Deciphering the Dynamics of EGFR-TKI Resistance in Lung Cancer: Insights from Bibliometric Analysis.

Background: EGFR-TKI resistance poses a significant challenge in the treatment landscape of non-small cell lung cancer (NSCLC), prompting extensive research into mechanisms and therapeutic strategies. In this study, we conduct a bibliometric analysis to elucidate evolving research hotspots and trends in EGFR-TKI resistance, offering insights for clinical interventions and scientific inquiries. Methods: Publications spanning from 1996 to 2024, focusing on EGFR-TKI resistance in NSCLC, were sourced from the Web of Science Core Collection. Utilizing VOSviewer 1.6.19, CiteSpace 6.2. R2, and Scimago Graphica 1.0.35, we analyzed these articles to identify countries/regions and institutions, Journals, publications, key contributors, collaborations, and emerging topics. Results: An analysis of 8051 articles by 38,215 researchers from 86 countries shows growing interest in EGFR-TKI resistance mechanisms. Since 1996, publications have steadily increased, surpassing 500 per year after 2016, with a sharp rise in citations. Research articles make up 84% of publications, emphasizing scholarly focus. Global collaboration, especially among researchers in China, the US, and Japan, is strong. Leading institutions like Dana-Farber and Harvard, along with journals such as "Lung Cancer", are key in sharing findings. Professors Yi-Long Wu and William Pao are prominent contributors. Keyword analysis reveals core themes, including first-generation EGFR-TKIs, emerging agents like osimertinib, and research on the T790M mutation. Conclusion: EGFR-TKI resistance remains a critical issue in NSCLC treatment, driving ongoing research efforts worldwide. Focusing future research on clear identification of resistance mechanisms will guide post-resistance treatment strategies, necessitating further exploration, alongside the validation of emerging drugs through clinical trials. Moreover, "chemo+" treatments following EGFR-TKI resistance require more clinical data and real-world evidence for assessing safety and patient outcomes. As research advances, a multidisciplinary approach will be key to overcoming these challenges. Continued innovation in treatment could greatly enhance patient survival and quality of life.

The transcription factor MYC2 positively regulates terpene trilactone biosynthesis through activating GbGGPPS expression in Ginkgo biloba.

Terpene trilactones (TTLs) have important medicinal value, but their low content in Ginkgo biloba leaves makes their exploitation extremely costly, thereby limiting the development of TTL-related industries. It was found that exogenous methyl jasmonate (MeJA) treatment increased the accumulation of TTLs, but the molecular mechanism is still unclear. Here, we identified two bHLH transcription factors in G. biloba, with the protein subcellular localizations in the nucleus. Expression of GbMYC2s was strongly induced by MeJA treatment, and the interactions between GbJAZs and GbMYC2s were demonstrated by yeast two-hybrid and bimolecular fluorescence complementation experiments. Overexpression of GbMYC2_4 and GbMYC2_5 enhanced Arabidopsis root sensitivity and significantly increased TTL content. In addition, GbGGPPS was found to be a common target of GbMYC2_4 and GbMYC2_5 by yeast one-hybrid, electrophoretic mobility shift, and dual-luciferase reporter assays and DAP-seq, and they achieved regulation of GbGGPPS by binding to the G-box. Further findings revealed that GbMYC2_4 and GbMYC2_5 bind the G-box not universally but selectively. Our study revealed that jasmonic acid signaling mediates TTL biosynthesis through the GbJAZ-GbMYC2-GbGGPPS module, which enriches the terpenoid biosynthesis regulatory networks and provides a research basis and target genes for enhancing TTL content through genetic engineering.

Senescent endothelial cells: a potential target for diabetic retinopathy.

Diabetic retinopathy (DR) is a diabetic complication that results in visual impairment and relevant retinal diseases. Current therapeutic strategies on DR primarily focus on antiangiogenic therapies, which particularly target vascular endothelial growth factor and its related signaling transduction. However, these therapies still have limitations due to the intricate pathogenesis of DR. Emerging studies have shown that premature senescence of endothelial cells (ECs) in a hyperglycemic environment is involved in the disease process of DR and plays multiple roles at different stages. Moreover, these surprising discoveries have driven the development of senotherapeutics and strategies targeting senescent endothelial cells (SECs), which present challenging but promising prospects in DR treatment. In this review, we focus on the inducers and mechanisms of EC senescence in the pathogenesis of DR and summarize the current research advances in the development of senotherapeutics and strategies that target SECs for DR treatment. Herein, we highlight the role played by key factors at different stages of EC senescence, which will be critical for facilitating the development of future innovative treatment strategies that target the different stages of senescence in DR.

SO3 removal by submicron absorbents synthesized via inhibition method: The product layer grows like parallel peaks.

Injecting calcium hydroxide powder into the flue gas is an effective strategy for SO3 removal. However, commercial calcium hydroxide has several disadvantages, including large particle size, low efficiency, and unsuitability for excessive grinding. In this work, sub-micron calcium hydroxide was synthesized by an inhibition method and its performance for SO3 removal from flue gas was investigated on a pilot-scale platform (120 Nm3/h). When the concentration of sodium alginate solution was 100 mg/L, the average particle size of calcium hydroxide decreased from 13.66 µm to 0.84 µm, which improved the SO3 removal (92.1 %) and conversion of the absorbent. The results of the fixed-bed experiments indicate that the absorption kinetics of the reaction is consistent with the Bangham model. In addition, density functional theory verifies that calcium hydroxide captures SO3 by chemisorption. The AFM image shows that the calcium sulfate whiskers produced during the reaction grow like parallel peaks on the adsorbent surface. The calculations suggest that the driving force for SO3 adsorption originates from Ca-p orbital (Ca(OH)2) and O-s orbital (SO3) hybridization. This study complements the island growth mechanism for gas-solid two-phase reactions and provides an effective method for removing SO3 from flue gas in coal-fired power plants. In addition, it will provide an important reference for the development of submicron adsorbents.

Exploring the mechanism of enterotoxicity mediated by the microbiome-butyrate-PPAR axis in podophyllotoxin through the toxicological evidence chain (TEC) concept.

Podophyllotoxin (PPT) is a lignan derived from the roots and stems of the Podophyllum plant. However, its enterotoxicity restricts its clinical application. The underlying mechanisms by which PPT exerts its action remain largely elusive. This study aimed to evaluate the molecular mechanisms underlying PPT-induced enterotoxicity utilizing the concept of toxicological evidence chain. Changes in body weight, behavior, and histopathological and biochemical markers in rats were observed. Additionally, microbiome, metabolome, and transcriptome analyses were integrated to identify potential microorganisms, metabolic markers, and major pathways using a co-occurrence network. Our findings suggested that PPT induced pathological changes in rats, including weight loss, diarrhea, and inflammation accompanied by increased levels of IFN-γ, IL-5, IL-6, GRO/KC, and IL-12p70. The decrease in butyrate levels in the PPT group may be related to the enrichment of Firmicutes. The reduction of butyrate levels may impair the expression of PPARγ, subsequently promoting Escherichia-Shigella proliferation. Additionally, the suppression of PPARs pathway may result in the increased production of inflammatory factors, contributing to enterotoxicity. This study offers a novel understanding of the molecular mechanisms underlying PPT-induced enterotoxicity, making a significant contribution to developing strategies to mitigate PPT toxicity and prevent associated diseases.

Plasma proteome mediate the impact of PM2.5 on stroke: A 2-step Mendelian randomization study.

The objectives of this study were to measure the mediation effect of plasma proteins and to clarify their mediating role in the relationship between stroke risk and particulate matter 2.5 (PM2.5) exposure. The possible mediating role of plasma proteins on the causative link between PM2.5 exposure and stroke incidence were examined using a two-step Mendelian randomization (MR) approach based on two-sample Mendelian randomization (TSMR). The findings revealed a significant positive causal relationship between PM2.5 exposure and stroke, with an inverse variance weighted odds ratio of 1.219 (95 % CI: 1.002 - 1.482, P < 0.05). Additionally, a positive causal association was identified between PM2.5 exposure and several plasma proteins, including FAM134B, SAP, ITGB7, Elafin, and DCLK3. Among these, FAM134B, ITGB7, Elafin, and DCLK3 also demonstrated a positive causal association with stroke, whereas only SAP was found to be negatively causally associated with stroke. Remarkably, four plasma proteins, namely DCLK3, FAM134B, Elafin, and ITGB7, were identified as mediators, accounting for substantial proportions (14.5 %, 13.6 %, 11.1 %, and 9.9 %) of the causal association between PM2.5 and stroke. These results remained robust across various sensitivity analyses. Consequently, the study highlights the significant and independent impact of PM2.5 on stroke risk and identifies specific plasma proteins as potential targets for preventive interventions against PM2.5-induced stroke.

Pericyte in retinal vascular diseases: A multifunctional regulator and potential therapeutic target.

Retinal vascular diseases (RVDs), in particular diabetic retinopathy, retinal vein occlusion, and retinopathy of prematurity, are leading contributors to blindness. The pathogenesis of RVD involves vessel dilatation, leakage, and occlusion; however, the specific underlying mechanisms remain unclear. Recent findings have indicated that pericytes (PCs), as critical members of the vascular mural cells, significantly contribute to the progression of RVDs, including detachment from microvessels, alteration of contractile and secretory properties, and excessive production of the extracellular matrix. Moreover, PCs are believed to have mesenchymal stem properties and, therefore, might contribute to regenerative therapy. Here, we review novel ideas concerning PC characteristics and functions in RVDs and discuss potential therapeutic strategies based on PCs, including the targeting of pathological signals and cell-based regenerative treatments.

The immune cells have complex causal regulation effects on cancers.

BACKGROUND: There was a large body of evidence linking immune cells to cancer risk. However, the causal relationship between immune cells, cancer, and what genes play an important role is unclear. METHODS: In this study, we performed comprehensive two-sample Mendelian randomization analysis (TSMR) to determine the causal relationship between immune cells and common cancers. We also performed Multimarker Analysis of Genomic Annotation (MAGMA) on immune cells causally associated with cancer to identify their relevant genes and used data summary-based MR (SMR) analysis to investigate the causal relationship between their gene expression, methylation, and cancer, and further used drug prediction and molecular docking to validate the medicinal value of the targets. Finally, reverse TSMR analysis was performed on cancer and immune cells to rule out reverse causality. RESULTS: After FDR correction (PFDR < 0.05), the results showed that 2 immune cells were associated with lung cancer risk, and 1 immune cell was significantly associated with pancreatic cancer risk. The expression of OSBPL10, CHD4, SMDT1, PHETA2, and NAGA was positively and causally related to the risk of lung cancer by SMR analysis and HEIDI test. We also found that increased expression of ANP32E decreased the risk of pancreatic cancer and that the methylation level of OSBPL10, CHD4, SULF2, CENPM, and CYP2D6 had a causal association with lung cancer. The methylation level of FCGR3A was causally associated with pancreatic cancer. The results of molecular docking indicated a strong affinity between the drugs and proteins that possessed existing structural information. CONCLUSION: This data-driven Mendelian randomization (MR) study demonstrates the causal role of immune cells in cancers. In addition, this study identifies candidate genes that may be potential anti-cancer drug targets.

Synthesis and characterization of TiO2/hydrochar matrix composites for enhanced ammonia degradation.

This study explores the limitations of TiO2 as a photocatalyst, focusing on its narrow bandwidth and high electron-hole complexation probabilities that restrict its applications. A novel one-pot synthesis method for TiO2/hydrochar matrix composites is presented, with variations achieved through control of hydrothermal temperature, time, and loading concentration. The efficacy of these composites in ammonia removal is investigated, revealing optimal performance for the composite denoted as 3Ti-160-7, synthesized with a titanium salt concentration of 0.3 mol L-1, a hydrothermal temperature of 160 °C, and a hydrothermal time of 7 hours. Comparative analyses with commercial TiO2 (P25) and hydrochar demonstrate superior performance of 3Ti-160-7, exhibiting significantly lower ammonia concentration and reduced NO and NO2 concentrations. This research underscores the cost-effectiveness and application potential of TiO2/hydrochar matrix composites, offering valuable insights for the enhancement of photocatalytic activity and broader applicability in addressing TiO2-related challenges.

[Tumor-associated Macrophage: 
Emerging Targets for Modulating the Tumor Microenvironment].

Tumor-associated macrophage (TAM) play a crucial role in the immune microenvironment of lung cancer. Through changes in their phenotype and phagocytic functions, TAM contribute to the initiation and progression of lung cancer. By promoting the formation of an immune-suppressive microenvironment and accelerating the growth of abnormal tumor vasculature, TAM facilitate the invasion and metastasis of lung cancer. Macrophages can polarize into different subtypes with distinct functions and characteristics in response to various stimuli, categorized as anti-tumor M1 and pro-tumor M2 types. In tumor tissues, TAM typically polarize into the alternatively activated M2 phenotype, exhibiting inhibitory effects on tumor immunity. This article reviews the role of anti-angiogenic drugs in modulating TAM phenotypes, highlighting their potential to reprogram M2-type TAM into an anti-tumor M1 phenotype. Additionally, the functional alterations of TAM play a significant role in anti-angiogenic therapy and immunotherapy strategies. In summary, the regulation of TAM polarization and function opens up new avenues for lung cancer treatment and may serve as a novel target for modulating the immune microenvironment of tumors.
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Seasonal characterization of chemical and optical properties of water-soluble organic aerosol in Beijing.

Water-soluble organic aerosol (WSOA) plays a crucial role in altering radiative forcing and impacting human health. However, our understanding of the seasonal variations of WSOA in Chinese megacities after the three-year clean air action plan is limited. In this study, we analyzed PM2.5 filter samples collected over one year (2020-2021) in Beijing to characterize the seasonal changes in the chemical and optical properties of WSOA using an offline aerosol mass spectrometer along with spectroscopy techniques. The mean mass concentration of WSOA during the observation period was 8.84 ± 7.12 µg m-3, constituting approximately 64-67 % of OA. Our results indicate the contribution of secondary OA (SOA) increased by 13-28 % due to a substantial reduction in primary emissions after the clean air action plan. The composition of WSOA exhibited pronounced seasonal variations, with a predominant contribution from less oxidized SOA in summer (61 %) and primary OA originating from coal combustion and biomass burning during the heating season (34 %). The mass absorption efficiency of WSOA at 365 nm in winter was nearly twice that in summer, suggesting that WSOA from primary emissions possesses a stronger light-absorbing capability than SOA. On average, water-soluble brown carbon accounted for 33-48 % of total brown carbon absorption. Fluorescence analysis revealed humic-like substances as the most significant fluorescence component of WSOA, constituting 82 %. Furthermore, both absorption and fluorescence chromophores were associated with nitrogen-containing compounds, highlighting the role of nitrogen-containing species in influencing the optical properties of WSOA. The results are important for chemical transport models to accurately simulate the WSOA and its climate effects.

A rare huge bladder inflammatory myofibroblastic tumor treated by en bloc resection with diode laser: a case report and literature review.

Background: Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm with malignant potential. Bladder IMT is even rarer and mainly treated by surgical resection However, partial or radical cystectomy would affect the quality of life of patients due to major surgical trauma, and classical TURBT is hard to avoid intraoperative complications including obturator nerve reflex and bleeding etc. Therefore, the safe and effective better choice of surgical approaches become critical to bladder IMT. Case presentation: A 42-year-old male patient was admitted to the department of urology with persistent painless gross hematuria for more than 10 days without the presentation of hypertension. Preoperative routine urine examination of red blood cells was 7738.9/HPF (normal range ≤ 3/HPF). CTU indicated a space occupying lesion (6.0 cm×5.0 cm) in the left posterior wall of the bladder with heterogeneous enhancement in the excretory phase. MRI also indicated bladder tumor with slightly equal SI on T1WI and mixed high SI on T2WI (6.0 cm×5.1cm×3.5cm) in the left posterior wall of the bladder. En bloc resection of bladder IMT with 1470 nm diode laser in combination of removing the enucleated tumor by the morcellator system was performed. Postoperative pathological examination revealed bladder IMT, with IHC positive for Ki-67 (15-20%), CK AE1/AE3, SMA, and Desmin of bladder IMT and negative for ALK of bladder IMT as well as FISH negative for ALK gene rearrangement. Second TUR with 1470 nm diode laser was performed within 6 weeks to reduce postoperative risk of recurrence due to highly malignant potential for the high expression of Ki-67 (15-20%) and negative ALK in IHC staining. The second postoperative pathology report showed chronic inflammation concomitant with edema of the bladder mucosa without bladder IMT, furthermore no tumor was observed in muscularis propria layer of bladder. No recurrence occurred during the period of 24-month follow-up. Conclusion: En bloc resection of bladder IMT in combination of the following second transurethral resection with 1470 nm diode laser is a safe and effective surgical approach for the huge bladder IMT with highly malignant potential.

Bronchial Cryo-Denervation for Severe Asthma: A Pilot Study.

INTRODUCTION: Targeting the parasympathetic nervous system innervating the airway with pharmacologic products has been proved to improve the clinical outcomes of severe asthma. Bronchial cryo-denervation (BCD) is a novel non-pharmacologic treatment for severe asthma using an endobronchial cryo-balloon administered via bronchoscopy to denervate parasympathetic pulmonary nerves. Preclinical studies have demonstrated that BCD significantly disrupted vagal innervation in the lung. METHODS: A total of 15 patients with severe asthma were enrolled in this prospective, single-center pilot study. Patients underwent bifurcated BCD treatment at a 30-day interval after baseline assessment. Follow-up through 12 months included assessment of adverse events, technical feasibility, and changes in pulmonary function; asthma control questionnaire-7 (ACQ-7); and asthma control test (ACT). RESULTS: BCD was performed on all 15 severe asthma patients, with technical feasibility of 96.7%. There were no device-related and 2 procedure-related serious adverse events through 12 months, which resolved without sequelae. The most frequent nonserious procedure-related adverse event was increased cough in 60% (9 of 15) patients. Pulmonary function remained unchanged, and significant improvements from baseline ACQ-7 (mean, -1.19, p = 0.0032) and ACT (mean, 3.18, p = 0.0011) scores were observed since the first month's follow-up after a single lung airway treatment, with similar trends till the end of the 12-month follow-up. CONCLUSION: This study provides the first clinical evidence of the safety, feasibility, and initial efficacy of BCD in patients with severe asthma.

Ripks and Neuroinflammation.

Neuroinflammation is an immune response in the central nervous system and poses a significant threat to human health. Studies have shown that the receptor serine/threonine protein kinase family (RIPK) family, a popular research target in inflammation, has been shown to play an essential role in neuroinflammation. It is significant to note that the previous reviews have only examined the link between RIPK1 and neuroinflammation. However, it has yet to systematically analyze the relationship between the RIPK family and neuroinflammation. Activation of RIPK1 promotes neuroinflammation. RIPK1 and RIPK3 are responsible for the control of cell death, including apoptosis, necrosis, and inflammation. RIPK1 and RIPK3 regulate inflammatory responses through the release of damage in necroptosis. RIPK1 and RIPK3 regulate inflammatory responses by releasing damage-associated molecular patterns (DAMPs) during necrosis. In addition, activated RIPK1 nuclear translocation and its interaction with the BAF complex leads to upregulation of chromatin modification and inflammatory gene expression, thereby triggering inflammation. Although RIPK2 is not directly involved in regulating cell death, it is considered an essential target for treating neurological inflammation. When the peptidoglycan receptor detects peptidoglycan IE-DAP or MDP in bacteria, it prompts NOD1 and NOD2 to recruit RIPK2 and activate the XIAP E3 ligase. This leads to the K63 ubiquitination of RIPK2. This is followed by LUBAC-mediated linear ubiquitination, which activates NF-KB and MAPK pathways to produce cytokines and chemokines. In conclusion, there are seven known members of the RIPK family, but RIPK4, RIPK5, RIPK6, and RIPK7 have not been linked to neuroinflammation. This article seeks to explore the potential of RIPK1, RIPK2, and RIPK3 kinases as therapeutic interventions for neuroinflammation, which is associated with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), ischemic stroke, Parkinson's disease (PD), multiple sclerosis (MS), and traumatic brain injury (TBI).

Polyhexamethylene guanidine accelerates the macrophage foamy formation mediated pulmonary fibrosis.

Polyhexamethylene guanidine (PHMG) is manufactured and applied extensively due to its superior disinfectant capabilities. However, the inhalatory exposure to PHMG aerosols is increasingly recognized as a potential instigator of pulmonary fibrosis, prompting an urgent call for elucidation of the underlying pathophysiological mechanisms. Within this context, alveolar macrophages play a pivotal role in the primary immune defense in the respiratory tract. Dysregulated lipid metabolism within alveolar macrophages leads to the accumulation of foam cells, a process that is intimately linked with the pathogenesis of pulmonary fibrosis. Therefore, this study examines PHMG's effects on alveolar macrophage foaminess and its underlying mechanisms. We conducted a 3-week inhalation exposure followed by a 3-week recovery period in C57BL/6 J mice using a whole-body exposure system equipped with a disinfection aerosol generator (WESDAG). The presence of lipid-laden alveolar macrophages and downregulation of pulmonary tissue lipid transport proteins ABCA1 and ABCG1 were observed in mice. In cell culture models involving lipid-loaded macrophages, we demonstrated that PHMG promotes foam cell formation by inhibiting lipid efflux in mouse alveolar macrophages. Furthermore, PHMG-induced foam cells were found to promote an increase in the release of TGF-ß1, fibronectin deposition, and collagen remodeling. In vivo interventions were subsequently implemented on mice exposed to PHMG aerosols, aiming to restore macrophage lipid efflux function. Remarkably, this intervention demonstrated the potential to retard the progression of pulmonary fibrosis. In conclusion, this study underscores the pivotal role of macrophage foaming in the pathogenesis of PHMG disinfectants-induced pulmonary fibrosis. Moreover, it provides compelling evidence to suggest that the regulation of macrophage efflux function holds promise for mitigating the progression of pulmonary fibrosis, thereby offering novel insights into the mechanisms underlying inhaled PHMG disinfectants-induced pulmonary fibrosis.

The improvement of postoperative blood pressure and associated factors in patients with hormone-negative adrenal adenoma and hypertension.

OBJECTIVE: To investigate the effect of adrenal surgery on blood pressure (BP) improvements in patients with hormone-negative adrenal adenoma (HNA) concomitant with hypertension and analyze associated prognostic factors. METHODS: We retrospectively reviewed the clinical data of patients with HNA and hypertension and patients with aldosterone-producing adenoma (APA) and hypertension who underwent adrenal surgery at our center between 2019 and 2022. Hypertension outcomes were evaluated in all patients and subjects were divided into three groups according to follow-up BP and the administration of anti-hypertensive agents: a clinical curation group, an improvement group, and a no-improvement group. Logistic regression analysis was performed to predict factors associated with clinical curation in patients with HNA post-surgery. RESULTS: Of the 182 patients with HNA, clinical curation was achieved in 58 patients (31.9%), improvement in 72 (39.5%), and no improvement in 52 (28.6%). The clinical curation, improvement and no improvement rates in patients with APA were 64.8% (n = 118), 15.9% (n = 29), and 19.2% (n = 35). Multivariate logistic regression analysis indicated that a duration of hypertension ≤6 years and a plasma aldosterone level >160 pg/ml were both independent factors for the clinical curation of hypertension in patients with HNA after adrenal surgery. CONCLUSION: Adrenal surgery can cure or improve hypertension in most patients with HNA, especially in a short duration of hypertension and high plasma levels of aldosterone.

The Resistance of Soybean Variety Heinong 84 to Apple Latent Spherical Virus Is Controlled by Two Genetic Loci.

Apple latent spherical virus (ALSV) is widely used as a virus-induced gene silencing (VIGS) vector for function genome study. However, the application of ALSV to soybeans is limited by the resistance of many varieties. In this study, the genetic locus linked to the resistance of a resistant soybean variety Heinong 84 was mapped by high-throughput sequencing-based bulk segregation analysis (HTS-BSA) using a hybrid population crossed from Heinong 84 and a susceptible variety, Zhonghuang 13. The results showed that the resistance of Heinong 84 to ALSV is controlled by two genetic loci located on chromosomes 2 and 11, respectively. Cleaved amplified polymorphic sequence (CAPS) markers were developed for identification and genotyping. Inheritance and biochemical analyses suggest that the resistance locus on chromosome 2 plays a dominant dose-dependent role, while the other locus contributes a secondary role in resisting ALSV. The resistance locus on chromosome 2 might encode a protein that can directly inhibit viral proliferation, while the secondary resistance locus on chromosome 11 may encode a host factor required for viral proliferation. Together, these data reveal novel insights on the resistance mechanism of Heinong 84 to ALSV, which will benefit the application of ALSV as a VIGS vector.

Immunogenic profiling of metastatic uveal melanoma discerns a potential signature related to prognosis.

BACKGROUND: Uveal melanoma (UM) is an aggressive intraocular malignant tumor. The present study aimed to identify the key genes associated with UM metastasis and established a gene signature to analyze the relationship between the signature and prognosis and immune cell infiltration. Later, a predictive model combined with clinical variables was developed and validated. METHODS: Two UM gene expression profile chip datasets were downloaded from TCGA and GEO databases. Immune-related genes (IRGs) were obtained from IMPORT database. First, these mRNAs were intersected with IRGs, and weighted gene co-expression network analysis (WGCNA) was used to identify the co-expression of genes primarily associated with metastasis of UM. Univariate Cox regression analysis screened the genes related to prognosis. LASSO-Cox established a risk score to distinguish high-risk group and low-risk group. Then the GSEA enrichment pathway and immune cell infiltration of the two groups were compared. And combined with clinical variables, a predictive model was constructed. The time-dependent receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) curve were used to verify the stability and accuracy of the final predictive model, and a nomogram was then drawn. RESULTS: The MEblack, MEpurple, and MEblue modules were significantly associated with the metastasis of UM patients (P value < 0.001, = 0.001, = 0.022, respectively). Four genes (UBXN2B, OTUD3, KAT8, LAMTOR2) were obtained by Pearson correlation analysis, weighted gene correlation network analysis (WGCNA), univariate Cox, and LASSO-Cox. And a novel prognostic risk score was established. Immune-related prognostic signature can well classify UM patients into high-risk and low-risk groups. Kaplan-Meier curve showed that the OS of high-risk patients was worse than that of low-risk patients. In addition, the risk score played an important role in evaluating the signaling pathway and immune cell infiltration of UM patients in high-risk and low-risk groups. Both the training set and validation set of the model showed good predictive accuracy in the degree of differentiation and calibration (e.g., 1-year overall survival: AUC = 0.930 (0.857-1.003)). Finally, a nomogram was established to serve in clinical practice. SIGNIFICANCE: UM key gene signature and prognosis predictive model might provide insights for further investigation of the pathogenesis and development of UM at the molecular level, and provide theoretical basis for determining new prognostic markers of UM and immunotherapy.

Regenerative braking system effectively reduces the formation of brake wear particles.

Brake wear particles (BWPs) are considered one of the most significant non-exhaust particle emission sources from motor vehicles. Previous studies have primarily focused on BWPs from conventional fuel vehicles (CFVs), with limited research available on BWPs from new energy vehicles (NEVs). We developed an independent BWP emission testing system applicable to NEVs and conducted BWP emission tests on representative NEVs and CFVs under various testing cycles via a chassis dynamometer. The BWP emission characteristics of the NEVs equipped with regenerative braking system significantly differed from those of gasoline vehicles. For transient emission characteristics, gasoline vehicles exhibited higher peak concentrations during brake events than brake drag events, while those with regenerative braking exhibited the opposite feature. Under continuous braking, the concentration of ultrafine particles emitted by NEVs was reduced by more than 3 orders of magnitude compared to gasoline vehicles. In terms of single-particle morphology, BWPs could be mainly divided into three categories: carbonaceous particles, iron-rich particles, and mixed metal particles. We obtained realistic emission characteristics of BWPs from NEVs, which could provide data support and a scientific basis for the formulation of relevant emission standards and control measures in the future.

Unlocking the secrets of aging: Epigenetic reader BRD4 as the target to combatting aging-related diseases.

BACKGROUND: Aging, a complex and profound journey, leads us through a labyrinth of physiological and pathological transformations, rendering us increasingly susceptible to aging-related diseases. Emerging investigations have unveiled the function of bromodomain containing protein 4 (BRD4) in manipulating the aging process and driving the emergence and progression of aging-related diseases. AIM OF REVIEW: This review aims to offer a comprehensive outline of BRD4's functions involved in the aging process, and potential mechanisms through which BRD4 governs the initiation and progression of various aging-related diseases. KEY SCIENTIFIC CONCEPTS OF REVIEW: BRD4 has a fundamental role in regulating the cell cycle, apoptosis, cellular senescence, the senescence-associated secretory phenotype (SASP), senolysis, autophagy, and mitochondrial function, which are involved in the aging process. Several studies have indicated that BRD4 governs the initiation and progression of various aging-related diseases, including Alzheimer's disease, ischemic cerebrovascular diseases, hypertension, atherosclerosis, heart failure, aging-related pulmonary fibrosis, and intervertebral disc degeneration (IVDD). Thus, the evidence from this review supports that BRD4 could be a promising target for managing various aging-related diseases, while further investigation is warranted to gain a thorough understanding of BRD4's role in these diseases.