In this paper, we propose unsupervised and supervised feature selection methods for use with incomplete data, further introducing an L2,1 norm and a reconstruction error minimization method. Specifically, the proposed feature selection objective functions take advantage of an indicator matrix reflecting unobserved information in incomplete data sets, and we present pairwise constraints, minimizing the L2,1-norm-robust loss functionand performing error reconstruction simultaneously. Furthermore, we derive two alternative iterative algorithms to effectively optimize the proposed objective functions and the convergence of the proposed algorithms is proven theoretically. Extensive experimental studies were performed on both real and synthetic incomplete data sets to demonstrate the performance of the proposed methods

Unsupervised and Supervised Feature Selection for Incomplete Data via L2,1-Norm and Reconstruction Error Minimization

Feature selection has been widely used in machine learning and data mining since it can alleviate the burden of the so-called curse of dimensionality of high-dimensional data. However, in previous works, researchers have designed feature selection methods with the assumption that all the information from a data set can be observed. In this paper, we propose unsupervised and supervised feature selection methods for use with incomplete data, further introducing an L2,1 norm and a reconstruction error minimization method. Specifically, the proposed feature selection objective functions take advantage of an indicator matrix reflecting unobserved information in incomplete data sets, and we present pairwise constraints, minimizing the L2,1-norm-robust loss functionand performing error reconstruction simultaneously. Furthermore, we derive two alternative iterative algorithms to effectively optimize the proposed objective functions and the convergence of the proposed algorithms is proven theoretically. Extensive experimental studies were performed on both real and synthetic incomplete data sets to demonstrate the performance of the proposed methods

Nrf2-mediated macrophage function in benign prostatic hyperplasia: Novel molecular insights and implications

One of the most common urological diseases is benign prostatic hyperplasia (BPH), with a high prevalence in the middle-aged and elderly male population. Patient's mental and physical health is affected significantly by this condition, causing them considerable discomfort. During the development of BPH, a synergistic effect occurs in response to inflammation, oxidative stress, and apoptosis induced by the activation of macrophages. The nuclear factor erythroid2-related factor 2 (Nrf2) signaling pathway can mediate macrophage activation and inhibit prostate hyperplasia by suppressing pro-inflammatory factors, anti-oxidative stress disorder, and initiating apoptosis. The purpose of this study was to review the mechanism of action of Nrf2 signaling pathway-mediated macrophage activation on the immune microenvironment of BPH and to summarize the Chinese medicine based on Nrf2 to provide an overview of BPH treatment options