Immune-checkpoint inhibitor-mediated myocarditis: CTLA4, PD1 and LAG3 in the heart.

Immune-checkpoint inhibitors (ICIs) have revolutionized oncology, with nearly 50% of all patients with cancer eligible for treatment with ICIs. However, patients on ICI therapy are at risk for immune-related toxicities that can affect any organ. Inflammation of the heart muscle, known as myocarditis, resulting from ICI targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4), programmed cell death protein 1 (PD1) and PD1 ligand 1 (PDL1) is an infrequent but potentially fatal complication. ICI-mediated myocarditis (ICI-myocarditis) is a growing clinical entity given the widespread use of ICIs, its increased clinical recognition and growing use of combination ICI treatment, a well-documented risk factor for ICI-myocarditis. In this Review, we approach ICI-myocarditis from a basic and mechanistic perspective, synthesizing the recent data from both preclinical models and patient samples. We posit that mechanistic understanding of the fundamental biology of immune-checkpoint molecules may yield new insights into disease processes, which will enable improvement in diagnostic and therapeutic approaches. The syndrome of ICI-myocarditis is novel, and our understanding of immune checkpoints in the heart is in its nascency. Yet, investigations into the pathophysiology will inform better patient risk stratification, improved diagnostics and precision-based therapies for patients.

Cardiomyocyte LGR6 alleviates ferroptosis in diabetic cardiomyopathy via regulating mitochondrial biogenesis.

AIMS: The majority of people with diabetes are susceptible to cardiac dysfunction and heart failure, and conventional drug therapy cannot correct the progression of diabetic cardiomyopathy. We assessed the potential role and therapeutic value of LGR6 (G protein-coupled receptor containing leucine-rich repeats 6) in diabetic cardiomyopathy. METHODS AND RESULTS: Type 2 diabetes models were established using high-fat diet/streptozotocin-induced diabetes in mice. LGR6 knockout mice were generated. Recombinant adeno-associated virus serotype 9 carrying LGR6 under the cardiac troponin T promoter was injected into diabetic mice. Cardiomyocytes incubated with high glucose (HG) were used to imitate diabetic cardiomyopathy in vitro. The molecular mechanism was explored through RNA sequencing and a chromatin immunoprecipitation assay. We found that LGR6 expression was upregulated in diabetic hearts and HL1 cardiomyocytes treated with HG. The LGR6 knockout aggravated, but cardiomyocyte-specific LGR6 overexpression ameliorated, cardiac dysfunction and remodeling in diabetic mice. Mechanistically, in vivo and in vitro experiments revealed that LGR6 deletion aggravated, whereas LGR6 overexpression alleviated, ferroptosis and disrupted mitochondrial biogenesis by regulating STAT3/Pgc1a signaling. STAT3 inhibition and Pgc1a activation abrogated LGR6 knockout-induced mitochondrial dysfunction and ferroptosis in diabetic mice. In addition, LGR6 activation by recombinant RSPO3 treatment ameliorated cardiac dysfunction, ferroptosis and mitochondrial dysfunction in diabetic mice. CONCLUSIONS: We identified a previously undescribed signaling pathway of the LGR6-STAT3-Pgc1a axis that plays a critical role in ferroptosis and mitochondrial disorders during diabetic cardiomyopathy and provides an option for treatment of diabetic hearts.

Regulated vascular smooth muscle cell death in vascular diseases.

Regulated cell death (RCD) is a complex process that involves several cell types and plays a crucial role in vascular diseases. Vascular smooth muscle cells (VSMCs) are the predominant elements of the medial layer of blood vessels, and their regulated death contributes to the pathogenesis of vascular diseases. The types of regulated VSMC death include apoptosis, necroptosis, pyroptosis, ferroptosis, parthanatos, and autophagy-dependent cell death (ADCD). In this review, we summarize the current evidence of regulated VSMC death pathways in major vascular diseases, such as atherosclerosis, vascular calcification, aortic aneurysm and dissection, hypertension, pulmonary arterial hypertension, neointimal hyperplasia, and inherited vascular diseases. All forms of RCD constitute a single, coordinated cell death system in which one pathway can compensate for another during disease progression. Pharmacologically targeting RCD pathways has potential for slowing and reversing disease progression, but challenges remain. A better understanding of the role of regulated VSMC death in vascular diseases and the underlying mechanisms may lead to novel pharmacological developments and help clinicians address the residual cardiovascular risk in patients with cardiovascular diseases.

Resolution of inflammation, an active process to restore the immune microenvironment balance: A novel drug target for treating arterial hypertension.

The resolution of inflammation, the other side of the inflammatory response, is defined as an active and highly coordinated process that promotes the restoration of immune microenvironment balance and tissue repair. Inflammation resolution involves several key processes, including dampening proinflammatory signaling, specialized proresolving lipid mediator (SPM) production, nonlipid proresolving mediator production, efferocytosis and regulatory T-cell (Treg) induction. In recent years, increasing attention has been given to the effects of inflammation resolution on hypertension. Furthermore, our previous studies reported the antihypertensive effects of SPMs. Therefore, in this review, we aim to summarize and discuss the detailed association between arterial hypertension and inflammation resolution. Additional, the association between gut microbe-mediated immune and hypertension is discussed. This findings suggested that accelerating the resolution of inflammation can have beneficial effects on hypertension and its related organ damage. Exploring novel drug targets by focusing on various pathways involved in accelerating inflammation resolution will contribute to the treatment and control of hypertensive diseases in the future.

EDIL3/Del-1 prevents aortic dissection through enhancing internalization and degradation of apoptotic vascular smooth muscle cells.

Thoracic aortic dissection (TAD) is a severe disease, characterized by numerous apoptotic vascular smooth muscle cells (VSMCs). EDIL3/Del-1 is a secreted protein involved in macrophage efferocytosis in acute inflammation. Here, we aimed to investigate whether EDIL3 promoted the internalization and degradation of apoptotic VSMCs during TAD. The levels of EDIL3 were decreased in the serum and aortic tissue from TAD mice. Global edil3 knockout (edil3-/-) mice and edil3-/- bone marrow chimeric mice exhibited a considerable exacerbation in ß-aminopropionitrile monofumarate (BAPN)-induced TAD, accompanied with increased apoptotic VSMCs accumulating in the damaged aortic tissue. Two types of phagocytes, RAW264.7 cells and bone marrow-derived macrophages (BMDMs) were used for in vitro efferocytosis assay. edil3-deficient phagocytes exhibited inefficient internalization and degradation of apoptotic VSMCs. Instead, EDIL3 promoted the internalization phase through interacting with phosphatidylserine (PtdSer) on apoptotic VSMCs and binding to the macrophage ITGAV/αv-ITGB3/ß3 integrin. In addition, EDIL3 accelerated the degradation phase through activating LC3-associated phagocytosis (LAP). Mechanically, following the engulfment, EDIL3 enhanced the activity of SMPD1/acid sphingomyelinase in the phagosome through blocking ITGAV-ITGB3 integrin, which facilitates phagosomal reactive oxygen species (ROS) production by NAPDH oxidase CYBB/NOX2. Furthermore, exogenous EDIL3 supplementation alleviated BAPN-induced TAD and promoted apoptotic cell clearance. EDIL3 may be a novel factor for the prevention and treatment of TAD.Abbreviations: BAPN: ß-aminopropionitrile monofumarate; BMDM: bone marrow-derived macrophage; C12FDG: 5-dodecanoylaminofluorescein-di-ß-D-galactopyranoside; CTRL: control; CYBB/NOX2: cytochrome b-245, beta polypeptide; DCFH-DA: 2',7'-dichlorofluorescin diacetate; EDIL3/Del-1: EGF-like repeats and discoidin I-like domains 3; EdU: 5-ethynyl-2'-deoxyuridine; EVG: elastic van Gieson; H&E: hematoxylin and eosin; IL: interleukin; LAP: LC3-associated phagocytosis; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; NAC: N-acetylcysteine; PtdSer: phosphatidylserine; rEDIL3: recombinant EDIL3; ROS: reactive oxygen species; SMPD1: sphingomyelin phosphodiesterase 1; TAD: thoracic aortic dissection; TEM: transmission electron microscopy; VSMC: vascular smooth muscle cell; WT: wild-type.

Identification of a Novel Inhibitor of Cimex lectularius Acetylcholinesterase.

Acetylcholinesterase (AChE) stands as a primary target of commercial insecticides, notably organophosphates and carbamates. Despite their widespread use in agricultural and indoor pest control, concerns over their high toxicity and the emergence of resistance have restricted their efficacy. In this study, we conducted high-throughput virtual screening against both wild-type (WT) and resistant Cimex lectularius AChE utilizing a library encompassing 1 270 000 compounds. From this screening, we identified 100 candidate compounds and subsequently assessed their inhibitory effects on purified AChE enzymes. Among these candidates, AE027 emerged as a potent inhibitor against both WT and resistant AChE, exhibiting IC50 values of 10 and 43 µM, respectively. Moreover, the binding of AE027 significantly stabilized AChE, elevating its melting temperature by approximately 7 °C. Through molecular docking and molecular dynamics simulation, we delineated the binding mode of AE027, revealing its interaction with a site adjacent to the catalytic center, which is distinct from known inhibitors, with differing poses observed between WT and resistant AChE. Notably, the resistance mutation F348Y, positioned at a site directly interfacing with AE027, impedes ligand binding through steric hindrance. Furthermore, we evaluated the toxicity and pharmacokinetic properties of AE027 utilizing bioinformatics tools. These findings lay a crucial foundation for the development of a novel generation of insecticides that can combat both WT and resistant pest populations effectively and safely.

Insight into the mechanism of chlorinated nitroaromatic compounds anaerobic reduction with mackinawite (FeS) nanoparticles.

Anaerobic biotechnology for wastewaters treatment can nowadays be considered as state of the art methods. Nonetheless, this technology exhibits certain inherent limitations when employed for industrial wastewater treatment, encompassing elevated substrate consumption, diminished electron transfer efficiency, and compromised system stability. To address the above issues, increasing interest is being given to the potential of using conductive non-biological materials, e,g., iron sulfide (FeS), as a readily accessible electron donor and electron shuttle in the biological decontamination process. In this study, Mackinawite nanoparticles (FeS NPs) were studied for their ability to serve as electron donors for p-chloronitrobenzene (p-CNB) anaerobic reduction within a coupled system. This coupled system achieved an impressive p-CNB removal efficiency of 78.3 ± 2.9% at a FeS NPs dosage of 1 mg/L, surpassing the efficiencies of 62.1 ± 1.5% of abiotic and 30.6 ± 1.6% of biotic control systems, respectively. Notably, the coupled system exhibited exclusive formation of aniline (AN), indicating the partial dechlorination of p-CNB. The improvements observed in the coupled system were attributed to the increased activity in the electron transport system (ETS), which enhanced the sludge conductivity and nitroaromatic reductases activity. The analysis of equivalent electron donors confirmed that the S2- ions dominated the anaerobic reduction of p-CNB in the coupled system. However, the anaerobic reduction of p-CNB would be adversely inhibited when the FeS NPs dosage exceeded 5 g/L. In a continuous operation, the p-CNB concentration and HRT were optimized as 125 mg/L and 40 h, respectively, resulting in an outstanding p-CNB removal efficiency exceeding 94.0% after 160 days. During the anaerobic reduction process, as contributed by the predominant bacterium of Thiobacillus with a 6.6% relative abundance, a mass of p-chloroaniline (p-CAN) and AN were generated. Additionally, Desulfomonile was emerged with abundances ranging from 0.3 to 0.7%, which was also beneficial for the reduction of p-CNB to AN. The long-term stable performance of the coupled system highlighted that anaerobic technology mediated by FeS NPs has a promising potential for the treatment of wastewater containing chlorinated nitroaromatic compounds, especially without the aid of organic co-substrates.

The effect of multimorbidity patterns on physical and cognitive function in diabetes patients: a longitudinal cohort of middle-aged and older adults in China.

Background: The prevalence of diabetes has increased rapidly, and comorbid chronic conditions are common among diabetes patients. However, little is known about the pattern of multimorbidity in diabetes patients and the effect on physical and cognitive function. This study aimed to assess the disease clusters and patterns of multimorbidity in diabetes patients using a novel latent class analysis (LCA) approach in middle-aged and older adults and explore the association between different clusters of multimorbidity in diabetes and the effect on physical and cognitive function. Methods: This national observational study included 1,985 diabetes patients from the four waves of the China Health and Retirement Longitudinal Study (CHARLS) in 2011 to 2018. Thirteen chronic diseases were used in latent class analysis to identify the patterns of multimorbidity in diabetes, which span the cardiovascular, physical, psychological, and metabolic systems. Cognitive function is assessed via a structured questionnaire in three domains: memory, executive function, and orientation. We combined activities of daily living (ADL) with instrumental activities of daily living (IADL) to measure physical function. Linear mixed models and negative binomial regression models were used to analyze the association between patterns of multimorbidity in diabetes and the effect on cognitive function and disability, respectively. Results: A sample of 1,985 diabetic patients was identified, of which 1,889 (95.2%) had multimorbidity; their average age was 60.6 years (standard deviation (SD) = 9.5), and 53.1% were women. Three clusters were identified: "cardio-metabolic" (n = 972, 51.5%), "mental-dyslipidemia-arthritis" (n = 584, 30.9%), and "multisystem morbidity" (n = 333, 17.6%). Compared with diabetes alone, the "multisystem morbidity" class had an increased association with global cognitive decline. All patterns of multimorbidity were associated with an increased risk of memory decline and disability; however, the "multisystem morbidity" group also had the strongest association and presented a higher ADL-IADL disability (ratio = 4.22, 95% CI = 2.52, 7.08) and decline in memory Z scores (ß = -0.322, 95% CI = -0.550, -0.095, p = 0.0058). Conclusion: Significant longitudinal associations between different patterns of multimorbidity in diabetes patients and memory decline and disability were observed in this study. Future studies are needed to understand the underlying mechanisms and common risk factors for multimorbidity in diabetes patients and to propose treatments that are more effective.

Maresin-1 ameliorates hypertensive vascular remodeling through its receptor LGR6.

Hypertensive vascular remodeling is defined as the changes in vascular function and structure induced by persistent hypertension. Maresin-1 (MaR1), one of metabolites from Omega-3 fatty acids, has been reported to promote inflammation resolution in several inflammatory diseases. This study aims to investigate the effect of MaR1 on hypertensive vascular remodeling. Here, we found serum MaR1 levels were reduced in hypertensive patients and was negatively correlated with systolic blood pressure (SBP). The treatment of MaR1 reduced the elevation of blood pressure and alleviated vascular remodeling in the angiotensin II (AngII)-infused mouse model. In addition, MaR1-treated vascular smooth muscle cells (VSMCs) exhibited reduced excessive proliferation, migration, and phenotype switching, as well as impaired pyroptosis. However, the knockout of the receptor of MaR1, leucine-rich repeat-containing G protein-coupled receptor 6 (LGR6), was seen to aggravate pathological vascular remodeling, which could not be reversed by additional MaR1 treatment. The mechanisms by which MaR1 regulates vascular remodeling through LGR6 involves the Ca2+/calmodulin-dependent protein kinase II/nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signaling pathway. Overall, supplementing MaR1 may be a novel therapeutic strategy for the prevention and treatment of hypertension.

Epidermal Growth Factor-Like Repeats and Discoidin I-Like Domains 3 Deficiency Attenuates Dilated Cardiomyopathy by Inhibiting Ubiquitin Specific Peptidase 10 Dependent Smad4 Deubiquitination.

BACKGROUND: Dilated cardiomyopathy (DCM) is the leading cause of heart failure with a poor prognosis. Recent studies suggest that endothelial to mesenchymal transition (EndMT) may be involved in the pathogenesis and cardiac remodeling during DCM development. EDIL3 (epidermal growth factor-like repeats and discoidin I-like domains 3) is an extracellular matrix glycoprotein that has been reported to promote EndMT in various diseases. However, the roles of EDIL3 in DCM still remain unclear. METHODS AND RESULTS: A mouse model of DCM and human umbilical vein endothelial cells were used to explore the roles and mechanisms of EDIL3 in DCM. The results indicated that EndMT and EDIL3 were activated in DCM mice. EDIL3 deficiency attenuated cardiac dysfunction and remodeling in DCM mice. EDIL3 knockdown alleviated EndMT by inhibiting USP10 (ubiquitin specific peptidase 10) dependent Smad4 deubiquitination in vivo and in vitro. Recombinant human EDIL3 promoted EndMT via reinforcing deubiquitination of Smad4 in human umbilical vein endothelial cells treated with IL-1ß (interleukin 1ß) and TGF-ß (transforming growth factor beta). Inhibiting USP10 abolished EndMT exacerbated by EDIL3. In addition, recombinant EDIL3 also aggravates doxorubicin-induced EndMT by promoting Smad4 deubiquitination in HUVECs. CONCLUSIONS: Taken together, these results indicate that EDIL3 deficiency attenuated EndMT by inhibiting USP10 dependent Smad4 deubiquitination in DCM mice.

Kielin/chordin-like protein deficiency aggravates pressure overload-induced cardiac dysfunction and remodeling via P53/P21/CCNB1 signaling in mice.

Targeting cardiac remodeling is regarded as a key therapeutic strategy for heart failure. Kielin/chordin-like protein (KCP) is a secretory protein with 18 cysteine-rich domains and associated with kidney and liver fibrosis. However, the relationship between KCP and cardiac remodeling remains unclear. Here, we aimed to investigate the role of KCP in cardiac remodeling induced by pressure overload and explore its potential mechanisms. Left ventricular (LV) KCP expression was measured with real-time quantitative PCR, western blotting, and immunofluorescence staining in pressure overload-induced cardiac remodeling in mice. Cardiac function and remodeling were evaluated in wide-type (WT) mice and KCP knockout (KO) mice by echocardiography, which were further confirmed by histological analysis with hematoxylin and eosin and Masson staining. RNA sequence was performed with LV tissue from WT and KO mice to identify differentially expressed genes and related signaling pathways. Primary cardiac fibroblasts (CFs) were used to validate the regulatory role and potential mechanisms of KCP during fibrosis. KCP was down-regulated in the progression of cardiac remodeling induced by pressure overload, and was mainly expressed in fibroblasts. KCP deficiency significantly aggravated pressure overload-induced cardiac dysfunction and remodeling. RNA sequence revealed that the role of KCP deficiency in cardiac remodeling was associated with cell division, cell cycle, and P53 signaling pathway, while cyclin B1 (CCNB1) was the most significantly up-regulated gene. Further investigation in vivo and in vitro suggested that KCP deficiency promoted the proliferation of CFs via P53/P21/CCNB1 pathway. Taken together, these results suggested that KCP deficiency aggravates cardiac dysfunction and remodeling induced by pressure overload via P53/P21/CCNB1 signaling in mice.

Trifluoromethyl quinoline derivative targets inhibiting HDAC1 for promoting the acetylation of histone in cervical cancer cells.

Cervical cancer is the leading cause of death among gynecological malignant tumors, especially due to the poor prognosis of patients with advanced tumors due to recurrence, metastasis, and chemotherapy resistance. Therefore, exploring new antineoplastic drugs with high efficacy and low toxicity may bring new expectations in patients with cervical cancer. Natural products and their derivatives exert an antitumor activity. Therefore, in this work, combined with network pharmacology analysis and experimental validation, we investigated the anti-cervical cancer activity and molecular mechanism of a new trifluoromethyl quinoline (FKL) derivative in vivo and in vitro. FKL117 inhibited the proliferation of cervical cancer cells in a dose and time-dependent manner, induced apoptosis in HeLa cells, arrested the cell cycle in the G2/M phase, and regulated the expression of the apoptotic and cell cycle-related proteins Bcl-2, Bax, cyclin B1, and CDC2. We used online databases to obtain HDAC1 as one of the possible targets of FKL117 and the target binding and binding affinity were modeled by molecular docking. The results showed that FKL117 formed a hydrogen bond with HDAC1 and had good binding ability. We found that FKL117 targeted to inhibit the expression and function of HDAC1 and increased the acetylation of histone H3 and H4, which was also confirmed in vivo. The migration of HMGB1 from the nucleus to the cytoplasm further verified the above results. In conclusion, our study suggested that FKL117 might be used as a novel candidate for targeting the inhibition of HDAC1 against cervical cancer.

IGF1R stimulates autophagy, enhances viability, and promotes insulin secretion in pancreatic ß cells in gestational diabetes mellitus by upregulating ATG7.

Gestational diabetes mellitus (GDM) is a prevalent metabolic disturbance in pregnancy. This article investigated the correlations between serum IGF1R and ATG7 with insulin resistance (IR) in GDM patients. Firstly, 100 GDM patients and 100 healthy pregnant women were selected as study subjects. The levels of serum IGF1, IGF1R, and ATG7 and their correlations with the insulin resistance index homeostasis model assessment of insulin resistance (HOMA-IR) were measured and analyzed by ELISA and Pearson. Additionally, in mouse pancreatic ß cells, IGF1R, ATG7, Beclin-1, and LC3-II/LC3-I levels, cell viability/apoptosis, and insulin level were assessed by western blot, CCK-8, flow cytometry, and ELISA. The GDM group exhibited obviously raised serum IGF1 level and diminished serum IGF1R/ATG7 levels. The IGF1 level was positively correlated with HOMA-IR, while IGF1R/ATG7 levels were negatively correlated with HOMA-IR in GDM patients. Collectively, IGF1R stimulated cell viability, suppressed apoptosis, amplified insulin secretion, and increased ATG7 expression to induce cell autophagy, which could be partially averted by ATG7 silencing.

Resolvin D1 attenuates Ang II-induced hypertension in mice by inhibiting the proliferation, migration and phenotypic transformation of vascular smooth muscle cells by blocking the RhoA/mitogen-activated protein kinase pathway.

The proliferation, migration and phenotypic transformation of vascular smooth muscle cells contribute to vascular remodeling and hypertension. Resolvin D1 (RvD1) is a specialized pro-resolving lipid mediator that has been shown to have anti-inflammatory effects and can protect against different cardiovascular diseases. However, the role and mechanism of RvD1 in hypertension are not clear. The current study investigated the role of RvD1 in Ang II-induced hypertensive mice and Ang II-stimulated rat vascular smooth muscle cells. The results showed that RvD1 treatment significantly attenuated hypertension and vascular remodeling, as indicated by decreases in blood pressure, aortic media thickness and collagen deposition. In addition, RvD1 inhibited the proliferation, migration and phenotypic transformation of vascular smooth muscle cells (VSMCs) in vivo and in vitro . Notably, the protective effects of RvD1 were mediated by the Ras homolog gene family member A (RhoA)/mitogen-activated protein kinase (MAPK) signaling pathway. In conclusion, our findings demonstrated the potential benefits of RvD1 as a promising therapeutic agent in the treatment of vascular remodeling and hypertension.

Expansion of Pathogenic Cardiac Macrophages in Immune Checkpoint Inhibitor Myocarditis.

BACKGROUND: Immune checkpoint inhibitors (ICIs), antibodies targeting PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1) or CTLA4 (cytotoxic T-lymphocyte-associated protein 4), have revolutionized cancer management but are associated with devastating immune-related adverse events including myocarditis. The main risk factor for ICI myocarditis is the use of combination PD-1 and CTLA4 inhibition. ICI myocarditis is often fulminant and is pathologically characterized by myocardial infiltration of T lymphocytes and macrophages. Although much has been learned about the role of T-cells in ICI myocarditis, little is understood about the identity, transcriptional diversity, and functions of infiltrating macrophages. METHODS: We used an established murine ICI myocarditis model (Ctla4+/-Pdcd1-/- mice) to explore the cardiac immune landscape using single-cell RNA-sequencing, immunostaining, flow cytometry, in situ RNA hybridization, molecular imaging, and antibody neutralization studies. RESULTS: We observed marked increases in CCR2 (C-C chemokine receptor type 2)+ monocyte-derived macrophages and CD8+ T-cells in this model. The macrophage compartment was heterogeneous and displayed marked enrichment in an inflammatory CCR2+ subpopulation highly expressing Cxcl9 (chemokine [C-X-C motif] ligand 9), Cxcl10 (chemokine [C-X-C motif] ligand 10), Gbp2b (interferon-induced guanylate-binding protein 2b), and Fcgr4 (Fc receptor, IgG, low affinity IV) that originated from CCR2+ monocytes. It is important that a similar macrophage population expressing CXCL9, CXCL10, and CD16α (human homologue of mouse FcgR4) was expanded in patients with ICI myocarditis. In silico prediction of cell-cell communication suggested interactions between T-cells and Cxcl9+Cxcl10+ macrophages via IFN-γ (interferon gamma) and CXCR3 (CXC chemokine receptor 3) signaling pathways. Depleting CD8+ T-cells or macrophages and blockade of IFN-γ signaling blunted the expansion of Cxcl9+Cxcl10+ macrophages in the heart and attenuated myocarditis, suggesting that this interaction was necessary for disease pathogenesis. CONCLUSIONS: These data demonstrate that ICI myocarditis is associated with the expansion of a specific population of IFN-γ-induced inflammatory macrophages and suggest the possibility that IFN-γ blockade may be considered as a treatment option for this devastating condition.

DEL-1 deficiency aggravates pressure overload-induced heart failure by promoting neutrophil infiltration and neutrophil extracellular traps formation.

Recent studies have shown that neutrophils play an important role in the development and progression of heart failure. Developmental endothelial locus-1 (DEL-1) is an anti-inflammatory glycoprotein that has been found to have protective effects in various cardiovascular diseases. However, the role of DEL-1 in chronic heart failure is not well understood. In a mouse model of pressure overload-induced non-ischemic cardiac failure, we found that neutrophil infiltration in the heart increased and DEL-1 levels decreased in the early stages of heart failure. DEL-1 deficiency worsened pressure overload-induced cardiac dysfunction and remodeling in mice. Mechanistically, DEL-1 deficiency promotes neutrophil infiltration and the formation of neutrophil extracellular traps (NETs) through the regulation of P38 signaling. In vitro experiments showed that DEL-1 can inhibit P38 signaling and NETs formation in mouse neutrophils in a MAC-1-dependent manner. Depleting neutrophils, inhibiting NETs formation, and inhibiting P38 signaling all reduced the exacerbation of heart failure caused by DEL-1 deletion. Overall, our findings suggest that DEL-1 deficiency worsens pressure overload-induced heart failure by promoting neutrophil infiltration and NETs formation.

The association between outdoor air pollution and body mass index, central obesity, and visceral adiposity index among middle-aged and elderly adults: a nationwide study in China.

Background: Previous animal studies have suggested that air pollution (AP) exposure may be a potential risk factor for obesity; however, there is limited epidemiological evidence available to describe the association of obesity with AP exposure. Methods: A retrospective cross-sectional study was conducted on 11,766 participants across mainland China in 2015. Obesity was assessed using body mass index (BMI), waist circumference (WC), and visceral adiposity index (VAI). The space-time extremely randomized tree (STET) model was used to estimate the concentration of air pollutants, including SO2, NO2, O3, PM1, PM2.5, and PM10, matched to participants' residential addresses. Logistic regression models were employed to estimate the associations of obesity with outdoor AP exposure. Further stratified analysis was conducted to evaluate whether sociodemographics or lifestyles modified the effects. Results: Increased AP exposure was statistically associated with increased odds of obesity. The odds ratio (ORs) and 95% confidence interval (CI) of BMI-defined obesity were 1.21 (1.17, 1.26) for SO2, 1.33 (1.26, 1.40) for NO2, 1.15 (1.10, 1.21) for O3, 1.38 (1.29, 1.48) for PM1, 1.19 (1.15, 1.22) for PM2.5, and 1.11 (1.09, 1.13) for PM10 per 10 µg/m3 increase in concentration. Similar results were found for central obesity. Stratified analyses suggested that elderly participants experienced more adverse effects from all 6 air pollutants than middle-aged participants. Furthermore, notable multiplicative interactions were found between O3 exposure and females as well as second-hand smokers in BMI-defined obesity. Conclusions: This study suggested that outdoor AP exposure had a significant association with the risk of obesity in the middle-aged and elderly Chinese population. Elderly individuals and women may be more vulnerable to AP exposure.

Uterine giant cell tumor of soft tissue: A case report.

INTRODUCTION: Giant cell tumor of soft tissue (GCT-ST) is a rare primary soft tissue tumor. GCT-ST mainly occurs in the trunk and extremities. There is no standard treatment for GCT-ST. This paper reports a rare case of primary uterine GCT-ST. CASE PRESENTATION: A 48-year-old female patient underwent a transabdominal subhysterectomy for uterine leiomyoma. Postoperative pathological examination showed GCT-ST with unclear tissue boundary (10.0 × 6.0 × 5.0 cm). A small amount of GCT-ST tissue could be seen on the local edge of the leiomyoma. Residual tumor tissue was found around the uterine cavity. The patient reported persistent lower abdominal distension pain 3 months after the operation. Pelvic and abdominal imaging showed a huge tumor and multiple pelvic and abdominal organ metastasis. No pulmonary metastasis was found. Exploratory surgery revealed widespread metastases in the abdominal and peritoneal cavities, involving both ovaries, right tubal serous membrane, appendix serous membrane, bladder, pelvic peritoneum, and abdominal wall incision. After surgery, the patient had 6 cycles of docetaxel and carboplatin but stopped treatments due to economic reasons. The patient died 3 months later because of multiple organs failure. CONCLUSION: GCT-ST is generally benign but has unpredictable behavior. A massive recurrence with wide invasion is possible after subtotal resection.