SALL4 in gastrointestinal tract cancers: upstream and downstream regulatory mechanisms.

Effective therapeutic targets and early diagnosis are major challenges in the treatment of gastrointestinal tract (GIT) cancers. SALL4 is a well-known transcription factor that is involved in organogenesis during embryonic development. Previous studies have revealed that SALL4 regulates cell proliferation, survival, and migration and maintains stem cell function in mature cells. Additionally, SALL4 overexpression is associated with tumorigenesis. Despite its characterization as a biomarker in various cancers, the role of SALL4 in GIT cancers and the underlying mechanisms are unclear. We describe the functions of SALL4 in GIT cancers and discuss its upstream/downstream genes and pathways associated with each cancer. We also consider the possibility of targeting these genes or pathways as potential therapeutic options for GIT cancers.

zDHHC20-driven S-palmitoylation of CD80 is required for its costimulatory function.

CD80 is a transmembrane glycoprotein belonging to the B7 family, which has emerged as a crucial molecule in T cell modulation via the CD28 or CTLA4 axes. CD80-involved regulation of immune balance is a finely tuned process and it is important to elucidate the underlying mechanism for regulating CD80 function. In this study we investigated the post-translational modification of CD80 and its biological relevance. By using a metabolic labeling strategy, we found that CD80 was S-palmitoylated on multiple cysteine residues (Cys261/262/266/271) in both the transmembrane and the cytoplasmic regions. We further identified zDHHC20 as a bona fide palmitoyl-transferase determining the S-palmitoylation level of CD80. We demonstrated that S-palmitoylation protected CD80 protein from ubiquitination degradation, regulating the protein stability, and ensured its accurate plasma membrane localization. The palmitoylation-deficient mutant (4CS) CD80 disrupted these functions, ultimately resulting in the loss of its costimulatory function upon T cell activation. Taken together, our results describe a new post-translational modification of CD80 by S-palmitoylation as a novel mechanism for the regulation of CD80 upon T cell activation.

Bioinspired Structural Composite Flexible Material with High Cushion Performance.

Impacts occur everywhere, and they pose a serious threat to human health and production safety. Flexible materials with efficient cushioning and energy absorption are ideal candidates to provide protection from impacts. Despite the high demand, the cushioning capacity of protective materials is still limited. In this study, an integrated bionic strategy is proposed, and a bioinspired structural composite material with highly cushioning performance is developed on the basis of this strategy. The results demonstrated that the integrated bionic material, an S-spider web-foam, has excellent energy storage and dissipation as well as cushioning performance. Under impact loading, S-spider web-foam can reduce peak impact forces by a factor of 3.5 times better than silicone foam, achieving unprecedented cushioning performance. The results of this study deepen the understanding of flexible cushioning materials and may provide new strategies and inspiration for the preparation of high-performance flexible cushioning materials.

Prevalence, contemporary trends and associated factors of potentially inappropriate prescription of edoxaban in real-world clinical practice: A subanalysis of the SUNSHINE registry.

AIM: As the direct oral anticoagulant most recently approved in China, data pertaining to clinical edoxaban use are still scarce. This study investigated the prevalence of and contemporary trends in edoxaban prescription among Chinese patients as well as factors associated with its inappropriate use in a multicentre registry of patients treated in real-world clinical practice. METHODS: This real-world, prospective, multicentre and non-interventional study included 1005 inpatients treated with edoxaban. According to National Medical Products Administration and European Heart Rhythm Association guidelines, edoxaban therapy was determined to be appropriate or inappropriate in each case. RESULTS: The median patient age was 70.0 years (interquartile range 61.0-78.0 years) and 46.3% were women. Overall, 456 (45.4%) patients received inappropriate edoxaban therapy, and common issues included an inappropriately low dosage (183, 18.2%) or wrong drug selection (109, 10.8%), high dosage (73, 7.3%), unreasonable off-label use (49, 4.9%), contraindicated medication combinations (27, 2.7%) and incorrect administration timing (16, 1.6%). Several factors, such as age ≥75 years (odds ratio [OR] = 1.921, 95% confidence interval [CI] 1.355-2.723, P < 0.001), weight >60 kg (OR = 2.657, 95%CI 1.970-3.583, P < 0.001), severe renal insufficiency (OR = 1.988, 95% CI 1.043-3.790, P = 0.037), current anaemia (OR = 1.556, 95% CI 1.151-2.102, P = 0.004) and history of bleeding (OR = 2.931, 95% CI 1.605-5.351, P < 0.001) were associated with an increased risk of inappropriate edoxaban therapy, whereas factors associated with cardiovascular specialties, such as admission to a cardiovascular department (OR = 0.637, 95% CI 0.464-0.873, P = 0.005), dronedarone use (OR = 0.065, 95% CI 0.026-0.165, P < 0.001) and amiodarone use (OR = 0.365, 95% CI 0.209-0.637, P < 0.001) decreased this risk. CONCLUSION: In this real-world study, 45.4% of patients received an inappropriate treatment with edoxaban. Multiple clinical characteristics can help identify patients who should receive edoxaban. Further development and implantation of educational activities and management strategies are needed to ensure the correct use of edoxaban.

Real-world safety of icosapent ethyl: analysis based on spontaneous reports in FAERS database.

BACKGROUND: The triglyceride-lowering drug, icosapent ethyl (IPE), was granted a new indication for the reduction of atherosclerotic cardiovascular disease risk in 2019. This study aimed to investigate the safety profile of IPE by mining the FDA Adverse Event Reporting System (FAERS) database. METHODS: The reporting odds ratio was used to analyze IPE's adverse events (AEs) based on the FAERS data from July 2012 to December 2022. We described the characteristics of AE reports and evaluated the clinical prioritization of AEs. Then we defined and analyzed nine interested adverse drug reactions (ADRs) in both overall and subgroups, and investigated the times to onset. RESULTS: The findings of our study strengthen the evidence for an increased risk of atrial fibrillation using IPE. IPE alone may not increase the risk of bleeding unless combined with antithrombotic drugs. Similar to statins, IPE alone can increase the risk of musculoskeletal pain, drug-related hepatic disorders, and hyperglycemia, but the risk could not double when IPE was combined with statins. Most ADRs occur in the early stage of treatment. CONCLUSIONS: This study provides a comprehensive real-world safety profile of IPE, which indicates that IPE is well-tolerated.

Composite Flexible Sensor Based on Bionic Microstructure to Simultaneously Monitor Pressure and Strain.

To achieve the human sense of touch, a strain sensor needs to be coupled with a pressure sensor to identify the compliance of the contacted material. However, monitoring the pressure-strain signals simultaneously and ensuring no coupling effect between the two signals is the technical bottleneck for the flexible tactile sensor to. Herein, a composite flexible sensor based on microstructures of lotus leaf is designed and manufactured, which integrates the capacitive pressure sensor and the resistance strain sensor into one pixel to realize the simultaneous detection of pressure and strain. The electrode layer of the capacitance sensor also plays the role of the resistance strain sensor, which greatly simplifies the structure of the composite flexible sensor and obtains the compact size to integrate more easily. The device can simultaneously detect pressure and deformation, and more importantly, there is no coupling effect between the two kinds of signals. Here, the sensor has high pressure sensitivity (0.784 kPa-1 when pressure less than 100 kPa), high strain sensitivity (gauge factor = 4.03 for strain 0-40%), and can identify materials with different compliance, which indicates the tactile ability as the human skin performs.

The dichotomous role of immunoproteasome in cancer: Friend or foe?

Immunoproteasome is a variant of proteasome with structural differences in 20S subunits optimizing them for the production of antigenic peptides with higher binding affinity to major histocompatibility complex (MHC)-I molecules. Apart from this primary function in antigen presentation, immunoproteasome is also responsible for the degradation of proteins, both unfolded proteins for the maintenance of protein homeostasis and tumor suppressor proteins contributing to tumor progression. The altered expression of immunoproteasome is frequently observed in cancers; however, its expression levels and effects vary among different cancer types exhibiting antagonistic roles in tumor development. This review focuses on the dichotomous role of immunoproteasome in different cancer types, as well as summarizes the current progression in immunoproteasome activators and inhibitors. Specifically targeting immunoproteasome may be a beneficial therapeutic intervention in cancer treatment and understanding the role of immunoproteasome in cancers will provide a significant therapeutic insight for the prevention and treatment of cancers.

Insights into Manganese Superoxide Dismutase and Human Diseases.

Redox equilibria and the modulation of redox signalling play crucial roles in physiological processes. Overproduction of reactive oxygen species (ROS) disrupts the body's antioxidant defence, compromising redox homeostasis and increasing oxidative stress, leading to the development of several diseases. Manganese superoxide dismutase (MnSOD) is a principal antioxidant enzyme that protects cells from oxidative damage by converting superoxide anion radicals to hydrogen peroxide and oxygen in mitochondria. Systematic studies have demonstrated that MnSOD plays an indispensable role in multiple diseases. This review focuses on preclinical evidence that describes the mechanisms of MnSOD in diseases accompanied with an imbalanced redox status, including fibrotic diseases, inflammation, diabetes, vascular diseases, neurodegenerative diseases, and cancer. The potential therapeutic effects of MnSOD activators and MnSOD mimetics are also discussed. Targeting this specific superoxide anion radical scavenger may be a clinically beneficial strategy, and understanding the therapeutic role of MnSOD may provide a positive insight into preventing and treating related diseases.

Prevalence, risk factors, and prediction of inappropriate use of non-vitamin K antagonist oral anticoagulants in elderly Chinese patients with atrial fibrillation: A study protocol.

Background: Atrial fibrillation (AF) is an arrhythmia that is prevalent globally, and its incidence grows exponentially with aging. Non-vitamin K antagonist oral anticoagulants (NOACs) have been developed in recent years, and it challenges the supremacy of warfarin for thromboembolism prophylaxis in AF. Nevertheless, there are limited data specifically evaluating the real-life use of NOACs in elderly patients with AF in China. Methods: This is a national, multicenter, non-interventional, cross-sectional study that enrolls patients with AF aged 75 years and above from 31 institutions across China. Data were collected using the Hospital Information System. The primary outcomes include (1) profiles of NOAC use in the elderly; (2) frequency of inappropriate NOAC use based on guidelines and approved labeling recommendations; (3) exploring potential risk factors related to NOACs inappropriate use; and (4) creating a prediction tool for inappropriate NOACs use. Conclusion: The results of this study reveal the prevalence, risk factors, and corresponding prediction tool of inappropriate NOACs use in older patients with AF in China, as well as provide valuable insights into the clinical application of NOACs in high-risk populations in the real-world setting. Clinical trial registration: www.ClinicalTrials.gov, identifier: NCT05361889.

Comparing Bayesian-Based Reconstruction Strategies in Topology-Based Pathway Enrichment Analysis.

The development of high-throughput omics technologies has enabled the quantification of vast amounts of genes and gene products in the whole genome. Pathway enrichment analysis (PEA) provides an intuitive solution for extracting biological insights from massive amounts of data. Topology-based pathway analysis (TPA) represents the latest generation of PEA methods, which exploit pathway topology in addition to lists of differentially expressed genes and their expression profiles. A subset of these TPA methods, such as BPA, BNrich, and PROPS, reconstruct pathway structures by training Bayesian networks (BNs) from canonical biological pathways, providing superior representations that explain causal relationships between genes. However, these methods have never been compared for their differences in the PEA and their different topology reconstruction strategies. In this study, we aim to compare the BN reconstruction strategies of the BPA, BNrich, PROPS, Clipper, and Ensemble methods and their PEA and performance on tumor and non-tumor classification based on gene expression data. Our results indicate that they performed equally well in distinguishing tumor and non-tumor samples (AUC > 0.95) yet with a varying ranking of pathways, which can be attributed to the different BN structures resulting from the different cyclic structure removal strategies. This can be clearly seen from the reconstructed JAK-STAT networks by different strategies. In a nutshell, BNrich, which relies on expert intervention to remove loops and cyclic structures, produces BNs that best fit the biological facts. The plausibility of the Clipper strategy can also be partially explained by intuitive biological rules and theorems. Our results may offer an informed reference for the proper method for a given data analysis task.

Visible-light-mediated photocatalytic cross-coupling of acetenyl ketones with benzyl trifluoroborate.

In this report, we describe a simple visible light-triggered Barbier-type reaction by employing acetenyl ketones with benzyl trifluoroborates. Through a radical-radical cross-coupling process, this photocatalytic protocol furnished a wide range of tertiary propargyl alcohols. Mechanistic investigation indicated that proton-coupled electron transfer (PCET) might be involved in the photochemical transformations.

S100a8/a9 Signaling Causes Mitochondrial Dysfunction and Cardiomyocyte Death in Response to Ischemic/Reperfusion Injury.

BACKGROUND: Myocardial ischemia-reperfusion (MI/R) injury is a significant clinical problem without effective therapy. Unbiased omics approaches may reveal key MI/R mediators to initiate MI/R injury. METHODS: We used a dynamic transcriptome analysis of mouse heart exposed to various MI/R periods to identify S100a8/a9 as an early mediator. Using loss/gain-of-function approaches to understand the role of S100a8/a9 in MI/R injury, we explored the mechanisms through transcriptome and functional experiment. Dynamic serum S100a8/a9 levels were measured in patients with acute myocardial infarction before and after percutaneous coronary intervention. Patients were prospectively followed for the occurrence of major adverse cardiovascular events. RESULTS: S100a8/a9 was identified as the most significantly upregulated gene during the early reperfusion stage. Knockout of S100a9 markedly decreased cardiomyocyte death and improved heart function, whereas hematopoietic overexpression of S100a9 exacerbated MI/R injury. Transcriptome/functional studies revealed that S100a8/a9 caused mitochondrial respiratory dysfunction in cardiomyocytes. Mechanistically, S100a8/a9 downregulated NDUF gene expression with subsequent mitochondrial complex I inhibition via Toll-like receptor 4/Erk-mediated Pparg coactivator 1 alpha/nuclear respiratory factor 1 signaling suppression. Administration of S100a9 neutralizing antibody significantly reduced MI/R injury and improved cardiac function. Finally, we demonstrated that serum S100a8/a9 levels were significantly increased 1 day after percutaneous coronary intervention in patients with acute myocardial infarction, and elevated S100a8/a9 levels were associated with the incidence of major adverse cardiovascular events. CONCLUSIONS: Our study identified S100a8/a9 as a master regulator causing cardiomyocyte death in the early stage of MI/R injury via the suppression of mitochondrial function. Targeting S100a8/a9-intiated signaling may represent a novel therapeutic intervention against MI/R injury. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03752515.

Cardiac Fibroblast-Specific Activating Transcription Factor 3 Promotes Myocardial Repair after Myocardial Infarction.

BACKGROUND: Myocardial ischemia injury is one of the leading causes of death and disability worldwide. Cardiac fibroblasts (CFs) have central roles in modulating cardiac function under pathophysiological conditions. Activating transcription factor 3 (ATF3) plays a self-protective role in counteracting CF dysfunction. However, the precise function of CF-specific ATF3 during myocardial infarction (MI) injury/repair remains incompletely understood. The aim of this study was to determine whether CF-specific ATF3 affected cardiac repair after MI. METHODS: Fifteen male C57BL/6 wild-type mice were performed with MI operation to observe the expression of ATF3 at 0, 0.5, 1.0, 3.0, and 7.0 days postoperation. Model for MI was constructed in ATF3TGfl/flCol1a2-Cre+ (CF-specific ATF3 overexpression group, n = 5) and ATF3TGfl/flCol1a2-Cre- male mice (without CF-specific ATF3 overexpression group, n = 5). In addition, five mice of ATF3TGfl/flCol1a2-Cre+ and ATF3TGfl/flCol1a2-Cre- were subjected to sham MI operation. Heart function was detected by ultrasound and left ventricular remodeling was observed by Masson staining (myocardial fibrosis area was detected by blue collagen deposition area) at the 28th day after MI surgery in ATF3TGfl/flCol1a2-Cre+ and ATF3TGfl/flCol1a2-Cre- mice received sham or MI operation. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect cell proliferation/cell cycle-related gene expression in cardiac tissue. BrdU staining was used to detect fibroblast proliferation. RESULTS: After establishment of an MI model, we found that ATF3 proteins were increased in the heart of mice after MI surgery and dominantly expressed in CFs. Genetic overexpression of ATF3 in CFs (ATF3TGfl/flCol1a2-Cre+ group) resulted in an improvement in the heart function as indicated by increased cardiac ejection fraction (41.0% vs. 30.5%, t = 8.610, P = 0.001) and increased fractional shortening (26.8% vs. 18.1%, t = 7.173, P = 0.002), which was accompanied by a decrease in cardiac scar area (23.1% vs. 11.0%, t = 8.610, P = 0.001). qRT-PCR analysis of CFs isolated from ATF3TGfl/flCol1a2-Cre+ and ATF3TGfl/flCol1a2-Cre- ischemic hearts revealed a distinct transcriptional profile in ATF3-overexpressing CFs, displaying pro-proliferation properties. BrdU-positive cells significantly increased in ATF3-overexpressing CFs than control CFs under angiotensin II stimuli (11.5% vs. 6.8%, t = 31.599, P = 0.001) or serum stimuli (31.6% vs. 20.1%, t = 31.599, P = 0.001). The 5(6)-carboxyfluorescein N-hydroxysuccinimidyl ester assay showed that the cell numbers of the P2 and P3 generations were higher in the ATF3-overexpressing CFs at 24 h (P2: 91.6% vs. 71.8%, t = 8.465, P = 0.015) and 48 h (P3: 81.6% vs. 51.1%, t = 9.029, P = 0.012) after serum stimulation. Notably, ATF3 overexpression-induced CF proliferation was clearly increased in the heart after MI injury. CONCLUSIONS: We identify that CF-specific ATF3 might contribute to be MI repair through upregulating the expression of cell cycle/proliferation-related genes and enhancing cell proliferation.

The optimal anticoagulant therapy for mechanical heart valves in a gallbladder cancer patient with hepatic metastases: A case report.

RATIONALE: Developing an optimal anticoagulant strategy poses a challenging task in patients with mechanical heart valves (MHVs) throughout their lifetime. We report an optimal anticoagulant therapy in a cancer patient with hepatic metastases after MHV replacement. PATIENT CONCERNS: A 68-year-old female with MHVs suffered from gallbladder cancer with hepatic metastases. Her international normalized ratio (INR) fluctuated owing to the declined hepatic function. DIAGNOSES: Gallbladder cancer and hepatic metastases, with a history of mechanic aortic valve replacement and mitral valve replacement. INTERVENTIONS: Warfarin was discontinued and Vitamin K1 was immediately administrated via intravenous infusion. low-molecular-weight heparin (LMWH) was regarded as a preferable option, and nadroparin at the dosage of 4100IU daily was administered. OUTCOMES: No adverse event occurred during the patient's hospitalization and two-week follow up after discharge. LESSONS: LMWH may represent a reasonable alternative regarding the inhibition of thrombus and bleeding in MHVs carriers with cancer and hepatic metastases.

Unlockable Nanocomplexes with Self-Accelerating Nucleic Acid Release for Effective Staged Gene Therapy of Cardiovascular Diseases.

Nucleic acid (NA)-based therapy is proposed to address serious diseases such as cardiovascular diseases (CVDs). Powerful NA delivery vehicles are essential for effective gene therapy. Herein, a novel type of delivery vehicle, an unlockable core-shell nanocomplex (Hep@PGEA) with self-accelerating NA release, is structurally designed. Hep@PGEA is composed of disulfide-bridged heparin nanoparticle (HepNP) core and low-toxicity PGEA cationic shell. In comparison with NA, heparin, a negatively charged polysaccharide macromolecule, exhibits stronger interactions with cationic species. Upon the breakdown of redox-responsive HepNP cores, unlocked heparin would interact with the outer cationic shells and replace the condensed NA to facilitate NA release. Such unique Hep@PGEA is successfully explored for effective miRNA-pDNA staged gene therapy of myocardial infarction (MI), one of the most serious CVDs. With the progression of MI, glutathione amounts in heart tissues increase. MiR-499 (for the inhibition of cardiomyocyte apoptosis) and plasmid encoding vascular endothelial growth factor (for the promotion of angiogenesis) are sequentially delivered for systemic treatment of MI. Such treatment produces impressive results in restoring heart function and suppressing cardiac hypertrophy. Due to the wide existence of redox agents in cells, the proposed unlockable delivery nanovehicle and staged therapy strategy can provide new methods to effectively treat different serious diseases.

Interleukin-3 stimulates matrix metalloproteinase 12 production from macrophages promoting thoracic aortic aneurysm/dissection.

Thoracic aortic aneurysm and dissection (TAAD) is due to degeneration of the aorta and causes a high mortality rate, while molecular mechanisms for the development of TAAD are still not completely understood. In the present study, 3-aminopropionitrile (BAPN) treatment was used to induce TAAD mouse model. Through transcriptome analysis, we found the expression levels of genes associated with interleukin-3 (IL-3) signaling pathway were up-regulated during TAAD development in mouse, which were validated by real-time PCR. IL-3 positive cells were increased in TAAD mouse aortas, especially for smooth muscle cells (SMCs). IL-3 deficiency reduced BAPN-induced TAAD formation. We then examined the matrix metalloproteinases (MMPs) expression during TAAD formation in both wild-type and IL-3 deficient mice, showing that MMP12 were significantly down-regulated in IL-3 deficient aortas. Mechanistically, we found recombinant IL-3 could increase MMP12 production and activity from macrophages in vitro Silencing of IL-3 receptor ß, which was mainly expressed in macrophages but not SMCs, diminished the activation of c-Jun N terminal kinase (JNK)/extracellular-regulated protein kinases 1/2 (ERK1/2)/AP-1 signals, and decreased MMP12 expression in IL-3 stimulated macrophages. Moreover, both circulating and aortic inflammation were decreased in IL-3 deficient aortas. Taken together, our results demonstrated that IL-3 stimulated the production of MMP12 from macrophages by a JNK- and ERK1/2-dependent AP-1 pathway, contributing to TAAD formation. Thus, the IL-3/IL-3Rß/MMP12 signals activation may be an important pathological mechanism for progression of TAAD.

The Complement C3a-C3aR Axis Promotes Development of Thoracic Aortic Dissection via Regulation of MMP2 Expression.

Thoracic aortic dissection (TAD), once ruptured, is devastating to patients, and no effective pharmaceutical therapy is available. Anaphylatoxins released by complement activation are involved in a variety of diseases. However, the role of the complement system in TAD is unknown. We found that plasma levels of C3a, C4a, and C5a were significantly increased in patients with TAD. Elevated circulating C3a levels were also detected in the developmental process of mouse TAD, which was induced by ß-aminopropionitrile monofumarate (BAPN) treatment, with enhanced expression of C1q and properdin in mouse dissected aortas. These findings indicated activation of classical and alternative complement pathways. Further, expression of C3aR was obviously increased in smooth muscle cells of human and mouse dissected aortas, and knockout of C3aR notably inhibited BAPN-induced formation and rupture of TAD in mice. C3aR antagonist administered pre- and post-BAPN treatment attenuated the development of TAD. We found that C3aR knockout decreased matrix metalloproteinase 2 (MMP2) expression in BAPN-treated mice. Additionally, recombinant C3a stimulation enhanced MMP2 expression and activation in smooth muscle cells that were subjected to mechanical stretch. Finally, we generated MMP2-knockdown mice by in vivo MMP2 short hairpin RNA delivery using recombinant adeno-associated virus and found that MMP2 deficiency significantly reduced the formation of TAD. Therefore, our study suggests that the C3a-C3aR axis contributes to the development of TAD via regulation of MMP2 expression. Targeting the C3a-C3aR axis may represent a strategy for inhibiting the formation of TAD.

Haplodeficiency of Ataxia Telangiectasia Mutated Accelerates Heart Failure After Myocardial Infarction.

BACKGROUND: Cell senescence is involved in the process of organ damage and repair; however, the underlying molecular mechanism needs to be further explored. METHODS AND RESULTS: Senescence-related genes (ie, p21, p53, and ataxia telangiectasia mutated [ATM]) were shown to be elevated after myocardial infarction (MI) in both mouse and human hearts. Ten- to 12-week-old male wild-type littermates (ATM+/+) and ATM heterozygous mice (ATM+/-) were subjected to MI. Cardiac echography showed that ATM haplodeficiency did not affect the survival rate but aggravated heart failure at day 28 post MI. Histologic analysis showed increased fibrosis in the noninfarct area of ATM+/- mice compared with that in ATM+/+ mice. Senescence-associated ß-galactosidase staining showed that the number of senescent fibroblasts was decreased when ATM was haplodeficient both in vivo and in vitro. Costaining of α-smooth muscle actin with p53 or p19 showed fewer senescent myofibroblasts in ATM+/- mouse hearts. Moreover, angiogenesis was also examined using the endothelial markers CD31 both at early (day 7) and late stages (day 28) after MI, and ATM haplodeficiency reduced angiogenesis after MI. Finally, cardiac fibroblasts were isolated from infarcted mouse heart and the medium were tested for its capacity of endothelial tubing formation, revealing that ATM haplodeficiency led to lower vascular endothelial growth factor production from cardiac fibroblast and reduced capacity of endothelial tube formation in vitro. CONCLUSIONS: The present study shows that ATM haplodeficiency decreases fibroblast senescence and vascular endothelial growth factor production and impaired angiogenesis in response to MI, leading to accelerated heart failure.

Factors influencing medication knowledge and beliefs on warfarin adherence among patients with atrial fibrillation in China.

OBJECTIVES: Warfarin is often used for ischemic stroke prevention in patients with atrial fibrillation (AF), but the factors affecting patient adherence to warfarin therapy have not been fully understood. METHODS: A cross-sectional survey was conducted in AF patients undergoing warfarin therapy at least 6 months prior to the study. The clinical data collected using questionnaires by phone interviews included the following: 1) self-reported adherence measured by the Morisky Medication Adherence Scale-8©; 2) beliefs about medicines surveyed by Beliefs about Medicines Questionnaire (BMQ); and 3) drug knowledge as measured by the Warfarin Related Knowledge Test (WRKT). Demographic and clinical factors associated with warfarin adherence were identified using a logistic regression model. RESULTS: Two hundred eighty-eight patients completed the survey and 93 (32.3%) of them were classified as nonadherent (Morisky Medication Adherence Scale-8 score <6). Major factors predicting warfarin adherence included age, cardiovascular disorders, WRKT, and BMQ; WRKT and BMQ were independently correlated with adherence to warfarin therapy by multivariate logistic regression analysis. Adherents were more likely to have greater knowledge scores and stronger beliefs in the necessity of their specific medications ([odds ratio {OR} =1.81, 95% confidence interval {CI} =1.51-2.15] and [OR =1.17, 95% CI =1.06-1.29], respectively). Patients with greater concerns about adverse reactions and more negative views of general harm were more likely to be nonadherent ([OR =0.76, 95% CI =0.69-0.84] and [OR =0.82, 95% CI =0.73-0.92], respectively). CONCLUSION: BMK and WRKT are related with patient behavior toward warfarin adherence. BMQ can be applied to identify patients at increased risk of nonadherence.