Endothelial phosphodiesterase 4B inactivation ameliorates endothelial-to-mesenchymal transition and pulmonary hypertension

Pulmonary hypertension (PH) is a fatal disorder characterized by pulmonary vascular remodeling and obstruction. The phosphodiesterase 4 (PDE4) family hydrolyzes cyclic AMP (cAMP) and is comprised of four subtypes (PDE4A–D). Previous studies have shown the beneficial effects of pan-PDE4 inhibitors in rodent PH;however, this class of drugs is associated with side effects owing to the broad inhibition of all four PDE4 isozymes. Here, we demonstrate that PDE4B is the predominant PDE isozyme in lungs and that it was upregulated in rodent and human PH lung tissues. We also confirmed that PDE4B is mainly expressed in the lung endothelial cells (ECs). Evaluation of PH in Pde4b wild type and knockout mice confirmed that Pde4b is important for the vascular remodeling associated with PH. In vivo EC lineage tracing demonstrated that Pde4b induces PH development by driving endothelial-to-mesenchymal transition (EndMT), and mechanistic studies showed that Pde4b regulates EndMT by antagonizing the cAMP-dependent PKA–CREB–BMPRII axis. Finally, treating PH rats with a PDE4B-specific inhibitor validated that PDE4B inhibition has a significant pharmacological effect in the alleviation of PH. Collectively, our findings indicate a critical role for PDE4B in EndMT and PH, prompting further studies of PDE4B-specific inhibitors as a therapeutic strategy for PH.

Postoperative Radiotherapy and N2 Non-small Cell Lung Cancer Prognosis: A Retrospective Study Based on Surveillance, Epidemiology, and End Results Database

The purpose of this study is to clarify the significance of postoperative radiotherapy for N2 lung cancer.This study aimed to investigate the effect of postoperative radiotherapy on the survival and prognosis of patients with N2 lung cancer.Data from 12,000 patients with N2 lung cancer were extracted from the Surveillance,Epidemiology,and End Results database(2004-2012).Age at disease onset and 5-year survival rates were calculated.Survival curves were plotted using the Kaplan-Meier method.The univariate log-rank test was performed.Multivariate Cox regression were used to examine factors affecting survival.Patients’median age was 67 years(mean 66.46±10.03).The 5-year survival rate was 12.55%.Univariate analysis revealed age,sex,pathology,and treatment regimen as factors affecting prognosis.In multivariate analysis,when compared to postoperative chemotherapy,postoperative chemoradiotherapy was better associated with survival benefits(hazard ratio[HR]=0.85,95%confidence interval[CI]:0.813-0.898,P<0.001).Propensity score matching revealed that patients who had received postoperative chemoradiotherapy had a better prognosis than did patients who had received postoperative chemotherapy(HR=0.869,95%CI:0.817-0.925,P<0.001).Female patients and patients aged<65 years had a better prognosis than did their counterparts.Patients with adenocarcinoma had a better prognosis than did patients with squamous cell carcinoma.Moreover,prognosis worsened with increasing disease T stage.Patients who had received postoperative chemoradiotherapy had a better prognosis than did patients who had received postoperative chemotherapy.Postoperative radiotherapy was an independent prognostic factor in this patient group.

Design and development of a mitochondrial-targeted photosensitizer for two-photon fluorescence imaging and photodynamic therapy

Mitochondria are well-acknowledged as ideal targets for tumor therapy due to their important role in energy supply and cellular signal regulation.Mitochondria-specific photosensitizers have been reported to be critical for inducing cell apoptosis.Two-photon fluorescence imaging provides a new technique for delineating biological structures and activities in deep tissues.Herein,we developed a new aggregation-induced emission(AIE)active photosensitizer by attaching a pyridinium group for mitochondrial target-ing.The rationally designed photosensitizer(TTTP)exhibited excellent photophysical properties,good biocompatibility,reactive oxygen species(ROS)stimulation ability,anticancer efficacy,and two-photon imaging properties.TTTP was highly taken up by cells and accumulated specifically in mitochondria but was selectively cytotoxic to cancer cells.Under light irradiation,the generation of ROS was significantly boosted,leading to actively induced apoptosis.The in vivo tumor photodynamic therapeutic efficacy of TTTP showed significant inhibition of tumor growth.Furthermore,the underlying mechanism of TTTP tu-mor suppression revealed that the apoptosis agonist Bax was markedly up-regulated while the antagonist Bcl-xL was down-regulated.This research provides a potential mitochondrial-targeted phototherapeutic agent for effective therapy and two-photon fluorescence imaging.

腹膜透析相关性腹膜炎细菌谱变迁及药敏分析

目的探讨腹膜透析相关性腹膜炎患者感染细菌谱变迁及耐药情况,以指导合理使用抗生素。方法收集2012至2021年十年间我院发生的342例次腹透相关性腹膜炎患者的基本资料,比较前、后五年感染细菌谱及耐药性变化,分析不同细菌类型临床特点。结果本研究中腹透液培养共有159例次阳性,其中革兰氏阳性(G^(+))菌的占比最高,但比例随时间逐渐下降,而革兰氏阴性(G^(-))菌比例随时间逐渐上升,后五年较前五年高(P<0.05)。G^(-)菌中大肠埃希菌最为常见,后五年较前五年占比更高(P<0.05)。与G^(+)菌组相比,G^(-)菌组患者的透析龄更长,住院费用更多,合并插管出口感染更多,因感染拔管比例更高。G^(-)菌组患者的血中性粒细胞百分比、C反应蛋白(CRP)水平、降钙素原(PCT)水平、腹透液的多形核细胞百分比也更高(P<0.05)。后五年细菌耐药率增多,大肠埃希菌对头孢类抗生素耐药率升高。结论G^(+)菌仍是腹透相关性腹膜炎的主要致病菌,但在后五年占比较前五年下降,而G^(-)菌占比逐渐上升,其中大肠埃希菌最常见。细菌的耐药率后五年较前五年高。相比G^(+)菌组,G^(-)菌组患者的炎症指标水平更高。

TVseer:A visual analytics system for television ratings

The television ratings provide an effective way to analyze the popularity of TV programs and audiences’watching habits.Most previous studies have analyzed the ratings from a single perspective.Few efforts have integrated analysis from different perspectives and explored the reasons for changes in ratings.In this paper,we design a visual analysis system called TVseer to analyze audience ratings from three perspectives:TV channels,TV programs,and audiences.The system can help users explore the factors that affect ratings,and assist them in decisions about program productions and schedules.There are six linked views in TVseer:the channel ratings view and program ratings view show ratings change information from the perspective of TV channels and programs respectively;the overlapping program competition view and the same-type program competition view indicate the competitive relationships among programs;the audience transfer view shows how audiences are moving among different channels;the audience group view displays audience groups based on their watching behavior.Besides,we also construct case studies and expert interviews to prove our system is useful and effective.