Development of an mRNA-based therapeutic vaccine mHTV-03E2 for high-risk HPV-related malignancies.

Human papillomavirus (HPV) 16 and 18 infections are related to many human cancers. Despite several preventive vaccines for high-risk (hr) HPVs, there is still an urgent need to develop therapeutic HPV vaccines for targeting pre-existing hrHPV infections and lesions. In this study, we developed a lipid nanoparticle (LNP)-formulated mRNA-based HPV therapeutic vaccine (mHTV)-03E2, simultaneously targeting the E2/E6/E7 of both HPV16 and HPV18. mHTV-03E2 dramatically induced antigen-specific cellular immune responses, leading to significant CD8+ T cell infiltration and cytotoxicity in TC-1 tumors derived from primary lung epithelial cells of C57BL/6 mice expressing HPV E6/E7 antigens, mediated significant tumor regression, and prolonged animal survival, in a dose-dependent manner. We further demonstrated significant T cell immunity against HPV16/18 E6/E7 antigens for up to 4 months post-vaccination in immunological and distant tumor rechallenging experiments, suggesting robust memory T cell immunity against relapse. Finally, mHTV-03E2 synergized with immune checkpoint blockade to inhibit tumor growth and extend animal survival, indicating the potential in combination therapy. We conclude that mHTV-03E2 is an excellent candidate therapeutic mRNA vaccine for treating malignancies caused by HPV16 or HPV18 infections.

Protein biomarkers and alternatively methylated cell-free DNA detect early stage pancreatic cancer.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at an advanced stage. Liquid biopsy approaches may facilitate detection of early stage PDAC when curative treatments can be employed. DESIGN: To assess circulating marker discrimination in training, testing and validation patient cohorts (total n=426 patients), plasma markers were measured among PDAC cases and patients with chronic pancreatitis, colorectal cancer (CRC), and healthy controls. Using CA19-9 as an anchor marker, measurements were made of two protein markers (TIMP1, LRG1) and cell-free DNA (cfDNA) pancreas-specific methylation at 9 loci encompassing 61 CpG sites. RESULTS: Comparative methylome analysis identified nine loci that were differentially methylated in exocrine pancreas DNA. In the training set (n=124 patients), cfDNA methylation markers distinguished PDAC from healthy and CRC controls. In the testing set of 86 early stage PDAC and 86 matched healthy controls, CA19-9 had an area under the receiver operating characteristic curve (AUC) of 0.88 (95% CI 0.83 to 0.94), which was increased by adding TIMP1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.06), LRG1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02) or exocrine pancreas-specific cfDNA methylation markers at nine loci (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02). In the validation set of 40 early stage PDAC and 40 matched healthy controls, a combined panel including CA19-9, TIMP1 and a 9-loci cfDNA methylation panel had greater discrimination (AUC 0.86, 95% CI 0.77 to 0.95) than CA19-9 alone (AUC 0.82; 95% CI 0.72 to 0.92). CONCLUSION: A combined panel of circulating markers including proteins and methylated cfDNA increased discrimination compared with CA19-9 alone for early stage PDAC.

Machine Learning Assisted MALDI Mass Spectrometry for Rapid Antimicrobial Resistance Prediction in Clinicals.

Antimicrobial susceptibility testing (AST) plays a critical role in assessing the resistance of individual microbial isolates and determining appropriate antimicrobial therapeutics in a timely manner. However, conventional AST normally takes up to 72 h for obtaining the results. In healthcare facilities, the global distribution of vancomycin-resistant Enterococcus fecium (VRE) infections underscores the importance of rapidly determining VRE isolates. Here, we developed an integrated antimicrobial resistance (AMR) screening strategy by combining matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) with machine learning to rapidly predict VRE from clinical samples. Over 400 VRE and vancomycin-susceptible E. faecium (VSE) isolates were analyzed using MALDI-MS at different culture times, and a comprehensive dataset comprising 2388 mass spectra was generated. Algorithms including the support vector machine (SVM), SVM with L1-norm, logistic regression, and multilayer perceptron (MLP) were utilized to train the classification model. Validation on a panel of clinical samples (external patients) resulted in a prediction accuracy of 78.07%, 80.26%, 78.95%, and 80.54% for each algorithm, respectively, all with an AUROC above 0.80. Furthermore, a total of 33 mass regions were recognized as influential features and elucidated, contributing to the differences between VRE and VSE through the Shapley value and accuracy, while tandem mass spectrometry was employed to identify the specific peaks among them. Certain ribosomal proteins, such as A0A133N352 and R2Q455, were tentatively identified. Overall, the integration of machine learning with MALDI-MS has enabled the rapid determination of bacterial antibiotic resistance, greatly expediting the usage of appropriate antibiotics.

Regulation Dipole Moments of N-Doped Graphene Coordinated with FePc Toward Highly Efficient Microwave Absorption Performance in C Band.

The development of composites with highly efficient microwave absorption (MA) performance deeply depends on polarization loss, which can be induced by charge redistribution. Considering the fact that polarization centers can be easily obtained in graphene, herein, iron phthalocyanine (FePc) is used as polarization site to coordinate with nitrogen-doped graphene (FePc/N-rGO) to optimize MA performance comprehensively. The factors influencing MA properties focus on the interaction between FePc and N-rGO, and the change of dipole moments. The density functional theory (DFT) results demonstrated that FePc has strong interaction with N defect sites in graphene. The charge loss for FePc and charge accumulation for N-rGO occurred, leading to great increase of dipole moment, and the increased dipole moment can be acted as a descriptor to evaluate the enhanced polarization loss. Due to high charge redistribution capacity of N defect sites and FePc polarization centers, the FePc/N-rGO showed excellent MA properties in C band, and the minimum reflection loss value can reach -49.3 dB at 5.4 GHz with thickness of 3.8 mm. In addition, the fabric loaded with FePc/N-rGO showed good heat dissipation property. This work opens the door to the development of MA performance bound to polarization site with dipole moment.

Phase-Transition of Mo2C Induced by Tungsten Doping as Heterointerface-Rich Electrocatalyst for Optimizing Hydrogen Evolution Activity.

Electrochemical hydrogen evolution reaction (HER) from water splitting driven by renewable energy is considered a promising method for large-scale hydrogen production, and as an alternative to noble-metal electrocatalysts, molybdenum carbide (Mo2C) has exhibited effective HER performance. However, the strong bonding strength of intermediate adsorbed H (Hads) with Mo active site slows down the HER kinetics of Mo2C. Herein, using phase-transition strategy, hexagonal ß-Mo2C could be easily transferred to cubic δ-Mo2C through electron injection triggered by tungsten (W) doping, and heterointerface-rich Mo2C-based composites, including ß-Mo2C, δ-Mo2C, and MoO2, are presented. Experimental results and density functional theory calculations reveal that W doping mainly contributes to the phase-transition process, and the generated heterointerfaces are the dominant factor in inducing remarkable electron accumulation around Mo active sites, thus weakening the Mo─H coupling. Wherein, the ß-Mo2C/MoO2 interface plays an important role in optimizing the electronic structure of Mo 3d orbital and hydrogen adsorption Gibbs free energy (ΔGH*), enabling these Mo2C-based composites to have excellent intrinsic catalytic activity like low overpotential (η10 = 99.8 mV), small Tafel slope (60.16 dec-1), and good stability in 1 m KOH. This work sheds light on phase-transition engineering and offers a convenient route to construct heterointerfaces for large-scale HER production.

The first-in-human preclinical evaluation of the new probe [123I]I-PSMA-7 for real-time intraoperative targeted biopsy and SPECT/CT imaging in prostate cancer.

PURPOSE: PSMA/PET has been increasingly used to detect PCa, and PSMA/PET-guided biopsy has shown promising results. However, it cannot be confirmed immediately whether the tissues are the targeted area. In this study, we aimed to develop a novel probe, [123I]I-PSMA-7. First, we hope that [123I]I-PSMA-7 can provide instant confirmation for prostate biopsy. Second, we hope it will help detect PCa. METHODS: We synthesized a high-affinity probe, [123I]I-PSMA-7, and evaluated its properties. We included ten patients with suspected PCa and divided them into two groups. The injection and biopsy were approximately 24 h apart. The activity in biopsy lesions was measured as the cpm by a γ-counter. Moreover, we enrolled 3 patients to evaluate the potential of [123I]I-PSMA-7 for detecting PCa. RESULTS: Animal experiments verified the safety, targeting and effectiveness of [123I]I-PSMA-7, and the tumor-to-muscle ratio was greatest at 24 h, which confirmed the results of this study in humans. After injection of 185MBq [123I]I-PSMA-7, 18/55 cores were positive, and the cpm was significantly greater (4345 ± 3547 vs. 714 ± 547, P < 0.001), with an AUC of 0.97 and a cutoff of 1312 (sens/spec of 94.40%/91.90%). At a lower dose, 10/55 biopsy cores were cancerous, and the cpm was 2446 ± 1622 vs. 153 ± 112 (P < 0.001). The AUC was 1, with a cutoff value of 490 (sens/spec of 100%). When the radiopharmaceuticals were added to 370 MBq, we achieved better SPECT/CT imaging. CONCLUSION: With the aid of [123I]I-PSMA-7 and via cpm-based biopsy, we can reduce the number of biopsies to a minimum operation. [123I]I-PSMA-7 PSMA SPECT/CT can also provide good imaging results. TRIAL REGISTRATION: Chinese Clinical trial registry ChiCTR2300069745, Registered 24 March 2023.

IRF1 regulation of ZBP1 links mitochondrial DNA and chondrocyte damage in osteoarthritis.

BACKGROUND: Z-DNA binding protein 1 (ZBP1) is a nucleic acid sensor that is involved in multiple inflammatory diseases, but whether and how it contributes to osteoarthritis (OA) are unclear. METHODS: Cartilage tissues were harvested from patients with OA and a murine model of OA to evaluate ZBP1 expression. Subsequently, the functional role and mechanism of ZBP1 were examined in primary chondrocytes, and the role of ZBP1 in OA was explored in mouse models. RESULTS: We showed the upregulation of ZBP1 in articular cartilage originating from OA patients and mice with OA after destabilization of the medial meniscus (DMM) surgery. Specifically, knockdown of ZBP1 alleviated chondrocyte damage and protected mice from DMM-induced OA. Mechanistically, tumor necrosis factor alpha induced ZBP1 overexpression in an interferon regulatory factor 1 (IRF1)-dependent manner and elicited the activation of ZBP1 via mitochondrial DNA (mtDNA) release and ZBP1 binding. The upregulated and activated ZBP1 could interact with receptor-interacting protein kinase 1 and activate the transforming growth factor-beta-activated kinase 1-NF-κB signaling pathway, which led to chondrocyte inflammation and extracellular matrix degradation. Moreover, inhibition of the mtDNA-IRF1-ZBP1 axis with Cyclosporine A, a blocker of mtDNA release, could delay the progression of DMM-induced OA. CONCLUSIONS: Our data revealed the pathological role of the mtDNA-IRF1-ZBP1 axis in OA chondrocytes, suggesting that inhibition of this axis could be a viable therapeutic approach for OA.

Polymer solubility mechanism in ionic liquids: 1H-NMR spectra and two-parameter hydrogen bonding analysis.

Understanding the polymer solubility in ionic liquids (ILs) is important for polymer processing or polymeric material preparation. Previously, two-parameter H-bonding analysis has been proposed to clarify that polymer solubility in ILs is dominated by H-bonding interactions (Y. F. Yuan et al., Phys. Chem. Chem. Phys., 2021, 23, 21893-21900). In the present work, 1H-NMR spectra are adopted to characterize the H-bonding interactions between polymers and ILs, which provide a microscopic relation between polymer solubility and two-parameter H-bonding analysis.

Differentiation of Native Vertebral Osteomyelitis: A Comprehensive Review of Imaging Techniques and Future Applications.

Native vertebral osteomyelitis, also termed spondylodiscitis, is an antibiotic-resistant disease that requires long-term treatment. Without proper treatment, NVO can lead to severe nerve damage or even death. Therefore, it is important to accurately diagnose the cause of NVO, especially in spontaneous cases. Infectious NVO is characterized by the involvement of 2 adjacent vertebrae and intervertebral discs, and common infectious agents include Staphylococcus aureus, Mycobacterium tuberculosis, Brucella abortus, and fungi. Clinical symptoms are generally nonspecific, and early diagnosis and appropriate treatment can prevent irreversible sequelae. Advances in pathologic histologic imaging have led physicians to look more forward to being able to differentiate between tuberculous and septic spinal discitis. Therefore, research in identifying and differentiating the imaging features of these 4 common NVOs is essential. Due to the diagnostic difficulties, clinical and radiologic diagnosis is the mainstay of provisional diagnosis. With the advent of the big data era and the emergence of convolutional neural network algorithms for deep learning, the application of artificial intelligence (AI) technology in orthopedic imaging diagnosis has gradually increased. AI can assist physicians in imaging review, effectively reduce the workload of physicians, and improve diagnostic accuracy. Therefore, it is necessary to present the latest clinical research on NVO and the outlook for future AI applications.

Predictive value of hematologic parameters and clinicopathological features of poorly differentiated thyroid carcinoma and anaplastic thyroid carcinoma.

PURPOSE: Poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) are rare, aggressive thyroid cancers with poor prognosis. At present, there are a limited number of research reports on PDTC and ATC. The study aimed to analysis the predictive value of hematologic parameters and clinicopathological features of PDTC and ATC. METHODS: This study retrospectively analyzed 67 patients at Tianjin Medical University Cancer Hospital from 2007 to 2019. We analyzed the clinicopathological features and survival outcomes of PDTC and ATC. RESULTS: This study showed that positive D-dimer, a high NLR, and a high PLR were more common in death patients. At the end of follow-up, 22 (32.8%) patients were alive at the time of study and 45 (67.2%) patients died from thyroid carcinoma. Disease-related death rates were 93.8% in ATC and 42.9% in the PDTC group. The median overall survival (OS) was 2.5 (0.3-84) months for patients with ATC, and 56 (3-113) months of PDTC patients. Univariate analysis showed that age at diagnosis and surgery were associations with OS in ATC patients, what's more, age at diagnosis, a high NLR, a high PLR, and positive D-dimer were associations with OS in PDTC patients. Multivariate analysis revealed that age at diagnosis was an independent association with OS in ATC patients. CONCLUSIONS: The hematologic parameters and clinicopathological features may provide predictive value of prognosis for patients with PTDC and ATC.

Retrospective analysis of reference intervals for dried blood spot based ms/ms newborn screening programs in Chinese preterm neonates: a nationwide study.

OBJECTIVES: Although recent discoveries regarding the biomarkers of newborn screening (NBS) programs by tandem mass spectrometry (MS/MS) highlight the critical need to establish reference intervals (RIs) specifically for preterm infants, no such RIs has been formally published yet. This study addressed the gap by offering a comprehensive set of reference intervals (RIs) for preterm neonates, and illustrating the dynamic changes of each biomarker with age. DESIGN AND METHODS: The NBS data of 199,693 preterm newborns (< 37 weeks of gestation) who met the inclusion and exclusion criteria from the NNSCP database were included in study analysis. The birth weight stratified dynamic trend of each biomarker were captured by their concentrations over age. Reference partitions were determined by the method of Harris and Boyd. RIs, corresponding to the 2.5th and 97.5th percentiles, as well as the 0.5th, 25th, 50th, 75th and 99.5th percentiles were calculated using a non-parametric rank approach. RESULTS: Increasing birth weight is associated with an elevation in the levels of arginine, citrulline, glycine, leucine and isobarics, methionine, ornithine, phenylalanine, and valine, whereas the levels of alanine, proline and tyrosine decrease. Additionally, two short-chain acylcarnitines (butyrylcarnitine + isobutyrylcarnitine and isovalerylcarnitine + methylbutyrylcarnitine) and a median-chain acylcarnitine (octenoylcarnitine) decrease, while four long-chain acylcarnitines (tetradecanoylcarnitine, palmitoylcarnitine, palmitoleylcarnitine and oleoylcarnitine) increase with increasing birth weight. Age impacts the levels of all MS/MS NBS biomarkers, while sex only affects the level of malonylcarnitine + 3-hydroxybutyrylcarnitine (C3-DC + C4-OH) in very low birth weight preterm neonates. CONCLUSION: The current study developed reference intervals (RIs) specific to birth weight, age, and/or sex for 35 MS/MS biomarkers, which can help in the timely evaluation of the health and disease of preterm neonates.

Up-to-date quality survey and evaluation of neonatal screening programs in China.

AIMS: To thoroughly evaluate the quality of the entire process of neonatal screening (NBS) in China. METHODS: We collected survey questionnaires from 54.4% (135/248) of NBS institutions in China and conducted on-site visits to 20 of these facilities to validate the data. The quality performance of the institutions was evaluated, and differences across various factors were analysed. RESULTS: Merely 62.5% of the provinces had acceptable performance in neonatal screening. Institutions with limited staff were more prone to organizational management shortcomings. Institutions in provinces with a per capita GDP below 10,000 USD exhibited lower quality control levels than those with a per capita GDP between 10,000 and 15,000 USD. Obstetrics departments have a lower awareness of quality control compared to other blood collection facilities. CONCLUSIONS: A nationwide, comprehensive quality control system for continuous enhancements in quality management, screening, diagnosis, and treatment is imperative to ensure prompt diagnosis and intervention.

Polystyrene microplastics induce pulmonary fibrosis by promoting alveolar epithelial cell ferroptosis through cGAS/STING signaling.

Polystyrene microplastics (PS-MPs) are new types of environmental pollutant that have garnered significant attention in recent years since they were found to cause damage to the human respiratory system when they are inhaled. The pulmonary fibrosis is one of the serious consequences of PS-MPs inhalation. However, the impact and underlying mechanisms of PS-MPs on pulmonary fibrosis are not clear. In this study, we studied the potential lung toxicity and PS-MPs-developed pulmonary fibrosis by long-term intranasal inhalation of PS-MPs. The results showed that after exposing to the PS-MPs, the lungs of model mouse had different levels of damage and fibrosis. Meanwhile, exposing to the PS-MPs resulted in a markedly decrease in glutathione (GSH), an increase in malondialdehyde (MDA), and iron overload in the lung tissue of mice and alveolar epithelial cells (AECs). These findings suggested the occurrence of PS-MP-induced ferroptosis. Inhibitor of ferroptosis (Fer-1) had alleviated the PS-MPs-induced ferroptosis. Mechanically, PS-MPs triggered cell ferroptosis and promoted the development of pulmonary fibrosis via activating the cGAS/STING signaling pathway. Inhibition of cGAS/STING with G150/H151 attenuated pulmonary fibrosis after PS-MPs exposure. Together, these data provided novel mechanistic insights of PS-MPs-induced pulmonary fibrosis and a potential therapeutic paradigm.

1G6-D7 Inhibits Homologous Recombination Repair by Targeting Extracellular HSP90α to Promote Apoptosis in Non-Small Cell Lung Cancer.

Despite recent advances in treatment, non-small cell lung cancer (NSCLC) continues to have a high mortality rate. Currently, NSCLC pathogenesis requires further investigation, and therapeutic drugs are still under development. Homologous recombination repair (HRR) repairs severe DNA double-strand breaks. Homologous recombination repair deficiency (HRD) occurs when HRR is impaired and causes irreparable double-strand DNA damage, leading to genomic instability and increasing the risk of cancer development. Poly(ADP-ribose) polymerase (PARP) inhibitors can effectively treat HRD-positive tumors. Extracellular heat shock protein 90α (eHSP90α) is highly expressed in hypoxic environments and inhibits apoptosis, thereby increasing cellular tolerance. Here, we investigated the relationship between eHSP90α and HRR in NSCLC. DNA damage models were established in NSCLC cell lines (A549 and H1299). The activation of DNA damage and HRR markers, apoptosis, proliferation, and migration were investigated. In vivo tumor models were established using BALB/c nude mice and A549 cells. We found that human recombinant HSP90α stimulation further activated HRR and reduced DNA damage extent; however, eHSP90α monoclonal antibody, 1G6-D7, effectively inhibited HRR. HRR inhibition and increased apoptosis were observed after LRP1 knockdown; this effect could not be reversed with hrHSP90α addition. The combined use of 1G6-D7 and olaparib caused significant apoptosis and HRR inhibition in vitro and demonstrated promising anti-tumor effects in vivo. Extracellular HSP90α may be involved in HRR in NSCLC through LRP1. The combined use of 1G6-D7 and PARP inhibitors may exert anti-tumor effects by inhibiting DNA repair and further inducing apoptosis of NSCLC cells.

Being Breastfed in Infancy and Risk of Colorectal Cancer and Precursor Lesions.

BACKGROUND & AIMS: Emerging evidence implicates the importance of perinatal and early-life exposures in colorectal cancer (CRC) development. However, it remains unclear whether being breastfed in infancy is associated with CRC risk in adult life, particularly early adulthood. METHODS: We prospectively investigated the association between history of being breastfed and risk of CRC and its precursor lesions among 66,634 women 46-93 years of age from the Nurses' Health Study and 92,062 women 27-68 years of age from the Nurses' Health Study II. Cox regression and logistic regression for clustered data were used to estimate hazard ratios for CRC and odds ratios for CRC precursors, respectively. RESULTS: During 3.5 million person-years of follow-up, we identified 1490 incident cases of CRC in 2 cohorts. Having been breastfed was associated with a 23% (95% confidence interval [CI], 10% to 38%) increased risk of CRC. The risk of CRC increased with duration of being breastfed (Ptrend < .001). These findings were validated using breastfeeding information from the mothers of a subset of participants. Among younger participants from the Nurses' Health Study II, a significant association was observed between being breastfed and increased risk of high-risk adenomas under 50 years of age (odds ratio, 1.46; 95% CI, 1.16 to 1.83). Consistently, having been breastfed was associated with increased risk of CRC among participants ≤55 years of age (hazard ratio, 1.38; 95% CI, 1.06 to 1.80). CONCLUSIONS: Being breastfed in infancy was associated with increased risk of CRC in adulthood, including among younger adults. However, further research is needed to understand the underlying biological mechanisms, as this association does not establish causation.

"Blue-free" orange ZnO-related light-emitting diode based on a natural interface layer of Ga2O3 and ZnGa2O4.

To fabricate a ZnO-related light-emitting diode (LED) with zero emission at blue wavelengths ("blue-free"), an ingenious strategy is employed. Specifically, for the first time to the best of our knowledge, a natural oxide interface layer, possessing remarkable visible emission potential, is introduced into the Au/i-ZnO/n-GaN metal-insulator-semiconductor (MIS) structure. The unique Au/i-ZnO/interface layer/n-GaN structure successfully eliminated the harmful blue emissions (400-500 nm) from the ZnO film, and the remarkable orange electroluminescence is mainly attributed to the impact ionization process of the natural interface layer at high electric field. It is worth mentioning that the device achieved ultra-low color temperature (2101 K) and excellent color rendering index (92.8) under electrical injection, indicating that the device could fulfill the requirements of electronic display systems and general illumination, and might even play unexpected roles in special lighting domains. The results obtained provide a novel and effective strategy for the design and preparation of ZnO-related LEDs.

TGF-ß1 promotes SCD1 expression via the PI3K-Akt-mTOR-SREBP1 signaling pathway in lung fibroblasts.

BACKGROUND: Lung fibroblast activation is associated with airway remodeling during asthma progression. Stearoyl-CoA desaturase 1 (SCD1) plays an important role in the response of fibroblasts to growth factors. This study aimed to explore the effects of SCD1 on fibroblast activation induced by transforming growth factor-ß1 (TGF-ß1) and the role of the phosphatidylinositol-3-kinase-AKT serine-threonine protein kinase-mechanistic target of rapamycin (PI3K-Akt-mTOR) pathway on the regulation of SCD1 expression in airway remodeling. METHODS: Female C57BL/6 mice were sensitized and challenged with house dust mites to generate a chronic asthma model. The inhibitor of SCD1 was injected i.g. before each challenge. The airway hyper-responsiveness to methacholine was evaluated, and airway remodeling and airway inflammation were assessed by histology. The effects of SCD1 on fibroblast activation were evaluated in vitro using an SCD1 inhibitor and oleic acid and via the knockdown of SCD1. The involvement of the PI3K-Akt-mTOR-sterol regulatory element-binding protein 1 (SREBP1) pathway in lung fibroblasts was investigated using relevant inhibitors. RESULTS: The expression of SCD1 was increased in fibroblasts exposed to TGF-ß1. The inhibition of SCD1 markedly ameliorated airway remodeling and lung fibroblast activation in peripheral airways. The knockdown or inhibition of SCD1 resulted in significantly reduced extracellular matrix production in TGF-ß1-treated fibroblasts, but this effect was reversed by the addition of exogenous oleic acid. The PI3K-Akt-mTOR-SREBP1 pathway was found to be involved in the regulation of SCD1 expression and lung fibroblast activation. CONCLUSIONS: The data obtained in this study indicate that SCD1 expression contributes to fibroblast activation and airway remodeling and that the inhibition of SCD1 may be a therapeutic strategy for airway remodeling in asthma.

Diagnostic efficiency of [68 Ga]Ga-DOTA-FAPI-04 in differentiating periprosthetic hip joint infection and aseptic failure.

PURPOSE: To assess the efficiency of [68 Ga]Ga-DOTA-FAPI-04 in diagnosing periprosthetic hip joint infection and establish a diagnostic standard of clinical significance based on uptake pattern. METHODS: [68 Ga]Ga-DOTA-FAPI-04 PET/CT was performed in patients with symptomatic hip arthroplasty from December 2019 to July 2022. The reference standard was based on the 2018 Evidence-Based and Validation Criteria. Two diagnostic criteria, SUVmax and uptake pattern, were used to diagnose PJI. Meanwhile, original data were imported into IKT-snap to draw the view of interest, A.K. was used to extract features of clinical cases, and unsupervised clustering analysis was applied according to the groups. RESULTS: A total of 103 patients were included, 28 of whom had PJI. The area under the curve of SUVmax was 0.898, which was better than that of all of the serological tests. The cutoff value of SUVmax was 7.53, and the sensitivity and specificity were 100 and 72%, respectively. The sensitivity, specificity and accuracy of the uptake pattern were 100, 93.1 and 95%, respectively. In radiomics analysis, the features of PJI were significantly different from those of aseptic failure. CONCLUSION: The efficiency of [68 Ga]Ga-DOTA-FAPI-04 PET/CT in diagnosing PJI showed promising results, and the diagnostic criteria of the uptake pattern were more clinically instructive. Radiomics also showed certain application prospects in the field of PJI. TRIAL REGISTRATION NUMBER: Trial registration: ChiCTR2000041204. Registered 24 September 2019.

Extracellular HSP90α promotes cellular senescence by modulating TGF-ß signaling in pulmonary fibrosis.

Recent findings suggest that extracellular heat shock protein 90α (eHSP90α) promotes pulmonary fibrosis, but the underlying mechanisms are not well understood. Aging, especially cellular senescence, is a critical risk factor for idiopathic pulmonary fibrosis (IPF). Here, we aim to investigate the role of eHSP90α on cellular senescence in IPF. Our results found that eHSP90α was upregulated in bleomycin (BLM)-induced mice, which correlated with the expression of senescence markers. This increase in eHSP90α mediated fibroblast senescence and facilitated mitochondrial dysfunction. eHSP90α activated TGF-ß signaling through the phosphorylation of the SMAD complex. The SMAD complex binding to p53 and p21 promoters triggered their transcription. In vivo, the blockade of eHSP90α with 1G6-D7, a specific eHSP90α antibody, in old mice attenuated the BLM-induced lung fibrosis. Our findings elucidate a crucial mechanism underlying eHSP90α-induced cellular senescence, providing a framework for aging-related fibrosis interventions.

HDM induce airway epithelial cell ferroptosis and promote inflammation by activating ferritinophagy in asthma.

Asthma is a disease characterized by airway epithelial barrier destruction, chronic airway inflammation, and airway remodeling. Repeated damage to airway epithelial cells by allergens in the environment plays an important role in the pathophysiology of asthma. Ferroptosis is a novel form of regulated cell death mediated by lipid peroxidation in association with free iron-mediated Fenton reactions. In this study, we explored the contribution of ferroptosis to house dust mite (HDM)-induced asthma models. Our in vivo and in vitro models showed labile iron accumulation and enhanced lipid peroxidation with concomitant nonapoptotic cell death upon HDM exposure. Treatment with ferroptosis inhibitors deferoxamine (DFO) and ferrostatin-1 (Fer-1) illuminated the role of ferroptosis and related damage-associated molecular patterns in HDM-treated airway epithelial cells. Furthermore, DFO and Fer-1 reduced HDM-induced airway inflammation in model mice. Mechanistically, NCOA4-mediated ferritin-selective autophagy (ferritinophagy) was initiated during ferritin degradation in response to HDM exposure. Together, these data suggest that ferroptosis plays an important role in HDM-induced asthma and that ferroptosis may be a potential treatment target for HDM-induced asthma.