Knockdown of LOX-1 ameliorates bone quality and generation of type H blood vessels in diabetic mice.

Our previous studies have shown that lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) is expressed in liver sinusoidal endothelial cells, and oxidized low-density lipoprotein induces liver sinusoidal dysfunction and defenestration through the LOX-1/ROS/NF-kB pathway, revealing that LOX-1 can mediate liver sinusoidal barrier function, involved in the regulation of non-alcoholic fatty liver disease. Here, we investigated whether, in the context of bone metabolic diseases, LOX-1 could affect bone quality and type H blood vessels in diabetic mice. We used db/db mice as model and found that LOX-1 knockdown can ameliorate bone quality and type H blood vessel generation in db/db mice. This further verifies our hypothesis that LOX-1 is involved in the regulation of bone quality and type H blood vessel homeostasis, thus inhibiting osteoporosis progression in db/db mice.

Effectiveness of Heart Failure Checklist Management in Patients with Chronic Heart Failure: An Open-Label, Single-Center Controlled Study During 18 Months of Follow-Up.

Background: The efficacy of chronic heart failure (CHF) checklist management in reducing adverse outcomes of heart failure patients is still uncertain. This study explores whether CHF checklist management is more useful than usual care in reducing adverse health outcomes in the medium- and long-term among CHF patients. Methods: In our prospective study, 132 patients with CHF were randomly assigned to CHF management group and usual care group by random number method. Patients in CHF management group were conducted through CHF checklist by cardiologists and general practitioner. Patients assigned to usual care were treated by non-stationary medical group without checklist. All groups were followed up for 18 months. Results: There was no significant difference in overall mortality rate between management group and control group during 18 months (12.3% [8/65] vs. 11.7% [7/60], P = 0. 912]). The re-hospitalization rate of heart failure in management group (18.5% [12/65]) was significantly lower than that in usual care group (38.3% [23/60]) after 18 months of follow-up (P = 0.013). Median NT-proBNP level (632.3 ng/l vs. 1678 ng/l, p = 0.004) was lower in management group than that in usual care group. Cardiac ultrasonography was performed at 18 months between the management and usual care group. LVEDD (55.88±7.11 mm vs. 60.92±8.06 mm) and LVESD (43.25±8.42mm vs. 48.41± 9.02mm) were decreased (P<0.01). LVEF was increased (45.36±10.64% vs. 39.96 ±10.15%, P<0.01). The utilization rate of ACEI/ARB/ARNI, ß-blocker were high in management group. Conclusion: CHF checklist management by cardiologists and general practitioners can significantly reduce the re-hospitalization and improve cardiac function. CHF management through heart failure checklist may improve prognosis in patients with CHF in the medium- and long-term.

Wilms' tumor 1 expression combined with genetic mutations for prognostic assessment in MDS.

Overexpression of Wilms' tumor (WT1) is frequently observed in myelodysplastic syndrome (MDS), which has been proposed as a prognostic marker. However, the prognostic role of WT1 expression in different contexts remains to be fully elucidated. We retrospectively assessed the relationships between WT1 levels and preexisting prognostic factors to further investigate its prognostic role under different contexts. In our study, WT1 expression was positively correlated with WHO 2016 classification and IPSS-R stratification. Lower WT1 expression was found in relation to TET2, TP53, CD101, or SRSF2 mutations, while mutant NPM1 patients possessed higher level. Notably, WT1 overexpression maintained its inferior prognostic effect on overall survival (OS) in TP53-wild patients but not in TP53-mutated group. In multivariate analysis, higher WT1 expression was a risk factors for OS in EB patients without TP53 mutations. Overall, WT1 expression was useful to predict prognosis for MDS and its prognostic role was impacted by some gene mutations.

High Co-Expression of PDCD1/TIGIT/CD47/KIR3DL2 in Bone Marrow Is Associated with Poor Prognosis for Patients with Myelodysplastic Syndrome.

Cellular immune disorder is a common characteristic of myelodysplastic syndrome (MDS). Abnormal natural killer (NK) cell function has been reported in MDS patients, and this is closely related to disease progression and poor prognosis. However, little is known about the association between the abnormal immune checkpoint (IC) that results in abnormal immune NK cell function and the prognosis of MDS. In this study, RNA-sequencing data from 80 patients in the GSE114922 dataset and bone marrow (BM) samples from 46 patients with MDS in our clinical center were used for overall survival (OS) analysis and validation. We found that the NK cell-related IC genes PDCD1, TIGIT, CD47, and KIR3DL2 had higher expression and correlated with poor OS for MDS patients. High expression of PDCD1 or TIGIT was significantly associated with poor OS for MDS patients younger than 60 years of age. Moreover, co-expression of PDCD1 and TIGIT had the greatest contribution to OS prediction. Interestingly, PDCD1, TIGIT, CD47, and KIR3DL2 and risk stratification based on the Revised International Prognostic Scoring System were used to construct a nomogram model, which could visually predict the 1-, 2-, and 3-year survival rates of MDS patients. In summary, high expression of IC receptors in the BM of MDS patients was associated with poor OS. The co-expression patterns of PDCD1, TIGIT, CD47, and KIR3DL2 might provide novel insights into designing combined targeted therapies for MDS.

[Expression of Wilms' Tumor 1 Gene in Bone Marrow of Patients with Myelodysplastic Syndrome and Its Clinical Significance].

OBJECTIVE: To investigate the expression level and clinical significance of Wilms' tumor 1 (WT1) in bone marrow of patients with myelodysplastic syndromes (MDS). METHODS: The clinical data of 147 MDS patients who accepted real-time quantitative polymerase chain reaction (RT-PCR) to detect the expression level of WT1 in bone marrow before treated in Nanfang Hospital, Southern Medical University from January 2017 to April 2021 were retrospectively analyzed. According to the expression level of WT1, the patients were divided into WT1+ group and WT1- group, their clinical characteristics and prognosis were analyzed. RESULTS: The positive rate of WT1 in 147 MDS patients was 82.3%. There were significant differences in bone marrow blast count, aberrant karyotypes, WHO 2016 classification, and IPSS-R stratification between WT1+ group and WT1- group (all P<0.05). Furthermore, the higher the malignant degree of MDS subtype and the risk stratification of IPSS-R, the higher expression level of WT1. Compared with WT1- group, there were no differences in overall survival (OS) time and the time of transformation to AML in WT1+ group (both P>0.05). In patients who did not accept transplantation, the median OS time of WT1+ patients was significantly shorter than that of WT1- patients (P=0.049). Besides, regarding WT1+ group, patients who underwent transplantation had longer OS time and lower mortality than those who received hypomethylating agents (P=0.002, P=0.005). CONCLUSION: WT1 expression level directly reflects the disease progression, and it is also associated with prognosis of MDS patients.

Fifteen-year mortality and prognostic factors in patients with dilated cardiomyopathy: persistent standardized application of drug therapy and strengthened management may bring about encouraging change in an aging society.

BACKGROUND: There is scarce data on the long-term mortality and associated prognostic factors in patients with dilated cardiomyopathy (DCM). The study aimed to investigate the all-cause mortality up to 15 years (mean 7.9 ± 5.7 years) in such patients, and the independent prognostic factors influencing their long-term mortality. METHODS: One hundred and sixty-six consecutive patients with DCM were prospectively enrolled from 2002 to 2003. The mean age of patients was 59.5 ± 10.4 years, and approximately 57% were male. They were followed up by telephone or outpatient visit at least every three months until 2019 or all-cause death occurred. Predictors of mortality were identified using multivariate logistic regression analysis. RESULTS: During the 15 years of follow-up, five patients were lost to follow-up, and the complete data records of 161 patients were included in the analysis. Patients were treated with angiotensin-converting-enzyme inhibitors (ACEI) or angiotensin-receptor blocker (ARB), ß-blockers, mineralocorticoid receptor antagonist (MRA), diuretics and digitalis from 2002 to 2004, and maintained at the maximum tolerated doses between 2004 and 2019. Our safety targets to maintain heart rate and blood pressure at 60-80 beats/min and 90-120/60-80 mmHg, respectively. All-cause mortality in the first five years was 55.9%. The independent risk factors for the 5-year mortality were age ≥ 70 years old (OR = 5.45, P = 0.006), systolic blood pressure (SBP) > 120 mmHg (OR = 3.63, P = 0.004), 6-minute walk distance (6MWD) < 450 m (OR = 3.84, P = 0.001). 15-year all-cause mortality was 65.8%. The independent risk factors for 15-year mortality were age ≥ 70 years old (OR = 16.07, P = 0.009), LVEF ≤ 35% (OR = 5.69, P = 0.003), and SBP > 120 mmHg (OR = 9.56, P < 0.001). CONCLUSIONS: This study was the first to demonstrate the 15-year survival rate of 34% in DCM patients. The DCM patients' first five-year all-cause mortality decreased significantly after continuous standardized treatment and intensive management. The mortality then plateaued in the following 10 years. Age ≥ 70 years, LVEF ≤ 35%, and SBP > 120 mmHg were independent predictors of 15-year all-cause mortality.

Bisphosphonate of Zoledronate Has Antiapoptotic Effect on Hypoxia/Reoxygenation Injury in Human Embryonic Stem Cell-Derived Cardiomyocytes Through Trk Signaling Pathway.

In this work, we investigated the in vitro and in vivo functions of bisphosphonate of zoledronate (Zd) in hypoxia/reoxygenation (H/R) injured human embryonic stem cell-derived cardiomyocytes (hES-CMs). In the in vitro setting, the effects of Zd on hES-CM survival and differentiation were examined. We found that low and medium concentrations (<2 µm) of Zd did not induce cell death of hES-CMs. 0.5 µm Zd protected H/R-induced hES-CM apoptosis but did not affect key differentiation proteins, including hcTnl, PECM-1 Cnx43 and Pan-Cadherin. In addition, Zd-induced TrkA/B phosphorylation and promoted VEGF to counter the apoptotic effect of H/R injury. In the in vivo animal model of myocardial infarction, Zd treatment promoted the survival of hES-CMs by inducing PECAM1 and hcTnl. Thus, we concluded that Zd protected H/R-induced hES-CM apoptosis in vitro and promoted hES-CM survival in vivo. These data may facilitate the development of human embryonic stem cells into clinical applications for patients with ischemic heart disease.

Fração de Ejeção do Ventrículo Esquerdo Aumentada, Diminuída ou Estável ao Longo do Tempo em uma Série de 626 Pacientes com Insuficiência Cardíaca que Receberam Tratamento Médico / Increased, Decreased, or Stable Left Ventricle Ejection Fraction over Time in a Series of 626 Heart Failure Patients Receiving Medical Treatment

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.

Abstract 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.

An efficient chromium(III)-catalyzed aerobic oxidation of methylarenes in water for the green preparation of corresponding acids.

A highly efficient method to oxidize methylarenes to their corresponding acids with a reusable Cr catalyst was developed. The reaction can be carried out in water with 1 atm oxygen and K2S2O8 as cooxidants, proceeds under green and mild conditions, and is suitable for the oxidation of both electron-deficient and electron-rich methylarenes, including heteroaryl methylarenes, even at the gram level. The excellent result, together with its simplicity of operation and the ability to continuously reuse the catalyst, makes this new methodology environmentally benign and cost-effective. The generality of this methodology gives it the potential for use on an industrial scale. Differing from the accepted oxidation mechanism of toluene, GC-MS studies and DFT calculations have revealed that the key benzyl alcohol intermediate is formed under the synergetic effect of the chromium and molybdenum in the Cr catalyst, which can be further oxidized to afford benzaldehyde and finally benzoic acid.

Increased, Decreased, or Stable Left Ventricle Ejection Fraction over Time in a Series of 626 Heart Failure Patients Receiving Medical Treatment. / Fração de Ejeção do Ventrículo Esquerdo Aumentada, Diminuída ou Estável ao Longo do Tempo em uma Série de 626 Pacientes com Insuficiência Cardíaca que Receberam Tratamento Médico.

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.

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 III­IV 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.

Echocardiographic Parameters Predict Short- and Long-Term Adverse Cardiovascular Events in Patients with Acute Myocardial Infarction.

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.

[Clinical Characteristics and Prognosis of Elderly Patients with Medium and High risk Myelodysplastic Syndrome].

OBJECTIVE: To investigate the clinical characteristics and prognosis of patients with medium and high risk myelodysplastic syndrome (MDS). METHODS: 97 MDS patients above the age of 60 treated in Nanfang Hospital, Southern Medical University from February 2011 to August 2020 were enrolled. The clinical characteristics and prognosis of the MDS patients with medium risk, high risk or very high risk based on IPSS-R category were retrospectively analyzed. According to the difference of treatment regimes, the patients were divided into the transplantation group, chemotherapy group and other treatment group, and the efficacy among the patients in the 3 groups were analyzed. RESULTS: MDS with excess blast (MDS-EB) in the elderly patients with medium and high risk MDS were the most common, 47.4% of the patients with abnormal chromosome karyotypes, and 23.7% with complex karyotypes (≥3). 97.3% of the patients showed at least one gene mutation, and TP53 mutations were detected in nearly 20% of the patients with medium and high risk. Multivariate analysis showed that IPSS-R category and treatment regimes were the factors affecting the prognosis of elderly patients with medium and high risk MDS. The median overall survival (OS) time of the patients in the 3 groups showed significant difference (P=0.012), and the median OS of the patients in the transplantation group was significantly longer than that in the chemotherapy group and other group (P=0.003,P=0.014,respectively), while there was no significant difference in median OS between chemotherapy group and other treatment group (P=0.685). CONCLUSION: Elderly MDS patients with medium and high risk can benefit from allogeneic hematopoietic stem cell transplantation, which will prolong their OS.

Relationships between peripheral reactive hyperemia index with coronary plaque burden and prognosis in patients with unstable angina pectoris complicated with type 2 diabetes mellitus.

BACKGROUND: Coronary plaque burden (CPB) is an important prognostic factor in patients with unstable angina pectoris (UAP). Our current study aims to investigate the relationships between peripheral reactive hyperemia index (RHI) with CPB and prognosis in patients with UAP complicated with type 2 diabetes mellitus (T2DM). METHODS: The clinical data of 187 UAP-T2DM patients who were treated in our center from June 2017 to January 2019 were retrospectively collected. RHI, CPB, and other clinical features were measured. The patients were followed up for 18 months and then divided into an adverse cardiovascular event (ACE) group (n=71, with ACEs) and a control group (n=116, without ACEs). The differences in RHI, CPB, and other clinical features between these two groups were compared, and the potential correlation between RHI and CPB was analyzed. RESULTS: Compared with the control group, the ACE group had significantly lower RHI (1.21±0.32 vs. 1.59±0.35, P=0.000) and left ventricular ejection fraction (LVEF) (42.92%±7.78% vs. 48.90%±6.76%, P=0.000) and a significantly higher left ventricular myocardial mass index (2.67±0.87 vs. 2.27±0.49 mg/g, P=0.000), carotid intima-media thickness (1.65±0.34 vs. 1.51±0.32 mm, P=0.000), number of coronary plaques (3.98±0.53 vs. 3.32±0.38, P=0.000), non-calcified plaque volume (32.89±12.56 vs. 22.58±9.97 mm3, P=0.000), calcified plaque volume (4.89±1.29 vs. 3.88±1.05 mm3, P=0.000), non-calcified plaque burden (5.70%±1.60% vs. 3.18%±1.08%, P=0.000), and calcified plaque burden (0.90%±0.22% vs. 0.65%±0.19%, P=0.000). Pearson linear correlation analysis showed that peripheral RHI was negatively correlated with plaque number, non-calcified plaque volume, calcified plaque volume, non-calcified plaque burden, and calcified plaque burden in patients with UAP complicated with T2DM (all P<0.05). CONCLUSIONS: Decreased peripheral RHI is associated with ACEs and CPB in patients with UAP complicated with T2DM.

Endothelium-specific endothelin-1 expression promotes pro-inflammatory macrophage activation by regulating miR-33/NR4A axis.

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.

[Correlation between U2AF1 Gene Mutation Characteristics and Clinical Manifestations and Prognosis in Patients with Myelodysplastic Syndrome].

OBJECTIVE: To investigate the correlation between U2AF1 gene mutation and clinical manifestations and prognosis in patients with myelodysplastic syndromes (MDS). METHODS: The clinical data of 203 MDS patients who accepted Next Generation Sequencing (NGS) was retrospectively analyzed in Nanfang Hospital, Southern Medical University from December 2012 to October 2019. According to whether the patients had U2AF1 gene mutation, the patients were divided into U2AF1 mutated group and non-mutated group, and the relationship between gene mutation characteristics and clinical manifestations and prognosis was analyzed. Then according to the difference of the mutation site of U2AF1, the patients in U2AF1 mutated group were divided into U2AF1S34 mutated group and U2AF1Q157/R156 mutated group, and the correlation between gene mutation characteristics and prognosis was analyzed. RESULTS: The incidence of U2AF1 mutation in MDS patients was approximately 11.3% (23/203), and the mutation frequency of U2AF1 allele was 32.5%. The male ratio in U2AF1 mutated group was significantly higher than that in U2AF1 non-mutated group (P=0.001). There was no patient who had complex karyotypes or TP53 gene mutation in U2AF1 mutated group. There were no significant differences in ages, blood parameters, bone marrow blasts, WHO 2016 classification, IPSS-R category, chromosomal abnormalities like del(5q), -7/del(7q), del(20q), +8, and gene mutation like ASXL1, DNMT3A, RUNX1, SF3B1, and SRSF2 mutation between U2AF1 mutated group and the non-mutated group. Compared with the non-mutated group, there was no significant difference in the overall survival time (P=0.377), the time of acute myeloid leukemia (AML) transformation (P=0.681), and the response rate to hypome- thylating agents in U2AF1 mutated group (P=0.556). Besides, no differences were observed in sex, diagnosis age, WHO 2016 classification, IPSS-R category, blood parameters, overall survival time, and AML transformation time between U2AF1S34 mutated group and U2AF1Q157/R156 mutated group. CONCLUSION: The U2AF1 gene mutation dose not affect the survival time, AML transformation time, and response rate to hypomethylating agents in MDS patients. Besides, there are no statistical differences in the clinical characteristics and prognosis of MDS patients between U2AF1S34 mutated group and U2AF1Q157/R156 mutated group. Transplantation shows no significant benefit for patients with U2AF1 mutation.

Diagnostic and prognostic value of autoantibodies against ß1-adrenoreceptors in patients with heart failure following acute myocardial infarction: A 5-year prospective study.

A number of studies have suggested that autoantibodies against ß1-adrenoreceptors (ß1R-AAbs) have an important role in pathophysiological processes of heart failure. The aim of the present study was to determine whether ß1R-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. ß1R-AAbs were detected by ELISA and major adverse cardiac events (MACEs) were recorded during the 5-year follow-up. The positive rate of ß1R-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 ß1R-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 ß1R-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, ß1R-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.

A validated UPLC-MS/MS method for quantitative determination of a potent neuroprotective agent Sarsasapogenin-AA13 in rat plasma: Application to pharmacokinetic studies.

Sarsasapogenin-AA13(AA13), a sarsasapogenin derivative, exhibited good neuroprotective and anti-inflammatory activities in vitro and therapeutic effects on learning and memory dysfunction in amyloid-ß-injected mice. A sensitive UPLC-MS/MS method was developed and validated to quantitatively determine AA13 in rat plasma and was further applied to evaluate the pharmacokinetic behaviour of AA13 in rats that were administered AA13 intravenously and orally. This method was validated to exhibit excellent linearity in the concentration range of 1-1000 ng/mL. The lower limit of quantification was 1 ng/mL for AA13 in rat plasma. Intra-day accuracy for AA13 was in the range of 90-114%, and inter-day accuracy was in the range of 97-103 %. The relative standard deviation of intra-day and inter-day assay was less than 15%. After a single oral administration of AA13 at the dose of 25 mg/kg, Cmax of AA13 was 1266.4 ± 316.1 ng/mL. AUC0-48 h was 6928.5 ± 1990.1 h·ng/mL, and t1/2 was 10.2 ± 0.8 h. Under intravenous administration of AA13 at a dosage of 250 µg/kg, AUC0-48 h was 785.7 ± 103.3 h⋅ng/mL, and t1/2 was 20.8 ± 7.2 h. Based on the results, oral bioavailability (F %) of AA13 in rats at 25 mg/kg was 8.82 %.

PKC-Mediated Endothelin-1 Expression in Endothelial Cell Promotes Macrophage Activation in Atherogenesis.

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.

Multiple Autoantibodies against Cardiovascular Receptors as Biomarkers in Hypertensive Heart Disease.

OBJECTIVES: The pathogenesis of hypertensive heart disease (HHD) remains unclear, which might include autoimmunity. The aim of the present study was to determine whether a relationship exists between the presence of autoantibodies against ß1, ß2, α1 adrenoreceptors, M2-muscarinic receptors, angiotensin II type1 receptors and HHD. METHODS: In the present study, 44 patients diagnosed with HHD, 36 patients with hypertension, and 40 controls were also enrolled. The measurement of these 5 autoantibodies was performed by enzyme-linked immunosorbent assay. RESULTS: The frequencies of autoantibodies against ß1, ß2, α1 adrenoreceptors, autoantibodies against M2-muscarinic receptors and autoantibodies against angiotensin II type1 receptors were significantly higher in patients with HHD, when compared to patients with hypertension and normal controls (all p < 0.001). In addition, the titers of these 5 autoantibodies significantly increased in patients with HHD. Patients who were positive for all 5 autoantibodies had larger left ventricular end-diastolic diameter (60.5 ± 4.9 vs. 57.8 ± 5.0 vs. 52.5 ± 5.3 mm) and worse left ventricular ejection fraction (45.0 ± 11.0 vs. 56.6 ± 10.4 vs. 57.8 ± 5.3%), when compared to patients not positive for all the 5 autoantibodies and patients negative for all the 5 autoantibodies (χ2 = 9.524, p = 0.009 and χ2 = 7.689, p = 0.021). Furthermore, a significant positive correlation was observed between each 2 autoantibodies of these 5 autoantibodies (all p < 0.001). CONCLUSION: Multiple autoantibodies of cardiovascular receptors may be involved in the pathogenesis and may be predictive factors of HHD.

Association of autoantibodies against the M2-muscarinic receptor with long-term outcomes in peripartum cardiomyopathy patients: A 5-year prospective study.

BACKGROUND: Peripartum cardiomyopathy (PPCM) is characterized by heart failure. Our previous study found that autoantibodies against the M2-muscarinic receptor (anti-M2-R) are increased in PPCM patients. We aimed to evaluate the association of anti-M2-R on prognosis of PPCM patients with standard treatment. METHODS: Synthetic peptides corresponding to the M2 receptor served as the target antigens in an enzyme-linked immunosorbent assay experiment. They were used to screen the sera of 80 PPCM patients, who were separated into anti-M2-R-negative and positive groups according to their anti-M2-R reactivity. Clinical assessment and echocardiography examination were performed at baseline and after 5 years with a standard treatment regimen. The endpoint events were compared after 5 years of follow-up. RESULTS: There were 76 PPCM patients who completed the final data analysis, including 36 in the anti-M2-R (+) group and 40 in the anti-M2-R (-) group. Both groups showed improvement in the left ventricular end-diastolic and end-systolic dimensions and the ejection fraction with standard treatment regimens for 5 years (all p<0.001). Patients in the anti-M2-R (-) group had greater tolerance and were more rapidly titrated to metoprolol, and they had better improvement in cardiac function than patients in the anti-M2-R (+) group (p<0.05). Patients in the anti-M2-R (-) group had a marked decrease in re-hospitalization (p<0.05), but not in all-cause mortality or cardiovascular mortality. Being positive for anti-M2-R increased the risk of PPCM (OR=4.7, 95% CI 1.8-12.2, p=0.002). CONCLUSIONS: PPCM patients, especially anti-M2-R (-) patients, have a relatively better prognosis than other patients. We posit that the presence of anti-M2-R may be involved in the pathogenesis of PPCM.