Objective: SHR-1210 is a new and promising anti-PD-1 agent for solid tumors. During the phase I study of SHR-1210, we encountered a novel but prevalent immune-related dermatologic toxicity: reactive capillary hemangio...Objective: SHR-1210 is a new and promising anti-PD-1 agent for solid tumors. During the phase I study of SHR-1210, we encountered a novel but prevalent immune-related dermatologic toxicity: reactive capillary hemangiomas(RCHs). Thus we tried to summarize the features of RCHs and estimate their relationship with tumor response.Methods: This prospective observational study systematically enrolled 98 patients with advanced solid tumors from April 27th,2016 to June 8th, 2017 in the context of the phase I clinical study of SHR-1210. This report focused on the skin toxicities. Patients underwent entire skin inspection every two weeks while taking medication. The clinical course of RCHs was recorded and their association with tumor response was estimated. The data cut-off date was November 15th, 2017.Results: After a median follow-up of 242(range, 29–567) days, RCHs were observed in 85.7%(84/98) of patients on cutaneous/mucosal surfaces; 84.5%(71/84) of the RCHs were evaluated as grade 1 adverse events. No grade 3 or 4 RCHs were observed. The time of onset of RCHs was dose dependent and shortest in the 400 mg-dose cohort(P < 0.001). Spontaneous and complete regression of RCHs was observed both during and after treatment. The objective response rate of tumors for patients with RCHs was 28.9%(24/83). However, no responders were observed among the patients without RCHs.Conclusions: RCHs were prevalent but manageable during treatment with SHR-1210. It might add to the expanding literature regarding immune-related dermatologic adverse events.展开更多
The asymmetric photocatalytic organic synthesis(APOS)process is a sustainable and environmentally benign method for the production of optically active chemicals with sunlight as an energy source.However,it still lacks...The asymmetric photocatalytic organic synthesis(APOS)process is a sustainable and environmentally benign method for the production of optically active chemicals with sunlight as an energy source.However,it still lacks efficient semiconductors with tunable band structures and has a low recycling stability.Herein,we report the synthesis of tetrahydroquinoline-linked covalent organic frameworks(QH-COFs)with irreversible tetrahydroquinoline linkage as efficient semiconductors for the visible-light-driven asymmetricα-alkylation of aldehydes by merging with a chiral secondary amine.Up to 94%ee was obtained over QH-COFs,and the activity of QH-COFs was significantly higher than those of inorganic semiconductors(e.g.,Ti O2,Bi VO4,and WO3)under similar conditions,which is mainly attributed to their narrow band gap and suitable band edge.As far as we know,QH-COFs are the most active semiconductors for asymmetricα-alkylation of aldehydes ever reported.The QH-COFs were prepared via a one-pot Povarov cascade imine formation and cycloaddition reaction using Sc(OTf)3/Yb(OTf)3 as Lewis acid catalysts.Attributed to the tetrahydroquinoline linkage,QH-COFs showed extremely high recycling stability,which made practicals application possible.This work not only opens up a new avenue for asymmetric photocatalysis but also provides an efficient and general method for the construction of robust COFs.展开更多
Background: The late detection of endometrial carcinoma (EC) at an advanced stage often results in a poorpatient prognosis. It is hence important to identify reliable biomarkers to facilitate early detection of EC. Si...Background: The late detection of endometrial carcinoma (EC) at an advanced stage often results in a poorpatient prognosis. It is hence important to identify reliable biomarkers to facilitate early detection of EC. Signaltransducer and activator of transcription (STAT) family members play an important role in several tumors, however,their impact on EC development and progression remains unclear. Methods: Machine learning methods were used toinvestigate the importance of STAT5B in EC. Results: Hence, we explored the UALCAN data mining platform andfound that while STAT1 and STAT2 were upregulated, STAT5A, STAT5B, and STAT6 were downregulated in EC.This high expression of STAT5B and STAT6 predicted favorable clinical outcomes, whereas the increased expressionof STAT1 and STAT2 predicted poor clinical outcomes. Subsequent pathway enrichment analysis revealed that theSTAT family was mainly involved in apoptosis pathway activation, cell cycle disruption, and epithelial–mesenchymaltransition. Drug sensitivity analysis demonstrated that STAT5A/5B expression was negatively correlated with drugresistance in EC. Further, the expression of STAT5B mRNA and protein was correlated with severalclinicopathological characteristics. Tumor Immune Estimation Resource (TIMER) analysis revealed that STAT5Bexpression was positively correlated with the abundance of infiltrating CD8+ T cells and neutrophils while its copynumber variation was associated with the overall immune cell infiltration. The data on the correlations betweenSTAT5B expression and related genes in uterine corpus endometrial carcinoma (UCEC) in cBio Cancer Portalshowed the closest correlation of STAT5B expression with that of KIAA0753 (also known as moonraker and OFIP),followed by COL27A1 in EC. Pathway enrichment analysis further showed that STAT5B-related genes were involvedin the mitogen-activated protein kinase (MAPK) and Ras signaling pathways. Conclusion: Collectively, our findingsprovided new insights into the role of the STAT family in EC. It also highlighted new targets for future research ondiagnostic and prognostic markers and STAT5B as a novel marker for drug sensitivity screening.展开更多
Liver regeneration following injury aids the restoration of liver mass and the recovery of liver function.In the present study we investigated the contribution of megakaryocytic leukemia 1(MKL1),a transcriptional modu...Liver regeneration following injury aids the restoration of liver mass and the recovery of liver function.In the present study we investigated the contribution of megakaryocytic leukemia 1(MKL1),a transcriptional modulator,to liver regeneration.We report that both MKL1 expression and its nuclear translocation correlated with hepatocyte proliferation in cell and animal models of liver regeneration and in liver failure patients.Mice with MKL1 deletion exhibited defective regenerative response in the liver.Transcriptomic analysis revealed that MKL1 interacted with E2F1 to program pro-regenerative transcription.MAPKAPK2 mediated phosphorylation primed MKL1 for its interaction with E2F1.Of interest,phospholipase d2 promoted MKL1 nuclear accumulation and liver regeneration by catalyzing production of phosphatidic acid(PA).PA administration stimulated hepatocyte proliferation and enhanced survival in a MKL1-dependent manner in a pre-clinical model of liver failure.Finally,PA levels was detected to be positively correlated with expression of pro-regenerative genes and inversely correlated with liver injury in liver failure patients.In conclusion,our data reveal a novel mechanism whereby MKL1 contributes to liver regeneration.Screening for small-molecule compounds boosting MKL1 activity may be considered as a reasonable approach to treat acute liver failure.展开更多
Slip boundary condition is commonly utilized to model elastic wave propagation through layered earth media. The same approach is used here to characterize acoustic wave propagation along a cased borehole with various ...Slip boundary condition is commonly utilized to model elastic wave propagation through layered earth media. The same approach is used here to characterize acoustic wave propagation along a cased borehole with various cement bond conditions. By modeling the cement layer between casing and formation as a viscoelastic slip interface with complex coupling rigidity parameters, one can not only reduce the complexity in the classical elastic wave modeling of the problem, but also efficiently model various complicated wave phenomena that are difficult for the existing modeling. More specifically, the new theory can well describe the effect of the cement bond condition change and the location of the change(i.e., whether it is in the first interface between casing and cement, or the second interface between cement and formation) on the acoustic waves,demonstrating the good modeling capability and predicting power. Application of the theory to field data shows that the theory can correctly model the acoustic wave characteristics and interpret the cement bond condition, thus providing a useful fundament theory for casing bond evaluation using acoustic logging.展开更多
To the Editor:Acute myocardial infarction(AMI)poses a substantial threat to human health.^([1])At present,AMI is mainly treated by reperfusion,drugs,and surgery,^([2])which only temporarily delay cell death and deteri...To the Editor:Acute myocardial infarction(AMI)poses a substantial threat to human health.^([1])At present,AMI is mainly treated by reperfusion,drugs,and surgery,^([2])which only temporarily delay cell death and deterioration.Sian Harding at el^([3])suggested that myocardial transfer of specific bone marrow cells(BMCs)and progenitor cell populations may enhance recovery of systolic and diastolic function after AMI.Although a few previous meta-analysis studies of BMCs transplantation for AMI have been published,the quality of these studies was varied due to marked heterogeneity^([4,5])or because they focused on a single outcome(e.g.,cardiac function)[5]and very few evaluated the clinical evens.^([6])In addition,the effects of BMCs transplantation over different lengths of follow-up periods were unclear.In an attempt to reach more reliable conclusions,we performed an updated meta-analysis of randomized controlled trials(RCTs)and conducted subgroup analyses according to follow-up periods.展开更多
基金supported by a grant from CAMS Initiative for Innovative Medicine (Grant No. CAMS-12M-1-010)
文摘Objective: SHR-1210 is a new and promising anti-PD-1 agent for solid tumors. During the phase I study of SHR-1210, we encountered a novel but prevalent immune-related dermatologic toxicity: reactive capillary hemangiomas(RCHs). Thus we tried to summarize the features of RCHs and estimate their relationship with tumor response.Methods: This prospective observational study systematically enrolled 98 patients with advanced solid tumors from April 27th,2016 to June 8th, 2017 in the context of the phase I clinical study of SHR-1210. This report focused on the skin toxicities. Patients underwent entire skin inspection every two weeks while taking medication. The clinical course of RCHs was recorded and their association with tumor response was estimated. The data cut-off date was November 15th, 2017.Results: After a median follow-up of 242(range, 29–567) days, RCHs were observed in 85.7%(84/98) of patients on cutaneous/mucosal surfaces; 84.5%(71/84) of the RCHs were evaluated as grade 1 adverse events. No grade 3 or 4 RCHs were observed. The time of onset of RCHs was dose dependent and shortest in the 400 mg-dose cohort(P < 0.001). Spontaneous and complete regression of RCHs was observed both during and after treatment. The objective response rate of tumors for patients with RCHs was 28.9%(24/83). However, no responders were observed among the patients without RCHs.Conclusions: RCHs were prevalent but manageable during treatment with SHR-1210. It might add to the expanding literature regarding immune-related dermatologic adverse events.
文摘The asymmetric photocatalytic organic synthesis(APOS)process is a sustainable and environmentally benign method for the production of optically active chemicals with sunlight as an energy source.However,it still lacks efficient semiconductors with tunable band structures and has a low recycling stability.Herein,we report the synthesis of tetrahydroquinoline-linked covalent organic frameworks(QH-COFs)with irreversible tetrahydroquinoline linkage as efficient semiconductors for the visible-light-driven asymmetricα-alkylation of aldehydes by merging with a chiral secondary amine.Up to 94%ee was obtained over QH-COFs,and the activity of QH-COFs was significantly higher than those of inorganic semiconductors(e.g.,Ti O2,Bi VO4,and WO3)under similar conditions,which is mainly attributed to their narrow band gap and suitable band edge.As far as we know,QH-COFs are the most active semiconductors for asymmetricα-alkylation of aldehydes ever reported.The QH-COFs were prepared via a one-pot Povarov cascade imine formation and cycloaddition reaction using Sc(OTf)3/Yb(OTf)3 as Lewis acid catalysts.Attributed to the tetrahydroquinoline linkage,QH-COFs showed extremely high recycling stability,which made practicals application possible.This work not only opens up a new avenue for asymmetric photocatalysis but also provides an efficient and general method for the construction of robust COFs.
文摘Background: The late detection of endometrial carcinoma (EC) at an advanced stage often results in a poorpatient prognosis. It is hence important to identify reliable biomarkers to facilitate early detection of EC. Signaltransducer and activator of transcription (STAT) family members play an important role in several tumors, however,their impact on EC development and progression remains unclear. Methods: Machine learning methods were used toinvestigate the importance of STAT5B in EC. Results: Hence, we explored the UALCAN data mining platform andfound that while STAT1 and STAT2 were upregulated, STAT5A, STAT5B, and STAT6 were downregulated in EC.This high expression of STAT5B and STAT6 predicted favorable clinical outcomes, whereas the increased expressionof STAT1 and STAT2 predicted poor clinical outcomes. Subsequent pathway enrichment analysis revealed that theSTAT family was mainly involved in apoptosis pathway activation, cell cycle disruption, and epithelial–mesenchymaltransition. Drug sensitivity analysis demonstrated that STAT5A/5B expression was negatively correlated with drugresistance in EC. Further, the expression of STAT5B mRNA and protein was correlated with severalclinicopathological characteristics. Tumor Immune Estimation Resource (TIMER) analysis revealed that STAT5Bexpression was positively correlated with the abundance of infiltrating CD8+ T cells and neutrophils while its copynumber variation was associated with the overall immune cell infiltration. The data on the correlations betweenSTAT5B expression and related genes in uterine corpus endometrial carcinoma (UCEC) in cBio Cancer Portalshowed the closest correlation of STAT5B expression with that of KIAA0753 (also known as moonraker and OFIP),followed by COL27A1 in EC. Pathway enrichment analysis further showed that STAT5B-related genes were involvedin the mitogen-activated protein kinase (MAPK) and Ras signaling pathways. Conclusion: Collectively, our findingsprovided new insights into the role of the STAT family in EC. It also highlighted new targets for future research ondiagnostic and prognostic markers and STAT5B as a novel marker for drug sensitivity screening.
基金This work was supported by grants from the National Natural Science Foundation of China(82200684,82121001,81725001,and 81700554)the Natural Science Foundation of Jiangsu Province(BK20221032).
文摘Liver regeneration following injury aids the restoration of liver mass and the recovery of liver function.In the present study we investigated the contribution of megakaryocytic leukemia 1(MKL1),a transcriptional modulator,to liver regeneration.We report that both MKL1 expression and its nuclear translocation correlated with hepatocyte proliferation in cell and animal models of liver regeneration and in liver failure patients.Mice with MKL1 deletion exhibited defective regenerative response in the liver.Transcriptomic analysis revealed that MKL1 interacted with E2F1 to program pro-regenerative transcription.MAPKAPK2 mediated phosphorylation primed MKL1 for its interaction with E2F1.Of interest,phospholipase d2 promoted MKL1 nuclear accumulation and liver regeneration by catalyzing production of phosphatidic acid(PA).PA administration stimulated hepatocyte proliferation and enhanced survival in a MKL1-dependent manner in a pre-clinical model of liver failure.Finally,PA levels was detected to be positively correlated with expression of pro-regenerative genes and inversely correlated with liver injury in liver failure patients.In conclusion,our data reveal a novel mechanism whereby MKL1 contributes to liver regeneration.Screening for small-molecule compounds boosting MKL1 activity may be considered as a reasonable approach to treat acute liver failure.
基金supported by the National Natural Science Foundation of China (Grant No. 41774141)
文摘Slip boundary condition is commonly utilized to model elastic wave propagation through layered earth media. The same approach is used here to characterize acoustic wave propagation along a cased borehole with various cement bond conditions. By modeling the cement layer between casing and formation as a viscoelastic slip interface with complex coupling rigidity parameters, one can not only reduce the complexity in the classical elastic wave modeling of the problem, but also efficiently model various complicated wave phenomena that are difficult for the existing modeling. More specifically, the new theory can well describe the effect of the cement bond condition change and the location of the change(i.e., whether it is in the first interface between casing and cement, or the second interface between cement and formation) on the acoustic waves,demonstrating the good modeling capability and predicting power. Application of the theory to field data shows that the theory can correctly model the acoustic wave characteristics and interpret the cement bond condition, thus providing a useful fundament theory for casing bond evaluation using acoustic logging.
基金supported by grants from the National Natural Science Foundation of China(No.81960614)International scientific and technological cooperation project(No.20YF3WA020).
文摘To the Editor:Acute myocardial infarction(AMI)poses a substantial threat to human health.^([1])At present,AMI is mainly treated by reperfusion,drugs,and surgery,^([2])which only temporarily delay cell death and deterioration.Sian Harding at el^([3])suggested that myocardial transfer of specific bone marrow cells(BMCs)and progenitor cell populations may enhance recovery of systolic and diastolic function after AMI.Although a few previous meta-analysis studies of BMCs transplantation for AMI have been published,the quality of these studies was varied due to marked heterogeneity^([4,5])or because they focused on a single outcome(e.g.,cardiac function)[5]and very few evaluated the clinical evens.^([6])In addition,the effects of BMCs transplantation over different lengths of follow-up periods were unclear.In an attempt to reach more reliable conclusions,we performed an updated meta-analysis of randomized controlled trials(RCTs)and conducted subgroup analyses according to follow-up periods.
