T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic malignancy with a poor prognosis, despite advancements in treatment. Many patients struggle with relapse or refractory disease. Investigating the role of the super-enhancer (SE) regulated gene ubiquitin-specific protease 20 (USP20) in T-ALL could enhance targeted therapies and improve clinical outcomes. Analysis of histone H3 lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) data from six T-ALL cell lines and seven pediatric samples identified USP20 as an SE-regulated driver gene. Utilizing the Cancer Cell Line Encyclopedia (CCLE) and BloodSpot databases, it was found that USP20 is specifically highly expressed in T-ALL. Knocking down USP20 with short hairpin RNA (shRNA) increased apoptosis and inhibited proliferation in T-ALL cells. In vivo studies showed that USP20 knockdown reduced tumor growth and improved survival. The USP20 inhibitor GSK2643943A demonstrated similar anti-tumor effects. Mass spectrometry, RNA-Seq, and immunoprecipitation revealed that USP20 interacted with hypoxia-inducible factor 1 subunit alpha (HIF1A) and stabilized it by deubiquitination. Cleavage under targets and tagmentation (CUT&Tag) results indicated that USP20 co-localized with HIF1A, jointly modulating target genes in T-ALL. This study identifies USP20 as a therapeutic target in T-ALL and suggests GSK2643943A as a potential treatment strategy.

Nipah virus (NiV) and related viruses form a distinct henipavirus genus within the Paramyxoviridae family. NiV continues to spillover into the humans causing deadly outbreaks with increasing human-bat interaction. NiV encodes the large protein (L) and phosphoprotein (P) to form the viral RNA polymerase machinery. Their sequences show limited homologies to those of non-henipavirus paramyxoviruses. We report two cryo-electron microscopy (cryo-EM) structures of the Nipah virus (NiV) polymerase L-P complex, expressed and purified in either its full-length or truncated form. The structures resolve the RNA-dependent RNA polymerase (RdRp) and polyribonucleotidyl transferase (PRNTase) domains of the L protein, as well as a tetrameric P protein bundle bound to the L-RdRp domain. L-protein C-terminal regions are unresolved, indicating flexibility. Two PRNTase domain zinc-binding sites, conserved in most Mononegavirales, are confirmed essential for NiV polymerase activity. The structures further reveal anchoring of the P protein bundle and P protein X domain (XD) linkers on L, via an interaction pattern distinct among Paramyxoviridae. These interactions facilitate binding of a P protein XD linker in the nucleotide entry channel and distinct positioning of other XD linkers. We show that the disruption of the L-P interactions reduces NiV polymerase activity. The reported structures should facilitate rational antiviral-drug discovery and provide a guide for the functional study of NiV polymerase.
Nipah Virus/chemistry* ; Cryoelectron Microscopy ; Viral Proteins/genetics* ; RNA-Dependent RNA Polymerase/genetics* ; Phosphoproteins/genetics* ; Humans ; Models, Molecular ; Protein Binding

ObjectiveTo explore the possible mechanisms of Wenyang Huazhuo Formula （温阳化浊方， WHF） in improving reproductive aging from the perspective of the ovarian mechanical microenvironment. MethodsThe experiment included five groups， 3-month group （20 female mice at 3 months of age）， 6-month group （20 female mice at 6 months of age）， 6-month + WHF group （20 female mice at 5 months of age treated with WHF）， 9-month group （20 female mice at 9 months of age）， and 9-month + WHF group （20 female mice at 8 months of age treated with WHF）. The 6-month + WHF group and 9-month + WHF group were orally administered WHF 41.2 g/（kg·d） once daily for 4 consecutive weeks. The other three groups received no intervention. Reproductive hormone levels were measured by ELISA. HE staining was used to count the numbers of various stages of follicles. Ovarian hyaluronic acid （HA） content and collagen fiber content were measured to evaluate the ovarian mechanical microenvironment. Superovulation was performed to observe the number of eggs obtained， as well as the number of offspring and birth weight to assess fertility. The in vitro fertilization and blastocyst culture of oocytes from female offspring in each group were observed to evaluate the effect of WHF on offspring reproductive potential. ResultsCompared with the 3-month group， the 6-month group and 9-month group showed significantly decreased serum levels of gonadotropin-releasing hormone （GnRH）， follicle-stimulating hormone （FSH）， and luteinizing hormone （LH）， decreased ovarian collagen content， and reduced numbers of primordial and secondary follicles. In contrast， the numbers of primary follicles， antral follicles， and atretic follicles increased. The levels of anti-Müllerian hormone （AMH）， ovarian HA content， and the fertilization rate， cleavage rate， and blastocyst formation rate of oocytes from offspring were significantly lower （P＜0.05）. Compared with the 6-month group， the 6-month + WHF group showed significantly reduced serum levels of GnRH， FSH， and LH， with a significant decrease in primary follicles， antral follicles， and atretic follicles as well as increase of AMH levels， ovarian HA content， number of primordial and secondary follicle， egg count， and offspring birth weight （P＜0.05）. Compared with the 9-month group， the 9-month + WHF group exhibited reduced GnRH， FSH， and collagen fiber content， as well as reduced number of primary follicles， antral follicles， and atretic follicles. However， AMH levels， ovarian HA content， number of primordial and secondary follicle， egg count， offspring numbers， birth weight， fertilization rate， cleavage rate， and blastocyst formation rate of oocytes from offspring all significantly increased （P＜0.05）. ConclusionWHF can significantly improve the ovarian reserve， fertility， and reproductive potential in offspring during reproductive mid-life and late-life stages. Its effect may be related to the remodeling of the mechanical microenvironment of aging ovaries. Moreover， the effect on the mechanical microenvironment remodeling of late-stage ovaries and the improvement of the offspring reproductive potential is more significant.

Objective:To explore the efficacy of interventional therapy for transplant renal artery stenosis (TRAS) and the 1-, 2-, and 3-year survival rates of recipients after treatment.Methods:This is a retrospective case series study. Forty TRAS recipients who underwent interventional treatment at Zhengzhou University People's Hospital between April 2016 and April 2021 were included as the study group. The Kaplan-Meier method was used to calculate the survival rates of the transplanted kidneys and recipients, and survival curves were plotted. The improvement in graft function and blood pressure after interventional therapy in the study group was further analyzed.Results:The 1- and 3-year graft survival rates in the study group after interventional therapy were 87.5% and 82.5%, respectively; the 1-, 2-, and 3-year recipient survival rates were all 100%. One month after interventional therapy, the peak systolic velocity (PSV) and resistance index (RI) of the transplanted kidneys were (235.4±135.1) cm/s and 0.60±0.07, respectively, which were significantly different from the pre-treatment values [(482.8±180.6) cm/s and 0.52±0.12, respectively; both P<0.001]. Serum creatinine levels at 1, 2, and 3 years after interventional therapy were (166.6±93.7) μmol/L, (137.4±57.2) μmol/L, and (137.4±57.9) μmol/L, respectively, all significantly lower than the pre-treatment level [(242.9±156.8) μmol/L; P=0.001, P<0.001, and P<0.001, respectively]. Systolic blood pressure at 1, 2, and 3 years after treatment was (138.5±11.1) mmHg (1 mmHg=0.133 kPa), (134.0±12.0) mmHg, and (130.8±10.8) mmHg, respectively, all significantly lower than the pre-treatment value [(153.8±9.8) mmHg; all P<0.001]. Diastolic blood pressure at 1, 2, and 3 years after treatment was (84.4±9.9) mmHg, (83.7±10.1) mmHg, and (81.9±6.9) mmHg, respectively, all significantly lower than the pre-treatment value [(93.5±12.8) mmHg; P=0.002, P=0.001, and P<0.001, respectively]. Conclusions:Interventional therapy can enable the majority of kidney transplant recipients diagnosed with TRAS to avoid the need for further dialysis, and it has positive effects on both transplant renal function and blood pressure control.

Decreased endometrial receptivity is a critical factor contributing to the decline in fertility among women of advanced age. With the increase of age, the endometrium exhibits diminished hormonal responsiveness, a phenomenon known as inflammaging, and an imbalance in immune cell populations. These changes impede the processes of endometrial epithelial-mesenchymal transition and decidualization, thereby negatively impacting embryo implantation and reducing overall fertility potential. Furthermore, adverse lifestyle choices, exposure to environmental factors, inflammatory conditions, and repeated interventions within the uterine cavity can result in pathological aging of the endometrium that does not align with its chronological age. This misalignment may be associated with the emergence of various reproductive disorders, even in younger women. This paper seeks to investigate the relationship between pathological aging of the endometrium and reproductive disorders, particularly in the context of embryo implantation, with the aim of providing new insights into the pathogenesis, clinical diagnosis, and treatment of reproductive disorders.

Objective To explore the effects of exosomes of mesenchymal stem cells(MSC-Exos)on the proliferation,apoptosis,migration and invasion of esophageal cancer ECA109 cells.Methods Human umbilical cord mesenchymal stem cells were cultured,exosomes were extracted and isolated,and identified by transmission electron microscopy.The nanoparticle size determination and protein characterization(TSG101,CD63)were measured by transmission electron microscope.There were the MSC-Exo group(MSC-Exos co-cultured with esophageal cancer ECA109 cells)and the blank control group(only esophageal cancer ECA109 cells),and cells were cultured for 0,24 and 48 h,respectively.CCK-8 proliferation test and scratch test were used to detect the proliferation and migration ability of esophageal cancer EAC109 cells in each group,respectively.After 48 h of culture,cell apoptosis and cell cycle changes were detected by flow cytometry.The protein expression levels of phosphoinositol 3-kinase phosphorylation(p-PI3K),rabbit phosphorylated protein kinase B phosphorylation(p-Akt)and β-catenin were detected by Western blot assay.Results After identification,the obtained MSC-Exos meeted the required standard.Transmission electron microscopy,particle size measurement and marker protein results confirmed that the extracted exosomes of mesenchymal stem cells meeted the identification criteria.At 0 h of cell culture,there were no significant differences in cell proliferation and migration healing rate between the two groups(P＞0.05).After 24 h culture,the cell proliferation ability was lower in the MSC-Exo group than that of the blank control group(P＜0.05).After 48 h culture,the cell proliferation and migration healing rate were lower in the MSC-Exo group than those of the blank control group(P＜0.05).The apoptosis rate of the MSC-Exo group was higher than that of the blank control group,and the proportion of G2+S phase cells was lower than that of blank control group(P＜0.05).The expression levels of p-PI3K,p-Akt and β-catenin protein were significantly lower in the MSC-Exo group than those in the blank control group(P＜0.05).Conclusion MSC-Exos can inhibit the proliferation and migration of esophageal cancer cells and promote cell apoptosis.The inhibitory effect of MSC-Exos on esophageal cancer cells may be related to inhibiting the activation of PI3K and Akt protein and the down-regulating expression of β-catenin protein.

Background and Aims:Perihilar cholangiocarcinoma(pCCA)is associated with poor prognosis.Radical resection remains the mainstay of treatment;however,high recurrence rates and limited overall survival(OS)after surgery.Metabolic syndrome(MetS)has been linked to unfavorable outcomes in various malignancies,but its impact on postoperative outcomes in pCCA is unclear.This study aimed to evaluate the influence of MetS on perioperative and long-term outcomes in patients undergoing radical resection for pCCA.Methods:A retrospective analysis was conducted on 223 patients who underwent radical resection for pCCA at the First Affiliated Hospital of Army Medical University between January 2018 and December 2023.Patients were categorized into a MetS group(n=50)and a non-MetS group(n=173)according to diagnostic criteria.Perioperative complications,overall survival(OS),and recurrence-free survival(RFS)were compared between groups.Prognostic factors were identified using multivariate analysis.Results:No significant differences were observed between the two groups regarding median hospital stay,overall complications,or severe complications(all P＞0.05).The 1-,3-,and 5-year OS rates in the MetS group were 62.3％,22.3％,and 0,respectively,compared with 78.2％,39.5％,and 22.0％in the non-MetS group.Corresponding RFS rates were 46.2％,16.9％,and 0 in the MetS group vs.63.8％,29.6％,and 18.8％in the non-MetS group.Median OS and RFS were significantly shorter in the MetS group than in the non-MetS group(15.0 vs.27.0 months;12.0 vs.21.0 months;P=0.021 and P=0.037,respectively).Multivariate analysis identified MetS and major vascular invasion as independent predictors of OS,while MetS,jaundice,R0 resection,and major vascular invasion were independent predictors of RFS(all P＜0.05).Conclusion:MetS is significantly associated with worse long-term survival and higher recurrence risk after radical resection for pCCA.Incorporating MetS into preoperative assessment and postoperative management strategies may help improve patient outcomes.

Decreased endometrial receptivity is a critical factor contributing to the decline in fertility among women of advanced age. With the increase of age, the endometrium exhibits diminished hormonal responsiveness, a phenomenon known as inflammaging, and an imbalance in immune cell populations. These changes impede the processes of endometrial epithelial-mesenchymal transition and decidualization, thereby negatively impacting embryo implantation and reducing overall fertility potential. Furthermore, adverse lifestyle choices, exposure to environmental factors, inflammatory conditions, and repeated interventions within the uterine cavity can result in pathological aging of the endometrium that does not align with its chronological age. This misalignment may be associated with the emergence of various reproductive disorders, even in younger women. This paper seeks to investigate the relationship between pathological aging of the endometrium and reproductive disorders, particularly in the context of embryo implantation, with the aim of providing new insights into the pathogenesis, clinical diagnosis, and treatment of reproductive disorders.

Background and Aims:Perihilar cholangiocarcinoma(pCCA)is associated with poor prognosis.Radical resection remains the mainstay of treatment;however,high recurrence rates and limited overall survival(OS)after surgery.Metabolic syndrome(MetS)has been linked to unfavorable outcomes in various malignancies,but its impact on postoperative outcomes in pCCA is unclear.This study aimed to evaluate the influence of MetS on perioperative and long-term outcomes in patients undergoing radical resection for pCCA.Methods:A retrospective analysis was conducted on 223 patients who underwent radical resection for pCCA at the First Affiliated Hospital of Army Medical University between January 2018 and December 2023.Patients were categorized into a MetS group(n=50)and a non-MetS group(n=173)according to diagnostic criteria.Perioperative complications,overall survival(OS),and recurrence-free survival(RFS)were compared between groups.Prognostic factors were identified using multivariate analysis.Results:No significant differences were observed between the two groups regarding median hospital stay,overall complications,or severe complications(all P＞0.05).The 1-,3-,and 5-year OS rates in the MetS group were 62.3％,22.3％,and 0,respectively,compared with 78.2％,39.5％,and 22.0％in the non-MetS group.Corresponding RFS rates were 46.2％,16.9％,and 0 in the MetS group vs.63.8％,29.6％,and 18.8％in the non-MetS group.Median OS and RFS were significantly shorter in the MetS group than in the non-MetS group(15.0 vs.27.0 months;12.0 vs.21.0 months;P=0.021 and P=0.037,respectively).Multivariate analysis identified MetS and major vascular invasion as independent predictors of OS,while MetS,jaundice,R0 resection,and major vascular invasion were independent predictors of RFS(all P＜0.05).Conclusion:MetS is significantly associated with worse long-term survival and higher recurrence risk after radical resection for pCCA.Incorporating MetS into preoperative assessment and postoperative management strategies may help improve patient outcomes.

Objective To explore the effects of exosomes of mesenchymal stem cells(MSC-Exos)on the proliferation,apoptosis,migration and invasion of esophageal cancer ECA109 cells.Methods Human umbilical cord mesenchymal stem cells were cultured,exosomes were extracted and isolated,and identified by transmission electron microscopy.The nanoparticle size determination and protein characterization(TSG101,CD63)were measured by transmission electron microscope.There were the MSC-Exo group(MSC-Exos co-cultured with esophageal cancer ECA109 cells)and the blank control group(only esophageal cancer ECA109 cells),and cells were cultured for 0,24 and 48 h,respectively.CCK-8 proliferation test and scratch test were used to detect the proliferation and migration ability of esophageal cancer EAC109 cells in each group,respectively.After 48 h of culture,cell apoptosis and cell cycle changes were detected by flow cytometry.The protein expression levels of phosphoinositol 3-kinase phosphorylation(p-PI3K),rabbit phosphorylated protein kinase B phosphorylation(p-Akt)and β-catenin were detected by Western blot assay.Results After identification,the obtained MSC-Exos meeted the required standard.Transmission electron microscopy,particle size measurement and marker protein results confirmed that the extracted exosomes of mesenchymal stem cells meeted the identification criteria.At 0 h of cell culture,there were no significant differences in cell proliferation and migration healing rate between the two groups(P＞0.05).After 24 h culture,the cell proliferation ability was lower in the MSC-Exo group than that of the blank control group(P＜0.05).After 48 h culture,the cell proliferation and migration healing rate were lower in the MSC-Exo group than those of the blank control group(P＜0.05).The apoptosis rate of the MSC-Exo group was higher than that of the blank control group,and the proportion of G2+S phase cells was lower than that of blank control group(P＜0.05).The expression levels of p-PI3K,p-Akt and β-catenin protein were significantly lower in the MSC-Exo group than those in the blank control group(P＜0.05).Conclusion MSC-Exos can inhibit the proliferation and migration of esophageal cancer cells and promote cell apoptosis.The inhibitory effect of MSC-Exos on esophageal cancer cells may be related to inhibiting the activation of PI3K and Akt protein and the down-regulating expression of β-catenin protein.