Approximately 30%–40%of growth hormone–secreting pituitary adenomas(GHPAs)harbor somatic activating mutations in GNAS(αsubunit of stimulatory G protein).Mutations in GNAS are associated with clinical features of sm...Approximately 30%–40%of growth hormone–secreting pituitary adenomas(GHPAs)harbor somatic activating mutations in GNAS(αsubunit of stimulatory G protein).Mutations in GNAS are associated with clinical features of smaller and less invasive tumors.However,the role of GNAS mutations in the invasiveness of GHPAs is unclear.GNAS mutations were detected in GHPAs using a standard polymerase chain reaction(PCR)sequencing procedure.The expression of mutation-associated maternally expressed gene 3(MEG3)was evaluated with RT-qPCR.MEG3 was manipulated in GH3 cells using a lentiviral expression system.Cell invasion ability was measured using a Transwell assay,and epithelial–mesenchymal transition(EMT)-associated proteins were quantified by immunofluorescence and western blotting.Finally,a tumor cell xenograft mouse model was used to verify the effect of MEG3 on tumor growth and invasiveness.The invasiveness of GHPAs was significantly decreased in mice with mutated GNAS compared with that in mice with wild-type GNAS.Consistently,the invasiveness of mutant GNASexpressing GH3 cells decreased.MEG3 is uniquely expressed at high levels in GHPAs harboring mutated GNAS.Accordingly,MEG3 upregulation inhibited tumor cell invasion,and conversely,MEG3 downregulation increased tumor cell invasion.Mechanistically,GNAS mutations inhibit EMT in GHPAs.MEG3 in mutated GNAS cells prevented cell invasion through the inactivation of the Wnt/β-catenin signaling pathway,which was further validated in vivo.Our data suggest that GNAS mutations may suppress cell invasion in GHPAs by regulating EMT through the activation of the MEG3/Wnt/β-catenin signaling pathway.展开更多
Background Postoperative delayed hyponatremia(PDH)is a major cause of readmission after endoscopic transsphenoidal surgery(eTSS)for pituitary adenomas(PAs).However,the risk factors associated with PDH have not been we...Background Postoperative delayed hyponatremia(PDH)is a major cause of readmission after endoscopic transsphenoidal surgery(eTSS)for pituitary adenomas(PAs).However,the risk factors associated with PDH have not been well established,and the development of a dynamic online nomogram for predicting PDH is yet to be realized.We aimed to investigate the predictive factors for PDH and construct a dynamic online nomogram to aid in its prediction.Methods We analyzed the data of 226 consecutive patients who underwent eTSS for PAs at the Department of Neurosurgery in Jinling Hospital between January 2018 and October 2020.An additional 97 external patients were included for external validation.PDH was defined as a serum sodium level below 137 mmol/L,occurring on the third postoperative day(POD)or later.Results Hyponatremia on POD 1-2(OR=2.64,P=0.033),prothrombin time(PT)(OR=1.78,P=0.008),and percentage of monocytes(OR=1.22,P=0.047)were identified as predictive factors for PDH via multivariable logistic regression analysis.Based on these predictors,a nomogram was constructed with great discrimination in internal validation(adjusted AUC:0.613-0.688)and external validation(AUC:0.594-0.617).Furthermore,the nomogram demonstrated good performance in calibration plot,Brier Score,and decision curve analysis.Subgroup analysis revealed robust predictive performance in patients with various clinical subtypes and mild to moderate PDH.Conclusions Preoperative PT and the percentage of monocytes were,for the first time,identified as predictive factors for PDH.The dynamic nomogram proved to be a valuable tool for predicting PDH after eTSS for PAs and demonstrated good generalizability.Patients could benefit from early identification of PDH and optimized treatment decisions.展开更多
Dear Editor,Sperm cooperation has been observed in multiple species(Pizzari and Foster,2008),yet its existenee and benefit for reproductive success in mammals remains underexplored.Here,combining tissue-clearing with ...Dear Editor,Sperm cooperation has been observed in multiple species(Pizzari and Foster,2008),yet its existenee and benefit for reproductive success in mammals remains underexplored.Here,combining tissue-clearing with deep three-dimensional(3D)imagi ng,we dem on strate that postcopulatory mouse sperm congregate into unidirectional sperm cooperative clusters at the utero-tubal junction(UTJ),a key physical barrier for passage into the oviduct.展开更多
基金supported by the Applied Basic Research Programs of Science and Technology Commission Foundation of Jiangsu Province(No.BE2015684).
文摘Approximately 30%–40%of growth hormone–secreting pituitary adenomas(GHPAs)harbor somatic activating mutations in GNAS(αsubunit of stimulatory G protein).Mutations in GNAS are associated with clinical features of smaller and less invasive tumors.However,the role of GNAS mutations in the invasiveness of GHPAs is unclear.GNAS mutations were detected in GHPAs using a standard polymerase chain reaction(PCR)sequencing procedure.The expression of mutation-associated maternally expressed gene 3(MEG3)was evaluated with RT-qPCR.MEG3 was manipulated in GH3 cells using a lentiviral expression system.Cell invasion ability was measured using a Transwell assay,and epithelial–mesenchymal transition(EMT)-associated proteins were quantified by immunofluorescence and western blotting.Finally,a tumor cell xenograft mouse model was used to verify the effect of MEG3 on tumor growth and invasiveness.The invasiveness of GHPAs was significantly decreased in mice with mutated GNAS compared with that in mice with wild-type GNAS.Consistently,the invasiveness of mutant GNASexpressing GH3 cells decreased.MEG3 is uniquely expressed at high levels in GHPAs harboring mutated GNAS.Accordingly,MEG3 upregulation inhibited tumor cell invasion,and conversely,MEG3 downregulation increased tumor cell invasion.Mechanistically,GNAS mutations inhibit EMT in GHPAs.MEG3 in mutated GNAS cells prevented cell invasion through the inactivation of the Wnt/β-catenin signaling pathway,which was further validated in vivo.Our data suggest that GNAS mutations may suppress cell invasion in GHPAs by regulating EMT through the activation of the MEG3/Wnt/β-catenin signaling pathway.
基金supported by Jiangsu Provincial Department of Science and Technology of China(grant no.BE2022821)the China Scholarship Council(CSCgrant no.202206090022)
文摘Background Postoperative delayed hyponatremia(PDH)is a major cause of readmission after endoscopic transsphenoidal surgery(eTSS)for pituitary adenomas(PAs).However,the risk factors associated with PDH have not been well established,and the development of a dynamic online nomogram for predicting PDH is yet to be realized.We aimed to investigate the predictive factors for PDH and construct a dynamic online nomogram to aid in its prediction.Methods We analyzed the data of 226 consecutive patients who underwent eTSS for PAs at the Department of Neurosurgery in Jinling Hospital between January 2018 and October 2020.An additional 97 external patients were included for external validation.PDH was defined as a serum sodium level below 137 mmol/L,occurring on the third postoperative day(POD)or later.Results Hyponatremia on POD 1-2(OR=2.64,P=0.033),prothrombin time(PT)(OR=1.78,P=0.008),and percentage of monocytes(OR=1.22,P=0.047)were identified as predictive factors for PDH via multivariable logistic regression analysis.Based on these predictors,a nomogram was constructed with great discrimination in internal validation(adjusted AUC:0.613-0.688)and external validation(AUC:0.594-0.617).Furthermore,the nomogram demonstrated good performance in calibration plot,Brier Score,and decision curve analysis.Subgroup analysis revealed robust predictive performance in patients with various clinical subtypes and mild to moderate PDH.Conclusions Preoperative PT and the percentage of monocytes were,for the first time,identified as predictive factors for PDH.The dynamic nomogram proved to be a valuable tool for predicting PDH after eTSS for PAs and demonstrated good generalizability.Patients could benefit from early identification of PDH and optimized treatment decisions.
基金the National Natural Science Foundation of China(Grant Nos.12032010 and 12272179)the Postgraduate Research&Practice Innovation Program of Jiangsu Province(Grant No.KYCX23_0349)the Project of Jiangsu Science and Technology Plan(Grant No.BE2022821).
基金This work was supported by the National Key Research and Development Program of China(2018YFC1004500 to YZ,2019YFA0802600 to YZ,2016YFA0500903 to ED,2017YFC1001401 to ED,2015CB943003 to YZ)the Strategic Priority Research Program of the CAS(XDA16020700 to HW)National Basic Research Program of China(81490742 to ED)+2 种基金National Natural Science Foundation of China(81490741 to HW,31671201 to YZ,31671568 to ED)Youth Inn ovation Promotion Association,CAS(Grant No.2016081 to YZ)The Eunice Kennedy Shriver Nation al Institute of Child Health and Human Development(grants HD088412 and P01HD087157)supports our studies of UTJ migration defects in mouse models.
文摘Dear Editor,Sperm cooperation has been observed in multiple species(Pizzari and Foster,2008),yet its existenee and benefit for reproductive success in mammals remains underexplored.Here,combining tissue-clearing with deep three-dimensional(3D)imagi ng,we dem on strate that postcopulatory mouse sperm congregate into unidirectional sperm cooperative clusters at the utero-tubal junction(UTJ),a key physical barrier for passage into the oviduct.
