Excessive accumulation of epicardial adipose tissue promotes microvascular obstruction formation after myocardial ischemia/reperfusion through modulating macrophages polarization.

BACKGROUND: Owing to its unique location and multifaceted metabolic functions, epicardial adipose tissue (EAT) is gradually emerging as a new metabolic target for coronary artery disease risk stratification. Microvascular obstruction (MVO) has been recognized as an independent risk factor for unfavorable prognosis in acute myocardial infarction patients. However, the concrete role of EAT in the pathogenesis of MVO formation in individuals with ST-segment elevation myocardial infarction (STEMI) remains unclear. The objective of the study is to evaluate the correlation between EAT accumulation and MVO formation measured by cardiac magnetic resonance (CMR) in STEMI patients and clarify the underlying mechanisms involved in this relationship. METHODS: Firstly, we utilized CMR technique to explore the association of EAT distribution and quantity with MVO formation in patients with STEMI. Then we utilized a mouse model with EAT depletion to explore how EAT affected MVO formation under the circumstances of myocardial ischemia/reperfusion (I/R) injury. We further investigated the immunomodulatory effect of EAT on macrophages through co-culture experiments. Finally, we searched for new therapeutic strategies targeting EAT to prevent MVO formation. RESULTS: The increase of left atrioventricular EAT mass index was independently associated with MVO formation. We also found that increased circulating levels of DPP4 and high DPP4 activity seemed to be associated with EAT increase. EAT accumulation acted as a pro-inflammatory mediator boosting the transition of macrophages towards inflammatory phenotype in myocardial I/R injury through secreting inflammatory EVs. Furthermore, our study declared the potential therapeutic effects of GLP-1 receptor agonist and GLP-1/GLP-2 receptor dual agonist for MVO prevention were at least partially ascribed to its impact on EAT modulation. CONCLUSIONS: Our work for the first time demonstrated that excessive accumulation of EAT promoted MVO formation by promoting the polarization state of cardiac macrophages towards an inflammatory phenotype. Furthermore, this study identified a very promising therapeutic strategy, GLP-1/GLP-2 receptor dual agonist, targeting EAT for MVO prevention following myocardial I/R injury.

Discovery of novel natural-product-derived mutant isocitrate dehydrogenases 1 inhibitors: Structure-based virtual screening, biological evaluation and structure-activity relationship study.

Mutations in IDH1 are commonly observed across various cancers, causing the conversion of α-KG to 2-HG. Elevated levels of 2-HG disrupt histone and DNA demethylation processes, promoting tumor development. Consequently, there is substantial interest in developing small molecule inhibitors targeting the mutant enzymes. Herein, we report a structure-based high-throughput virtual screening strategy using a natural products library, followed by hit-to-lead optimization. Through this process, we discover a potent compound, named 11s, which exhibited significant inhibition to IDH1 R132H and IDH1 R132C with IC50 values of 124.4 and 95.7 nM, respectively. Furthermore, 11s effectively reduced 2-HG formation, with EC50 values of 182 nM in U87 R132H cell, and 84 nM in HT-1080 cell. In addition, 11s significantly reduced U87 R132H and HT-1080 cell proliferation with GC50 values of 3.48 and 1.38 µM, respectively. PK-PD experiments further confirmed that compound 11s significantly decreased 2-HG formation in an HT-1080 xenograft mouse model, resulting in notable suppression of tumor growth without apparent loss in body weight.

Identification of a metabolism-linked genomic signature for prognosis and immunotherapeutic efficiency in metastatic skin cutaneous melanoma.

Metastatic skin cutaneous melanoma (MSCM) is the most rapidly progressing/invasive skin-based malignancy, with median survival rates of about 12 months. It appears that metabolic disorders accelerate disease progression. However, correlations between metabolism-linked genes (MRGs) and prognosis in MSCM are unclear, and potential mechanisms explaining the correlation are unknown. The Cancer Genome Atlas (TCGA) was utilized as a training set to develop a genomic signature based on the differentially expressed MRGs (DE-MRGs) between primary skin cutaneous melanoma (PSCM) and MSCM. The Gene Expression Omnibus (GEO) was utilized as a validation set to verify the effectiveness of genomic signature. In addition, a nomogram was established to predict overall survival based on genomic signature and other clinic-based characteristics. Moreover, this study investigated the correlations between genomic signature and tumor micro-environment (TME). This study established a genomic signature consisting of 3 genes (CD38, DHRS3, and TYRP1) and classified MSCM patients into low and high-risk cohorts based on the median risk scores of MSCM cases. It was discovered that cases in the high-risk cohort had significantly lower survival than cases in the low-risk cohort across all sets. Furthermore, a nomogram containing this genomic signature and clinic-based parameters was developed and demonstrated high efficiency in predicting MSCM case survival times. Interestingly, Gene Set Variation Analysis results indicated that the genomic signature was involved in immune-related physiological processes. In addition, this study discovered that risk scoring was negatively correlated with immune-based cellular infiltrations in the TME and critical immune-based checkpoint expression profiles, indicating that favorable prognosis may be influenced in part by immunologically protective micro-environments. A novel 3-genomic signature was found to be reliable for predicting MSCM outcomes and may facilitate personalized immunotherapy.

Macrophage-derived FGFR1 drives atherosclerosis through PLCγ-mediated activation of NF-κB inflammatory signaling pathway.

BACKGROUND: Atherosclerosis is a leading cause of cardiovascular morbidity and mortality. Atherosclerotic lesions show increased levels of proteins associated with the fibroblast growth factor receptor (FGFR) pathway. However, the functional significance and mechanisms governed by FGFR signaling in atherosclerosis are not known. In the present study, we investigated FGFR1 signaling in atherosclerosis development and progression. METHODS AND RESULTS: Examination of human atherosclerotic lesions and aortas of Apoe-/- mice fed a high-fat diet (HFD) showed increased levels of FGFR1 in macrophages. We deleted myeloid-expressed Fgfr1 in Apoe-/- mice and showed that Fgfr1 deficiency reduces atherosclerotic lesions and lipid accumulations in both male and female mice upon HFD feeding. These protective effects of myeloid Fgfr1 deficiency were also observed when mice with intact FGFR1 were treated with FGFR inhibitor AZD4547. To understand the mechanistic basis of this protection, we harvested macrophages from mice and show that FGFR1 is required for macrophage inflammatory responses and uptake of oxidized LDL. RNA sequencing showed that FGFR1 activity is mediated through phospholipase-C-gamma (PLCγ) and the activation of nuclear factor-κB (NF-κB) but is independent of FGFR substrate 2. CONCLUSION: Our study provides evidence of a new FGFR1-PLCγ- NF-κB axis in macrophages in inflammatory atherosclerosis, supporting FGFR1 as a potentially therapeutic target for atherosclerosis-related diseases.

Association of MAFLD and MASLD with all-cause and cause-specific dementia: a prospective cohort study.

BACKGROUND: Liver disease and dementia are both highly prevalent and share common pathological mechanisms. We aimed to investigate the associations between metabolic dysfunction-associated fatty liver disease (MAFLD), metabolic dysfunction-associated steatotic liver disease (MASLD) and the risk of all-cause and cause-specific dementia. METHODS: We conducted a prospective study with 403,506 participants from the UK Biobank. Outcomes included all-cause dementia, Alzheimer's disease, and vascular dementia. Multivariable Cox proportional hazards models were used for analyses. RESULTS: 155,068 (38.4%) participants had MAFLD, and 111,938 (27.7%) had MASLD at baseline. During a median follow-up of 13.7 years, 5,732 participants developed dementia (2,355 Alzheimer's disease and 1,274 vascular dementia). MAFLD was associated with an increased risk of vascular dementia (HR 1.32 [95% CI 1.18-1.48]) but a reduced risk of Alzheimer's disease (0.92 [0.84-1.0]). Differing risks emerged among MAFLD subtypes, with the diabetes subtype increasing risk of all-cause dementia (1.8 [1.65-1.96]), vascular dementia (2.95 [2.53-3.45]) and Alzheimer's disease (1.46 [1.26-1.69]), the lean metabolic disorder subtype only increasing vascular dementia risk (2.01 [1.25-3.22]), whereas the overweight/obesity subtype decreasing risk of Alzheimer's disease (0.83 [0.75-0.91]) and all-cause dementia (0.9 [0.84-0.95]). MASLD was associated with an increased risk of vascular dementia (1.24 [1.1-1.39]) but not Alzheimer's disease (1.0 [0.91-1.09]). The effect of MAFLD on vascular dementia was consistent regardless of MASLD presence, whereas associations with Alzheimer's disease were only present in those without MASLD (0.78 [0.67-0.91]). CONCLUSIONS: MAFLD and MASLD are associated with an increased risk of vascular dementia, with subtype-specific variations observed in dementia risks. Further research is needed to refine MAFLD and SLD subtyping and explore the underlying mechanisms contributing to dementia risk.

Biolimus-coated versus paclitaxel-coated balloons for coronary in-stent restenosis (BIO ASCEND ISR): a randomised, non-inferiority trial.

BACKGROUND: The treatment of in-stent restenosis (ISR) after drug-eluting stent (DES) implantation remains challenging in current clinical practice. AIMS: The study was conducted to investigate a novel biolimus-coated balloon (BCB) for the treatment of coronary DES-ISR compared with the best-investigated paclitaxel-coated balloon (PCB). METHODS: This was a prospective, multicentre, randomised, non-inferiority trial comparing a novel BCB with a clinically proven PCB for coronary DES-ISR. The primary endpoint was in-segment late lumen loss (LLL) at 9 months assessed by an independent core laboratory. Baseline and follow-up optical coherence tomography were performed in a prespecified subgroup of patients. RESULTS: A total of 280 patients at 17 centres were randomised to treatment with a BCB (n=140) versus a PCB (n=140). At 9 months, LLL in the BCB group was 0.23±0.37 mm compared to 0.25±0.35 mm in the PCB group; the mean difference between the groups was -0.02 (95% confidence interval [CI]: -0.12 to 0.07) mm; p-value for non-inferiority<0.0001. Similar clinical outcomes were also observed for both groups at 12 months. In the optical coherence tomography substudy, the neointimal area at 9 months was 2.32±1.04 mm2 in the BCB group compared to 2.37±0.93 mm2 in the PCB group; the mean difference between the groups was -0.09 (95% CI: -0.94 to 0.76) mm2; p=non-significant. CONCLUSIONS: This head-to-head comparison of a novel BCB shows similar angiographic outcomes in the treatment of coronary DES-ISR compared with a clinically proven PCB. (ClinicalTrials.gov: NCT04733443).

Metformin reduces new-onset atrial fibrillation risk rather than atrial fibrillation burden in type 2 diabetes patients: A case-control study.

Background: The effects of metformin on atrial fibrillation (AF) in type 2 diabetes patients remain unclear. We aimed to explore the effects of metformin on AF, including new-onset AF and AF burden, in type 2 diabetes patients with pacemakers. Methods and results: This retrospective study included a total of 227 patients. Based on the presence of paroxysmal AF, the patients were divided into a paroxysmal AF group (n = 80) and a non-AF group (n = 147). In the non-AF group, a significant association was observed between metformin use and a lower risk of new-onset AF in multivariable Cox hazards models (hazard ratio [HR]: 0.36; 95 % confidence interval [CI]: 0.14-0.91; p = 0.0311*) when adjusted for age, sex, body mass index (BMI), drinking, smoking, left atrial dimension, creatinine, complications, and drugs. In the paroxysmal AF group, univariable analysis indicated no association between the AF burden and metformin use (p = 0.817). Furthermore, when adjusted for metformin use, age, sex, BMI, drinking, smoking, cardiovascular disease, myocardial infarction, heart failure, stroke, and ejection fraction in multivariable Cox hazards models, we found a lower proportion of major adverse cardiovascular events (MACEs) both in the total (HR: 0.28; 95 % CI: 0.1-0.82; p = 0.0202*) and the non-AF group (HR: 0.19; 95 % CI: 0.05-0.79; p = 0.0223*) compared to that in the AF group (HR: 0.31; 95 % CI: 0.02-4.41; p = 0.3879). Conclusion: In type 2 diabetes patients with pacemakers, metformin reduced the probability of new-onset AF instead of addressing the AF burden. Furthermore, metformin therapy decreased the incidence of MACEs in type 2 diabetes patients without AF.

All-Inorganic Halide Perovskites Boost High-Ranged Figure-of-Merit in Bi0.4Sb1.6Te3 for Thermoelectric Cooling and Low-Grade Heat Recovery.

The all-inorganic halide perovskite CsPbX3 (X = Cl, Br, or I) offers various advantages, such as tunable electronic structure and high carrier mobility. However, its potential application in thermoelectric materials remains underexplored. In this study, we propose a simple yet effective method to synthesize a CsPbX3/Bi0.4Sb1.6Te3 (BST) nanocomposite by sintering a uniformly mixed raw powder. The intrinsic excitation of the BST system is suppressed by exploiting the rich phase structure and tunable electrical transport properties of CsPbX3, and the thermoelectric properties were synergistically optimized. Notably, for CsPbI3, its phase-transition-induced dislocation arrays together with low group velocities drastically reduce thermal conductivity. As a result, the composite achieves an ultrahigh average figure-of-merit (ZT) of 1.4 from 298 to 523 K. The two-pair TE module demonstrates a superior conversion efficiency of 7.3%. This study expands the potential applications of inorganic halide perovskites, into thermoelectrics.

Three Novel Cheiroid Hyphomycetes in Dictyocheirospora and Dictyosporium (Dictyosporiaceae) from Freshwater Habitats in Guangdong and Guizhou Provinces, China.

Over the past two decades, numerous novel species have been identified within Dictyosporiaceae, primarily in Dictyocheirospora and Dictyosporium. A recent monograph has revealed that these two genera exhibit a distinct preference for freshwater habitats, particularly in southern China. However, further investigation into the distribution and diversity of the two genera in Guangdong and Guizhou Provinces remains insufficient. In this study, we conducted an analysis of four intriguing cheiroid hyphomycetes collected from flowing rivers in these two regions. Through morphological and phylogenetic analyses incorporating combined LSU, SSU, ITS, and tef1-α sequence data, we have identified them as a novel species in Dictyocheirospora (Dictyoc. submersa sp. nov.), two novel species in Dictyosporium (Dictyos. guangdongense sp. nov. and Dictyos. variabilisporum sp. nov.), and one previously documented species (Dictyos. digitatum). Specifically, the identification of Dictyos. guangdongense is primarily based on its distinct morphology, characterized by complanate, cheiroid, and brown to dark brown conidia, with a hyaline, short, and atrophied appendage arising from the apical cell of the outer row. In addition, the morphological distinctions between Dictyocheirospora and Dictyosporium are further clarified based on our new data. This study also highlights a few phylogenetic matters regarding Dictyosporiaceae.

Bismuth Telluride Supported Sub-1 nm Polyoxometalate Cluster for High-Efficiency Thermoelectric Energy Conversion.

Size plays a crucial role in chemistry and material science. Subnanometer polyoxometalate (POM) clusters have gained attention in various fields, but their use in thermoelectrics is still limited. To address this issue, we propose the POM clusters as an effective second phase to enhance the thermoelectric properties of Bi0.4Sb1.6Te3. Thanks to their subnanometer size, POM clusters improve electrical transport behavior through the superposition of atomic orbitals and the interfacial scattering effect. Furthermore, their ultrasmall size strongly reduces thermal conductivity. Consequently, the introduction of a mere 0.1 mol % of POM into the Bi0.4Sb1.6Te3 matrix realizes a state-of-the-art zT value of 1.46 at 348 K, a 45% enhancement over Bi0.4Sb1.6Te3 (1.01), along with a maximum thermoelectric-conversion efficiency of the integrated module of 6.0%. The enhancement of carrier mobility and the suppression of thermal conduction achieved by introducing the subnanometer clusters hold promise for various applications, such as electronic devices and thermal management.

The long-term cost-effectiveness of once-weekly semaglutide versus sitagliptin for the treatment of type 2 diabetes in China.

BACKGROUND: To estimate the long-term cost-effectiveness of once-weekly semaglutide versus sitagliptin as an add-on therapy for type 2 diabetes patients inadequately controlled on metformin in China, to better inform healthcare decision making. METHODS: The Cardiff diabetes model which is a Monte Carlo micro-simulation model was used to project short-term effects of once-weekly semaglutide versus sitagliptin into long-term outcomes. Short-term data of patient profiles and treatment effects were derived from the 30-week SUSTAIN China trial, in which 868 type 2 diabetes patients with a mean age of 53.1 years inadequately controlled on metformin were randomized to receive once-weekly semaglutide 0.5 mg, once-weekly semaglutide 1 mg, or sitagliptin 100 mg. Costs and quality-adjusted life years (QALYs) were estimated from a healthcare system perspective at a discount rate of 5%. Univariate sensitivity analysis, scenario analysis, and probabilistic sensitivity analysis were conducted to test the uncertainty. RESULTS: Over patients' lifetime projections, patients in both once-weekly semaglutide 0.5 mg and 1 mg arms predicted less incidences of most vascular complications, mortality, and hypoglycemia, and lower total costs compared with those in sitagliptin arm. For an individual patient, compared with sitagliptin, once-weekly semaglutide 0.5 mg conferred a small QALY improvement of 0.08 and a lower cost of $5173, while once-weekly semaglutide 1 mg generated an incremental QALY benefit of 0.12 and a lower cost of $7142, as an add-on to metformin. Therefore, both doses of once-weekly semaglutide were considered dominant versus sitagliptin with more QALY benefits at lower costs. CONCLUSION: Once-weekly semaglutide may represent a cost-effective add-on therapy alternative to sitagliptin for type 2 diabetes patients inadequately controlled on metformin in China.

Spatial Heterogeneity of Nontuberculous Mycobacterial Pulmonary Disease in Shanghai: Insights from a Ten-Year Population-Based Study.

OBJECTIVE: To investigate the spatial heterogeneity of nontuberculous mycobacterial pulmonary disease (NTM-PD) in Shanghai. METHODS: A population-based retrospective study was conducted using presumptive pulmonary tuberculosis surveillance data of Shanghai between 2010 and 2019. The study described the spatial distribution of NTM-PD notification rates, employing hierarchical Bayesian mapping for high-risk areas and the Getis-Ord Gi* statistic to identify hot spots and explore associated factors. RESULTS: Of 1652 NTM-PD cases, the most common species was Mycobacterium kansasii complex (MKC) (41.9%), followed by Mycobacterium avium complex (MAC) (27.1%) and Mycobacterium abscessus complex (MABC) (16.2%). MKC-PD patients were generally younger males with a higher incidence of pulmonary cavities, while MAC-PD patients were more often farmers or had a history of tuberculosis treatment. MKC-PD hot spots were primarily located in the areas alongside the Huangpu River, while MAC-PD hot spots were mainly in the western agricultural areas. Patients with MKC-PD and MAC-PD exhibited a higher risk of spatial clustering compared to those with MABC-PD. CONCLUSIONS: Different types of NTM-PD exhibit distinct patterns of spatial clustering and are associated with various factors. These findings underscore the importance of environmental and host factors in the epidemic of NTM-PD.

MSC-Derived Exosomes Mitigate Myocardial Ischemia/Reperfusion Injury by Reducing Neutrophil Infiltration and the Formation of Neutrophil Extracellular Traps.

Introduction: Acute inflammatory storm is a major cause of myocardial ischemia/reperfusion (I/R) injury, with no effective treatment currently available. The excessive aggregation of neutrophils is correlated with an unfavorable prognosis in acute myocardial infarction (AMI) patients. Exosomes derived from mesenchymal stromal cells (MSC-Exo) have certain immunomodulatory potential and might be a therapeutic application. Therefore, we investigated the protective role of MSC-Exo in modulating neutrophil infiltration and formation of neutrophil extracellular traps (NETs) following myocardial I/R injury. Methods: Exosomes were isolated from the supernatant of MSCs using a gradient centrifugation method. We used flow cytometry, histochemistry, and immunofluorescence to detect the changes of neutrophils post-intravenous MSC-Exo injection. Additionally, cardiac magnetic resonance (CMR) and thioflavin S experiments were applied to detect microvascular obstruction (MVO). The NLR family pyrin domain containing 3 (NLRP3) inflammasome was examined for mechanism exploration. Primary neutrophils were extracted for in vitro experiment. Antibody of Ly6G was given to depleting the neutrophils in mice for verification the effect of MSC-Exo. Finally, we analyzed the MiRNA sequence of MSC-Exo and verified it in vitro. Results: MSC-Exo administration reduced neutrophil infiltration and NETs formation after myocardial I/R. MSC-Exo treatment also could attenuate the activation of NLRP3 inflammasome both in vivo and in vitro. At the same time, the infarction size and MVO following I/R injury were reduced by MSC-Exo. Moreover, systemic depletion of neutrophils partly negated the therapeutic effects of MSC-Exo. Up-regulation of miR-199 in neutrophils has been shown to decrease the expression of NETs formation after stimulation. Discussion: Our results demonstrated that MSC-Exo mitigated myocardial I/R injury in mice by modulating neutrophil infiltration and NETs formation. This study provides novel insights into the potential therapeutic application of MSC-Exo for myocardial ischemia/reperfusion injury.

Neutrophil and endothelial cell membranes coassembled roflumilast nanoparticles attenuate myocardial ischemia/reperfusion injury.

Aim: This study aimed to develop biomimetic nanoparticles (NPs) of roflumilast (ROF) for attenuating myocardial ischemia/reperfusion (MI/R) injury. Materials & methods: We synthesized biomimetic ROF NPs and assembled ROF NPs in neutrophil and endothelial cell membranes (NE/ROF NPs). The physical properties of NE/ROF NPs were characterized and biological functions of NE/ROF NPs were tested in vitro. Targeting characteristics, therapeutic efficacy and safety of NE/ROF NPs were examined in mice model of MI/R. Results: NE/ROF NPs exhibited significant anti-inflammatory and antiadhesion effects. Meanwhile, they was effective in reducing MI/R injury in mice. Furthermore, NE/ROF NPs exhibited stronger targeting capabilities and demonstrated good safety. Conclusion: NE/ROF NPs may be a versatile biomimetic drug-delivery system for attenuating MI/R injury.

Salvage Surgery for Initially Unresectable HCC With PVTT Converted by Locoregional Treatment Plus Tyrosine Kinase Inhibitor and Anti-PD-1 Antibody.

BACKGROUND: This study aimed to compare the survival outcomes of patients with initially unresectable hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) who underwent or did not undergo salvage surgery followed by a triple combination conversion treatment consisted of locoregional treatment (LRT), tyrosine kinase inhibitors (TKIs), and anti-PD-1 antibodies. METHODS: The data from 93 consecutive patients with initially unresectable HCC and PVTT across 4 medical centers were retrospectively reviewed. They were converted successfully by the triple combination treatment and underwent or did not undergo salvage resection. The baseline characteristics, conversion schemes, conversion treatment-related adverse events (CTRAEs), overall survival (OS), and progression-free survival (PFS) of the salvage surgery and non-surgery groups were compared. Multivariate Cox regression analysis was performed to identify independent risk factors for OS and PFS. Additionally, subgroup survival analysis was conducted by stratification of degree of tumor response and type of PVTT. RESULTS: Of the 93 patients, 44 underwent salvage surgery, and 49 did not undergo salvage surgery. The OS and PFS of the salvage surgery and non-surgery groups were not significantly different (P = .370 and .334, respectively). The incidence and severity of CTRAEs of the 2 groups were also comparable. Subgroup analyses revealed that for patients with complete response (CR) or types III-IV PVTT, there was a trend toward better survival in patients who did not undergo salvage surgery. Multivariate analysis showed that baseline α-fetoprotein and best tumor response per mRECIST criteria were independent prognostic factors for OS and PFS. CONCLUSIONS: For patients with initially unresectable HCC and PVTT who were successfully converted by the triple combination therapy, salvage liver resection may not be necessary, especially for the patients with CR or types III-IV PVTT.

Effects of the SEMA4B gene on hexavalent chromium [Cr(VI)]-induced malignant transformation of human bronchial epithelial cells.

Our previous study identified the potential of SEMA4B methylation level as a biomarker for hexavalent chromium [Cr(VI)] exposure. This study aimed to investigate the role of the SEMA4B gene in Cr(VI)-mediated malignant transformation of human bronchial epithelial (BEAS-2B) cells. In our population survey of workers, the geometric mean [95% confidence intervals (CIs)] of Cr in blood was 3.80 (0.42, 26.56) µg/L. Following treatment with various doses of Cr(VI), it was found that 0.5 µM had negligible effects on the cell viability of BEAS-2B cells. The expression of SEMA4B was observed to decrease in BEAS-2B cells after 7 days of treatment with 0.5 µM Cr(VI), and this downregulation continued with increasing passages of Cr(VI) treatment. Chronic exposure to 0.5 µM Cr(VI) enhanced the anchorage-independent growth ability of BEAS-2B cells. Furthermore, the use of a methylation inhibitor suppressed the Cr(VI)-mediated anchorage-independent growth in BEAS-2B cells. Considering that Cr levels exceeding 0.5 µM can be found in human blood due to occupational exposure, the results suggested a potential carcinogenic risk associated with occupational Cr(VI) exposure through the promotion of malignant transformation. The in vitro study further demonstrated that Cr(VI) exposure might inhibit the expression of the SEMA4B gene to promote the malignant transformation of BEAS-2B cells.

Trends in prevalence, risk factor control and medications in atherosclerotic cardiovascular disease among US Adults, 1999-2018.

Objectives: Trends in prevalence and treatments of atherosclerotic cardiovascular disease (ASCVD) remains to be documented, with frequent update of relevant guidelines. We aimed to characterize trends in prevalence of ASCVD, and risk factor control and medications among ASCVD adults. Methods: We conducted a cross-sectional analysis of data from 55,081 adults in the National Health and Nutrition Examination Surveys (NHANES) 1999-2018. Results: The age-standardized prevalence of ASCVD did not change significantly from 1999-2002 (7.9 %, 95 % CI 7.1 %-8.7 %) to 2015-2018 (7.5 %, CI 6.8 %-8.3 %) (P for trend =0.18), representing an estimated 19.9 million individuals with ASCVD in 2015-2018. The prevalence of premature ASCVD was 2.0 % (CI, 1.6 %-2.5 %). Over 60.0 % of ASCVD participants were at very-high risk. From 1999-2002 to 2015-2018, the percentage with lipid control (non-high-density lipoprotein cholesterol <100 mg/dL) increased from 7.0 % (CI, 3.5 %-12.3 %) to 26.4 % (CI, 16.2 %-38.9 %). The percentage with blood-pressure control (<130/80 mmHg) increased from 51.2 % (CI, 41.0 %-61.3 %) in 1999-2002 to 57.2 % (CI, 48.4 %-65.6 %) in 2011-2014, but then declined to 52.8 % (CI, 44.4 %-81.3 %) in 2015-2018. The percentage with glycemic control (HbA1c <7.0 %) decreased from 95.0 % (CI, 90.2 %-97.9 %) to 84.0 % (CI, 75.9 %-90.3 %). The percentage who achieved all 3 targets was 18.6 % (CI, 8.2 %-33.8 %) in 2015-2018. The percentage of ASCVD participants who were taking statins increased from 1999-2002 to 2011-2014, but then leveled off. Approximately 60 % of individuals with ASCVD and less than 40 % of those with premature ASCVD were taking statins in 2015-2018. The utilization of blood-pressure-lowering drugs remained largely constant over time, whereas the use of glucose-lowering drugs increased. Conclusions: Based on NHANES data from US adults, the estimated prevalence of ASCVD remained relatively stable between 1999 and 2018. Substantial undertreatment with stains was found in individuals with ASCVD, and the percentage achieving optimal lipid control was low.

Efficacy and safety of piecemeal submucosal tunneling endoscopic resection for giant esophageal leiomyoma.

BACKGROUND AND AIMS: Giant esophageal leiomyoma usually requires a thoracotomy or thoracoscopic surgery, which is more invasive than an endoscopic treatment. The purpose of this study is to evaluate the efficacy and safety of piecemeal submucosal tunneling endoscopic resection (P-STER) for giant leiomyoma originating from the muscularis propria (MP) layer of the esophagus. METHODS: This is a retrospective study. Patients with giant esophageal leiomyoma (transverse diameter ≥ 3 cm) who underwent P-STER were enrolled from November 2012 to May 2023. Clinical data and results were investigated. RESULTS: A total of 16 patients were enrolled for analysis. The lesion mean transverse diameter and longitudinal diameter were 4.22 ± 1.20 cm and 6.20 ± 1.57 cm, respectively. Our mean operation time was 195.38 ± 84.99 min. The mean number of piecemeal resected was 4.31 ± 2.36. An adverse event noted was an esophageal fistula that occurred in one case (6.25%) and was treated conservatively. The mean length of hospital stay was around 11.81 ± 7.30 days. The mean total hospitalization cost was U.S. dollars (USD) $5976.50 ± 2866.39. No recurrence or metastasis was found during the follow-up period. CONCLUSIONS: P-STER can be an effective and safe treatment for giant leiomyoma originating from the MP layer of the esophagus.

The blockade of neuropeptide FF receptor 1 and 2 differentially contributed to the modulating effects on fentanyl-induced analgesia and hyperalgesia in mice.

Neuropeptide FF (NPFF) plays a critical role in various physiological processes through the activation of neuropeptide FF receptor 1 and 2 (NPFFR1 and NPFFR2). Numerous evidence has indicated that NPFF exhibits opposite opioid-modulating effects on opioid-induced analgesia after supraspinal and spinal administrations, while the detailed role of NPFFR1 and NPFFR2 remains unclear. In this study, we employed pharmacological and genetic inhibition of NPFFR to investigate the modulating roles of central NPFFR1 and NPFFR2 in opioid-induced analgesia and hyperalgesia, using a male mouse model of acute fentanyl-induced analgesia and secondary hyperalgesia. Our findings revealed that intrathecal (i.t.) injection of the nonselective NPFFR antagonist RF9 significantly enhanced fentanyl-induced analgesia, whereas intracerebroventricular (i.c.v.) injection did not show the same effect. Moreover, NPFFR2 deficient (npffr2-/-) mice exhibited stronger analgesic responses to fentanyl compared to wild type (WT) or NPFFR1 knockout (npffr1-/-) mice. Intrathecal injection of RF9 in npffr1-/- mice also significantly enhanced fentanyl-induced analgesia. These results indicate a crucial role of spinal NPFFR2 in the enhancement of opioid analgesia. Contrastingly, hyperalgesia induced by fentanyl was markedly reversed in npffr1-/- mice but remained unaffected in npffr2-/- mice. Similarly, i.c.v. injection of the selective NPFFR1 antagonist RF3286 effectively prevented fentanyl-induced hyperalgesia in WT or npffr2-/- mice. Notably, co-administration of i.c.v. RF3286 and i.t. RF9 augmented fentanyl-induced analgesia while reducing hyperalgesia. Collectively, these findings highlight the modulating effects of blocking spinal NPFFR2 and supraspinal NPFFR1 on fentanyl-induced analgesia and hyperalgesia, respectively, which shed a light on understanding the pharmacological function of NPFF system in future studies.