The Role and Underlying Mechanisms of Exercise in Heart Failure.

Heart failure is a prevalent and life-threatening syndrome characterized by structural and/or functional abnormalities of the heart. As a global burden with high rates of morbidity and mortality, there is growing recognition of the beneficial effects of exercise on physical fitness and cardiovascular health. A substantial body of evidence supports the notion that exercise can play a protective role in the development and progression of heart failure and improve cardiac function through various mechanisms, such as attenuating cardiac fibrosis, reducing inflammation, and regulating mitochondrial metabolism. Further investigation into the role and underlying mechanisms of exercise in heart failure may uncover novel therapeutic targets for the prevention and treatment of heart failure.

Causal role of frontocentral beta oscillation in comprehending linguistic communicative functions.

Linguistic communication is often considered as an action serving the function of conveying the speaker's goal to the addressee. Although neuroimaging studies have suggested a role of the motor system in comprehending communicative functions, the underlying mechanism is yet to be specified. Here, by two EEG experiments and a tACS experiment, we demonstrate that the frontocentral beta oscillation, which represents action states, plays a crucial part in linguistic communication understanding. Participants read scripts involving two interlocutors and rated the interlocutors' attitudes. Each script included a critical sentence said by the speaker expressing a context-dependent function of either promise, request, or reply to the addressee's query. These functions were behaviorally discriminated, with higher addressee's will rating for the promise than for the reply and higher speaker's will rating for the request than for the reply. EEG multivariate analyses showed that different communicative functions were represented by different patterns of the frontocentral beta activity but not by patterns of alpha activity. Further tACS results showed that, relative to alpha tACS and sham stimulation, beta tACS improved the predictability of communicative functions of request or reply, as measured by the speaker's will rating. These results convergently suggest a causal role of the frontocentral beta activities in comprehending linguistic communications.

Bioinformatic prediction of miR-320a as a potential negative regulator of CDGSH iron-sulfur domain 2 (CISD2), involved in lung adenocarcinoma bone metastasis via MYC activation, and associated with tumor immune infiltration.

Background: Ferroptosis, a form of regulated cell death associated with iron-dependent lipid peroxidation, plays a role in cancer progression. However, the specific mechanisms of ferroptosis in lung adenocarcinoma (LUAD) bone metastasis (BM) remain unclear. Using bioinformatics analysis, this study sought to identify the ferroptosis-associated genes involved in BM in LUAD, thus providing potential novel targets for the treatment of BM in LUAD. Methods: The RNA expression dataset GSE10799 was acquired from the Gene Expression Omnibus (GEO) database, and intersected with the ferroptosis dataset to identify ferroptosis-related differentially expressed genes (DEGs). The expression of candidate genes and their correlation with the prognosis of LUAD patients were validated in The Cancer Genome Atlas (TCGA) database. A protein gene interaction network was constructed using GeneMania and Retrieval of Interacting Genes/Proteins (STRING) databases. The association between the candidate genes and immune cells was assessed via TCGA and Tumor IMmune Estimation Resource (TIMER) databases. The potential mechanisms were elucidated by a gene set enrichment analysis (GSEA). The relevant microRNAs (miRNAs or miRs) that bind to the 3'untranslated region (3'UTR) end of candidate genes' mRNA was explored using the TargetScan database. The expression of these candidate miRNAs in LUAD was validated and the correlation between candidate miRNAs and candidate mRNAs was tested using the TCGA database. Finally, the clinical data of 40 LUAD patients were retrospectively analyzed to evaluate the clinical value of candidate gene expression for LUAD BM patients. Results: In this research, 15 ferroptosis-related DEGs in LUAD BM were identified. TCGA database analysis indicated that patients with low levels of CDGSH iron-sulfur domain 2 (CISD2) in LUAD had better disease-specific survival (DSS), overall survival (OS), and a better progression-free interval (PFI) than those with high levels of CISD2. The TIMER database results show that the expression of CISD2 is correlated with the infiltration levels of various immune cells. The GSEA indicated that CISD2 might influence biological activity in LUAD by participating in cell-cycle regulation, mitochondrial translation, DNA damage repair, c-Myc (MYC) activation, and the P53 signaling pathway. Through the combined analysis of the TargetScan and TCGA databases, hsa-miR-320a was identified as the optimal upstream regulatory miRNA. The immunohistochemistry data indicated that the positive CISD2 expression rates and immunohistochemistry scores of the patients with BM were significantly higher than those of the patients without BM (P<0.05). The high expression of CISD2 is a significant risk factor for BM in LUAD. Conclusions: The downregulation of CISD2 expression may extend DSS, OS, and the PFI of LUAD patients. Thus, CISD2 could serve as a novel predictive biomarker for LUAD patients. Further, miR-320a might negatively regulate CISD2 and participate in LUAD BM by activating MYC. These data provide a potential perspective for developing anticancer therapies for LUAD-BM patients.

The Effects of Physician Vertical Integration on Referral Patterns, Patient Welfare, and Market Dynamics.

The growth of physician vertical integration raises concerns about distorted referral patterns, higher spending, and market foreclosure. Using 100% Medicare data, we combine reduced-form analysis with a discrete choice model to estimate the effects of physician vertical integration on patients' provider choices and welfare for two common "downstream" surgical procedures. Physician-hospital integration results in an approximately 10% increase in referrals to higher-priced facilities instead of lower-priced providers. Our counterfactual analysis implies that if all primary care physicians become integrated, total Medicare spending will increase by $315 million.

Protective role of the CD73-A2AR axis in cirrhotic cardiomyopathy through negative feedback regulation of the NF-κB pathway.

Background: Myocardial inflammation and apoptosis induced by cirrhosis are among the primary mechanisms of cirrhotic cardiomyopathy. CD73, a common extracellular nucleotidase also known as 5'-nucleotidase, is associated with the progression of inflammation and immunity in multiple organs. However, the mechanism by which CD73 contributes to myocardial inflammation and apoptosis in cirrhosis remains unclear. Methods: In this study, a cirrhotic cardiomyopathy model in mice was established by bile duct ligation. Myocardial-specific overexpression of CD73 was achieved by tail vein injection of AAV9 (adeno-associated virus)-cTNT-NT5E-mCherry, and cardiac function in mice was assessed using echocardiography. Myocardial inflammation infiltration and apoptosis were evaluated through pathological observation and ELISA assays. The expression of CD73, A2AR, apoptotic markers, and proteins related to the NF-κB pathway in myocardial tissue were measured. Results: In the myocardial tissue of the cirrhotic cardiomyopathy mouse model, the expression of CD73 and A2AR increased. Overexpression of CD73 in the myocardium via AAV9 injection and stimulation of A2AR with CGS 21680 inhibited myocardial inflammation and cardiomyocyte apoptosis induced by cirrhosis. Additionally, overexpression of CD73 suppressed the activation of the NF-κB pathway by upregulating the expression of the adenosine receptor A2A. Conclusion: Our study reveals that the CD73/A2AR signaling axis mitigates myocardial inflammation and apoptosis induced by cirrhosis through negative feedback regulation of the NF-κB pathway.

Cholinized-Polymer Functionalized Lipid-Based Drug Carriers Facilitate Liver Fibrosis Therapy via Ultrafast Liver-Targeting Delivery.

Here, we report novel cholinized-polymer functionalized lipid-based nanoparticles (CP-LNPs) for rapid and highly effective delivery of drugs to the liver, achieving targeting within 10 min and nearly 100% efficiency. In this study, CP-LNPs loaded with a promising antifibrotic agent curcumin (CP-LNPs/Cur) significantly improved the stability of curcumin under physiological conditions and its distribution in the liver. In vitro experiments demonstrated that CP-LNPs/Cur effectively suppressed the proliferation and migration of activated hepatic stellate cells (aHSCs), as evidenced by the decreased expression of α-SMA. Moreover, CP-LNPs/Cur attenuated oxidative stress levels in hepatocytes while improving mitochondrial physiological activity. In vivo antifibrosis studies have shown that CP-LNPs/Cur only require a low dose to significantly alleviate liver injury and collagen deposition, thereby preventing the progression of liver fibrosis. These findings indicated that CP-LNPs exhibit great potential in liver fibrosis therapy benefiting from the novel targeting strategy.

Improvement of model simulation for summer PM2.5 and O3 through coupling with two new potential HONO sources in the North China Plain.

A large fraction of fine particulate matter (PM2.5) and ozone (O3) in the troposphere originates from secondary formation through photochemical processes, which remarkably contributes to the deterioration of regional air quality in China. The photochemical reactions initiated by hydroxyl radicals (OH) play vital roles in secondary PM2.5 and O3 formation. In contrast, the OH levels in polluted areas are underestimated by current chemical transport models (CTMs) because of the strongly unknown daytime sources of tropospheric nitric acid (HONO), which has been recognized as the dominant source of primary OH in polluted areas of China. In this study, the atmospheric HONO levels at two urban sites were found to be significantly underestimated by the WRF-Chem model based on available information on HONO sources. The HONO levels could be well reproduced by the WRF-Chem model after incorporating two new potential HONO sources from the photochemical reactions of NOx, as proposed in our previous study based on chamber experiment results. Comparing the simulations with available information of HONO sources, the simulated levels of atmospheric OH, secondary inorganic and organic aerosols (SIA and SOA), PM2.5 and daily maximum 8-h average (MDA8) O3 were evidently elevated or were closer to the observations over the North China Plain (NCP), with elevation percentages of 0.48-20.1 %, and a decrement percentage of -5.79 % for pNO3-. Additionally, the compensating errors in modeling PM2.5 and the gap in MDA8 O3 levels between observation and simulation in 2 + 26 cities became evidently smaller. The results of this study indicated that the empirical parameterization of two new potential HONO sources through photochemical reactions of NOx improved the model performance in modeling PM2.5 and O3 by narrowing the gap in daytime HONO levels between simulation and observation, although their detailed chemical mechanisms are still unknown and should be further investigated and explicitly parameterized.

Clinical Characteristics of Peripheral Lymphocyte Subtypes in Chronic Active Epstein-Barr Virus Infection.

BACKGROUND: We aimed to analyze the clinical characteristics of peripheral Epstein-Barr virus (EBV)-infected lymphocyte subtypes in children with chronic active EBV infection (CAEBV). METHODS: The levels of peripheral EBV infection of CD4+ T cells, CD8+ T cells, and CD56+ natural killer (NK) cells were determined by flow cytometry and quantitative polymerase chain reaction (qPCR) in patients with CAEBV from July 2017 to July 2022. RESULTS: In total, 112 children with CAEBV were evaluated. Of these, CD4+ type, CD8+ type, and CD56+ type were defined in 44, 21, and 47 patients, respectively. Patients with CD8+ T-cell type had a significantly higher frequency of rash, while hepatomegaly was more common in patients with CD4+ T-cell type. Generally, patients with CD8+ T-cell type had the lowest overall survival rate (P = .017). Patients treated with chemotherapy and hematopoietic stem cell transplantation (HSCT) had a better prognosis (P = .001). In multivariate analysis, rash, hemophagocytic lymphohistiocytosis, CD8+ T-cell type, and no decrease of plasma EBV-DNA after treatment were independent indicators of poor prognosis (P = .002, .024, .022, and .012, respectively). CONCLUSIONS: In children with CAEBV, rash was more frequent in patients with CD8+ T-cell type, whereas patients with CD4+ T-cell type were more likely to develop hepatomegaly. Patients with CD8+ T-cell type had a poor prognosis despite receiving chemotherapy or further HSCT.

Market landscape and insurer-provider integration: the case of ambulatory surgery centers.

Insurer-provider integration is a new form of vertical integration, with increasing prominence in health care markets. While there are potential benefits from tighter alignment between providers and payers, risks of perverse impacts on health care markets loom large. Yet, little is known about this new wave of consolidation, which limits options for policy or regulatory responses. We focus on a dominant insurer's acquisitions of ambulatory surgery centers (ASCs) to document the growth and geographic spread of these ownership events. We found that a diverse swathe of the United States has experienced an insurer-led ASC takeover. The acquisitions are also more frequently in areas where the insurer holds a higher enrollee market share at baseline, although a linear prediction of the likelihood of ASC acquisition shows a more nuanced picture.

Comprehensive quantitative radiogenomic evaluation reveals novel radiomic subtypes with distinct immune pattern in glioma.

BACKGROUND: Accurate classification of gliomas is critical to the selection of immunotherapy, and MRI contains a large number of radiomic features that may suggest some prognostic relevant signals. We aim to predict new subtypes of gliomas using radiomic features and characterize their survival, immune, genomic profiles and drug response. METHODS: We initially obtained 341 images of 36 patients from the CPTAC dataset for the development of deep learning models. Further 1812 images of 111 patients from TCGA_GBM and 152 images of 53 patients from TCGA_LGG were collected for testing and validation. A deep learning method based on Mask R-CNN was developed to identify new subtypes of glioma patients and compared the survival status, immune infiltration patterns, genomic signatures, specific drugs, and predictive models of different subtypes. RESULTS: 200 glioma patients (mean age, 33 years ± 19 [standard deviation]) were enrolled. The accuracy of the deep learning model for identifying tumor regions achieved 88.3 % (98/111) in the test set and 83 % (44/53) in the validation set. The sample was divided into two subtypes based on radiomic features showed different prognostic outcomes (hazard ratio, 2.70). According to the results of the immune infiltration analysis, the subtype with a poorer prognosis was defined as the immunosilencing radiomic (ISR) subtype (n = 43), and the other subtype was the immunoactivated radiomic (IAR) subtype (n = 53). Subtype-specific genomic signatures distinguished celllines into ISR celllines (n = 9) and control celllines (n = 13), and identified eight ISR-specific drugs, four of which were validated by the OCTAD database. Three machine learning-based classifiers showed that radiomic and genomic co-features better predicted the radiomic subtypes of gliomas. CONCLUSIONS: These findings provide insights into how radiogenomic could identify specific subtypes that predict prognosis, immune and drug sensitivity in a non-invasive manner.

Correlation and risk factors of peripheral and cervicocephalic arterial atherosclerosis in patients with ischemic cerebrovascular disease.

Patients with ischemic cerebrovascular disease (ICVD) frequently develop concomitant peripheral artery disease (PAD) or renal artery stenosis (RAS), and multiterritorial atherosclerotic patients usually have a worse prognosis. We aimed to evaluate the status of peripheral atherosclerosis (AS) and cervicocephalic AS (CAS) in ICVD patients with AS, their correlation, and related risk factors contributing to coexisting cervicocephalic-peripheral AS (CPAS). Based on the severity and extent of AS evaluated by computed tomography angiography and ultrasound, the degree of AS was triple categorized to assess the correlation between CAS and PAD/RAS. CAS and PAD/RAS were defined as the most severe stenosis being ≥ 50% luminal diameter in cervicocephalic or lower limb arteries, and a peak systolic velocity at the turbulent site being ≥ 180 cm/s in the renal artery. Among 403 patients with symptom onset within 30 days, CAS, PAD, and RAS occurrence rates were 68.7%, 25.3%, and 9.9%, respectively. PAD was independently associated with the degree of extracranial and intracranial CAS (p = 0.042, OR = 1.428, 95% CI 1.014-2.012; p = 0.002, OR = 1.680, 95% CI 1.206-2.339), while RAS was independently associated with the degree of extracranial CAS (p = 0.001, OR = 2.880, 95% CI 1.556-5.329). Independent CPAS risk factors included an ischemic stroke history (p = 0.033), increased age (p < 0.01), as well as elevated fibrinogen (p = 0.021) and D-dimer levels (p = 0.019). In conclusion, the occurrence rates of RAS and PAD in ICVD patients with AS is relatively high, and with the severity of RAS or PAD increase, the severity of CAS also increase. Strengthening the evaluation of peripheral AS and controlling elevated fibrinogen might be crucial for preventing and delaying the progression of multiterritorial AS in ICVD patients with AS, thereby improving risk stratification and promoting more effective prevention and treatment strategies.

Associations between Total Atherosclerosis Burden of Baroreceptor-Resident Arteries and ECG Abnormalities after Acute Ischemic Stroke.

Electrocardiogram (ECG) abnormalities are the most common cardiac complications after acute ischemic stroke (AIS) and predict poor outcomes. The arterial baroreflex is an essential determinant of cardiovascular autonomic regulation, with receptors mainly residing in carotid sinuses and aortic arch. The atherosclerosis of these baroreceptor-resident arteries (BRA) is very common in AIS patients and might impair baroreflex function. However, the associations between the atherosclerosis of BRA and ECG abnormalities after AIS are still unknown. In total, 228 AIS patients within 7 days after onset without a pre-existing heart disease were prospectively recruited. With computed tomography angiography, atherosclerosis conditions in 10 segments of the carotid sinuses and aortic arch were scored and summed as the Total Atherosclerosis Burden of BRA (TAB-BRA), and asymptomatic coronary artery stenosis (ACAS) ≥50% was simultaneously assessed. We performed 12-lead ECG to dynamically detect abnormal repolarization, and 24 h Holter ECG to monitor arrhythmias and heart rate variability (HRV) parameters, which are reliable indicators to assess cardiac autonomic function. We found that TAB-BRA was positively associated with abnormal repolarization (OR 1.09; CI% 1.03-1.16; p = 0.003) and serious cardiac arrhythmias (OR 1.08; CI% 1.01-1.15; p = 0.021). In addition, TAB-BRA was an important predictor of abnormal repolarization, persisting over 3 days (OR 1.17; CI% 1.05-1.30; p = 0.003). However, ACAS ≥ 50% did not relate to these ECG abnormalities. TAB-BRA was negatively correlated with parasympathetic-related HRV parameters. Our results indicated that AIS patients with a high TAB-BRA are more likely to have ECG abnormalities and delayed normalization, which may relate to the decreased cardiac parasympathetic activity, but not the accompanied ACAS ≥ 50%.

Genetic Landscape and Its Prognostic Impact in Children With Langerhans Cell Histiocytosis.

CONTEXT.­: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm that predominantly affects young children. OBJECTIVE.­: To investigate genetic alterations and their correlation with clinical characteristics and prognosis in pediatric LCH. DESIGN.­: We performed targeted sequencing to detect mutations in LCH lesions from pediatric patients. RESULTS.­: A total of 30 genomic alterations in 5 genes of the MAPK pathway were identified in 187 of 223 patients (83.9%). BRAF V600E (B-Raf proto-oncogene, serine/threonine kinase) was the most common mutation (51.6%), followed by MAP2K1 (mitogen-activated protein kinase kinase 1) alterations (17.0%) and other BRAF mutations (13.0%). ARAF (A-Raf proto-oncogene, serine/threonine kinase) and KRAS (KRAS proto-oncogene, GTPase) mutations were relatively rare (2.2% and 0.9%, respectively). Additionally, FNBP1 (formin-binding protein 1)::BRAF fusion and MAP3K10 (mitogen-activated protein kinase kinase 10) mutations A17T and R823C were identified in 1 case each, with possible constitutive activation of ERK1/2 phosphorylation. BRAF V600E was more frequent in patients with risk organ involvement, while MAP2K1 mutation was more prevalent in patients with single-system LCH (P = .001). BRAF V600E was associated with craniofacial bone, skin, liver, spleen, and ear involvement (all P < .05). Patients with other BRAF mutations had a higher proportion of spinal column involvement (P = .006). Univariate analysis showed a significant difference in progression-free survival among the 4 molecular subgroups for patients treated with first-line therapy (P = .02). According to multivariate analysis, risk organ involvement was the strongest independent adverse prognostic factor (hazard ratio, 8.854; P < .001); BRAF or MAP2K1 mutation was not an independent prognostic factor. CONCLUSIONS.­: Most pediatric patients with LCH carry somatic mutations involving the MAPK pathway, correlating with clinical characteristics and outcomes for first-line chemotherapy.

Reducing Soil-Emitted Nitrous Acid as a Feasible Strategy for Tackling Ozone Pollution.

Severe ozone (O3) pollution has been a major air quality issue and affects environmental sustainability in China. Conventional mitigation strategies focusing on reducing volatile organic compounds and nitrogen oxides (NOx) remain complex and challenging. Here, through field flux measurements and laboratory simulations, we observe substantial nitrous acid (HONO) emissions (FHONO) enhanced by nitrogen fertilizer application at an agricultural site. The observed FHONO significantly improves model performance in predicting atmospheric HONO and leads to regional O3 increases by 37%. We also demonstrate the significant potential of nitrification inhibitors in reducing emissions of reactive nitrogen, including HONO and NOx, by as much as 90%, as well as greenhouse gases like nitrous oxide by up to 60%. Our findings introduce a feasible concept for mitigating O3 pollution: reducing soil HONO emissions. Hence, this study has important implications for policy decisions related to the control of O3 pollution and climate change.

Size-resolved water-soluble organic carbon and its significant contribution to aerosol liquid water.

Size-segregated aerosols collected in Beijing from 2021 to 2022 were used to investigate the contribution of organic aerosols to the aerosol liquid water content (ALWC), the influencing factors of ALWC, and the concentrations and size distribution characteristics of water-soluble organic carbon (WSOC) after clean air actions. The results showed that the concentration of WSOC in particulate matter (PM)1.8 was 3.52 ± 2.43 µg/m3 during the sampling period. Obvious changes were observed in the size distribution of WSOC after clean air actions, which may be attributed to the enhancement of atmospheric oxidation capacity and the decrease in PM concentration. The contribution of organic aerosols to the ALWC in fine PM was 18.1 % during the sampling period, which was more significant at lower particles concentration and smaller particle size ranges. The ambient relative humidity (RH) and the ratio of NO3-/SO42- had an apparent influence on ALWC. The continuous increase in the nitrate proportion significantly reduced the deliquescence point of the aerosols, making them prone to hygroscopic growth at lower RH. Analysis of the relation among nitrogen oxidation ratio (sulfur oxidation ratio), ALWC and PM1.8 mass concentrations suggests that organic matter has a significant effect on the formation of secondary inorganic aerosols in the initial phase of pollution formation and plays a crucial role in aerosol pollution formation in Beijing. These results are conducive to understanding the formation mechanism of aerosols and provide scientific data and theoretical support for the formulation of more effective emission-reduction measures.

Paraventricular thalamus to nucleus accumbens circuit activation decreases long-term relapse of alcohol-seeking behaviour in male mice.

BACKGROUND: Some studies have highlighted the crucial role of aversion in addiction treatment. The pathway from the anterior paraventricular thalamus (PVT) to the shell of the nucleus accumbens (NAc) has been reported as an essential regulatory pathway for processing aversion and is also closely associated with substance addiction. However, its impact on alcohol addiction has been relatively underexplored. Therefore, this study focused on the role of the PVT-NAc pathway in the formation and relapse of alcohol addiction-like behaviour, offering a new perspective on the mechanisms of alcohol addiction. RESULTS: The chemogenetic inhibition of the PVT-NAc pathway in male mice resulted in a notable decrease in the establishment of ethanol-induced conditioned place aversion (CPA), and NAc-projecting PVT neurons were recruited due to aversive effects. Conversely, activation of the PVT-NAc pathway considerably impeded the formation of ethanol-induced conditioned place preference (CPP). Furthermore, during the memory reconsolidation phase, activation of this pathway effectively disrupted the animals' preference for alcohol-associated contexts. Whether it was administered urgently 24 h later or after a long-term withdrawal of 10 days, a low dose of alcohol could still not induce the reinstatement of ethanol-induced CPP. CONCLUSIONS: Our results demonstrated PVT-NAc circuit processing aversion, which may be one of the neurobiological mechanisms underlying aversive counterconditioning, and highlighted potential targets for inhibiting the development of alcohol addiction-like behaviour and relapse after long-term withdrawal.

Empagliflozin Induces Vascular Relaxation in Rat Coronary Artery Due to Activation of BK Channels.

Purpose: The aim of this study was to investigate the effects and mechanisms of SGLT2 inhibitor empagliflozin on diabetic coronary function. Methods: A rat diabetic model was established by injection of streptozotocin. Rats in the treated group were administered empagliflozin by gavage and rat coronary vascular tensions were measured after eight weeks. Large conductance calcium activated K+ channel currents were recorded using a patch clamp technique, while human coronary artery smooth muscle cells were used to explore the underlying mechanisms. Results: After incubation with empagliflozin (10, 30, 100, 300, 1000 µmol/L), the Δ relaxation % of rat coronary arteries were 2.459 ± 1.304, 3.251 ± 1.119, 6.946 ± 3.407, 28.36 ± 11.47, 86.90 ± 3.868, respectively. Without and with empagliflozin in the bath solution, BK channel opening probabilities at a membrane potential of +60 mV were 0.0458 ± 0.0517 and 0.3413 ± 0.2047, respectively (p < 0.05, n = 4 cells). After incubation with iberiotoxin, the Δ tensions of rat coronary arteries in the control (Ctrl), untreated (DM), low empagliflozin (10 mg/kg/d)-treated (DM+L-EMPA) and high empagliflozin (30mg/kg/d)-treated (DM+H-EMPA) group were 103.20 ± 5.85, 40.37 ± 22.12, 99.47 ± 28.51, 78.06 ± 40.98, respectively (p < 0.01 vs Ctrl, n = 3-7; p < 0.001 vs DM+L-EMPA, n = 5-7). Empagliflozin restored high glucose-induced downregulation of Sirt1, Nrf2, and BK-ß1, while the effect of empagliflozin disappeared in the presence of EX-527, a Sirt1 selective inhibitor. Conclusion: Empagliflozin has a vasodilation effect on the coronary arteries in a concentration-dependent manner and can activate BK channels via the Sirt1-Nrf2 mechanism.

Correlation between telomere shortening in maternal peripheral blood and fetal aneuploidy.

BACKGROUND: This study aimed to assess whether maternal telomere length is a more accurate predictor of trisomy 21 than maternal age while also exploring the factors influencing maternal and fetal telomere length. METHODS: Forty mothers with fetuses carrying extra maternal copies of chromosome 21 were defined as trisomy 21 cases, and 18 mothers with normal karyotype fetuses were defined as controls. Telomere lengths of maternal blood lymphocytes and amniotic fluid cells were determined using real-time polymerase chain reaction. Fetal and maternal telomere lengths were compared between the two groups. Moreover, we analyzed the factors influencing maternal and fetal telomere length in the trisomy 21 pedigree. A logistic regression model was used to analyze the correlation between maternal telomere length and trisomy 21 risk. In addition, receiver operating characteristic (ROC) curve analysis was used to determine the accuracy of using maternal telomere length as an indicator of trisomy 21 risk. RESULTS: The study revealed that both maternal and fetal telomere lengths were significantly shorter in trisomy 21 cases than in the controls. In the trisomy 21 group, the maternal age, occupation, and nationality showed no significant correlation with their telomere length; fetal telomere length exhibited a positive correlation with maternal telomere length. Furthermore, maternal telomere length shortening is associated with trisomy 21 (OR = 0.311; 95% CI, 0.109-0.885, P < 0.05). The results of ROC curve analysis indicated that a combined assessment of maternal age and maternal telomere length predicted fetal chromosome trisomy more effectively than a single assessment (area under the curve 0.808, 95% CI, 0.674-0.941, P < 0.001). CONCLUSION: Maternal age combined with maternal telomere length proved to be a superior predictor of trisomy risk. Additionally, maternal telomere length was found to influence fetal telomere length.

Genetic and clinical characteristics of primary hemophagocytic lymphohistiocytosis in children.

To analyze the genetic variation and prognosis of primary hemophagocytic lymphohistiocytosis (pHLH) in children and the clinical features of isolated central nervous system HLH (CNS-HLH). We retrospectively analyzed the clinical and genetic data of 480 HLH children admitted to our hospital from September 2017 to September 2022. There were 66 patients (13.75%) with pHLH, and the median age was 3.21 years (0.17-12.92 years). Variants in UNC13D (22/66, 33.33%), PRF1 (20/66, 30.30%) and XIAP (11/66, 16.67%) were the most common. More CNS involvement was observed in pHLH patients than in secondary hemophagocytic lymphohistiocytosis (sHLH) patients (50% vs. 25.3%, P = 0.001). Eight pHLH patients had isolated CNS-HLH at onset, which progressed to systemic HLH within 10-30 days to several years. Among them, five patients who underwent hematopoietic stem cell transplantation (HSCT) survived without CNS sequelae, and the three patients who did not undergo HSCT died of disease progression or recurrence. Determination of natural killer (NK) cell cytotoxicity and CD107a levels had low sensitivity and specificity in the diagnosis of pHLH, especially in patients with PRF1 and XIAP mutations. The 3-year overall survival (OS) was significantly lower in pHLH patients than in sHLH patients (74.5% ± 14.7% vs. 89.2% ± 3.53%, P = 0.021) and in patients with CNS involvement than in those without (53.8% ± 26.07% vs. 94.4% ± 10.58%, P = 0.012). There was a significant difference in OS among pHLH patients with different gene variants (P = 0.032); patients with PRF1 variants had poor 3-year OS, and patients with XIAP variants had good 3-year OS (50% ± 28.22% and 100%, respectively). pHLH patients with distinct variants have different prognoses. Isolated CNS-HLH patients are easily misdiagnosed, and HSCT may be beneficial for these patients. Determination of NK cell cytotoxicity and CD107a levels cannot precisely distinguish pHLH from sHLH.

Optical Genome Mapping Reveals Novel Structural Variants in Lymphoblastic Lymphoma.

BACKGROUND: Accurate histologic and molecular genetic diagnosis is critical for the pathogenesis study of pediatric patients with lymphoblastic lymphoma (LBL). Optical genome mapping (OGM) as all-in-one process allows the detection of most major genomic risk markers, which addresses some of the limitations associated with conventional cytogenomic testing, such as low resolution and throughput, difficulty in ascertaining genomic localization, and orientation of segments in duplication, inversions, and insertions. Here, for the first time, we examined the cytogenetics of 5 children with LBL using OGM. METHODS: OGM was used to analyze 5 samples of pediatric LBL patients treated according to the modified NHL-BFM95 backbone regimen. Whole-exon Sequencing (WES) was used to confirm the existence of structural variants (SVs) identified by OGM with potentially clinical significance on MGI Tech (DNBSEQ-T7) platform. According to the fusion exon sequences revealed by WES, the HBS1L :: AHI1 fusion mRNA in case 4 was amplified by cDNA-based PCR. RESULTS: In total, OGM identified 251 rare variants (67 insertions, 129 deletions, 3 inversion, 25 duplications, 15 intrachromosomal translocations, and 12 interchromosomal translocations) and 229 copy number variants calls (203 gains and 26 losses). Besides all of the reproducible and pathologically significant genomic SVs detected by conventional cytogenetic techniques, OGM identified more SVs with definite or potential pathologic significance that were not detected by traditional methods, including 2 new fusion genes, HBS1L :: AHI1 and GRIK1::NSDHL , which were confirmed by WES and/or Reverse Transcription-Polymerase Chain Reaction. CONCLUSIONS: Our results demonstrate the feasibility of OGM to detect genomic aberrations, which may play an important role in the occurrence and development of lymphomagenesis as an important driving factor.