Phenylacetyl glutamine (PAGln) enhances cardiomyocyte death after myocardial infarction through ß1 adrenergic receptor.

This study aims to explore the roles of phenylacetyl glutamine (PAGln) on myocardial infarction (MI) pathogenesis. Here, using targeted metabolomics analysis, it was found that the plasma metabolite PAGln was upregulated in coronary artery disease (CAD) patients and MI mice and could be an independent risk factor for CAD. In vivo and in vitro functional experiments revealed that PAGln pretreatment enhanced MI-induced myocardial injury and cardiac fibrosis, as evident by the increased infarct size, cardiomyocyte death, and the upregulated expression of cardiac fibrosis markers (Col1a1 and α-SMA). Combined with RNA-sequencing analysis and G protein-coupled receptor (GPCR) inhibitor, we found that the GPCR signaling activation is essential for PAGln-mediated effects on cardiomyocyte death. Furthermore, drug affinity responsive target stability and cellular thermal shift assay demonstrated that PAGln could interact with ß1-adrenergic receptor (AR). Moreover, ß1-AR blocker treatment indeed extended the cardiac remodeling after PAGln-enhanced MI. These results suggest that PAGln might be a potential therapeutic target for extending the cardiac remodeling window in MI patients that signals via ß1-AR.

Short-term antithrombotic strategies after left atrial appendage occlusion: a systematic review and network meta-analysis.

Background: Percutaneous left atrial appendage occlusion (LAAO) has emerged as a stroke prevention strategy in patients with nonvalvular atrial fibrillation (NVAF), and these patients were required to receive antithrombotic therapy post-procedure. However, the optimal antithrombotic strategy after LAAO remains controversial. This study explored the safety and efficacy of different antithrombotic strategies after LAAO through a network comparison method. Methods: We systematically searched the MEDLINE, Embase, and Cochrane Library databases for studies that reported the interested efficacy and safety outcomes (stroke, device-related thrombus (DRT), and major bleeding) of different antithrombotic strategies [DAPT (dual antiplatelet therapy), DOACs (direct oral anticoagulants), and VKA (vitamin k antagonist)] in patients who had experienced LAAO. Pairwise comparisons and network meta-analysis were performed for the interested outcomes. Risk ratios (RRs) with their confidence intervals (CIs) were calculated using a random-effects model. The rank of the different strategies was calculated using the surface under the cumulative ranking curve (SUCRA). Results: Finally, 10 observational studies involving 1,674 patients were included. There was no significant difference in stroke, DRT, and major bleeding among the different antithrombotic strategies (DAPT, DOACs, and VKA). Furthermore, DAPT ranked the worst in terms of stroke (SUCRA: 19.8%), DRT (SUCRA: 3.6%), and major bleeding (SUCRA: 6.6%). VKA appeared to be superior to DOACs in terms of stroke (SUCRA: 74.9% vs. 55.3%) and DRT (SUCRA: 82.3% vs. 64.1%) while being slightly inferior to DOACs in terms of major bleeding (SUCRA: 71.0% vs. 72.4%). Conclusion: No significant difference was found among patients receiving DAPT, DOACs, and VKA in terms of stroke, DRT, and major bleeding events after LAAO. The SUCRA indicated that DAPT was ranked the worst among all antithrombotic strategies due to the higher risk of stroke, DRT, and major bleeding events, while VKAs were ranked the preferred antithrombotic strategy. However, DOACs are worthy of consideration due to their advantage of convenience.

Warfarin anticoagulation management during the COVID-19 pandemic: The role of internet clinic and machine learning.

Background: Patients who received warfarin require constant monitoring by hospital staff. However, social distancing and stay-at-home orders, which were universally adopted strategies to avoid the spread of COVID-19, led to unprecedented challenges. This study aimed to optimize warfarin treatment during the COVID-19 pandemic by determining the role of the Internet clinic and developing a machine learning (ML) model to predict anticoagulation quality. Methods: This retrospective study enrolled patients who received warfarin treatment in the hospital anticoagulation clinic (HAC) and "Internet + Anticoagulation clinic" (IAC) of the Nanjing Drum Tower Hospital between January 2020 and September 2021. The primary outcome was the anticoagulation quality of patients, which was evaluated by both the time in therapeutic range (TTR) and international normalized ratio (INR) variability. Anticoagulation quality and incidence of adverse events were compared between HAC and IAC. Furthermore, five ML algorithms were used to develop the anticoagulation quality prediction model, and the SHAP method was introduced to rank the feature importance. Results: Totally, 241 patients were included, comprising 145 patients in the HAC group and 96 patients in the IAC group. In the HAC group and IAC group, 73.1 and 69.8% (p = 0.576) of patients achieved good anticoagulation quality, with the average TTR being 79.9 ± 20.0% and 80.6 ± 21.1%, respectively. There was no significant difference in the incidence of adverse events between the two groups. Evaluating the five ML models using the test set, the accuracy of the XGBoost model was 0.767, and the area under the receiver operating characteristic curve was 0.808, which showed the best performance. The results of the SHAP method revealed that age, education, hypertension, aspirin, and amiodarone were the top five important features associated with poor anticoagulation quality. Conclusion: The IAC contributed to a novel management method for patients who received warfarin during the COVID-19 pandemic, as effective as HAC and with a low risk of virus transmission. The XGBoost model could accurately select patients at a high risk of poor anticoagulation quality, who could benefit from active intervention.

The Use of Oral Anticoagulation Is Not Associated With a Reduced Risk of Mortality in Patients With COVID-19: A Systematic Review and Meta-Analysis of Cohort Studies.

Background: Hypercoagulability and thromboembolic events are associated with poor prognosis in coronavirus disease 2019 (COVID-19) patients. Whether chronic oral anticoagulation (OAC) improve the prognosis is yet controversial. The present study aimed to investigate the association between the chronic OAC and clinical outcomes in COVID-19 patients. Methods: PubMed, Embase, Web of Science, and the Cochrane Library were comprehensively searched to identify studies that evaluated OAC for COVID-19 until 24 July 2021. Random-effects model meta-analyses were performed to pool the relative risk (RR) and 95% confidence interval (CI) of all-cause mortality and intensive care unit (ICU) admission as primary and secondary outcomes, respectively. According to the type of oral anticoagulants [direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs)], subgroup and interaction analyses were performed to compare DOACs and VKAs. Meta-regression was performed to explore the potential confounders on all-cause mortality. Results: A total of 12 studies involving 30,646 patients met the inclusion criteria. The results confirmed that chronic OAC did not reduce the risk of all-cause mortality (RR: 0.92; 95% CI 0.82-1.03; p = 0.165) or ICU admission (RR: 0.65; 95% CI 0.40-1.04; p = 0.073) in patients with COVID-19 compared to those without OAC. The chronic use of DOACs did not reduce the risk of all-cause mortality compared to VKAs (P interaction = 0.497) in subgroup and interaction analyses. The meta-regression failed to detect any potential confounding on all-cause mortality. Conclusion: COVID-19 patients with chronic OAC were not associated with a lower risk of all-cause mortality and ICU admission compared to those without OAC, and the results were consistent across DOACs and VKA subgroups. Systematic Review Registration: clinicaltrials.gov, identifier CRD42021269764.

Stress increases MHC-I expression in dopaminergic neurons and induces autoimmune activation in Parkinson's disease.

The expression of major histocompatibility complex class I (MHC-I), a key antigen-presenting protein, can be induced in dopaminergic neurons in the substantia nigra, thus indicating its possible involvement in the occurrence and development of Parkinson's disease. However, it remains unclear whether oxidative stress induces Parkinson's disease through the MHC-I pathway. In the present study, polymerase chain reaction and western blot assays were used to determine the expression of MHC-I in 1-methyl-4-phenylpyridinium (MPP+)-treated SH-SY5Y cells and a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease mouse model. The findings revealed that MHC-I was expressed in both models. To detect whether the expression of MHC-I was able to trigger the infiltration of cytotoxic T cells, immunofluorescence staining was used to detect cytotoxic cluster of differentiation 8 (CD8)+ T cell infiltration in the substantia nigra of MPTP-treated mice. The results indicated that the presentation of MHC-I in dopaminergic neurons was indeed accompanied by an increase in the number of CD8+ T cells. Moreover, in MPTP-induced Parkinson's disease model mice, the genetic knockdown of endogenous MHC-I, which was caused by injecting specific adenovirus into the substantia nigra, led to a significant reduction in CD8+ T cell infiltration and alleviated dopaminergic neuronal death. To further investigate the molecular mechanisms of oxidative stress-induced MHC-I presentation, the expression of PTEN-induced kinase 1 (PINK1) was silenced in MPP+-treated SH-SY5Y cells using specific small interfering RNA (siRNA), and there was more presentation of MHC-I in these cells compared with control siRNA-treated cells. Taken together, MPP+-/MPTP-induced oxidative stress can trigger MHC-I presentation and autoimmune activation, thus rendering dopaminergic neurons susceptible to immune cells and degeneration. This may be one of the mechanisms of oxidative stress-induced Parkinson's disease, and implies the potential neuroprotective role of PINK1 in oxidative stress-induced MHC-I presentation. All animal experiments were approved by the Southern Medical University Ethics Committee (No. 81802040, approved on February 25, 2018).

Meta-analysis of postoperative antithrombotic therapy after left atrial appendage occlusion.

OBJECTIVE: This meta-analysis explored the safety and effectiveness of different anticoagulant regimens after left atrial appendage occlusion (LAAO). METHODS: Databases, such as PubMed, MEDLINE, EMBASE, Web of Science, and Cochrane Library, were searched to identify eligible studies according to the inclusion criteria. The incidences of events, including device-related thrombus (DRT) formation, stroke, systemic thromboembolism, bleeding, cardiovascular mortality, and all-cause mortality, were analyzed using R version 3.2.3. RESULTS: The screening retrieved 32 studies, including 36 study groups and 4,474 patients. The incidence of outcomes after LAAO was calculated via meta-analysis. In the subgroup analysis, the rates of DRT formation, cardiovascular mortality, and all-cause mortality were significantly different among different antithrombotic methods. Single antiplatelet therapy was associated with the highest rate of adverse events, followed by dual antiplatelet therapy (DAPT). Vitamin K antagonists (VKAs) and new oral anticoagulants (NOACs) carried lower rates of adverse events. CONCLUSIONS: Anticoagulant therapy had better safety and efficacy than antiplatelet therapy. Thus, for patients with nonabsolute anticoagulant contraindications, anticoagulant therapy rather than DAPT should be actively selected. NOACs displayed potential for further development, and these treatments might represent alternatives to VKAs in the future.

Fabrication of Reduction-Sensitive Amphiphilic Cyclic Brush Copolymer for Controlled Drug Release.

The cyclic brush polymers, due to the unique topological structure, have shown in the previous studies higher delivery efficacy than the bottlebrush analogues as carriers for drug and gene transfer. However, to the best of knowledge, the preparation of reduction-sensitive cyclic brush polymers for drug delivery applications remains unexplored. For this purpose, a reduction-sensitive amphiphilic cyclic brush copolymer, poly(2-hydroxyethyl methacrylate-g-poly(ε-caprolactone)-disulfide link-poly(oligoethyleneglycol methacrylate)) (P(HEMA-g-PCL-SS-POEGMA)) with reducible block junctions bridging the hydrophobic PCL middle layer and the hydrophilic POEGMA outer corona is designed and synthesized successfully in this study via a "grafting from" approach using sequential ring-opening polymerization (ROP) and atom transfer free radical polymerization (ATRP) from a cyclic multimacroinitiator PHEMA. The resulting self-assembled unimolecular core-shell-corona (CSC) micelles show sufficient salt stability and efficient destabilization in the intracellular reducing environment for a promoted drug release toward a greater therapeutic efficacy relative to the reduction-insensitive analogues. The overall results demonstrate the reducible cyclic brush copolymers developed herein provides an elegant solution to the tradeoff between extracellular stability and intracellular high therapeutic efficacy toward efficient anticancer drug delivery.

Fabrication of Thermosensitive Cyclic Brush Copolymer with Enhanced Therapeutic Efficacy for Anticancer Drug Delivery.

Adaptation of cyclic brush polymer for drug delivery applications remains largely unexplored. Herein, cyclic brush copolymer of poly(2-hydroxyethyl methacrylate-g-poly(N-isopropylacrylamide-st-N-hydroxyethylacrylamide)) (cb-P(HEMA-g-P(NIPAAm-st-HEAAm))), comprising a cyclic core of PHEMA and thermosensitive brushes of statistical copolymer of P(NIPAAm-st-HEAAm), is designed and synthesized successfully via a graft-from approach using atom transfer free radical polymerization from a cyclic multimacroinitiator. The composition of the brush is optimized to endow the resulting cyclic brush copolymer with a lower critical solution temperature (LCST) slightly above the physiological temperature, but lower than the localized temperature of tumor tissue, which is suitable for the hyperthermia-triggered anticancer drug delivery. Critical aggregation concentration determination reveals better stability for the unimolecular nanoparticle formed by the cyclic brush copolymer than that formed by the bottlebrush analogue. The dramatically increased size with elevated temperatures from below to above the LCST confirms hyperthermia-induced aggregation for both formulations. Such structural destabilization promotes significantly the drug release at 40 °C. Most importantly, the drug-loaded cyclic brush copolymer shows enhanced in vitro cytotoxicity against HeLa cells than the bottlebrush counterpart. The better stability and higher therapeutic efficacy demonstrates that the thermosensitive cyclic brush copolymer is a better formulation than bottle brush copolymer for controlled drug release applications.

DEL RBC transfusion should be avoided in particular blood recipient in East Asia due to allosensitization and ineffectiveness.

Previously, both primary and secondary anti-D alloimmunizations induced by "Asian type" DEL (RHD1227A allele) were observed in two incidents. We investigated how often these alloimmunization events occur. The transfusions of any D-negative patients were investigated in the First Affiliated Hospital of Xi'an Jiaotong University Medical College, China, during the entire 2009. The antigens of D, C, c, E, and e were routinely serotyped. The "Asian type" DEL variant was genotyped and the RHD heterozygote was determined through two published methods. The changes in anti-D levels were monitored by the indirect antiglobulin test (IAT) and flow cytometry. Thirty D-negative transfused patients were included in the study. We focused on 11 recipients who were transfused with packed red blood cells (RBCs) from DEL donors at least one time. Of those 11 recipients, seven were anti-D negative before transfusion and four were anti-D positive (one patient with an autoantibody). One of the seven pre-transfusion anti-D negative patients produced a primary-response anti-D after being transfused with 400 ml of DEL blood twice. All four pre-transfusion antibody positive patients were not observed hemoglobin (Hb) levels increased, as expected after transfusions. Two patients had an increase in anti-D from 1:8 to 1:64 by IAT, which was also shown by flow cytometry. None of the patients experienced an acute hemolytic episode. Our data indicated that the primary anti-D induced by DEL transfusion or the secondary anti-D elevated by DEL in a truly D-negative patient might not be unusual. We suggest that a truly D-negative childbearing-aged woman should avoid DEL transfusion to protect her from primary anti-D allosensitization. In addition, anti-D positive recipients should also avoid DEL red cell transfusion due to the delayed hemolytic transfusion reaction (DHTR).

[PTEN: a new target in inhibiting of tumor invasion and metastasis].

Invasion and metastasis are both the main biological characteristics in malignant tumor which are influence tumor therapeutic effect and prognosis. The tumor cells interact with vascular endothelial cells and cell matrix, penetrate vascular endothelial and degrade the extracellular matrix, and metastasis to the local and distant by the interactions of a variety of signaling molecules. PTEN protein has protein phosphatase and lipid phosphatase dual activity which is produced by PTEN gene. As a tumor suppressor gene, regulates the cell signal pathways to sustain the normal physiological functions, negatively regulates of tumor cell growth and cell cycle, induces apoptosis, and inhibits invasion, infiltrating and metastasis of tumor cells. This article is reviewed about how PTEN participates in inhibiting tumor cell invasion and metastasis.

[Correlation between DNA methylation of the ABO gene promoter CpG island and leukemia].

Recent studies have found that ABO blood group antigen is also closely related to the onset and development of many diseases. More and more attention is being paid to the decrease of A/B blood group antigen caused by some tumors. This study was purpose to investigate the correlation between DNA methylation of the ABO gene promoter CpG island and leukemia. The relative contents of ABH antigen on the surface of RBC from kinds of blood disease patients and healthy individuals were detected by using flow cytometry and confocal laser scanning microscopy. The DNA sequences and CpG methylation of ABO gene promoter in patients with hematopathy and healthy individuals, as well as the -102 site methylation of ABO gene promoter in patients with hematopathy and healthy individuals were detected by PCR and MSP-PCR respectively. The results showed that RBC from leukemia patients displayed different degree of A/B antigen decrease. The sequences of ABO gene promotor of patients with hematopathy were not different from healthy individuals indicating high conservation of promoter sequences. Comparison of sequences between patients with hematopathy and healthy individual indicated that CpG islands on ABO gene promoter either from blood disease patients or from healthy individual had no methylated site in AA patients, but C residues at position -102, -101, -100, -99 and -97 on the promoter of ABO gene in AML, CML, ALL and some MDS patients were methylated. It is concluded that methylation of CpG islands in promoter of ABO gene may result in AB antigen decrease in patients with leukemia. The methylation sites -102, -101, -100, -99 and -97 may be specific for leukemia. The methylation of site -102 can be used as a molecular marker in differential diagnosis for leukemias.