BACKGROUND:Whether lipid-modifying drugs directly impact the outcome of sepsis remains uncertain.Therefore,systematic investigations are needed to explore the potential impact of lipid-related therapies on sepsis outc...BACKGROUND:Whether lipid-modifying drugs directly impact the outcome of sepsis remains uncertain.Therefore,systematic investigations are needed to explore the potential impact of lipid-related therapies on sepsis outcomes and to elucidate the underlying mechanisms involving circulating inflammatory cytokines,which may play critical roles in the pathogenesis of sepsis.This study aimed to utilize drug-target Mendelian randomization to assess the direct causal effects of genetically proxied lipid-modifying therapies on sepsis outcomes.METHODS:First,a two-sample Mendelian randomization study was conducted to validate the causal associations among high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C),and sepsis.A subsequent drug-target Mendelian randomization study assessed the direct causal effects of genetical y proxied lipid-modifying therapies on the risk of sepsis,sepsis-related critical care admission,and sepsis-related death.The identified lipid-modifying drug targets were subsequently explored for direct causal relationships with 36 circulating inflammatory cytokines.Finally,enrichment analyses of the identified cytokines were conducted to explore the potential relationships of lipid-modifying drugs with the inflammatory response.RESULTS:Genetically proxied cholesteryl ester transfer protein(CETP) inhibitors were significantly associated with sepsis-related critical care admission(OR=0.84,95% CI [0.74,0.95],P=0.008,) and sepsisrelated death(OR=0.68,95% CI [0.52,0.88],P=0.004).The genetically proxied CETP inhibitors were strongly associated with the levels of 15 circulating inflammatory cytokines.Enrichment analyses indicated that CETP inhibitors may modulate inflammatory cytokines and influence the inflammatory response pathway.CONCLUSION:This study supports a causal effect of genetically proxied CETP inhibitors in reducing the risk of sepsis-related critical care admission and death.These findings suggest that the underlying mechanism may involve the modulation of some circulating inflammatory cytokines,influencing the inflammatory response pathway.展开更多
BACKGROUND: Sepsis, a common acute and critical disease, leads to 11 million deaths annually worldwide. Probiotics are living microorganisms that are beneficial to the host and may benefit sepsis outcomes, but their e...BACKGROUND: Sepsis, a common acute and critical disease, leads to 11 million deaths annually worldwide. Probiotics are living microorganisms that are beneficial to the host and may benefit sepsis outcomes, but their effects are stil inconclusive. This study aimed to evaluate the overal eff ect of probiotics on the prognosis of patients with sepsis.DATA RESOURCES: We searched several sources for published/presented studies, including Pub Med, EMBASE, Web of Science, the Cochrane Library and the US National Library of Medicine Clinical Trials Register(www.clinicaltrials.gov) updated through July 30, 2023, to identify all relevant randomized controlled trials(RCTs) or observational studies that assessed the effectiveness of probiotics or synbiotics in patients with sepsis and reported mortality. We focused primarily on mortality during the study period and analyzed secondary outcomes, including 28-day mortality, in-intensive care unit(ICU) mortality and other outcomes.RESULTS: Data from 405 patients in five RCTs and 108 patients in one cohort study were included in the analysis. The overall quality of the studies was satisfactory, but clinical heterogeneity existed. All adult studies reported a tendency for probiotics to reduce the mortality of patients with sepsis, and most studies reported a decreasing trend in the incidence of infectious complications, length of ICU stay and duration of antibiotic use. There was only one RCT involving children.CONCLUSION: Probiotics show promise for improving the prognosis of patients with sepsis, including reducing mortality and the incidence of infectious complications, particularly in adult patients. Despite the limited number of studies, especially in children, these findings will be encouraging for clinical practice in the treatment of sepsis and suggest that gut microbiota-targeted therapy may improve the prognosis of patients with sepsis.展开更多
The post-transcriptional regulation of mRNA is a crucial component of gene expression.The disruption of this process has detrimental effects on the normal development and gives rise to various diseases.Searching for n...The post-transcriptional regulation of mRNA is a crucial component of gene expression.The disruption of this process has detrimental effects on the normal development and gives rise to various diseases.Searching for novel post-transcriptional regulators and exploring their roles are essential for understanding development and disease.Through a multimodal analysis of red blood cell trait genome-wide association studies(GWAS)and transcriptomes of erythropoiesis,we identify FAM46C,a non-canonical RNA poly(A)polymerase,as a necessary factor for proper red blood cell development.FAM46C is highly expressed in the late stages of the erythroid lineage,and its developmental upregulation is controlled by an erythroidspecific enhancer.We demonstrate that FAM46C stabilizes mRNA and regulates erythroid differentiation in a polymerase activity-dependent manner.Furthermore,we identify transcripts of lysosome and mitochondria components as highly confident in vivo targets of FAM46C,which aligns with the need of maturing red blood cells for substantial clearance of organelles and maintenance of cellular redox homeostasis.In conclusion,our study unveils a unique role of FAM46C in positively regulating lysosome and mitochondria components,thereby promoting erythropoiesis.展开更多
Pelvic organ prolapse(POP),whose etiology is influenced by genetic and clinical risk factors,considerably impacts women’s quality of life.However,the genetic underpinnings in non-European populations and comprehensiv...Pelvic organ prolapse(POP),whose etiology is influenced by genetic and clinical risk factors,considerably impacts women’s quality of life.However,the genetic underpinnings in non-European populations and comprehensive risk models integrating genetic and clinical factors remain underexplored.This study constructed the first polygenic risk score(PRS)for POP in the Chinese population by utilizing 20 disease-associated variants from the largest existing genome-wide association study.We analyzed a discovery cohort of 576 cases and 623 controls and a validation cohort of 264 cases and 200 controls.Results showed that the case group exhibited a significantly higher PRS than the control group.Moreover,the odds ratio of the top 10%risk group was 2.6 times higher than that of the bottom 10%.A high PRS was significantly correlated with POP occurrence in women older than 50 years old and in those with one or no childbirths.As far as we know,the integrated prediction model,which combined PRS and clinical risk factors,demonstrated better predictive accuracy than other existing PRS models.This combined risk assessment model serves as a robust tool for POP risk prediction and stratification,thereby offering insights into individualized preventive measures and treatment strategies in future clinical practice.展开更多
Dear Editor,Coronavirus disease 2019(COVID-19)is a serious respiratory disease caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Since the emergence of SARS-CoV-2,extensive research has been conduc...Dear Editor,Coronavirus disease 2019(COVID-19)is a serious respiratory disease caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Since the emergence of SARS-CoV-2,extensive research has been conducted to develop safe and effective vaccines against COVID-19,including messenger RNA(mRNA),viral vector,inactivated vaccines and protein subunit vaccines.展开更多
Dr.Kha-Ti Lim(Qiaozhi Lin,林巧稚)was born in Kulangsu,Fujian province,on December 23rd 1901(Figure 1)[1].Although unmarried and childless throughout her life,she earned the title of“Mother of Ten Thousand Infants”by...Dr.Kha-Ti Lim(Qiaozhi Lin,林巧稚)was born in Kulangsu,Fujian province,on December 23rd 1901(Figure 1)[1].Although unmarried and childless throughout her life,she earned the title of“Mother of Ten Thousand Infants”by personally delivering more than 50,000 newborns.She conducted pioneering research on subjects including fetal intrauterine respiration,female pelvic disorders,and gynecological tumors.Dr.Lim has been recognized as a founding figure of modern obstetrics and gynecology in China.She was the sole female member of the inaugural Chinese Academy of Sciences,serving as a member of its academic division.Additionally,she held the distinction of being the first Chinese director of obstetrics and gynecology at Peking Union Medical College Hospital(PUMCH).In 2009,Dr.Lim was honored as one of the“100 Inspirational Figures since the Founding of People’s Republic of China”and was bestowed the title of“Exemplary Striver”in 2019.展开更多
Uterine myomas are the most prevalent benign gynecological tumors,affecting over 70%of women[1].They are often associated with significant morbidity,including anemia and infertility.In contrast,uterine sarcomas,althou...Uterine myomas are the most prevalent benign gynecological tumors,affecting over 70%of women[1].They are often associated with significant morbidity,including anemia and infertility.In contrast,uterine sarcomas,although rare,are highly malignant,with a five-year survival rate of 50%-55%in early stages and a stark decline to 8%-12%in advanced stages[2],[3].展开更多
Background:Septic shock is a life-threatening disease with high mortality rates,and the relevant hub genes and biomarkers are poorly understood.We aimed to identify hub genes and prognostic biomarkers of mRNAs/lncRNAs...Background:Septic shock is a life-threatening disease with high mortality rates,and the relevant hub genes and biomarkers are poorly understood.We aimed to identify hub genes and prognostic biomarkers of mRNAs/lncRNAs in septic shock to rapidly and accurately diagnose infection,identify patients at a high risk of developing septic shock,and predict prognosis.Methods:Gene expression profiles of 279 patients with septic shock and 100 healthy controls were analyzed using bioinformatics methods.We screened for differentially expressed genes(DEGs),identified hub genes,and investigated the correlations between mRNA/lncRNA expression and disease severity/prognosis.Protein level validation was performed using blood proteomic data from an independent cohort study.Results:The protein–protein interaction network constructed using upregulated DEGs contained 102 nodes and 222 edges,with LTF,MMP8,MMP9,CEACAM8,CTSG,LCN2,and PRTN3 identified as hub genes.There was a possible association between LCN2 mRNA upregulation and increased severity of septic shock(odds ratio:1.518;95%confidence interval:0.999–2.305;P=0.050),approaching statistical significance,and BCL2A1 mRNA upregulation correlated with higher mortality risk(odds ratio:1.178;95%confidence interval:1.035–1.341;P=0.013).No significant prognostic correlation was observed for lncRNAs.The validation cohort confirmed significant upregulation of MMP9,CTSG,LCN2,LTF,and MMP8 proteins in patients with septic shock,with MMP9,LCN2,CTSG,and LTF exhibiting strong diagnostic performance(area under the curve>0.8).Conclusion:Seven hub genes related to septic shock were identified,including MMP9,LCN2,CTSG,and LTF,which could potentially function as candidate biotargets and biomarkers for the diagnosis and prognostic prediction of septic shock,though further validation is needed.Notably,LCN2 showed a trend toward association with disease severity,while BCL2A1 correlated with mortality risk.展开更多
文摘BACKGROUND:Whether lipid-modifying drugs directly impact the outcome of sepsis remains uncertain.Therefore,systematic investigations are needed to explore the potential impact of lipid-related therapies on sepsis outcomes and to elucidate the underlying mechanisms involving circulating inflammatory cytokines,which may play critical roles in the pathogenesis of sepsis.This study aimed to utilize drug-target Mendelian randomization to assess the direct causal effects of genetically proxied lipid-modifying therapies on sepsis outcomes.METHODS:First,a two-sample Mendelian randomization study was conducted to validate the causal associations among high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C),and sepsis.A subsequent drug-target Mendelian randomization study assessed the direct causal effects of genetical y proxied lipid-modifying therapies on the risk of sepsis,sepsis-related critical care admission,and sepsis-related death.The identified lipid-modifying drug targets were subsequently explored for direct causal relationships with 36 circulating inflammatory cytokines.Finally,enrichment analyses of the identified cytokines were conducted to explore the potential relationships of lipid-modifying drugs with the inflammatory response.RESULTS:Genetically proxied cholesteryl ester transfer protein(CETP) inhibitors were significantly associated with sepsis-related critical care admission(OR=0.84,95% CI [0.74,0.95],P=0.008,) and sepsisrelated death(OR=0.68,95% CI [0.52,0.88],P=0.004).The genetically proxied CETP inhibitors were strongly associated with the levels of 15 circulating inflammatory cytokines.Enrichment analyses indicated that CETP inhibitors may modulate inflammatory cytokines and influence the inflammatory response pathway.CONCLUSION:This study supports a causal effect of genetically proxied CETP inhibitors in reducing the risk of sepsis-related critical care admission and death.These findings suggest that the underlying mechanism may involve the modulation of some circulating inflammatory cytokines,influencing the inflammatory response pathway.
基金supported by the National High Level Hospital Clinical Research Funding (2022-PUMCH-B-109)Chinese Academy of Medical Science Innovation Fund for Medical Sciences (CIFMS)(2021-I2M-1-020)。
文摘BACKGROUND: Sepsis, a common acute and critical disease, leads to 11 million deaths annually worldwide. Probiotics are living microorganisms that are beneficial to the host and may benefit sepsis outcomes, but their effects are stil inconclusive. This study aimed to evaluate the overal eff ect of probiotics on the prognosis of patients with sepsis.DATA RESOURCES: We searched several sources for published/presented studies, including Pub Med, EMBASE, Web of Science, the Cochrane Library and the US National Library of Medicine Clinical Trials Register(www.clinicaltrials.gov) updated through July 30, 2023, to identify all relevant randomized controlled trials(RCTs) or observational studies that assessed the effectiveness of probiotics or synbiotics in patients with sepsis and reported mortality. We focused primarily on mortality during the study period and analyzed secondary outcomes, including 28-day mortality, in-intensive care unit(ICU) mortality and other outcomes.RESULTS: Data from 405 patients in five RCTs and 108 patients in one cohort study were included in the analysis. The overall quality of the studies was satisfactory, but clinical heterogeneity existed. All adult studies reported a tendency for probiotics to reduce the mortality of patients with sepsis, and most studies reported a decreasing trend in the incidence of infectious complications, length of ICU stay and duration of antibiotic use. There was only one RCT involving children.CONCLUSION: Probiotics show promise for improving the prognosis of patients with sepsis, including reducing mortality and the incidence of infectious complications, particularly in adult patients. Despite the limited number of studies, especially in children, these findings will be encouraging for clinical practice in the treatment of sepsis and suggest that gut microbiota-targeted therapy may improve the prognosis of patients with sepsis.
基金funded by the Starting Fund from Zhejiang University to N.L.and grants to X.L.from National Natural Science Foundation of China(82170120 and 81670108)CAMS Initiative for Innovative Medicine(2017-12M-B&R-04)+2 种基金Medical Epigenetics Research Cen-ter,CAMS(2018PT31015)the State Key Laboratory of Medical Molecular Biology(2060204)Haihe L aboratory of Cell Ecosystem Innovation Fund(22HHXBSS00008).
文摘The post-transcriptional regulation of mRNA is a crucial component of gene expression.The disruption of this process has detrimental effects on the normal development and gives rise to various diseases.Searching for novel post-transcriptional regulators and exploring their roles are essential for understanding development and disease.Through a multimodal analysis of red blood cell trait genome-wide association studies(GWAS)and transcriptomes of erythropoiesis,we identify FAM46C,a non-canonical RNA poly(A)polymerase,as a necessary factor for proper red blood cell development.FAM46C is highly expressed in the late stages of the erythroid lineage,and its developmental upregulation is controlled by an erythroidspecific enhancer.We demonstrate that FAM46C stabilizes mRNA and regulates erythroid differentiation in a polymerase activity-dependent manner.Furthermore,we identify transcripts of lysosome and mitochondria components as highly confident in vivo targets of FAM46C,which aligns with the need of maturing red blood cells for substantial clearance of organelles and maintenance of cellular redox homeostasis.In conclusion,our study unveils a unique role of FAM46C in positively regulating lysosome and mitochondria components,thereby promoting erythropoiesis.
基金funded by the National Natural Science Foundation of China(Nos.82171621 to Lei Li,82271656 to Lan Zhu,82171614 to Na Chen)the National High Level Hospital Clinical Research Funding(No.2022-PUMCH-A-231 to Lei Li)+2 种基金the National Key Research and Development Program of China(Nos.2023YFC2706000,2023YFC2706001,2021YFC2701301 to Lan Zhu,2021YFC2701400 to Shan Deng)Beijing Natural Science Foundation(No.7232125 to Na Chen)CAMS Initiative Fund to Medical Sciences(No.2022-I2M-C&T-B-029 to Na Chen).
文摘Pelvic organ prolapse(POP),whose etiology is influenced by genetic and clinical risk factors,considerably impacts women’s quality of life.However,the genetic underpinnings in non-European populations and comprehensive risk models integrating genetic and clinical factors remain underexplored.This study constructed the first polygenic risk score(PRS)for POP in the Chinese population by utilizing 20 disease-associated variants from the largest existing genome-wide association study.We analyzed a discovery cohort of 576 cases and 623 controls and a validation cohort of 264 cases and 200 controls.Results showed that the case group exhibited a significantly higher PRS than the control group.Moreover,the odds ratio of the top 10%risk group was 2.6 times higher than that of the bottom 10%.A high PRS was significantly correlated with POP occurrence in women older than 50 years old and in those with one or no childbirths.As far as we know,the integrated prediction model,which combined PRS and clinical risk factors,demonstrated better predictive accuracy than other existing PRS models.This combined risk assessment model serves as a robust tool for POP risk prediction and stratification,thereby offering insights into individualized preventive measures and treatment strategies in future clinical practice.
基金supported by grants from the National Key R&D Program of China(2023YFC2507102)Special Foundation for Taishan Scholars Program of Shandong Province(No.tsqnz20240855)+3 种基金National High-Level Hospital Clinical Research Funding(2022-PUMCH-A-114)the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(CIFMS2022-I2M-2-001,CIFMS2022-I2M-1-011 and 2022-I2M-CoV19-003)the National Natural Science Foundation of China(82341064 and 82271656)State Key Laboratory Special Fund(2060204).
文摘Dear Editor,Coronavirus disease 2019(COVID-19)is a serious respiratory disease caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Since the emergence of SARS-CoV-2,extensive research has been conducted to develop safe and effective vaccines against COVID-19,including messenger RNA(mRNA),viral vector,inactivated vaccines and protein subunit vaccines.
基金supported by the National High Level Hospital Clinical Research Funding(2022-PUMCH-D-003,2022-PUMCH-B-087)the National Natural Science Foundation of China(82271656)+1 种基金Beijing Municipal Natural Science Foundation(No.Z220013)CAMS Initiative for Innovative Medicine(2021-I2M-1-004).
文摘Dr.Kha-Ti Lim(Qiaozhi Lin,林巧稚)was born in Kulangsu,Fujian province,on December 23rd 1901(Figure 1)[1].Although unmarried and childless throughout her life,she earned the title of“Mother of Ten Thousand Infants”by personally delivering more than 50,000 newborns.She conducted pioneering research on subjects including fetal intrauterine respiration,female pelvic disorders,and gynecological tumors.Dr.Lim has been recognized as a founding figure of modern obstetrics and gynecology in China.She was the sole female member of the inaugural Chinese Academy of Sciences,serving as a member of its academic division.Additionally,she held the distinction of being the first Chinese director of obstetrics and gynecology at Peking Union Medical College Hospital(PUMCH).In 2009,Dr.Lim was honored as one of the“100 Inspirational Figures since the Founding of People’s Republic of China”and was bestowed the title of“Exemplary Striver”in 2019.
基金supported by the Independent Research Fund of the State Key Laboratory of Complex,Severe,and Rare Diseases(2025-I-PY-010)Beijing Municipal Natural Science Foundation(Z220013)+4 种基金the National Natural Science Foundation of China(82271656,82530054,and 82171621)the National Key R&D Program of China(2023YFC2706001)the National High Level Hospital Clinical Research Funding(2025-PUMCH-C-037 and 2022-PUMCHC-060)CAMS Initiative for Innovative Medicine(2021-I2M-1-004)Barnhart Family Distinguished Professorship from the University of Texas MD Anderson Cancer Center.
文摘Uterine myomas are the most prevalent benign gynecological tumors,affecting over 70%of women[1].They are often associated with significant morbidity,including anemia and infertility.In contrast,uterine sarcomas,although rare,are highly malignant,with a five-year survival rate of 50%-55%in early stages and a stark decline to 8%-12%in advanced stages[2],[3].
基金supported by the National High Level Hospital Clinical Research Funding[grant number 2022-PUMCH-B-109]the Chinese Academy of Medical Science Innovation Fund for Medical Sciences(CIFMS)[grant number 2021-I2M-1-020].
文摘Background:Septic shock is a life-threatening disease with high mortality rates,and the relevant hub genes and biomarkers are poorly understood.We aimed to identify hub genes and prognostic biomarkers of mRNAs/lncRNAs in septic shock to rapidly and accurately diagnose infection,identify patients at a high risk of developing septic shock,and predict prognosis.Methods:Gene expression profiles of 279 patients with septic shock and 100 healthy controls were analyzed using bioinformatics methods.We screened for differentially expressed genes(DEGs),identified hub genes,and investigated the correlations between mRNA/lncRNA expression and disease severity/prognosis.Protein level validation was performed using blood proteomic data from an independent cohort study.Results:The protein–protein interaction network constructed using upregulated DEGs contained 102 nodes and 222 edges,with LTF,MMP8,MMP9,CEACAM8,CTSG,LCN2,and PRTN3 identified as hub genes.There was a possible association between LCN2 mRNA upregulation and increased severity of septic shock(odds ratio:1.518;95%confidence interval:0.999–2.305;P=0.050),approaching statistical significance,and BCL2A1 mRNA upregulation correlated with higher mortality risk(odds ratio:1.178;95%confidence interval:1.035–1.341;P=0.013).No significant prognostic correlation was observed for lncRNAs.The validation cohort confirmed significant upregulation of MMP9,CTSG,LCN2,LTF,and MMP8 proteins in patients with septic shock,with MMP9,LCN2,CTSG,and LTF exhibiting strong diagnostic performance(area under the curve>0.8).Conclusion:Seven hub genes related to septic shock were identified,including MMP9,LCN2,CTSG,and LTF,which could potentially function as candidate biotargets and biomarkers for the diagnosis and prognostic prediction of septic shock,though further validation is needed.Notably,LCN2 showed a trend toward association with disease severity,while BCL2A1 correlated with mortality risk.
基金supported by the National Natural Science Foundation of China(82171620 and 81830043)the National Key R&D Program of China(2021YFC2701403 and 2018YFC2002201)the National High Level Hospital Clinical Research Funding(2022-PUMCH-A-205 and 2022-PUMCH-A-114)。
