OBJECTIVES: To investigate the genomic characteristics and prognostic factors of juvenile myelomonocytic leukemia (JMML) with RAS mutations. METHODS: A retrospective analysis was conducted on the clinical data of JMML children with RAS mutations treated at the Hematology Hospital of Chinese Academy of Medical Sciences, from January 2008 to November 2022. RESULTS: A total of 34 children were included, with 17 cases (50%) having isolated NRAS mutations, 9 cases (27%) having isolated KRAS mutations, and 8 cases (24%) having compound mutations. Compared to children with isolated NRAS mutations, those with NRAS compound mutations showed statistically significant differences in age at onset, platelet count, and fetal hemoglobin proportion (P<0.05). Cox proportional hazards regression model analysis revealed that hematopoietic stem cell transplantation (HSCT) and hepatomegaly (≥2 cm below the costal margin) were factors affecting the survival rate of JMML children with RAS mutations (P<0.05); hepatomegaly was a factor affecting survival in the non-HSCT group (P<0.05). CONCLUSIONS Children with NRAS compound mutations have a later onset age compared to those with isolated NRAS mutations. At initial diagnosis, children with NRAS compound mutations have poorer peripheral platelet and fetal hemoglobin levels than those with isolated NRAS mutations. Liver size at initial diagnosis is related to the prognosis of JMML children with RAS mutations. HSCT can improve the prognosis of JMML children with RAS mutations.
Humans ; Leukemia, Myelomonocytic, Juvenile/therapy* ; Mutation ; Male ; Female ; Child, Preschool ; Retrospective Studies ; Child ; Infant ; GTP Phosphohydrolases/genetics* ; Membrane Proteins/genetics* ; Adolescent ; Hematopoietic Stem Cell Transplantation ; Proportional Hazards Models ; Proto-Oncogene Proteins p21(ras)/genetics* ; Prognosis

OBJECTIVES: To summarize the clinical and genetic characteristics of epilepsy with intellectual disability caused by SETD1B gene variants in children. METHODS: A retrospective analysis was conducted on the clinical data of three children with SETD1B gene variants diagnosed and treated at the Department of Pediatric Neurology of Xiangya Hospital of Central South University. Relevant literature was reviewed to summarize the clinical characteristics of this condition. RESULTS: All three children presented with symptoms during infancy or early childhood, including mild intellectual disability and myoclonic seizures, with two cases exhibiting eyelid myoclonia. After treatment with three or more antiepileptic drugs, two cases achieved seizure control or partial control, while one case remained refractory. Each of the three children was found to have a heterozygous variant in the SETD1B gene (one deletion, one frameshift, and one missense variant). To date, 54 cases with SETD1B gene variants have been reported, involving a total of 56 variants, predominantly missense variants (64%, 36/56). The main clinical manifestations included varying degrees of developmental delay (96%, 52/54) and seizures (81%, 44/54). Among the 44 patients with seizures, myoclonic (20%, 9/44) and absence seizures (34%, 15/44) were common, with eyelid myoclonia reported in six cases. Approximately one-fifth of these patients had poorly controlled seizures. CONCLUSIONS The primary phenotypes associated with SETD1B gene variants are intellectual disability and seizures, and seizures exhibit distinct characteristics. Eyelid myoclonia is not uncommon.
Humans ; Intellectual Disability/complications* ; Epilepsy/complications* ; Male ; Female ; Histone-Lysine N-Methyltransferase/genetics* ; Child, Preschool ; Child ; Retrospective Studies

OBJECTIVE: To observe the efficacy and safety of 21-day venetoclax (VEN) plus azacitidine (AZA) (21-day VA) in newly diagnosed unfit acute myeloid leukemia (AML) patients in the real-world. METHODS: The clinical data of patients with unfit-AML who received 21-day VA regimen from December 2020 to July 2024 in our center and completed at least 1 cycle of therapeutic effect assessment was retrospectively collected to analyze the safety, efficacy and its influencing factors. RESULTS: A total of 59 patients were enrolled in our study, with a median age of 67(48-87) years old. After 1 cycle of therapy, the composite complete remission (cCR) rate was 74.5%, 54.2% of cases were negative for minimal residual disease (MRD). Among them, the MRD negative rate of patients with NPM1 mutation was significantly higher than that of patients without NPM1 mutation ( P =0.032). The median follow-up of patients was 19(2-38) months, the best cCR and MRD negative rates were 78% and 64.4%, respectively, the median overall survival (OS) time was 12 months, and the median progression free survival (PFS) time was 5 months. Multivariate Cox regression analysis showed less than 4 cycles of VA chemotherapy were independent risk factor for PFS and OS ( P < 0.05). After achieving remission, anemia and thrombocytopenia improved with the increase of the number of chemotherapy cycle. CONCLUSION In real-world, 21-day VA regimen still shows significant efficacy in the treatment of newly diagnosed unfit-AML, without adversely affecting remission rate and MRD negative rate of the first cycle.
Humans ; Leukemia, Myeloid, Acute/drug therapy* ; Aged ; Middle Aged ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use* ; Sulfonamides/therapeutic use* ; Azacitidine/therapeutic use* ; Aged, 80 and over ; Male ; Female ; Retrospective Studies ; Nucleophosmin ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Remission Induction ; Mutation ; Treatment Outcome

Objective·To investigate the effects and molecular mechanisms of phosphatidylethanolamine(PE)on macrophage senescence and its senescence-associated secretory phenotype(SASP),as well as its pathophysiological role in liver injury.Methods·A macrophage senescence model was established using doxorubicin(DOX),followed by PE treatment.A mouse liver injury model was generated via intraperitoneal co-administration of PE and lipopolysaccharide(LPS)to investigate the effects of PE on liver injury.Senescence markers and SASP factors,including senescence-associated β-galactosidase(SA-β-gal),cell cycle inhibitor p21,tumor necrosis factor-α(TNF-α),and interleukin-6(IL-6),were evaluated using SA-β-gal staining,quantitative real-time PCR,and Western blotting.RNA sequencing(RNA-seq)was performed,followed by Gene Ontology(GO)cellular component enrichment analysis,Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis,Gene Set Variation Analysis(GSVA),and Gene Set Enrichment Analysis(GSEA),to explore the molecular mechanisms and signaling pathways by which PE promotes macrophage senescence.The expression of endoplasmic reticulum(ER)stress-related proteins,including inositol-requiring enzyme 1 α(IRE1α),spliced X-box binding protein 1(XBP1s),activating transcription factor 6(ATF6),ATF4,and C/EBP homologous protein(CHOP),was analyzed through in vivo and in vitro experiments.Results·PE significantly promoted the expression of senescence markers SA-β-gal,p21,p16 and SASP factors.RNA-seq analysis revealed that ER stress was involved in PE-induced promotion of SASP.Further experiments demonstrated that PE activated the ER stress signaling pathway,promoting macrophage senescence and the expression of SASP factors.In vivo experiments further confirmed that PE exacerbated LPS-induced liver injury in mice through ER stress.Conclusion·PE promotes macrophage senescence and the expression of SASP factors by activating ER stress signaling pathway,thereby aggravating LPS-induced liver injury.

Aim To investigate the effect of Huangqi injection(HI)and Huangqi oral solution(HO)on cisplatin-induced nephrotoxicity(CIN)based on un-targeted metabolomics technology and the underlying mechanisms.Methods Sprague Dawley(SD)rats were randomly divided into the blank group,cisplatin(CDDP)model group,HI treatment group,and HO treatment group,then the CIN model was built with low dose multiple intraperitoneal injections of CDDP.Pre-liminary evaluation of the renal protective efficacy of HI and HO was performed by measuring serum creatinine(Scr),blood urea nitrogen(BUN),and organ indi-ces.Further screening and identification of potential biomarkers(PBs)related to CIN and HI/HO pharma-cological effects were attained through metabolomics studies of renal tissues,and pathway enrichment analy-sis was conducted.Results HI and HO significantly restored the abnormal increase in renal function indica-tors and abnormal decrease in organ indices caused by CDDP,as well as significantly improved the abnormal renal metabolic profile induced by CDDP,indicating that both HI and HO had good alleviating effects on CIN.HI significantly reversed 47 out of 54 CIN related PBs,mainly involving metabolic pathways such as glycerophospholipid metabolism,tryptophan metabo-lism,pantothenate and CoA biosynthesis;HO signifi-cantly reversed 18 out of 54 CIN related PBs,mainly involving metabolic pathways such as taurine and hypo-taurine metabolism,ascorbate and aldarate metabo-lism,pentose and glucuronate interconversions.Con-clusions Both HI and HO have significant alleviating effects on CIN.In the short term,HI salleviating effect is superior to that of HO.Overall,the mechanisms by which both alleviate CIN are mainly related to regula-ting lipid metabolism,amino acid metabolism.

Background:Rhei Radix et Rhizoma has been traditionally used as a potent laxative for centuries due to its remarkable efficacy.Raw pieces of Rhei Radix et Rhizoma(RP)are known for their strong laxative effects,often accompanied by side effects,while steamed Rhei Radix et Rhizoma pieces(SP)possess a milder laxative effect and are widely used clinically.However,there is a lack of comprehensive evidence examining the mechanisms underlying SP's effectiveness,particularly from a bioavailability perspective.Objective:This study aimed to investigate the impact of the steaming process on the in vivo disposition of RP and SP through pharmacokinetics,tissue distribution,and excretion assays.Methods:An ultra-performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous quantitative analysis of prototype anthraquinones and their glucuronide metabolites.Pharmacokinetic,tissue distribution,and excre-tion assays were conducted in constipation rats following oral administration of RP and SP.Blood,tissue,urine,and fecal samples were collected and analyzed to compare the absorption,distribution,metabolism,and excretion profiles of anthraquinones,high-lighting differences in bioavailability and safety between RP and SP.Results:Compared with the RP group,the SP group showed significantly reduced area under the plasma concentration-time curve,mean residence time,and half-life time values for rhein-8-O-β-D-glucopyranoside,rhein,emodin,aloe-emodin,and their glucuronide metabolites.The clearance values were significantly increased in the SP group.These results demonstrate that SP led to lower exposure levels and higher elimination rates of these components compared with RP.Additionally,these compo-nents were primarily distributed in the large intestine,where they exerted their laxative effects.Glucuronide metabolites were mainly excreted through urination,while prototype components were excreted in both urine and feces.Notably,the cumulative excretion of aloe-emodin,emodin,rhein,and their glucuronide metabolites was significantly higher in both urine and feces after SP administra-tion,indicating that SP enhances the excretion of these components compared with RP.Conclusion:The findings suggest that SP reduced anthraquinone exposure levels while enhancing their excretion,demonstrating that the steaming process significantly promotes the elimination of key components.This study provides a comprehensive analysis of how steaming alters the in vivo disposition of Rhei Radix et Rhizoma,offering a scientific basis for the improved safety and clinical use of SP.These insights not only clarify the mechanistic differences between RP and SP but also contribute to a broader understanding of processing-induced modifications in Chinese medicines.This research paves the way for optimizing Chinese medicine processing techniques to enhance the safety and efficacy of herbal therapies.

Background: Rhei Radix et Rhizoma has been traditionally used as a potent laxative for centuries due to its remarkable efficacy. Raw pieces of Rhei Radix et Rhizoma (RP) are known for their strong laxative effects, often accompanied by side effects, while steamed Rhei Radix et Rhizoma pieces (SP) possess a milder laxative effect and are widely used clinically. However, there is a lack of comprehensive evidence examining the mechanisms underlying SP's effectiveness, particularly from a bioavailability perspective. Objective: This study aimed to investigate the impact of the steaming process on the in vivo disposition of RP and SP through pharmacokinetics, tissue distribution, and excretion assays. Methods: An ultra-performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous quantitative analysis of prototype anthraquinones and their glucuronide metabolites. Pharmacokinetic, tissue distribution, and excretion assays were conducted in constipation rats following oral administration of RP and SP. Blood, tissue, urine, and fecal samples were collected and analyzed to compare the absorption, distribution, metabolism, and excretion profiles of anthraquinones, highlighting differences in bioavailability and safety between RP and SP. Results: Compared with the RP group, the SP group showed significantly reduced area under the plasma concentration-time curve, mean residence time, and half-life time values for rhein-8-O-β-D-glucopyranoside, rhein, emodin, aloe-emodin, and their glucuronide metabolites. The clearance values were significantly increased in the SP group. These results demonstrate that SP led to lower exposure levels and higher elimination rates of these components compared with RP. Additionally, these components were primarily distributed in the large intestine, where they exerted their laxative effects. Glucuronide metabolites were mainly excreted through urination, while prototype components were excreted in both urine and feces. Notably, the cumulative excretion of aloe-emodin, emodin, rhein, and their glucuronide metabolites was significantly higher in both urine and feces after SP administration, indicating that SP enhances the excretion of these components compared with RP. Conclusion: The findings suggest that SP reduced anthraquinone exposure levels while enhancing their excretion, demonstrating that the steaming process significantly promotes the elimination of key components. This study provides a comprehensive analysis of how steaming alters the in vivo disposition of Rhei Radix et Rhizoma, offering a scientific basis for the improved safety and clinical use of SP. These insights not only clarify the mechanistic differences between RP and SP but also contribute to a broader understanding of processing-induced modifications in Chinese medicines. This research paves the way for optimizing Chinese medicine processing techniques to enhance the safety and efficacy of herbal therapies.

Background:Rhei Radix et Rhizoma has been traditionally used as a potent laxative for centuries due to its remarkable efficacy.Raw pieces of Rhei Radix et Rhizoma(RP)are known for their strong laxative effects,often accompanied by side effects,while steamed Rhei Radix et Rhizoma pieces(SP)possess a milder laxative effect and are widely used clinically.However,there is a lack of comprehensive evidence examining the mechanisms underlying SP's effectiveness,particularly from a bioavailability perspective.Objective:This study aimed to investigate the impact of the steaming process on the in vivo disposition of RP and SP through pharmacokinetics,tissue distribution,and excretion assays.Methods:An ultra-performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous quantitative analysis of prototype anthraquinones and their glucuronide metabolites.Pharmacokinetic,tissue distribution,and excre-tion assays were conducted in constipation rats following oral administration of RP and SP.Blood,tissue,urine,and fecal samples were collected and analyzed to compare the absorption,distribution,metabolism,and excretion profiles of anthraquinones,high-lighting differences in bioavailability and safety between RP and SP.Results:Compared with the RP group,the SP group showed significantly reduced area under the plasma concentration-time curve,mean residence time,and half-life time values for rhein-8-O-β-D-glucopyranoside,rhein,emodin,aloe-emodin,and their glucuronide metabolites.The clearance values were significantly increased in the SP group.These results demonstrate that SP led to lower exposure levels and higher elimination rates of these components compared with RP.Additionally,these compo-nents were primarily distributed in the large intestine,where they exerted their laxative effects.Glucuronide metabolites were mainly excreted through urination,while prototype components were excreted in both urine and feces.Notably,the cumulative excretion of aloe-emodin,emodin,rhein,and their glucuronide metabolites was significantly higher in both urine and feces after SP administra-tion,indicating that SP enhances the excretion of these components compared with RP.Conclusion:The findings suggest that SP reduced anthraquinone exposure levels while enhancing their excretion,demonstrating that the steaming process significantly promotes the elimination of key components.This study provides a comprehensive analysis of how steaming alters the in vivo disposition of Rhei Radix et Rhizoma,offering a scientific basis for the improved safety and clinical use of SP.These insights not only clarify the mechanistic differences between RP and SP but also contribute to a broader understanding of processing-induced modifications in Chinese medicines.This research paves the way for optimizing Chinese medicine processing techniques to enhance the safety and efficacy of herbal therapies.

Aim To investigate the effect of Huangqi injection(HI)and Huangqi oral solution(HO)on cisplatin-induced nephrotoxicity(CIN)based on un-targeted metabolomics technology and the underlying mechanisms.Methods Sprague Dawley(SD)rats were randomly divided into the blank group,cisplatin(CDDP)model group,HI treatment group,and HO treatment group,then the CIN model was built with low dose multiple intraperitoneal injections of CDDP.Pre-liminary evaluation of the renal protective efficacy of HI and HO was performed by measuring serum creatinine(Scr),blood urea nitrogen(BUN),and organ indi-ces.Further screening and identification of potential biomarkers(PBs)related to CIN and HI/HO pharma-cological effects were attained through metabolomics studies of renal tissues,and pathway enrichment analy-sis was conducted.Results HI and HO significantly restored the abnormal increase in renal function indica-tors and abnormal decrease in organ indices caused by CDDP,as well as significantly improved the abnormal renal metabolic profile induced by CDDP,indicating that both HI and HO had good alleviating effects on CIN.HI significantly reversed 47 out of 54 CIN related PBs,mainly involving metabolic pathways such as glycerophospholipid metabolism,tryptophan metabo-lism,pantothenate and CoA biosynthesis;HO signifi-cantly reversed 18 out of 54 CIN related PBs,mainly involving metabolic pathways such as taurine and hypo-taurine metabolism,ascorbate and aldarate metabo-lism,pentose and glucuronate interconversions.Con-clusions Both HI and HO have significant alleviating effects on CIN.In the short term,HI salleviating effect is superior to that of HO.Overall,the mechanisms by which both alleviate CIN are mainly related to regula-ting lipid metabolism,amino acid metabolism.

Objective·To investigate the effects and molecular mechanisms of phosphatidylethanolamine(PE)on macrophage senescence and its senescence-associated secretory phenotype(SASP),as well as its pathophysiological role in liver injury.Methods·A macrophage senescence model was established using doxorubicin(DOX),followed by PE treatment.A mouse liver injury model was generated via intraperitoneal co-administration of PE and lipopolysaccharide(LPS)to investigate the effects of PE on liver injury.Senescence markers and SASP factors,including senescence-associated β-galactosidase(SA-β-gal),cell cycle inhibitor p21,tumor necrosis factor-α(TNF-α),and interleukin-6(IL-6),were evaluated using SA-β-gal staining,quantitative real-time PCR,and Western blotting.RNA sequencing(RNA-seq)was performed,followed by Gene Ontology(GO)cellular component enrichment analysis,Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis,Gene Set Variation Analysis(GSVA),and Gene Set Enrichment Analysis(GSEA),to explore the molecular mechanisms and signaling pathways by which PE promotes macrophage senescence.The expression of endoplasmic reticulum(ER)stress-related proteins,including inositol-requiring enzyme 1 α(IRE1α),spliced X-box binding protein 1(XBP1s),activating transcription factor 6(ATF6),ATF4,and C/EBP homologous protein(CHOP),was analyzed through in vivo and in vitro experiments.Results·PE significantly promoted the expression of senescence markers SA-β-gal,p21,p16 and SASP factors.RNA-seq analysis revealed that ER stress was involved in PE-induced promotion of SASP.Further experiments demonstrated that PE activated the ER stress signaling pathway,promoting macrophage senescence and the expression of SASP factors.In vivo experiments further confirmed that PE exacerbated LPS-induced liver injury in mice through ER stress.Conclusion·PE promotes macrophage senescence and the expression of SASP factors by activating ER stress signaling pathway,thereby aggravating LPS-induced liver injury.