Discovery of 1,2,3triazolo4,5-pyrimidine derivatives as highly potent, selective, and cellularly active USP28 inhibitors

Ubiquitin specific peptidase 28 (USP28) is closely associated to the occurrence and development of various malignancies, and thus has been validated as a promising therapeutic target for cancer therapy. To date, only few USP28 inhibitors with moderate inhibitory activity have been reported, highly potent and selective USP28 inhibitors with new chemotypes remain to be discovered for pathologically investigating the roles of deubiquitinase. In this current study, we reported the synthesis and biological evaluation of new [1,2,3]triazolo[4,5-]pyrimidine derivatives as potent USP28 inhibitors. Especially, compound potently inhibited USP28 (IC = 1.10 ± 0.02 μmol/L,  = 40 nmol/L), showing selectivity over USP7 and LSD1 (IC > 100 μmol/L). Compound was cellularly engaged to USP28 in gastric cancer cells. Compound reversibly bound to USP28 and directly affected its protein levels, thus inhibiting the proliferation, cell cycle at S phase, and epithelial-mesenchymal transition (EMT) progression in gastric cancer cell lines. Docking studies were performed to rationalize the potency of compound . Collectively, compound could serve as a new tool compound for the development of new USP28 inhibitors for exploring the roles of deubiquitinase in cancers.

PreoperativepredictionofmassivepostpartumhemorrhageinplacentapreviabyMRI / 实用放射学杂志

Objective ToinvestigatethevalueofpreoperativeMRIforplacentapreviainpredictionofmassivepostpartumhemorrhage. Methods AretrospectiveanalysisoftheclinicalhistoryandprenatalMRIfeaturesof362patientswithplacentapreviawereperformed. Ofthese,54casesexperiencedseverepostpartum hemorrhage.Results Univariateanalysisshowedthattheageofpregnantwomen (χ2＝3.951,P＝0.047),gestationalage(χ2＝6.257,P＝0.012),numberofcesareansections(χ2＝36.372,P＝0.001)andgemellary pregnancy(χ2＝7.933,P＝0.005)wereassociated with massivepostpartum hemorrhage.Amongthe MRIsigns,Uterinebulging (OR,46.712;95%CI,13.067－166.987),placentalprotrusionsign (OR,22.787;95% CI,4.595－113),andintroplacentalT2dark band(OR,14.757;95%CI,7.149－30.461)indicatedhighriskwithmassivepostpartumhemorrhage.Myometrialthinningorlocalized interruption,unevenplacentalsignal,abnormalbloodvesselsbelowtheplacenta,abundantbloodvesselsinloweruterusandcervix, cervicalshorteningandothersignsfortheevaluationofseverepostpartumhemorrhagewerealsostatisticallysignificant.Conclusion MRIcanpredictmostoftheseverepostpartumhemorrhagebeforesurgeryandisveryhelpfultoimprovethepatientprognosis.

Value of MR placental protusion sign in predicting postpartum hemorrhage in patients with placenta previa / 中国医学影像技术

Objective To explore the MRI findings of placental protusion sign in predicting postpartum hemorrhage in patients with placenta previa.Methods Totally 354 placenta previa patients with whole clinical data underwent MR scaning 2 weeks before operation.Association of postpartum hemorrhage and placental protusion sign was analyzed.Results Among 354 patients with placental previa,the age of the pregnant women (x2 =4.34,P=0.04),gestational age at delivery (x2 =5.19,P=0.02) and the number of cesarean sections (x2 =44.85,P＜0.01) had associated with postpartum hemorrhage.Eight cases had placental protusion sign in MRI,while 6 cases occurred postpartum hemorrhage.The incidence of postpartum hemorrhage was 75.00％ (6/8) and 12.72％ (44/346) in patients with placenta accreta and with placental abruption,respectively (x2 =20.14,P＜0.01).The sensitivity,specificity,odds ratio (95％ confidence interval) and positive likelihood ratio of predicting postpartum hemorrhage was 12.00％ (6/50),99.34％ (302/304),20.59 (4.03,105.23) and 15.68,respectively.Conclusion MRI placental protrusion sign has important clinical reference value in predicting postpartum hemorrhage.

MRI features of placenta accreta / 中华放射学杂志

ObjectiveTo investigate the MRI features of placenta accreta.MethodsFrom Apr 2009 to Jun 2011,15 patients with placenta accrete received MRI examination.In them,placenta accrcta was diagnosed based on clinical manifestations or postoperative histopathologv.The MR features of placenta accreta in thcm( study group) were retrospectively analyzed and compared with those in 15 pregnant women without placenta accreta (control group)with Fisher exact test.ResultsIn the 15 patients with placenta accreta,uterine bulging and(or) a focal outward contour bulge was detected in 14 patients; heterogeneous signal intensity in the placenta was detected in 15 patients; dark intraplacental bands on T2-weighted images was detected in 15 patients; and increased subplacental vascularity was detected in 11 patients on T1- weighted images.In the study group,14 patients showed at least three of the above four features,and in all of them uterine bulging and(or) a focal outward contour bulge,heterogeneous signal intensity in the placenta and dark intraplacental bands on T2-weighted images were detected; one patient showed heterogeneous signal intensity in the placenta,dark intraplacental bands on T2-weighted images and increased subplacental vascularity.In the control group,none patient had three of the above features.Uterine bulging and(or) a focal outward contour bulge,heterogeneous signal intensity in the placenta,dark intraplacental bands on T2-weighted images and increased subplacental vascularity were detected in 3,6,3 and 4 patients (P=0.000,0.001,0.000 and 0.027 ),respectively.ConclusionsThe main MRI features of placenta accreta are uterine bulging and(or) a focal outward contour bulge,heterogeneous signal intensity in the placenta and dark intraplacental bands on T2-weighted images Besides,increased subplacental vascularity also could provide useful information for the diagnosis of placenta accreta.