Objective: To examine the efficacy and safety of endothelin receptor antagonists (ERA) combined with phosphodiesterase 5 inhibitors (PDE5i) in the treatment of pulmonary artery hypertension (PAH). Methods: Computer-based retrieval was performed on PubMed, Cochrane Library, CNKI, Wanfang, and VIP database (up to February 12th, 2021). Randomized controlled trials about endothelin receptor antagonists (ERAs) or PDE5i in patients with PAH were collected. The change of 6-minute walking distance (6MWD) in 12-16 weeks was used as primary outcome index. Case fatality rate, worsening clinical events, WHO functional class (FC) improvement, adverse events (AEs), serious adverse events (SAE) were the key secondary outcomes indicators. STATA 16.0 software was used for network meta-analysis, and the pooled estimates of odds ratios (ORs) or weighted mean differences (WMDs) and 95% confidence intervals (CIs) of the results were shown. To help explain ORs and WMDs, we used the surface under the cumulative ranking curve (SUCRA) to calculate the probability of each intervention. Results: We included 29 trials with 5 949 participants. In network meta-analysis, Bosentan combined with Sildenafil (WMD=53.93, 95%CI=6.19-101.66) had shown the greatest improvement in 6MWD compared with placebo, followed by Bosentan combined with Tadalafil (WMD=50.84, 95%CI=7.05-94.62), Ambrisentan combined with Tadalafil (WMD=46.67, 95%CI=15.88-77.45), Bosentan (WMD=29.44, 95%CI=5.86-53.02), Ambrisentan (WMD=23.90, 95%CI=0.31-47.48) and Macitentan (WMD=21.57, 95%CI=2.45-40.69). According to SUCRA, the effects of different intervention measures on improving 6MWD in patients with arterial pulmonary hypertension were as follows: Bosentan+Sildenafil (82.9%)>Bosentan+Tadalafil (78.4%)>Ambrisentan+Tadalafil (77.1%)>Bosentan (49.2%)>Sildenafil (48.5%)>Ambrisentan (40.3%)>Macitentan (37.3%)>Tadalafil (33.0%)>Placebo (3.3%). For the WHO functional class, Sildenafil (OR=2.90, 95%CI=1.04-8.08) was optimal compared with placebo, followed by Bosentan (OR=2.15, 95%CI=1.15-4.04), and there was no significant difference in the rest. For clinical worsening, Bosentan combined with Tadalafil (OR=0.08, 95%CI=0.01-0.49) performed best compared with placebo, followed by Bosentan (OR=0.20, 95%CI=0.11-0.38), Bosentan combined with Sildenafil (OR=0.21, 95%CI=0.09-0.46), Ambrisentan combined with Tadalafil (OR=0.27, 95%CI=0.15-0.50), Sildenafil (OR=0.33, 95%CI=0.17-0.66) and Tadalafil (OR=0.44, 95%CI=0.21-0.90). There was no statistical difference between all interventions and placebo in terms of the incidence of adverse events and serious adverse events. For case fatality rate, Ambrisentan (OR=0.28, 95%CI=0.11-0.74) was statistically superior to placebo and there was no statistics difference in the rest. Conclusions: The combination therapy of ERAs and PDE5i performed well in the short-term improvement of motor function. Furthermore, there was no significant difference with monotherapy in terms of safety. However, it is worth emphasizing that the choice of treatment should be based on the patient's individualized situation and the patient's requirements.目的： 通过网状Meta分析确定内皮素受体拮抗剂联合5型磷酸二酯酶抑制剂治疗动脉性肺动脉高压（PAH）的有效性和安全性。 方法： 使用标准检索式［（“Pulmonary Arterial Hypertension”OR“PAH”）AND（“Bosentan”OR“Ambrisentan”OR“Macitentan”OR“Sildenafil”OR“Tadalafil”）］检索PubMed和Cochrane Library数据库；使用检索词“肺动脉高压”“波生坦”“安立生坦”“马西腾坦”“西地那非”“他达拉非”检索中国知网（CNKI）、万方数据和维普等中文数据库。检索时间截至2021年2月12日。阅读所有文献筛选纳入比较3种内皮素受体拮抗剂和2种5型磷酸二酯酶抑制剂以及联合治疗方案治疗动脉性肺动脉高压的随机对照临床试验（RCT）。以随访12~16周6 min步行距离作为主要结果指标，病死率、临床恶化率、WHO心功能提升、不良事件（AE）和严重不良事件（SAE）作为关键的次要结果指标。使用STATA 16.0软件进行网状Meta分析，合并估计结果的优势比（OR）或加权平均差（WMD）和95%置信区间（CI）。使用累积排名曲线下面积（SUCRA）来计算各干预项的概率，帮助解释OR或WMD。 结果： 共纳入29篇文献，包含5 949例PAH患者。网状Meta分析结果显示，在改善6 min步行距离方面，与安慰剂比较，波生坦+西地那非提升最大（WMD=53.93，95%CI：6.19~101.66），其次为波生坦+他达拉非（WMD=50.84，95%CI：7.05~94.62），安立生坦+他达拉非（WMD=46.67，95%CI：15.88~77.45），波生坦（WMD=29.44，95%CI：5.86~53.02），安立生坦（WMD=23.90，95%CI：0.31~47.48），马西腾坦（WMD=21.57，95%CI：2.45~40.69）。不同干预措施对提高动脉性肺动脉高压患者6 min步行距离的效果，根据SUCRA排序依次为：波生坦+西地那非（82.9%）>波生坦+他达拉非（78.4%）>安立生坦+他达拉非（77.1%）>波生坦（49.2%）>西地那非（48.5%）>安立生坦（40.3%）>马西腾坦（37.3%）>他达拉非（33.0%）>安慰剂（3.3%）。在提高WHO心功能分级方面，与安慰剂相比，西地那非最优（OR=2.90，95%CI：1.04~8.08），其次为波生坦（OR=2.15，95%CI：1.15-4.04），其余差异均无统计学意义。在降低临床恶化率方面，相较于安慰剂，波生坦+他达拉非最优（OR=0.08，95%CI：0.01~0.49），其次依次为波生坦（OR=0.20，95%CI：0.11~0.38），波生坦+西地那非（OR=0.21，95%CI：0.09~0.46），安立生坦+他达拉非（OR=0.27，95%CI：0.15~0.50），西地那非（OR=0.33，95%CI：0.17~0.66），他达拉非（OR=0.44，95%CI：0.21~0.90）。在不良事件发生率与严重不良事件发生率方面，所有干预措施与安慰剂相比差异均无统计学意义。在病死率方面，安立生坦（OR=0.28，95%CI：0.11~0.74）在统计学上优于安慰剂，其余差异均无统计学意义。 结论： 内皮素受体拮抗剂与5型磷酸二酯酶抑制剂联合治疗方案在短期改善运动功能方面均表现较好。并且在安全性方面，与单药治疗并无明显差异。然而，未来在选择治疗方案时，应该根据患者的个体化情况以及患者的需求进行选择。.
MTHFR is a crucial enzyme in folate metabolism. This study aimed to determine the relationship between MTHFR genetic polymorphism and elimination and toxicities of methotrexate (MTX). To do that, the study enrolled 145 patients diagnosed with acute lymphoblastic leukemia, who received chemotherapy following the Chinese Children's Cancer Group Acute Lymphoblastic Leukemia (CCCG-ALL)-2015 protocol (clinical trial number: ChiCTR-IPR-14005706). We analyzed the effects of MTHFR C677T and A1298C polymorphisms on MTX elimination and toxicities. Patients with the MTHFR C677T TT genotype could tolerate a significantly higher MTX dose than those with the CC/CT genotype. However, patients with C677T TT genotypes had an increased risk of hypokalemia (1.369 to CC and 1.409 to CT types). The MTX infusion rate in patients with the MTHFR A1298C AC genotype was slightly lower than that in those with CC or AA genotypes. Patients with the A1298C AA genotype had a 1.405-fold higher risk of hepatotoxicity than those with the AC genotype (P > 0.05). There was no significant difference between the prevalence of other toxicities among MTHFR C677T or A1298C genotypes (P > 0.05). Neither MTHFR C677T nor A1298C polymorphisms were significantly associated with delayed MTX clearance. To conclude, MTHFR polymorphisms were not good predictors of MTX-related toxicities.
Abstract Research in the last few years has revealed that leukaemic cells can remodel the bone marrow niche into a permissive environment favouring leukaemic stem cell expansion. Tumour‐associated macrophages (TAMs) are prominent components of the tumour microenvironment and play an important role in the onset and progression of solid tumours. However, little is known about their role in the development of acute lymphoblastic leukaemia (ALL). Using a unique mouse model of T‐ALL induced by injection of EL4 T‐cell lymphoma cells to syngeneic C57BL/6 mice, we report herein that ALL leads to the invasion of leukaemia‐associated monocyte‐derived cells (LAMs) into the bone marrow and spleen of T‐ALL mice. Furthermore, we found that leukaemia cells could polarize bone marrow–derived macrophages (BMDMs) into LAMs. In turn, LAMs were able to protect leukaemia cells from drug‐induced apoptosis in vitro. Therapies targeted against the TAMs by inhibiting colony stimulating factor‐1 receptor (CSF‐1R) have emerged as a promising approach for cancer treatment. In this study, we demonstrate that CSF‐1R inhibition inhibits the viability of BMDMs, blocks LAMs polarization and reduces the abundance of LAMs in T‐ALL mice. In vivo, combination treatment of CSF‐1R inhibitor and vincristine (VCR) dramatically increased the survival of T‐ALL mice and delayed leukaemia progression compared with VCR monotherapy. Finally, these data reinforce the role of microenvironments in leukaemia and suggest that macrophages are a potential target for the development of novel therapeutic strategies in T‐ALL.
RNA editing from A (adenine nucleotide) to I (hypoxanthine nucleotide) mediated by ADARs has attracted more and more attention as an important post-transcriptional processing method. This research investigates the regulatory mechanism of A-to-I-edited miR-1251-5p in lung adenocarcinoma (LUAD).
Objective To explore comprehensive intervention of chronicle disease under Third-Grade-Hospital-Community Health Integrated Management Mode.Methods Jiangsu Shengze Hospital explored comprehensive intervention of chronicle disease under Third-Grade-Hospital-Community Health Integrated Management Mode by establishing the Three-Level Chronicle Disease Comprehensive Intervention System and Chronicle Disease Management and Service Team,thereby developing the community′s comprehensive intervention of chronicle disease.Results The health-related-knowledge awareness rate and healthy-behavior formation rate have shown significant change(P0.01),increased from 46.17% and 38.25% to 85.45% and 82.13% respectively,as compared to pre-intervention data.Management rate and control rate of high blood pressure improved from 51.99% and 40.90% pre-intervention to the current 92.07% and 64.94%;Management rate and control rate of diabetes and coronary heart disease improved.All data have shown significant differences(P0.01) post-intervention.Conclusion Establishing comprehensive intervention of chronicle disease under Third-Grade-Hospital-Community Health Integrated Management Mode,reinforcing health education and promotion of community residents and raising the management and control rate of chronicle disease patients are entirely feasible.They serve as important exemplifications and are worthy of popularizing.
To analyze the clinical features, epidemiological characteristics, risk factors, and complication characteristics of pulmonary tuberculosis (PTB) combined with extrapulmonary tuberculosis (EPTB) in elderly patients (aged > 60 years). Clinical data were collected from pathogen positive elderly patients with PTB hospitalized in a teaching hospital in Zhejiang from 2017 to 2023. We retrospectively analyzed the risk factors for complications of EPTB in elderly patients with PTB by univariate and multivariate logistic regression models. We also described the characteristics of complications in PTB with EPTB. A total of 781 PTB elderly patients were enrolled, of whom 86 (11.01%) had complicated EPTB. The most commonly invasive sites for EPTB were thoracic spine (17.53%), cervical lymph nodes (13.40%), and meninges (12.37%). 60 < aged < 80 years (OR = 2.876, 95%CI 1.290-6.412; P = 0.010), anaemia (OR = 2.212, 95%CI 1.135-3.967; P = 0.018) and osteoporosis (OR = 4.925, 95%CI 1.501-16.160; P = 0.009) were the independent risk factors for PTB with EPTB infection. PTB with EPTB had a higher proportion of multiple serous cavity effusion (19.8% vs. 12.2%) and longer hospitalisation (17 vs. 15, P = 0.004). 60 < aged < 80 years, anaemia and osteoporosis were found to be independent risk factors for PTB with EPTB in elderly patients. We compared the epidemiological and clinical characteristics of PTB with EPTB. These results are important for improving the diagnosis of EPTB, reducing complications, and improving prognosis.
Ventricular septal defects (VSD) are the most common form of congenital heart disease, which is the leading non-infectious cause of death in children; nevertheless, the exact cause of VSD is not yet fully understood. Long non-coding RNAs (lncRNAs) have been shown to play key roles in various biological processes, such as imprinting control, circuitry controlling pluripotency and differentiation, immune responses and chromosome dynamics. Notably, a growing number of lncRNAs have been implicated in disease etiology, although an association with VSD has not been reported. In the present study, we conducted an integrated analysis of dysregulated lncRNAs, focusing specifically on the identification and characterization of lncRNAs potentially involving in initiation of VSD. Comparison of the transcriptome profiles of cardiac tissues from VSD-affected and normal hearts was performed using a second-generation lncRNA microarray, which covers the vast majority of expressed RefSeq transcripts (29,241 lncRNAs and 30,215 coding transcripts). In total, 880 lncRNAs were upregulated and 628 were downregulated in VSD. Furthermore, our established filtering pipeline indicated an association of two lncRNAs, ENST00000513542 and RP11-473L15.2, with VSD. This dysregulation of the lncRNA profile provides a novel insight into the etiology of VSD and furthermore, illustrates the intricate relationship between coding and ncRNA transcripts in cardiac development. These data may offer a background/reference resource for future functional studies of lncRNAs related to VSD.
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