Purpose: Hematopoietic stem cell transplantation (HSCT) is the curative treatment for severe combined immunodeficiency disease (SCID). The natural survival age of this disease does not exceed 1 year, when the age is less than 3.5 months, before the onset of infection is the best time for performing HSCT. Here, we conducted a completely new treatment option for SCID patients without suitable donors using post-transplant cyclophosphamide (PT/Cy) as Graft versus host disease (GVHD) prophylaxis. It is necessary to observe its efficacy and safety, further more to observe the immunological reconstitution patterns of SCID patients under a new transplantation system. Methods: A total of 10 patients without a suitable donor were selected haplo-identical family donors as donor sources between March 2022 and March 2025. A modified transplant protocol with PTCy (25-35 mg/kg/day on days +3 and +4) was performed, including fludarabine 160 mg/m2 divided into 4 days on day -8 to -5, Melphalan 100 mg/m2divided into two days on day -3, -2, Cyclophosphamide 20mg/kg/day on day -5, -4 and porcrine anti-human lymphocyte immunoglobulin 25mg/kg/d on day -8 to -6. Low dose FK506 or CSA combined with MMF were added as GVHD prophylaxis. Results: From March 2022 to March 2024, 10 infants with newly diagnosed SCID were treated with this update conditioning regimen. Among these cases, there were 9 boys (90%) and 1 girl (10%), 9 cases of X-SCID (90%), and 1 case of Lig-IV (10%). All 10 cases were from haploidentical related donors, the median age at transplantation was 4 months (2～12). The median times for neutrophil and platelet engraftment were 15 (11～21) days and 32 (17～60) days, respectively. Three months post-transplantation, 10 cases (100%) achieved complete donor chimerism. In these group of patients，9 (90%) cases, we observed that the absolute count of NK lymphocytes returned to normal levels 2 months post-transplantation, and the absolute count of CD3+ lymphocytes was greater than 300 cells/ml 3 months post-transplantation. The median follow-up post-transplantation was 28 (30～50) months. Nine patients achieved long-term disease-free survival, and 1 patient died 27 months post-transplantation due to pulmonary fibrosis caused by COVID-19 infection, which was ineffective despite rescue efforts. We observed that the modified conditioning regimen for SCID patients showed lower toxicity, lower incidence of GVHD, and a significantly higher overall survival rate (90%) compared to traditional regimens.Conclusion: Our modified protocol provides a new treatment method for SCID patients without suitable donor, expanded donor pool. Using the reduced intensity conditioning regimen, reduced toxicity and heavy economic burden, lower rate of GVHD increased high quality of life. Due to the small sample size, further confirmation is needed with a larger number of cases.

OBJECTIVE:To retrospectively analyze the clinical data of newly diagnosed acute myeloid leukemia (AML) patients treated with venetoclax combined with azacitidine (Ven/Aza) or standard "3+7" regimen and similar regimens, collect real-world study data, compare the treatment response and adverse events between the two regimens, as well as perform survival analysis. METHODS:To retrospectively analyze the efficacy, survival, and adverse reactions of newly diagnosed AML patients treated with Ven/Aza (24 cases) and "3+7" regimens (117 cases ) in our hospital from September 2009 to March 2023, as well as factors influencing outcomes. A propensity score matching (PSM) was performed on age and Eastern Cooperative Oncology Group performance status (ECOG PS) to obtain a 1:1 matched cohort of 20 pairs, and the efficacy and survival before and after the matching were compared. RESULTS:The median age of patients in the Ven/Aza group was 69 years, while that in the "3+7" group was 56 years (P <0.001). Objective remission rate (ORR) was 62.5% in Ven/Aza group and 74.8% in "3+7" group (P >0.05). The median overall survival (OS) in the Ven/Aza group was 522 days, while that in the "3+7" group was 1 002 days (P >0.05). After controlling the two variables of age and ECOG PS, a PSM cohort of 20 pairs was obtained, in which the ORR was 65% in Ven/Aza group and 60% in "3+7" group (P >0.05). The median OS was 522 days and 629 days, and median progression-free survival (PFS) was 531 days and 198 days between the two groups, respectively. There were no statistically significant differences in OS and PFS between the two groups (both P >0.05). Additionally, the incidence of adverse events in the Ven/Aza group was significantly reduced. CONCLUSION:The overall cohort shows that the "3+7" regimen has advantages in efficacy and survival, but Ven/Aza regimen is relatively safer. After performing PSM on age and ECOG PS, the Ven/Aza group showed improved efficacy, and a longer median PFS compared to "3+7" group.

Objective: The Pulmonary Arterial Denervation in Patients With Pulmonary Hypertension Associated With the Left Heart Failure (PADN-5) study proved that pulmonary artery denervation (PADN) is associated with significant improvements in hemodynamic and clinical outcomes in patients with combined pre- and post-capillary pulmonary hypertension (CpcPH). This study aimed to assess the 3-year clinical results of PADN in patients who had heart failure with preserved ejection fraction (HFpEF) developing into CpcPH (HFpEF-CpcPH). Methods: In this post hoc analysis of the PADN-5 trial, 38 patients with HFpEF were included in screening out of 98 patients with CpcPH who were randomly assigned to treatment with sildenafil and sham PADN (sham PADN (plus sildenafil) group, abbreviated as sham group) or PADN (PADN group). HFpEF in the PADN-5 trial was defined as a left ventricular ejection fraction ≥50%, and CpcPH was defined as a mean pulmonary arterial pressure ≥25 mmHg, a pulmonary arterial wedge pressure >15 mmHg, and a pulmonary vascular resistance >3.0 WU. The changes in the 6-minute walk distance (6-MWD) and the plasma concentration of N-terminal pro-brain natriuretic peptide (NT-proBNP) at 6-month and 3-year follow-up, as well as the clinical endpoint of the occurrence of clinical worsening, defined as cardiopulmonary-related death, rehospitalization, or heart or lung transplantation at 3-year follow-up were examined. Results: Thirty-eight patients with HFpEF-CpcPH were assigned to the PADN group ( n = 19) or the sham group ( n = 19). At the 6-month follow-up, 6-MWD (433 (275, 580)m vs. 342 (161, 552)m), and reductions in NT-proBNP (−47% (−99%, 331%) vs. −12% (−82%, 54%)) were significantly improved in the PADN group (all P < 0.05). Over the 3-year follow-up period, PADN treatment resulted in marked increases in 6-MWD (450 (186, 510)m vs. 348 (135, 435)m) and reductions in NT-proBNP (−55% (−99%, 38%) vs. −10% (−80%, 95%)) (all P < 0.05). Clinical worsening was experienced by 12 patients (63%) in the sham group, but by only 5 patients (26%) in the PADN group (hazard ratio = 0.149, 95% confidence interval: 0.038–0.584, P = 0.006). The 6-MWD and PADN treatments were independent predictors of clinical deterioration in patients with HFpEF-CpcPH. Conclusions: PADN therapy is associated with improvements in exercise capacity and clinical outcomes. PADN therapy may have a potential role in patients with HFpEF-CpcPH for whom current treatment options are limited.

BACKGROUND:Posterior fossa malformation (PFM) is a relatively uncommon prenatal brain malformation. Genetic diagnostic approaches, including chromosome karyotyping, copy number variant (CNV) testing, and whole-exome sequencing (WES), have been applied in several cases of fetal structural malformations. However, the clinical value of appropriate genetic diagnostic approaches for different types of PFMs has not been confirmed. Therefore, in this study, we aimed to analyze the value of different combined genetic diagnostic approaches for various types of fetal PFMs. METHODS:This retrospective study was conducted at Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital. Fifty-one pregnant women diagnosed with fetal PFMs who underwent genetic testing in our hospital from January 1, 2017 to December 31, 2022 were enrolled; women with an isolated enlarged cisterna magna were excluded. All participants were categorized into two groups according to the presence of other abnormalities: isolated and non-isolated PFMs groups. Different combined approaches, including karyotype analysis, CNV testing, and trio-based WES, were used for genetic analysis. The detection rates of karyotype analysis, CNV testing, and WES were measured in the isolated and non-isolated groups. RESULTS:In isolated PFMs, pathogenic/likely pathogenic (P/LP) CNVs were detected in four cases (36.36%, 4/11), whereas G-banding karyotyping and WES showed negative results. In non-isolated PFMs, a sequential genetic approach showed a detection rate of 47.5% (19/40); karyotyping revealed aneuploidies in five cases (16.67%, 5/30), CNV testing showed P/LP CNVs in five cases (16.13%, 5/31), and WES identified P/LP variants (in genes CEP20, TMEM67, OFD1, PTPN11, ARID1A, and SMARCA4) in nine cases (40.91%, 9/22). WES showed a detection rate of 83.33% (5/6) in fetuses with Joubert syndrome. Only six patients (five with Blake's pouch cyst and one with unilateral cerebellar hemisphere dysplasia) survived. CONCLUSIONS:We recommend CNV testing for fetuses with isolated PFMs. A sequential genetic approach (karyotyping, CNV testing, and WES) may be beneficial in fetuses with non-isolated PFMs. Particularly, we recommend WES as the first-line genetic diagnostic tool for Joubert syndrome.

Objective To investigate the superiority of transrectal high frequency ultrasound(TRUS) in precise assessment of middle compartment prolapse in comparison with routine transperineal ultrasound (TPUS). Methods Prospectively analyzed and compared detection rates of entire cervical length and uterine descent on TPUS and TRUS in 101 patients with pelvic organ prolapse (POP). Results Detection rates of entire cervix on TRUS were significantly higher than those on TPUS both at rest and during Valsalva maneuver (90.10% VS 49.50%, 92.08% VS 9.90% respectively, both P ＜0.05). Uterine descent was able to be evaluated in 92.08% of patients by TRUS and in 5.94% of patients by TPUS, which was statistically significant( P ＜0.05). The interobserver repeatability for the measurements of anterior lip, cervical canal and posterior lip on TRUS were excellent. The mean lengths of anterior lip, cervical canal and posterior lip were significantly increased during Valsalva maneuver than those measured at rest ( P ＜0.05). And mean length of anterior lip was longer than posterior lip both at rest and during Valsalva( P ＜0.05). Conclusion TRUS can significantly raise detection rates of entire cervix, and make the direct evaluation of uterine descent feasible. TRUS can be used as a complementary method to TPUS to attain more comprehensive and accurate presurgical imaging information in middle compartment prolapse patients.

This study aimed to investigate the association between simple markers in fetal abdominal plane, intra-abdominal umbilical venous diameter (DIUV) and abdominal circumference (AC) discordance at 15–20 weeks’ gestation, and adverse pregnancy outcomes in monochorionic diamniotic (MCDA) twins. We performed a retrospective analysis of MCDA twins with two live fetuses examined at 15–20 weeks from Jun 2020 to Dec 2021 at Beijing Obstetrics and Gynecology Hospital. Measurement of fetal AC and DIUV was performed according to standard protocols. Twin pregnancies with major fetal structural anomalies, chromosomal abnormalities, miscarriage, and twin reversed arterial perfusion sequence were excluded. DIUV and AC discordance in MCDA twins with an adverse pregnancy outcome was compared with a normal pregnancy outcome. Furthermore, the performance of DIUV and AC discordance in predicting adverse pregnancy outcomes in MCDA twins was assessed. A total of 105 women with MCDA twin pregnancies were enrolled, contributing 179 visits. Adverse pregnancy outcomes occurred in 33.3% (35/105) of cases in our study. The intra-observer and inter-observer intraclass correlation coefficient (ICC) of both AC and DIUV were very good or excellent. There was no statistical difference in AC and DIUV discordance (%) between 15–16, 17–18, and 19–20 weeks (χ2 = 3.928, P = 0.140; χ2 = 2.840, P = 0.242). Both AC and DIUV discordance were greater in twins with adverse pregnancy outcomes than that in twins with normal pregnancy outcome at each pregnancy periods. Both AC discordance (OR 1.2, 95% CI 1.1–1.3) and DIUV discordance (OR 1.2, 95% CI 1.1–1.2) were associated with adverse pregnancy outcomes. The AUC for predicting adverse pregnancy outcomes by AC discordance was 0.75 (95% CI 0.68–0.83), with a sensitivity of 58.7% (95% CI 51.9–64.5) and a specificity of 86.2% (95% CI 81.7–88.4). The AUC for predicting adverse pregnancy outcomes by DIUV was 0.78 (95% CI 0.70–0.86), with sensitivity and specificity of 65.1% (95% CI 58.1–70.3) and 86.2% (95% CI 81.7–88.4), respectively. The AC discordance and DIUV discordance could predict adverse pregnancy outcomes in MCDA twins. When these simple markers occurred, intensive surveillance was recommended.

Abstract Objective To evaluate the detection rate of fetal chromosomal abnormalities in congenital heart defects (CHD), further dig the potential diagnostic value of Chromosomal Microarray Analysis (CMA) technology for different phenotypes, and explore the possible genetic pathogenic factors of CHD. Methods We analyzed the CMA of 427 cases of CHD fetuses, and divided CHD into different groups according to two dimensions. According to whether they were combined with ECA, they were divided into isolated CHD and non-isolated CHD; According to the cardiac phenotype, they were divided into ten groups. The correlation between numerical chromosomal abnormalities (NCA), and copy number variations (CNVs, except likely benign and benign CNVs) with CHD was analyzed by Mantel test. Results In general, CHD with ECAs were more likely to have a genetic abnormality than those without ECAs (39.3% vs. 14.8%, P<0.05). The genetic abnormality rate of 427 fetuses was 21.8% (93/427), the detection rate of NCA was 12.9% (55/427), the most relevant were skeletal, Craniofacial, VSD, AVSD (P<0.05); and the detection rate of pCNVs was 8.9% (38/427), the most relevant were IAA, A, IAA, B, RAA, TAPVC, CoA, TOF and thymic abnormality. 22q11.2DS and had the highest detection, the detection rate of 22q11.2DS in the subgroups were IAA, B, RAA, PS, CoA, TOF and thymic abnormality. Overall analysis of cases, the CNV deletion fragment larger than 1 Mb may be pathogenic. In CNV, deletion was more likely to be pathogenic than duplication. In addition, we detected 12 CNV syndromes; among of them, 9 syndromes that may be related to CHD. gene LIMK1 and MYH11 have been identified as part of a common pathway between cardiovascular and neurological development; candidate genes are considered to be related to heart and/or involved in embryonic development, FLI1, NIPBL, DLL1, PTPN11, TBX5. Conclusion Increased risk of genetic abnormalities in non-isolated CHD; CHD phenotype most related to NCA, pCNV and 22q11.2DS was found; and 12 CNV syndromes and 7 meaningful candidate genes were detected.

Resumo Fundamento: A fração de ejeção (FE) tem sido utilizada em análises fenotípicas e na tomada de decisões sobre o tratamento de insuficiência cardíaca (IC). Assim, a FE tornou-se parte fundamental da prática clínica diária. Objetivo: Este estudo tem como objetivo investigar características, preditores e desfechos associados a alterações da FE em pacientes com diferentes tipos de IC grave. Métodos: Foram incluídos neste estudo 626 pacientes com IC grave e classe III–IV da New York Heart Association (NYHA). Os pacientes foram classificados em três grupos de acordo com as alterações da FE, ou seja, FE aumentada (FE-A), definida como aumento da FE ≥10%, FE diminuída (FE-D), definida como diminuição da FE ≥10%, e FE estável (FE-E), definida como alteração da FE <10%. Valores p inferiores a 0,05 foram considerados significativos. Resultados: Dos 377 pacientes com IC grave, 23,3% apresentaram FE-A, 59,5% apresentaram FE-E e 17,2% apresentaram FE-D. Os resultados mostraram ainda 68,2% de insuficiência cardíaca com fração de ejeção reduzida (ICFEr) no grupo FE-A e 64,6% de insuficiência cardíaca com fração de ejeção preservada (ICFEp) no grupo FE-D. Os preditores de FE-A identificados foram faixa etária mais jovem, ausência de diabetes e fração de ejeção do ventrículo esquerdo (FEVE) menor. Já os preditores de FE-D encontrados foram ausência de fibrilação atrial, baixos níveis de ácido úrico e maior FEVE. Em um seguimento mediano de 40 meses, 44,8% dos pacientes foram vítimas de morte por todas as causas. Conclusão: Na IC grave, a ICFEr apresentou maior percentual no grupo FE-A e a ICFEp foi mais comum no grupo FE-D.

BACKGROUND:Ejection fraction (EF) has been used in phenotype analyses and to make treatment decisions regarding heart failure (HF). Thus, EF has become a fundamental part of daily clinical practice. OBJECTIVE:This study aims to investigate the characteristics, predictors, and outcomes associated with EF changes in patients with different types of severe HF. METHODS:A total of 626 severe HF patients with New York Heart Association (NYHA) class III-IV were enrolled in this study. The patients were classified into three groups according to EF changes, namely, increased EF (EF-I), defined as an EF increase ≥10%, decreased EF (EF-D), defined as an EF decrease ≥10%, and stable EF (EF-S), defined as an EF change <10%. A p-value lower than 0.05 was considered significant. RESULTS:Out of 377 severe HF patients, 23.3% presented EF-I, 59.5% presented EF-S, and 17.2% presented EF-D. The results further showed 68.2% of heart failure with reduced ejection fraction (HFrEF) in the EF-I group and 64.6% of heart failure with preserved ejection fraction (HFpEF) in the EF-D group. The predictors of EF-I included younger age, absence of diabetes, and lower left ventricular ejection fraction (LVEF). The predictors of EF-D were absence of atrial fibrillation, lower uric acid level, and higher LVEF. Within a median follow-up of 40 months, 44.8% of patients suffered from all-cause death. CONCLUSION:In severe HF, HFrEF presented the highest percentage in the EF-I group, and HFpEF was most common in the EF-D group.

目的:分析不同性别重症心力衰竭(心衰)患者的临床特点及预后影响因素.方法:入选我院2011年1月至2016年12月因心衰住院的NYHA心功能分级Ⅲ～Ⅳ级患者848例,记录患者的一般临床资料及用药情况,实验室指标和超声心动图参数.通过电话或门诊进行随访,记录发生全因死亡时间.比较不同性别重症心衰患者临床特点,Cox回归分析全因死亡影响因素.结果:(1)基线资料:中位随访时间41(1 d,93个月)个月,失访56例,纳入分析792例.其中女性290例,男性502例.NYHA心功能分级Ⅲ级400例,Ⅳ级392例;射血分数降低的心衰(HFrEF)361例(45.6％),射血分数中间值的心衰(HFmrEF)145例(18.3％),射血分数保留的心衰(HFpEF)286例(36.1％).(2)在重症心衰患者中,男性以HFrEF为主,NYHA心功能分级Ⅳ级多见;女性以HFpEF为主,NYHA心功能分级Ⅲ级多见,两者基础疾病以冠心病最多见.与男性患者相比,女性患者瓣膜病比例高,年龄大,多伴有糖尿病、心房颤动病史,左心室射血分数(LVEF)高,肌酐清除率(Ccr)低(P均<0.05).NYHA心功能分级Ⅳ级患者N末端B型利钠肽原(NT-proBNP)水平显著高于NYHA心功能分级Ⅲ级患者(P均<0.05).(3)不同类型重症心衰患者亚组比较显示,各类型心衰基础疾病均以冠心病为主,占55％左右.HFpEF女性患者多,年龄最大,心房颤动比例最高,NT-proBNP值最低;HFrEF男性患者为主,心房颤动比例最低,NT-proBNP最高.三种类型心衰全因死亡率相似.(4)患者全因死亡共345例(43.6％),其中男性215例(42.9％),女性130例(44.8％),预后相似.年龄、NYHA心功能分级Ⅳ级、冠心病病史、血红蛋白、血尿酸、血钠、NT-proBNP≥3300 ng/L、服用血管紧张素转换酶抑制剂(ACEI)/血管紧张素Ⅱ受体拮抗剂(ARB)类药物、男性是重症心衰患者全因死亡的独立影响因素.结论:重症心衰患者男性以HFrEF及NYHA心功能分级Ⅳ级为主,年龄低,而女性以高龄、HFpEF为主,NYHA心功能Ⅲ级多,两者预后相似.年龄、NYHA心功能分级Ⅳ级、冠心病病史、血红蛋白、血尿酸、血钠、NT-proBNP≥3300 ng/L、服用ACEI/ARB类药物、男性是重症心衰患者全因死亡的独立影响因素.

Objective: This study aimed to find echocardiographic parameters that can predict short- and long-term adverse cardiovascular events in patients with AMI. Methods: A total of 126 patients with AMI admitted to our hospital from July to December 2012 were enrolled in this study. All patients underwent echocardiographic examination within 12 hours after admission and received regular follow-ups until December 2018. The primary endpoint was a composite of the major adverse cardiovascular events (MACEs). Results: In the first year of this study, a primary endpoint occurred in 35 patients and the predictor derived from the echocardiography of 1-year primary endpoint was LVEF<40% (OR: 9.000, 95% CI 3.242-24.987, p<0.0001) and the area under the curve (AUC) for the predictor was 0.676 (95% CI 0.561-0.790, p=0.002). For the total 5 years, 57 patients underwent primary endpoint. The results of the 5-year primary endpoint were: E/E'>15 (OR: 4.094, 95% CI 1.726-9.710, P=0.001), the wall motion score index was (WMSI)>1.5 (OR: 12.791, 95% CI 1.511-108.312, P=0.019), and the AUC was 0.691 (95% CI 0.595-0.787 P<0.0001). Conclusion: LVEF is correlated with a short-term outcome (1-year), and WMSI and E/E' can predict a long-term outcome (5-year) in patients with acute myocardial infarction.

BACKGROUND:Synovial inflammation and its associated activation of angiogenesis play critical roles in rheumatoid arthritis (RA). Exosomes, as carriers of genetic information including circular RNAs (circRNAs), have been explored as delivery vehicles for therapeutic molecules. However, the effects of synovial mesenchymal stem cells (SMSCs)-derived exosomal circRNAs and their mechanisms of action in RA progression remain unclear.METHODS:SMSCs-derived exosomes (SMSCs-Exos) were administered to a co-culture of RA fibroblast-like synoviocytes (RA-FLS) and human dermal microvascular endothelial cells (HDMECs) in vitro as well as to a collagen-induced arthritis (CIA) mouse model in vivo. Their effects on VEGF expression and angiogenic activity in vitro and the therapeutic efficacy in vivo were evaluated. Exosomes from circEDIL3-overexpressing SMSCs (Ad-circEDIL3-SMSCs-Exos) were used to further determine the role of circEDIL3 in SMSCs-Exo-based therapy.RESULTS:Both SMSCs-Exos and Ad-circEDIL3-SMSCs-Exos significantly downregulated the expression of VEGF induced by the IL-6/sIL-6R complex in the supernatants of RA-FLS and HDMECs co-culture as well as in the cell lysate of co-cultured RA-FLS, and the extent of reduction was more pronounced in the latter. Subsequent experiments showed that angiogenic activity was significantly downregulated by SMSCs-Exos and Ad-circEDIL3-SMSCs-Exos due to reduced VEGF expression. CircEDIL3 functioned as a sponge for miR-485-3p, which targeted PIAS3. PIAS3 is known to suppress STAT3 activity and reduce downstream VEGF. Injection of SMSCs-Exos or Ad-circEDIL3-SMSCs-Exos reduced synovial VEGF and consequently ameliorated arthritis severity in the CIA mouse model.CONCLUSION:The intracellular transfer of circEDIL3 by SMSCs-Exos may be a potential novel therapeutic strategy for RA.

目的 探讨老年重症射血分数保留心力衰竭(HFpEF)患者临床特点并对其预后因素进行分析.方法 入选2011-2016年北京朝阳医院住院的纽约心脏协会(NYHA)心功能分级Ⅲ～Ⅳ级重症HFpEF患者308例,记录患者一般资料、生化指标、超声心电图等参数.按年龄分为＜75岁组和≥75岁组.采用Kaplan-Meier生存曲线及Cox回归对患者预后及其影响因素进行分析.结果(1)共纳入分析286例,NYHA Ⅲ级171例,Ⅳ级115例,平均年龄71.3岁,死亡131例.≥75岁组142例,死亡80例,＜75岁组144例,死亡51例.(2)≥75岁组女性多见;伴随高血压、糖尿病、卒中等疾病多;糖化血红蛋白、老年营养风险指数(GNRI)＜92比例高于＜75岁组;白蛋白、血红蛋白、肌酐清除率、左室舒张末期内径(LVEDD)及地高辛和β受体阻滞剂使用率明显低于＜75岁组.≥75岁组死亡率明显高于＜75岁组,P＜0.001.(3)Cox多因素回归分析显示≥75岁组NT-proBNP、未服用血管紧张素转换酶抑制剂(ACEI)或血管紧张素受体拮抗剂(ARB)、左室肥厚是其预后的独立危险因素.结论 老年重症HFpEF患者一般状况差,伴随疾病多,死亡率高,预后差.NT-proBNP、未服用ACEI/ARB类药物、左室肥厚是其预后的独立危险因素.

The hallmark of atherogenesis is characterized as endothelial dysfunction and subsequent macrophage activation. Although our previous study has demonstrated that endothelin-1 (ET-1) plays an important role in atherogenesis, the underlying mechanism remains deeply investigation. Enhanced atherosclerotic plaques were observed in endothelium-specific ET-1 overexpression ApoE(-/-) mice (eET-1/ApoE(-/-)) concomitant with increased secretion of pro-inflammatory adhesion molecules and cytokines. The conditional media used for culturing human umbilical vein endothelial cells (HUVECs) with AdET-1 infection and subjected to OX-LDL stimulation, was collected and utilized for bone marrow-derived macrophages (BMDMs) culturing. RT-PCR analysis showed increased genes expression related to classical M1 macrophages but decreased alternative activated M2 macrophages genes expression in macrophage culturing with the conditional media. Furthermore, consistent regulations of macrophage polarization were observed using isolated exosomes from the conditional media. More importantly, we noticed that miR-33 was enriched in the exosomes derived by HUVECs with AdET-1 infection, while bioinformatics analysis further indicated that miR-33 directly targeted NR4A and miR-33/NR4A axis was required for the effect of endothelial-specific ET-1 overexpression on pro-inflammatory macrophage activation. By contrast, such effects could be reversed by ET-1 knockdown. Taken together, our study indicated that the exosomes derived by HUVECs with AdET-1 infection can transfer miR-33 to macrophages and subsequently promote pro-inflammatory macrophage activation by directly targeting to NR4A. These evidences clearly revealed that miR-33/NR4A axis was the important mechanism underlying the effect of ET-1 on macrophage activation and indicated that ET-1 may act as a promising target for atherosclerosis management.

The antitumor enzyme L-asparaginase (L-Asp) has commonly been used for the treatment of acute lymphoblastic leukemia. However, the effects of L-Asp on acute myeloid leukemia (AML) and their underlying mechanisms have not been fully elucidated. In the present study, the effects of L-Asp on cell proliferation and apoptosis were investigated using the AML cell lines U937, HL-60 and KG-1a. The effects of combining L-Asp with mitoxantrone (MIT) and cytarabine (Ara-c) were also analyzed. The combination of MIT and Ara-C is known as MA therapy, and is a widely used therapeutic regimen for the treatment of elderly patients with refractory AML. When applied alone, L-Asp inhibited cell proliferation and induced apoptosis in each of the cell lines tested. Furthermore, the combined use of L-Asp with MA therapy further potentiated the inhibition of cell proliferation while increasing the induction of apoptosis. These findings provide evidence for the potential antitumor effect of L-Asp in AML, and indicate that improved efficacy maybe achieved by combining L-Asp with MIT and Ara-c. This combination may provide a promising new therapeutic strategy for the treatment of AML.

Objective To determine the possible association of anti-β1-adrenergic receptors (anti-β1-AR), anti-β2-AR and anti-α1-AR with carvedilol treatment in patients with heart failure (HF). Methods A total of 267 HF patients were prospectively enrolled. Blood samples were measured by an enzyme-linked immunosorbent assay. All of the patients received carvedilol for their HF. Each patient was followed up for six months and their cardiac function was measured. Results The final analysis encompassed 137 patients comprising 65 patients with three autoantibodies (positive group) and 72 patients without all three autoantibodies but with one or two autoantibodies (negative group). The frequency and geometric mean titer of anti-β1-AR, anti-β2-AR, and anti-α1-AR were significantly lower in the group without all three autoantibodies after six months of carvedilol treatment (all P < 0.01; from 100% to 57%, 50%, and 49%, respectively; and from 1: 118, 1: 138, and 1: 130 to 1: 72, 1: 61, and 1: 67, respectively). Furthermore, 28 patients in the positive group demonstrated complete ablation of autoantibodies. In addition, left ventricular remodelling and function was significantly improved by the use of carvedilol combined with the standard treatment regime for six months in the positive group (P < 0.01) when compared to the negative group (P < 0.05). Conclusions Carvedilol treatment significantly decreases frequency and geometric mean titer in patients with all three autoantibodies, even up to complete ablation, and significantly improved cardiac function and remodelling. The effect of carvedilol is probably correlated to the presence of all three autoantibodies.

Acute myeloid leukemia with normal karyotype (NK-AML) is a group of diseases with high heterogeneity and immunological processes are significantly associated with its initiation and development. The implication of the immunogenomic landscape in the prognosis of patients with NK-AML has remained largely elusive. In the present study, the expression profiles of immune-related genes (IRGs) were examined and their association with overall survival (OS) was determined in 60 patients with NK-AML from The Cancer Genome Atlas dataset and 104 patients from the Gene Expression Omnibus (GEO) dataset no. GSE71014. Univariate Cox regression analysis was used to identify 42 and 203 IRGs in the two respective cohorts, which were significantly associated with OS in NK-AML. A risk model was constructed based on the regression coefficient and expression values of nine survival-associated IRGs shared between the two datasets [zinc finger CCCH-type containing, antiviral 1 like; transferrin receptor; suppressor of cytokine signaling 1; ELAV like RNA binding protein 1; roundabout guidance receptor 3; unc-93 homolog B1, Toll-like receptor signaling regulator; protein tyrosine phosphatase non-receptor type 6; interleukin 2 receptor subunit alpha (IL2RA) and IL3RA]. Using this risk model, patients with NK-AML may be divided into high- and low-risk groups in prognostic predictions. The area under the receiver operating characteristic curve for predicting OS was 0.793. The prognostic role of this risk model was successfully verified in another independent cohort (GEO dataset no. GSE71014). The prognostic risk score was positively associated with age and fms related receptor tyrosine kinase 3 mutation and correlated with infiltration by T regulatory cells. In conclusion, the results of the present study provided an IRG score model for prognostic stratification of adult patients with NK-AML, as well as further insight into the implication of IRGs in NK-AML that may lead to the development of novel immunotherapy approaches for this disease.

ObjectiveWe aimed to investigate the immunologic mechanisms by which arsenic trioxide (As2O3) may inhibit T helper 17 (Th17) cell differentiation while promoting regulatory T (Treg) cell generation by modulating signal transducer and activator of transcription 3 (STAT3) in treatment-naïve rheumatoid arthritis (RA) patients.MethodsNaïve CD4+T cells isolated by fluorescence-activated cell sorting from treatment-naïve RA patients and healthy controls were used to investigate the effect of As2O3 on the process of polarization and the related cytokines. STAT3 transfection experiments were conducted with small interfering RNA (siRNA) and lentivirus STAT3 to verify the mechanism of As2O3 on Th17-Treg balance in vitro. A collagen-induced arthritis (CIA) model was used to detect the clinical scores, histopathological change, bone destruction, Th17-Treg proportion and joint tissue immunohistochemistry.ResultsWe found that As2O3 prevented activated naïve CD4+T-cells from differentiating into Th17 cells and reduced cytokine production by activated Th17 cells by downregulating their signature transcription factors, STAT3 and orphan nuclear receptors. Notably, As2O3 reduced Th17 cells frequency while increasing Treg cells frequency under specific polarizing conditions in treatment-naïve RA patients by transfecting siRNA STAT3 and lentivirus STAT3. Furthermore, we noticed that applying As2O3 in the CIA model attenuated the infiltration of joint inflammation and bone destruction, and significantly improved the imbalanced Treg-Th17 ratio.ConclusionsThese data indicate that As2O3 may be a potential immune modulator for treatment-naïve RA patients that helps to balance of Treg and Th17 cells through modulating STAT3.

A number of studies have suggested that autoantibodies against β1-adrenoreceptors (β1R-AAbs) have an important role in pathophysiological processes of heart failure. The aim of the present study was to determine whether β1R-AAbs are implicated in cardiac dysfunction following acute myocardial infarction (AMI) and their association with prognosis. A total of 33 cases with systolic heart failure (SHF), 49 with diastolic heart failure (DHF) and 44 with normal heart function following AMI were recruited. β1R-AAbs were detected by ELISA and major adverse cardiac events (MACEs) were recorded during the 5-year follow-up. The positive rate of β1R-AAbs in the SHF group (45.5%) was significantly higher compared with that in the DHF (22.4%; P<0.05) and normal (15.9%; P<0.05) groups. The area under the receiver operating characteristics curve for the diagnosis of SHF was 0.630 (95% CI: 0.514-0.747, P=0.026). During a median follow-up period of 51.0±15.4 months, the positive rate of β1R-AAbs in the MACEs group was significantly higher compared with that in the non-MACEs group (P<0.05). Multivariate logistic regression analysis indicated that the left ventricular ejection fraction and diabetes were independent predictors of 5-year MACEs following AMI, whereas β1R-AAbs were not. Kaplan-Meier analysis revealed that the cumulative MACEs-free survival rate was the lowest in the SHF group, followed by the DHF and normal groups (P<0.05). Therefore, β1R-AAbs were indicated to be of value for early diagnosis of SHF after AMI but not as independent predictors for the prognosis of patients with AMI.

BACKGROUND Atherosclerosis is a chronic inflammatory disease triggered by endothelial dysfunction and exaggerated by macrophage infiltration. Although endothelin-1 (ET-1) plays an important role in vascular inflammation and reactive oxygen species production, the individual effect of ET-1 in atherogenesis remains unclear. METHODS AND RESULTS ET-1 expression was increased in mouse atherosclerotic plaques and human umbilical vein endothelial cells (HUVECs) administrated by oxidized low-density lipoprotein stimulation. Moreover, the immunofluorescence co-staining showed upregulated ET-1 expression in endothelial cells. Real-time polymerase chain reaction demonstrated that ET-1 overexpression promoted adhesion molecules and chemokines secretion in HUVECs. Following this intervention, the migration of macrophages and the pro-inflammatory cytokines were increased. More importantly, the endothelial dysfunction regulated by ET-1 and subsequently the effect on macrophage activation were mediated by ETA receptor and largely reversed by protein kinase C (PKC) inhibitor. Eight-week-old male ApoE(-/-) mice and eET-1/ApoE(-/-) mice were fed with high-fat diet for 12 weeks. eET-1/ApoE(-/-) significantly increased atherosclerotic lesions in the whole aorta and aortic sinus, which accompanied by the induction of inflammatory cytokines and macrophages infiltration. CONCLUSIONS ET-1 accelerates atherogenesis by promoting adhesion molecules and chemokines, as well as subsequent macrophage activation. Collected, these evidence suggest that ET-1 might be a potential target for the treatment of atherogenesis.