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 (PD...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.展开更多
Cryotherapy is a minimally invasive treatment.With increasing rate of breast cancer detection,ablation therapy has become an alternative approach for the treatment of this pathology due to its advantages of minimally ...Cryotherapy is a minimally invasive treatment.With increasing rate of breast cancer detection,ablation therapy has become an alternative approach for the treatment of this pathology due to its advantages of minimally invasive,fewer complications,good efficacy,and repeatability.Preclinical and clinical studies of cryotherapy for breast cancer published through December 2022 were identified through a literature search using PubMed,ClinicalTrials.gov,and CNKI.This article reviews the progress of cryoablation in the treatment of breast cancer.展开更多
Functional refractories, including submerged entry ,mzzle （SEN） , ladle shroud and monolithic stopper, are ,he key refractories for continuous casting. Drh,en by the demand （f high-speed continuous casting, traditi...Functional refractories, including submerged entry ,mzzle （SEN） , ladle shroud and monolithic stopper, are ,he key refractories for continuous casting. Drh,en by the demand （f high-speed continuous casting, traditional （unetional refractories ji,il to meet the needs of long span life, and high perfomance .[imctional refractories for continuous casting are hwreasingly required. Through structure and material de.sign, the performance of functional refiactories is significant5 improved. In this paper, some research adt,ances on functional refractories for continuous casting wetr mentiotted. Through numerical qmdeling and hot simulation, the service life of non-pretreating ladle shroud u,as increased front 8 h to more ＇ban 12 h. Thraugh the water modeling, the flow patterns in the mold wetr significantly improved attd through hot simulation and material design, the sen;ice liJb and eliability oJ SEN were also significantly improved.展开更多
Four-hole submerged entry nozzles （SEN） with dif- ferent structures were researched using the water simula- tion test by particle image velocimetry （PIV） and DJSO0 hydraulic measurement system to get suitable SEN ...Four-hole submerged entry nozzles （SEN） with dif- ferent structures were researched using the water simula- tion test by particle image velocimetry （PIV） and DJSO0 hydraulic measurement system to get suitable SEN for high efficiency continuous casting. The influences of the exit area ratio （2： 1：2, 3：2： 3, 1： 1：1 and 1：2： 1）, upper guide island angle θ （20°, 40°, 60° and 80°） , and lower guide island angle α （60°, 80°, 100° and 120°） on the vortex position in the mold and fluctuations were researched. The results show that the exit area ratio and the upper and low guide island angles have ob- vious influence on the flow field; the flow field in the mold is suitable at 1：2：1 of the exit area ratio, 80° of upper guide island angle, and 100° of lower guide island angle.展开更多
目的评价伏诺拉生治疗胃食管反流(GERD)的有效性和安全性,为临床用药提供循证依据。方法计算机检索PubMed、the Cochrane Library、Web of Science、中国知网、万方数据、维普网和中国生物医学文献数据库,收集伏诺拉生(试验组)对比安慰...目的评价伏诺拉生治疗胃食管反流(GERD)的有效性和安全性,为临床用药提供循证依据。方法计算机检索PubMed、the Cochrane Library、Web of Science、中国知网、万方数据、维普网和中国生物医学文献数据库,收集伏诺拉生(试验组)对比安慰剂或质子泵抑制剂(对照组)的随机对照试验(RCT),检索时限为建库起至2022年6月。筛选文献、提取资料后采用Cochrane系统评价员手册5.1.0推荐的偏倚评估工具对纳入文献质量进行评价;采用RevMan 5.4软件进行Meta分析、敏感性分析和发表偏倚分析。结果共纳入9项RCT,共计1882例患者。Meta分析结果显示,试验组患者的总体有效率[OR=1.94,95%CI(1.45,2.58),P<0.00001]、治愈率[OR=2.27,95%CI(1.33,3.86),P=0.003]、缓解率[OR=1.81,95%CI(1.28,2.55),P=0.0007]均显著高于对照组;两组患者的药物不良事件发生率及腹泻、鼻咽炎、上呼吸道感染、碱性磷酸酶升高发生率比较,差异均无统计学意义(P>0.05)。亚组分析结果显示,治疗2周时,试验组患者的治愈率显著高于对照组(P<0.05);治疗4、8周时,两组患者的治愈率比较,差异均无统计学意义(P>0.05)。洛杉矶分级A/B级患者中,两组患者治疗2、4、8周时的治愈率比较,差异均无统计学意义(P>0.05);洛杉矶分级C/D级患者中,试验组患者治疗2、4、8周时的治愈率均显著高于对照组(P<0.05)。敏感性分析和发表偏倚分析结果显示,本研究所得结果稳健且存在发表偏倚的可能性较小。结论伏诺拉生治疗GERD的有效性和安全性均较好。展开更多
基金This work was supported by Beijing Natural Science Foundation[Z220019 to Jing Wang,China]National High Level of Hospital Clinical Research Funding[2022-PUMCH-D-002 to Jing Wang,China]+3 种基金National Key Research and Development Program of China Grants[2019YFA0801703 and 2019YFA0801804 to Jing Wang]Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences[2022-I2M-JB-007 to Chen Wang,2021-I2M-1-016 to Hongmei Zhao,2021-I2M-1-049 to Jing Wang,2021-I2M-1-005 to Yanjiang Xing,China]Haihe Laboratory of Cell Ecosystem Innovation Fund[22HHXBSS00010 to Jing Wang,China]National Natural Science Foundation of China[82241004 to Jing Wang].
文摘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.
文摘Cryotherapy is a minimally invasive treatment.With increasing rate of breast cancer detection,ablation therapy has become an alternative approach for the treatment of this pathology due to its advantages of minimally invasive,fewer complications,good efficacy,and repeatability.Preclinical and clinical studies of cryotherapy for breast cancer published through December 2022 were identified through a literature search using PubMed,ClinicalTrials.gov,and CNKI.This article reviews the progress of cryoablation in the treatment of breast cancer.
文摘Functional refractories, including submerged entry ,mzzle （SEN） , ladle shroud and monolithic stopper, are ,he key refractories for continuous casting. Drh,en by the demand （f high-speed continuous casting, traditional （unetional refractories ji,il to meet the needs of long span life, and high perfomance .[imctional refractories for continuous casting are hwreasingly required. Through structure and material de.sign, the performance of functional refiactories is significant5 improved. In this paper, some research adt,ances on functional refractories for continuous casting wetr mentiotted. Through numerical qmdeling and hot simulation, the service life of non-pretreating ladle shroud u,as increased front 8 h to more ＇ban 12 h. Thraugh the water modeling, the flow patterns in the mold wetr significantly improved attd through hot simulation and material design, the sen;ice liJb and eliability oJ SEN were also significantly improved.
基金The National Natrual Science Foundation of China(Grant No.51372231)
文摘Four-hole submerged entry nozzles （SEN） with dif- ferent structures were researched using the water simula- tion test by particle image velocimetry （PIV） and DJSO0 hydraulic measurement system to get suitable SEN for high efficiency continuous casting. The influences of the exit area ratio （2： 1：2, 3：2： 3, 1： 1：1 and 1：2： 1）, upper guide island angle θ （20°, 40°, 60° and 80°） , and lower guide island angle α （60°, 80°, 100° and 120°） on the vortex position in the mold and fluctuations were researched. The results show that the exit area ratio and the upper and low guide island angles have ob- vious influence on the flow field; the flow field in the mold is suitable at 1：2：1 of the exit area ratio, 80° of upper guide island angle, and 100° of lower guide island angle.
