Alzheimer disease(AD) is the most common cau se of dementia today. Th e characteristic histopathologic changes include neurofibrillary tangles, neurit ic plaques, neuronal loss, and amyloid angiopathy. The noted Alzheimer symptom is the dysfunction of learning a nd memory. Potassium channels play a key role in it. A 113-pS tetraethylammoniu m-sensitive potassium channel was consistently absent from AD fibroblasts and o lfactory neuroblasts. Cp20, a memory-associated protein, amyloid precuror prote in and presenilin which are all tightly associated with genetic Alzheimer diseas e can regulate the activities of potassium channels. The changes of potassium ch annels subtype need further study. Potassium channels are maybe the important dr ug targets in the treatment of Alzheimer disease.

Pulmonary arterial hypertension (PAH) is a clinical hemodynamic syndrome characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance leading to right heart failure and death. Vascular remodeling is the most prominent histopathological feature of PAH, which is regulated by many factors. Endoplasmic reticulum stress, calcium disorder and mitochondrial dysfunction are involved in the vascular cell proliferation and apoptosis by regulating intracellular calcium homeostasis and cellular metabolism. Epigenetic phenomenon such as DNA damage and abnormal expression of miRNA are also involved in the regulation of abnormal proliferation of vascular cells. Vascular cell phenotype switching including endothelial-mesenchymal transition and smooth muscle cell phenotype switching play an important role in abnormal proliferation of vascular cells. Vascular remodeling is produced by a variety of cells and molecular pathways, and aiming at multiple targets which is expected to find a new breakthrough in the treatment of PAH,and to improve abnormal vascular remodeling, delay or even reverse the progression of PAH.
Cell Proliferation ; Cells, Cultured ; Humans ; Hypertension, Pulmonary ; physiopathology ; MicroRNAs ; genetics ; Myocytes, Smooth Muscle ; pathology ; Pulmonary Artery ; pathology ; Vascular Remodeling ; genetics

ObjectiveTo investigate the effectiveness and safety of nanoknife ablation guided by real-time virtual sonography (RVS) in the treatment of locally advanced pancreatic cancer (LAPC). MethodsA retrospective analysis was performed for the clinical data of 27 patients with LAPC who attended The Fifth Affiliated Hospital of Zhengzhou University from April 2018 to October 2019, and according to the treatment method, the patients were divided into combination group (12 patients treated with IRE combined with chemotherapy) and control group (15 patients treated with chemotherapy alone). The chemotherapy regimen was gemcitabine combined with tegafur, gimeracil and oteracil potassium for both groups. Adverse reactions and complications were observed for the combination group during the perioperative period, and the two groups were compared in terms of the changes in myocardial enzymes, blood amylase, and carbohydrate antigen 19-9 (CA19-9) before treatment and at different time points after treatment, as well as remission rate (RR) and disease control rate (DCR) at 3 months after treatment and survival status during follow-up. The Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups, and the Wilcoxon test was used for comparison within each group; the Fisher’s exact test was used for comparison of categorical data between groups; the Kaplan-Meier method was used to analyze the survival status during follow-up. ResultsIn the combination group, there were 12 cases of adverse reactions and mild complications during the perioperative period, i.e., 9 Clavien-Dindo grade I cases and 3 grade II cases. All patients in the combination group experienced a transient increase in myocardial enzymes, which returned to normal within 7 days, and there were no significant changes in creatine kinase and lactate dehydrogenase on day 7 after treatment (P＞0.05); 9 patients had a significant increase in blood amylase on day 1 after surgery, which significantly decreased on day 7 after surgery and basically returned to normal on day 14 after surgery, and there was no significant change in blood amylase on days 7、14， and 1 month after surgery (P＞0.05). Before treatment, the level of CA19-9 was higher than the normal value in both groups, and the combination group had a significant reduction in CA19-9 at 1, 2, and 3 months after treatment (all P＜005); in the control group, the level of CA19-9 firstly decreased for a short time and then increased, while there was no significant change in CA19-9 at 1, 2, and 3 months after treatment (all P＞0.05). At 3 months after treatment, the combination group had significantly higher RR and DCR than the control group (RR: 75.0% vs 26.7%, P=0.021; DCR: 91.6% vs 53.3%, P=0043). During the median follow-up time of 13 months, compared with the control group, the combination group had significantly higher median progression-free survival time (10 months vs 5 months, P=0.014) and median overall survival time (18 months vs 10 months, P=0.034). ConclusionRVS-guided percutaneous nanoknife ablation has marked clinical effect and high safety in the treatment of LAPC and can be used as a new treatment option for patients who refuse or cannot tolerate laparotomy for ablation therapy.

Objective:To study the complications of irreversible electroporation (nano-knife) ablation on locally advanced pancreatic cancer, and to analyse the causes of complications and related treatment.Methods:The clinical data of 36 patients with locally advanced pancreatic cancer treated with nano-knife ablation at the Fifth Affiliated Hospital of Zhengzhou University from January 2016 to March 2019 were studied retrospectively. The types and incidence of postoperative complications were analyzed. The complications were classified according to the Clavien-Dindo classification, and the severity of the complications was evaluated.Results:There were 15 patients (41.7%) who developed various degrees of complications, including splenic infarction, atrial fibrillation, portal vein thrombosis, pancreatic fistula, pseudoaneurysm, gastrointestinal bleeding, liver abscess and severe pancreatitis. Among them, 6 patients (16.7%) had grade III complication or above. Three (8.3%) patients with grade Ⅲ complications died of upper gastrointestinal bleeding 3 months after operation.Conclusions:Various complications might occur after nano-knife ablation, with postoperative gastrointestinal and abdominal bleeding being the main complications which resulted in death. Measures which can effectively reduce occurrence of complications need to be studied.

AIM: To compare the results calculated by population pharmacokinetic analysis tools Phoenix NLME, Monolix, R nlmixr package and CPhaMAS cloud platform with the gold standard sofeware NONMEM. METHODS: Fifty sparse sampling data sets based on a one-compartment model and fifty dense sampling data sets based on a two-compartment model were simulated, and the above five analysis tools were used to calculate the population typical value, individual variability and individual pharmacokinetic parameters. RESULTS: The population typical value and individual variability calculated by CPhaMAS and Phoenix NLME had the highest matching degree with NONMEM, followed by nlmixr. Monolix had the lowest matching degree, but Monolix and nlmixr might be more robust. The correspondence between clearance and distribution volume was better than the absorption rate constant. Except the absorption rate constant calculated by Monolix and intercompartmental clearance calculated by nlmixr, the correlation coefficients of individual pharmacokinetic parameters calculated by all analytical tools were greater than 0.99. CONCLUSION: The results calculated by the above four population pharmacokinetic analysis tools are highly correlated with that of NONMEM.

Objective    To study the feasibility and safety of CT-guided preoperative Hookwire localization of pulmonary nodules in clinical application. Methods    Clinical data of 102 patients who were scheduled to undergo surgical treatment for pulmonary nodules from June 2015 to April 2020 in the North Ward of Thoracic Surgery Department of Ruijin Hospital were retrospectively analyzed. There were 38 males and 64 females, aged 23-82 (53.2±12.8) years. Results    All 102 patients with pulmonary nodules underwent CT-guided preoperative Hookwire localization successfully, with a localization success rate of 100.0%. The localization time was 27.0 (11-67) min; the number of times to adjust the angle during the positioning process was 6.9 (3-14); the needle depth of the positioning needle was 41.5 (16.3-69.1) mm. A total of 48 (47.1%) patients had a small amount of bleeding in the lung tissue in the positioning area after positioning; 53 (51.9%) patients had a small amount of pneumothorax after positioning; 16 (15.7%) patients were found that the positioning needle completely shedded from the lung tissue in the subsequent surgery. One patient was transferred to open thoracotomy because of extensive dense adhesion in the thorax, and the remaining 101 patients were operated on under thoracoscopy. Postoperative pathology showed that 5 (4.9%) patients were adenocarcinoma in situ, 28 (27.5%) were microinvasive adenocarcinoma, 36 (35.3%) patients were invasive carcinoma and 32 (31.3%) patients were benign lesions. No patients had complications or adverse events related to preoperative positioning. Conclusion    Pre-operative CT-guided localization of Hookwire intrapulmonary nodules is safe and effective, and can meet the intraoperative localization needs of thoracic surgeons in most clinical situations, and is not inferior to other preoperative localization methods currently used in clinics.

Pulmonary hypertension (PH) is a life-threatening disease characterized by pulmonary vascular remodeling, in which hyperproliferation of pulmonary artery smooth muscle cells (PASMCs) plays an important role. The cysteine 674 (C674) in the sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase 2 (SERCA2) is the critical redox regulatory cysteine to regulate SERCA2 activity. Heterozygous SERCA2 C674S knock-in mice (SKI), where one copy of C674 was substituted by serine to represent partial C674 oxidative inactivation, developed significant pulmonary vascular remodeling resembling human PH, and their right ventricular systolic pressure modestly increased with age. In PASMCs, substitution of C674 activated inositol requiring enzyme 1 alpha (IRE1α) and spliced X-box binding protein 1 (XBP1s) pathway, accelerated cell cycle and cell proliferation, which reversed by IRE1α/XBP1s pathway inhibitor 4μ8C. In addition, suppressing the IRE1α/XBP1s pathway prevented pulmonary vascular remodeling caused by substitution of C674. Similar to SERCA2a, SERCA2b is also important to restrict the proliferation of PASMCs. Our study articulates the causal effect of C674 oxidative inactivation on the development of pulmonary vascular remodeling and PH, emphasizing the importance of C674 in restricting PASMC proliferation to maintain pulmonary vascular homeostasis. Moreover, the IRE1α/XBP1s pathway and SERCA2 might be potential targets for PH therapy.