Multisystem Langerhans Cell Histiocytosis following Treatment of Initially Presumed Atopic Dermatitis with Dupilumab: A Case Report of an Extremely Confusing Scenario.

Introduction: Atopic dermatitis (AD) is a common chronic, recurrent, and non-infectious inflammatory skin disease. Dupilumab is a human monoclonal antibody with clinical efficacy in severe AD and has a good safety profile. Case Presentation: We hereby describe a previously unreported case of multisystem Langerhans cell histiocytosis (MS-LCH) that is associated with a history of AD treatment using dupilumab. Conclusion: A single case of MS-LCH with a history of dupilumab treatment for AD was described for the first time. This case highlights that given its susceptibility to skin involvement, LCH needs to be considered as a differential diagnosis for skin lesions that are not improved by established therapies.

MRI study on the influence of lumbosacral vertebral body and disc factors on lumbar lordosis in children.

PURPOSE: To evaluate the influence of vertebral and disc wedging on the contribution of lumbar lordosis and the change of disc thickness before and after walking based on MRI. METHODS: Cross-sectional study. A total of 96 normally developing children, aged 5.7 ± 3.0 years old, 55 boys and 41 girls. They were divided into 3 groups: Pre-walking group, Walking group, and Post-walking group. PARAMETERS: lumbar lordosis Angle (LLA), the sum of the lumbar disc wedge Angle (∑D), the sum of the lumbar vertebral body wedge Angle (∑B), disc height (DH). RESULTS: (1) LLA, ∑D, ∑B, and DHL1-S1 were 33.2 ± 8.7°, 14.1 ± 8.6°, 11.9 ± 8.6°, and 6.9 ± 1.2 mm, 7.6 ± 1.4 mm, 8.2 ± 1.6 mm, 8.9 ± 1.7 mm, 8.5 ± 1.8 mm. (2) The difference in LLA values between the Pre-walking and the Post-walking group was statistically significant. DH were significantly different among the three groups. (3) In the Post-walking group, LLA value of girls was significantly higher than that of boys, and DHL3 - 4 and DHL4 - 5 values of girls were significantly lower than that of boys. (4) Age had a low positive correlation with LLA and ∑D and a moderate to strong positive correlation with DH; LLA showed a moderate positive correlation with ∑D, and a low positive correlation with ∑B and DH. CONCLUSION: Age and walking activity are the influencing factors of lumbar lordosis and disc thickening. Walking activity can significantly increase lumbar lordosis, and age is the main factor promoting lumbar disc thickening. DHL4-5 was the thickest lumbar intervertebral disc with the fastest intergroup thickening. Disc wedging contributes more to lumbar lordosis than vertebral wedging.

Predictors of lung cancer subtypes and lymph node status in non-small-cell lung cancer: intravoxel incoherent motion parameters and extracellular volume fraction.

OBJECTIVE: To determine the performance of intravoxel incoherent motion (IVIM) parameters and the extracellular volume fraction (ECV) in distinguishing between different subtypes of lung cancer and predicting lymph node metastasis (LNM) status in patients with non-small-cell lung cancer (NSCLC). METHODS: One hundred sixteen patients with lung cancer were prospectively recruited. IVIM, native, and postcontrast T1 mapping examinations were performed, and the T1 values were measured to calculate the ECV. The differences in IVIM parameters and ECV were compared between NSCLC and small-cell lung cancer (SCLC), adenocarcinoma (Adeno-Ca) and squamous cell carcinoma (SCC), and NSCLC without and with LNM. The assessment of each parameter's diagnostic performance was based on the area under the receiver operating characteristic curve (AUC). RESULTS: The apparent diffusion coefficient (ADC), true diffusion coefficient (D), and ECV values in SCLC were considerably lower compared with NSCLC (all p < 0.001, AUC > 0.887). The D value in SCC was substantially lower compared with Adeno-Ca (p < 0.001, AUC = 0.735). The perfusion fraction (f) and ECV values in LNM patients were markedly higher compared with those without LNM patients (p < 0.01, < 0.001, AUC > 0.708). CONCLUSION: IVIM parameters and ECV can serve as non-invasive biomarkers for assisting in the pathological classification and LNM status assessment of lung cancer patients. CRITICAL RELEVANCE STATEMENT: IVIM parameters and ECV demonstrated remarkable potential in distinguishing pulmonary carcinoma subtypes and predicting LNM status in NSCLC. KEY POINTS: Lung cancer is prevalent and differentiating subtype and invasiveness determine the treatment course. True diffusion coefficient and ECV showed promise for subtyping and determining lymph node status. These parameters could serve as non-invasive biomarkers to help determine personalized treatment strategies.

Effectiveness and mechanism of Huoxin pill on heart failure after percutaneous coronary intervention: Study protocol for a double-blind, randomised, placebo-controlled parallel trial.

Background: Coronary heart disease (CHD) is the most common cardiovascular disease facing human beings. Cardiac remodelling is an important pathological factor for the progression of heart failure (HF) after CHD. At present, Chinese medicine is widely used in the treatment of HF, but there are still some drugs lack of evidence-based and mechanism evidence. Multi-omics techniques can deep explore candidate pathogenic factors and construct gene regulatory networks.This trial is intended to evaluate the effect on Huoxin pill (HXP) in the treatment of HF after programmable communication interface (PCI). Meantime, multi-omics analysis technique will be used to target the fundamental pathological links of cardiac remodelling, so as to study the mechanism of HXP in the treatment of HF after PCI. Methods: This study is a randomized, double-blind, placebo-controlled trial. Sixty patients with HF undergoing PCI are recruited from the First Affiliated Hospital of Henan University of CM. All selected patients will be randomly attributed to receive conventional treatment + HXP or placebo. The packaging, dosage and smell of placebo and heart activating pill were identical. The primary outcome is NYHA cardiac function grade, while the secondary outcomes included Lee's HF score, exercise tolerance test, and quality of life evaluation. Additional indicators include cardiac ultrasound, electrocardiogram, 24-h dynamic electrocardiogram, myocardial injury indicators, and energy metabolism indicators. Discussion: This study may provide a new treatment option for patients with HF after PCI and provide evidence for the treatment of CHD and HF with HXP. Trial registration: 2023-10-08 registered in China Clinical Trial Registry, registration number ChiCTR2300076402.

Comparison of warfarin, rivaroxaban, and dabigatran for effectiveness and safety in atrial fibrillation patients with different CHA2DS2-VASc scores: a retrospective cohort study.

BACKGROUND: This retrospective cohort study aims to compare the effectiveness and safety of warfarin, rivaroxaban, and dabigatran in atrial fibrillation (AF) patients with different CHA2DS2-VASc scores in northern China. METHODS: A retrospective cohort study was performed to evaluate anticoagulation in AF patients at the second affiliated hospital of Harbin Medical University from September 2018 to August 2019. Patients included in this study (n = 806) received warfarin (n = 300), or rivaroxaban (n = 203), or dabigatran (n = 303). Baseline characteristics and follow-up data including adherence, bleeding events and ischemic stroke (IS) events were collected. RESULTS: Patients receiving rivaroxaban (73.9%) or dabigatran (73.6%) showed better adherence than those receiving warfarin (56.7%). Compared with warfarin-treated patients, dabigatran-treated patients had lower incidence of bleeding events (10.9% vs 19.3%, χ2 = 8.385, P = 0.004) and rivaroxaban-treated patients had lower incidence of major adverse cardiovascular events (7.4% vs 13.7%, χ2 = 4.822, P = 0.028). We classified patients into three groups based on CHA2DS2-VASc score (0-1, 2-3, ≥ 4). In dabigatran intervention, incidence of bleeding events was higher in patients with score 0-1 (20.0%) than those with score 2-3 (7.9%, χ2 = 5.772, P = 0.016) or score ≥ 4 (8.6%, χ2 = 4.682, P = 0.030). Patients with score 0-1 in warfarin or rivaroxaban therapy had a similar but not significant increase of bleeding compared with patients with score 2-3 or score ≥ 4, respectively. During the follow-up, 33 of 806 patients experienced IS and more than half (19, 57.6%) were patients with score ≥ 4. Comparing patients with score 0-1 and 2-3, the latter had an significant reduction of IS in patients prescribed warfarin and non-significant reduction in rivaroxaban and dabigatran therapy. CONCLUSION: Compared with warfarin therapy, patients with different CHA2DS2-VASc scores receiving either rivaroxaban or dabigatran were associated with higher persistence. AF patients with score ≥ 4 were more likely to experience IS events while hemorrhagic tendency preferred patients with low score 0-1.

Optimizing twin-beam dual-energy CT reconstruction: Quantitative consistency and stability assessment in reference to 120 kV: An observational study.

The split filter CT can filter X-ray beam. Theoretically, the split filter CT not only provides a good low-energy beam, but also provides a more robust CT value. The aim of this study was to compare conventional single-energy computed tomography (SECT) and twin-beam dual-energy (TBDE) CT regarding the quantitative consistency and stabilities of HU measurements at different abdominal organs. Forty-four patients were prospectively enrolled to randomly receive SECT and TBDE protocols at either body part of a thorax-abdominal examination. Their overlapping scan coverage was subjected to further image analysis. For TBDE scans, composed images(c-images) and virtual monoenergetic images (VMIs) at 60, 70, 80, and 90 kiloelectron volt (keV) were reconstructed. The attenuations were measured at 5 abdominal organs and compared between SECT and TBDE to characterize quantitative consistency by intraclass correlation coefficients (ICCs), whereas their standard deviations were used to assess the Hounsfield Unit (HU) stability. The c-images, 70 keV and 80 keV VMIs from TBDE provided consistent HU values (all ICCs > 0.8) with the SECT measurements; moreover, these TBDE images had superior HU stability over SECT images in all abdominal measurements except for fat tissue. The best HU stability can be achieved in 80 keV VMIs with the lowest noise level. The c-images and VMIs derived from TBDE can produce consistent values as SECT. The 80 keV images displayed better HU stability and a lower noise level across various abdominal organs.

Neglected Mycobacterium Avium Complex Infection in a Patient with Prolonged Pneumonia.

BACKGROUND: Non-tuberculous mycobacterial pulmonary infections (NTM-PD) are becoming increasingly common in clinical practice, and early detection and accurate determination of the infecting pathogen is crucial for subsequent treatment. We report a case of NTM-PD in a healthy middle-aged female with Mycobacterium tuberculosis complex group (MAC) infection confirmed by mNGS examination. METHODS: Appropriate laboratory tests, chest CT scan, bronchoscopic alveolar lavage fluid (BALF) examination, and macrogenomic next-generation sequencing (mNGS) were performed to establish the diagnosis. RESULTS: Chest CT showed multiple inflammatory lesions in the right middle lobe, and BALF sent for mNGS finally confirmed the diagnosis of MAC infection. After symptomatic treatment with azithromycin combined with ethambutol and rifampicin, the patient improved and was discharged from the hospital. CONCLUSIONS: In patients with pulmonary infections, pathogens should be clarified early to determine the diagnosis. mNGS of BALF samples have high specificity in detecting pathogens of infectious diseases, especially complex mixed infectious disease pathogens.

Co-delivery Nano System of MS-275 and V-9302 Induces Pyroptosis and Enhances Anti-Tumor Immunity Against Uveal Melanoma.

In the treatment of uveal melanoma (UVM), histone deacetylase inhibitors (HDACi) have emerged as a promising epigenetic therapy. However, their clinical efficacy is hindered by the suboptimal pharmacokinetics and the strong self-rescue of tumor cells. To overcome these limitations, reactive oxygen species (ROS)-responsive nanoparticles (NPs) are designed that encapsulate HDACi MS-275 and the glutamine metabolism inhibitor V-9302. Upon reaching the tumor microenvironment, these NPs can disintegrate, thereby releasing MS-275 to increase the level of ROS and V-9302 to reduce the production of glutathione (GSH) related to self-rescue. These synergistic effects lead to a lethal ROS storm and induce cell pyroptosis. When combined with programmed cell death protein 1 monoclonal antibodies (α-PD-1), these NPs facilitate immune cell infiltration, improving anti-tumor immunity, converting "immune-cold" tumors into "immune-hot" tumors, and enhancing immune memory in mice. The findings present a nano-delivery strategy for the co-delivery of epigenetic therapeutics and metabolic inhibitors, which induces pyroptosis in tumors cells and improves the effectiveness of chemotherapy and immunotherapy.

Incidence, outcome, and prognostic factors of prolonged mechanical ventilation among children in Chinese mainland: a multi-center survey.

Objective: To evaluate the incidence, outcome, and prognostic factors of prolonged mechanical ventilation (PMV) in children in Mainland China. Methods: A prospective study was conducted in 11 pediatric intensive care units (PICUs) from May 1, 2021, to April 30, 2022. All pediatric patients on mechanical ventilation meeting the criteria for PMV were included in the study. Results: Out of 5,292 patients receiving mechanical ventilation, 278 children met the criteria for PMV (5.3%). After excluding case with incomplete data or lost to follow-up, the study included 250 patients. Among them, 115 were successfully weaned from mechanical ventilation, 90 died, and 45 were still on mechanical ventilation. The 6-month survival rate was 64%. The primary associated conditions of PMV were lower airway diseases (36%), central nervous system diseases (32%), and neuromuscular diseases (14%). The stepwise multiple logistic regression analysis indicated that the utilization of vasoactive agents and an elevated pediatric logistic organ dysfunction-2 (PELOD-2) score on the day of PMV diagnosis were significantly associated with an increased of PMV death. Specifically, the odds ratio (OR) for vasoactive agent use was 2.86; (95% CI: 0.15-0.84; P = 0.018), and for the PELOD-2 score, it was 1.37; 95% CI: 1.17-1.61; P < .001). Conversely, early rehabilitation intervention was negatively associated with the risk of PMV death (OR = 0.45; 95% CI: 0.22-0.93; P = .032). Furthermore, the tracheotomy timing emerged as an independent predictor of failure to wean from PMV, with an OR of 1.08, (95% CI: 1.01-1.16; P = .030). Conclusions: The study revealed a 5.3% incidence of PMV in children requiring mechanical ventilation in China. The use of vasoactive agents and a higher PELOD-2 score at PMV diagnosis were significantly associated with an increased risk of PMV death, whereas early rehabilitation intervention was identified as crucial for improving patient outcomes. The timing of tracheostomy was identified as a high-risk factor for failure to wean from mechanical ventilation.

Biochar-based composites for removing chlorinated organic pollutants: Applications, mechanisms, and perspectives.

Chlorinated organic pollutants constitute a significant category of persistent organic pollutants due to their widespread presence in the environment, which is primarily attributed to the expansion of agricultural and industrial activities. These pollutants are characterized by their persistence, potent toxicity, and capability for long-range dispersion, emphasizing the importance of their eradication to mitigate environmental pollution. While conventional methods for removing chlorinated organic pollutants encompass advanced oxidation, catalytic oxidation, and bioremediation, the utilization of biochar has emerged as a prominent green and efficacious method in recent years. Here we review biochar's role in remediating typical chlorinated organics, including polychlorinated biphenyls (PCBs), triclosan (TCS), trichloroethene (TCE), tetrachloroethylene (PCE), organochlorine pesticides (OCPs), and chlorobenzenes (CBs). We focus on the impact of biochar material properties on the adsorption mechanisms of chlorinated organics. This review highlights the use of biochar as a sustainable and eco-friendly method for removing chlorinated organic pollutants, especially when combined with biological or chemical strategies. Biochar facilitates electron transfer efficiency between microorganisms, promoting the growth of dechlorinating bacteria and mitigating the toxicity of chlorinated organics through adsorption. Furthermore, biochar can activate processes such as advanced oxidation or nano zero-valent iron, generating free radicals to decompose chlorinated organic compounds. We observe a broader application of biochar and bioprocesses for treating chlorinated organic pollutants in soil, reducing environmental impacts. Conversely, for water-based pollutants, integrating biochar with chemical methods proved more effective, leading to superior purification results. This review contributes to the theoretical and practical application of biochar for removing environmental chlorinated organic pollutants.

Synthesis and proton-conductive behaviour of two MOFs with covalently bonded imidazoles in the channels.

Immobilization of imidazole molecules as proton carriers into MOFs to facilitate proton conduction is a general strategy for developing high proton conductive materials. Herein, we designed two imidazole substituted phthalic acid ligands and constructed two novel MOFs, {[Zr6(OH)16(H3L1)4]Cl8·20H2O}n [Zr-MOF; H3L1 = 2-(1H-imidazol-4-yl) methylaminoterephthalic acid] and {Gd(HCOO)(H2L2)2}n [Gd-MOF; H3L2 = 5-(1H-imidazol-4-yl)methylaminoisophthalic acid] and fully studied their porous nature, stability and water-assisted proton conduction. The resulting Zr-MOF exhibits a high proton conductivity of 1.82 × 10-2 S cm-1 at 98% RH and 80 °C, while Gd-MOF has a proton conductivity of 3.01 × 10-3 S cm-1 at 98% RH and 60 °C.

Model prediction of radioactivity levels in the environment and food around the world's first AP 1000 nuclear power unit.

Objectives: Model prediction of radioactivity levels around nuclear facilities is a useful tool for assessing human health risks and environmental impacts. We aim to develop a model for forecasting radioactivity levels in the environment and food around the world's first AP 1000 nuclear power unit. Methods: In this work, we report a pilot study using time-series radioactivity monitoring data to establish Autoregressive Integrated Moving Average (ARIMA) models for predicting radioactivity levels. The models were screened by Bayesian Information Criterion (BIC), and the model accuracy was evaluated by mean absolute percentage error (MAPE). Results: The optimal models, ARIMA (0, 0, 0) × (0, 1, 1)4, and ARIMA (4, 0, 1) were used to predict activity concentrations of 90Sr in food and cumulative ambient dose (CAD), respectively. From the first quarter (Q1) to the fourth quarter (Q4) of 2023, the predicted values of 90Sr in food and CAD were 0.067-0.77 Bq/kg, and 0.055-0.133 mSv, respectively. The model prediction results were in good agreement with the observation values, with MAPEs of 21.4 and 22.4%, respectively. From Q1 to Q4 of 2024, the predicted values of 90Sr in food and CAD were 0.067-0.77 Bq/kg and 0.067-0.129 mSv, respectively, which were comparable to values reported elsewhere. Conclusion: The ARIMA models developed in this study showed good short-term predictability, and can be used for dynamic analysis and prediction of radioactivity levels in environment and food around Sanmen Nuclear Power Plant.

A Case of Organizing Pneumonia Resembling Lung Cancer.

BACKGROUND: Organizing pneumonia (OP) is a pathologic diagnosis with clinical and imaging manifestations that often resemble other diseases, such as infections and cancers, which can lead to delays in diagnosis and inappropriate management of the underlying disease. In this article, we present a case of organized pneumonia that resembles lung cancer. METHODS: We report a case of initial suspicion of pulmonary malignancy, treated with anti-inflammatory medication and then reviewed with CT suggesting no improvement, and finally confirmed to be OP by pathological biopsy taken via transbronchoscopy. A joint literature analysis was performed to raise clinicians' awareness of the diagnosis and treatment of OP. RESULTS: Initially, because of the atypical auxiliary findings, we thought that the disease turned out to be a lung tumor, which was eventually confirmed as OP by pathological diagnosis. CONCLUSIONS: The diagnosis and treatment of OP requires a combination of clinical information and radiological expertise, as well as biopsy to obtain histopathological evidence. That is, clinical-imaging-pathological tripartite cooperation and comprehensive analysis.

Development of a CT-Based comprehensive model combining clinical, radiomics with deep learning for differentiating pulmonary metastases from noncalcified pulmonary hamartomas, a retrospective cohort study.

BACKGROUND: Clinical differentiation between pulmonary metastases and noncalcified pulmonary hamartomas (NCPH) often presents challenges, leading to potential misdiagnosis. However, the efficacy of a comprehensive model that integrates clinical features, radiomics, and deep learning (CRDL) for differential diagnosis of these two diseases remains uncertain. OBJECTIVE: This study evaluated the diagnostic efficacy of a Clinical Features, Radiomics, and Deep Learning (CRDL) model in differentiating pulmonary metastases from noncalcified pulmonary hamartomas (NCPH). METHODS: We retrospectively analyzed the clinical and imaging data of 256 patients from Hospital A and 85 patients from Hospital B, who were pathologically confirmed pulmonary hamartomas or pulmonary metastases after thoracic surgery. Employing Python 3.7 software suites, we extracted radiomic features and deep learning attributes from patient datasets. The cohort was divided into training set, internal validation set, and external validation set. The diagnostic performance of the constructed models was evaluated using receiver operating characteristic (ROC) curve analysis to determine their effectiveness in differentiating between pulmonary metastases and NCPH. RESULTS: Clinical features such as white blood cell count (WBC), platelet count (PLT), history of cancer, carcinoembryonic antigen (CEA) level, tumor marker status, lesion margin characteristics (smooth or blurred) and maximum diameter were found to have diagnostic value in differentiating between the two diseases. In the domains of radiomics and deep learning. Of the 1,130 radiomics features and 512 deep learning features, 24 and 7, respectively, were selected for model development. The area under the ROC curve (AUC) values for the four groups were 0.980, 0.979, 0.999, and 0.985 in the training set, 0.947, 0.816, 0.934, and 0.952 in the internal validation set, and 0.890, 0.904, 0.923, and 0.938 in the external validation set. This demonstrated that the CRDL model showed the greatest efficacy. CONCLUSIONS: The comprehensive model incorporating clinical features, radiomics, and deep learning shows promise for aiding in the differentiation between pulmonary metastases and hamartomas.

A potential antiviral role for CCR5+CD8+ T cells in children with hepatitis B.

While dysfunctional exhausted CD8+ T cells hamper viral control when children acquire hepatitis B virus (HBV) infection, it's crucial to recognize that CD8+ T cells have diverse phenotypes and functions. This study explored a subset of CD8+ T cells expressing C-C chemokine receptor type 5 (CCR5) in children with HBV infection. Thirty-six patients in the immune tolerant group, 33 patients in the immune active group, 55 patients in the combined response group, and 22 healthy control children were enrolled. The frequency, functional molecules, and effector functions of the CCR5+CD8+ T cell population in different groups were evaluated. The frequency of CCR5+CD8+ T cells correlated positively with the frequency of CCR5+CD4+ T cells and patient age, and it correlated negatively with alanine aminotransferase, aspartate transaminase, HBV DNA, hepatitis B surface antigen, and lactic dehydrogenase levels. CCR5+CD8+ T cells had higher levels of inhibitory and activated receptors and produced higher levels of IFN-γ, IL-2, and TNF-α than CCR5-CD8+ T cells. CCR5+CD8+ T cells were partially exhausted but possessed a stronger antiviral activity than CCR5-CD8+ T cells. The identification of this subset increases our understanding of CD8+ T cell functions and serves as a potential immunotherapeutic target for children with HBV infection.

1-Methyltryptophan treatment ameliorates high-fat diet-induced depression in mice through reversing changes in perineuronal nets.

Depression and obesity are prevalent disorders with significant public health implications. In this study, we used a high-fat diet (HFD)-induced obese mouse model to investigate the mechanism underlying HFD-induced depression-like behaviors. HFD-induced obese mice exhibited depression-like behaviors and a reduction in hippocampus volume, which were reversed by treatment with an indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyltryptophan (1-MT). Interestingly, no changes in IDO levels were observed post-1-MT treatment, suggesting that other mechanisms may be involved in the anti-depressive effect of 1-MT. We further conducted RNA sequencing analysis to clarify the potential underlying mechanism of the anti-depressive effect of 1-MT in HFD-induced depressive mice and found a significant enrichment of shared differential genes in the extracellular matrix (ECM) organization pathway between the 1-MT-treated and untreated HFD-induced depressive mice. Therefore, we hypothesized that changes in ECM play a crucial role in the anti-depressive effect of 1-MT. To this end, we investigated perineuronal nets (PNNs), which are ECM assemblies that preferentially ensheath parvalbumin (PV)-positive interneurons and are involved in many abnormalities. We found that HFD is associated with excessive accumulation of PV-positive neurons and upregulation of PNNs, affecting synaptic transmission in PV-positive neurons and leading to glutamate-gamma-aminobutyric acid imbalances in the hippocampus. The 1-MT effectively reversed these changes, highlighting a PNN-related mechanism by which 1-MT exerts its anti-depressive effect.

Metformin normalizes mitochondrial function to delay astrocyte senescence in a mouse model of Parkinson's disease through Mfn2-cGAS signaling.

BACKGROUND: Senescent astrocytes play crucial roles in age-associated neurodegenerative diseases, including Parkinson's disease (PD). Metformin, a drug widely used for treating diabetes, exerts longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined. METHODS: Long culture-induced replicative senescence model and 1-methyl-4-phenylpyridinium/α-synuclein aggregate-induced premature senescence model, and a mouse model of PD were used to investigate the effect of metformin on astrocyte senescence in vivo and in vitro. Immunofluorescence staining and flow cytometric analyses were performed to evaluate the mitochondrial function. We stereotactically injected AAV carrying GFAP-promoter-cGAS-shRNA to mouse substantia nigra pars compacta regions to specifically reduce astrocytic cGAS expression to clarify the potential molecular mechanism by which metformin inhibited the astrocyte senescence in PD. RESULTS: We showed that metformin inhibited the astrocyte senescence in vitro and in PD mice. Mechanistically, metformin normalized mitochondrial function to reduce mitochondrial DNA release through mitofusin 2 (Mfn2), leading to inactivation of cGAS-STING, which delayed astrocyte senescence and prevented neurodegeneration. Mfn2 overexpression in astrocytes reversed the inhibitory role of metformin in cGAS-STING activation and astrocyte senescence. More importantly, metformin ameliorated dopamine neuron injury and behavioral deficits in mice by reducing the accumulation of senescent astrocytes via inhibition of astrocytic cGAS activation. Deletion of astrocytic cGAS abolished the suppressive effects of metformin on astrocyte senescence and neurodegeneration. CONCLUSIONS: This work reveals that metformin delays astrocyte senescence via inhibiting astrocytic Mfn2-cGAS activation and suggest that metformin is a promising therapeutic agent for age-associated neurodegenerative diseases.

FBXO32-mediated degradation of PTEN promotes lung adenocarcinoma progression.

FBXO32, a member of the F-box protein family, is known to play both oncogenic and tumor-suppressive roles in different cancers. However, the functions and the molecular mechanisms regulated by FBXO32 in lung adenocarcinoma (LUAD) remain unclear. Here, we report that FBXO32 is overexpressed in LUAD compared with normal lung tissues, and high expression of FBXO32 correlates with poor prognosis in LUAD patients. Firstly, we observed with a series of functional experiments that FBXO32 alters the cell cycle and promotes the invasion and metastasis of LUAD cells. We further corroborate our findings using in vivo mouse models of metastasis and confirmed that FBXO32 positively regulates LUAD tumor metastasis. Using a proteomic-based approach combined with computational analyses, we found a positive correlation between FBXO32 and the PI3K/AKT/mTOR pathway, and identified PTEN as a FBXO32 interactor. More important, FBXO32 binds PTEN via its C-terminal substrate binding domain and we also validated PTEN as a bona fide FBXO32 substrate. Finally, we demonstrated that FBXO32 promotes EMT and regulates the cell cycle by targeting PTEN for proteasomal-dependent degradation. In summary, our study highlights the role of FBXO32 in promoting the PI3K/AKT/mTOR pathway via PTEN degradation, thereby fostering lung adenocarcinoma progression.