Corrigendum: Time to clinical improvement: an appropriate surrogate endpoint for pulmonary arterial hypertension medication trials.

[This corrects the article DOI: 10.3389/fcvm.2023.1142721.].

DPP-4 exacerbates LPS-induced endothelial cells inflammation via integrin-α5ß1/FAK/AKT signaling.

Endothelial dysfunction plays a pivotal role in the pathogenesis of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Dipeptidyl peptidase IV (DPP-4), a cell surface glycoprotein, has been implicated in endothelial inflammation and barrier dysfunction. In this study, the role of DPP-4 on lipopolysaccharide (LPS)-induced pulmonary microvascular endothelial cells (HPMECs) dysfunction and the underlying mechanism were investigated by siRNA-mediated knockdown of DPP-4. Our results indicated that LPS (1 µg/ml) challenge resulted in either the production and releasing of DPP-4, as well as the secretion of IL-6 and IL-8 in HPMECs. DPP-4 knockdown inhibited chemokine releasing and monolayer hyper-permeability in LPS challenged HPMECs. When cocultured with human polymorphonuclear neutrophils (PMNs), DPP4 knockdown suppressed LPS-induced neutrophil-endothelial adhesion, PMN chemotaxis and trans-endothelial migration. Western blotting showed that DPP-4 knockdown attenuated LPS-induced activation of TLR4/NF-κB pathway. Immunoprecipitation and liquid chromatography-tandem mass spectrometry revealed that DPP-4 mediated LPS-induced endothelial inflammation by interacting with integrin-α5ß1. Moreover, exogenous soluble DPP-4 treatment sufficiently activated integrin-α5ß1 downstream FAK/AKT/NF-κB signaling, thereafter inducing ICAM-1 upregulation in HPMECs. Collectively, our results suggest that endothelia synthesis and release DPP-4 under the stress of endotoxin, which interact with integrin-α5ß1 complex in an autocrine or paracrine manner to exacerbate endothelial inflammation and enhance endothelial cell permeability. Therefore, blocking DDP-4 could be a potential therapeutic strategy to prevent endothelial dysfunction in ALI/ARDS.

NLRP3 inflammasome mediates abnormal epithelial regeneration and distal lung remodeling in silica­induced lung fibrosis.

NOD-like receptor protein 3 (NLRP3) inflammasome is closely related to silica particle­induced chronic lung inflammation but its role in epithelial remodeling, repair and regeneration in the distal lung during development of silicosis remains to be elucidated. The present study aimed to determine the effects of the NLRP3 inflammasome on epithelial remodeling and cellular regeneration and potential mechanisms in the distal lung of silica­treated mice at three time points. Pulmonary function assessment, inflammatory cell counting, enzyme­linked immunosorbent assay, histological and immunological analyses, hydroxyproline assay and western blotting were used in the study. Single intratracheal instillation of a silica suspension caused sustained NLRP3 inflammasome activation in the distal lung. Moreover, a time­dependent increase in airway resistance and a decrease in lung compliance accompanied progression of pulmonary fibrosis. In the terminal bronchiole, lung remodeling including pyroptosis (membrane­distributed GSDMD+), excessive proliferation (Ki67+), mucus overproduction (mucin 5 subtype AC and B) and epithelial­mesenchymal transition (decreased E­Cadherin+ and increased Vimentin+), was observed by immunofluorescence analysis. Notably, aberrant spatiotemporal expression of the embryonic lung stem/progenitor cell markers SOX2 and SOX9 and ectopic distribution of bronchioalveolar stem cells were observed in the distal lung only on the 7th day after silica instillation (the early inflammatory phase of silicosis). Western blotting revealed that the Sonic hedgehog/Glioma­associated oncogene (Shh/Gli) and Wnt/ß­catenin pathways were involved in NLRP3 inflammasome activation­mediated epithelial remodeling and dysregulated regeneration during the inflammatory and fibrotic phases. Overall, sustained NLRP3 inflammasome activation led to epithelial remodeling in the distal lung of mice. Moreover, understanding the spatiotemporal profile of dysregulated epithelial repair and regeneration may provide a novel therapeutic strategy for inhalable particle­related chronic inflammatory and fibrotic lung disease.

Protein tyrosine phosphatase PTPRO represses lung adenocarcinoma progression by inducing mitochondria-dependent apoptosis and restraining tumor metastasis.

Emerging evidence indicates that protein activities regulated by receptor protein tyrosine phosphatases (RPTPs) are crucial for a variety of cellular processes, such as proliferation, apoptosis, and immunological response. Protein tyrosine phosphatase receptor type O (PTPRO), an RPTP, has been revealed as a putative suppressor in the development of particular tumors. However, the function and the underlying mechanisms of PTPRO in regulating of lung adenocarcinoma (LUAD) are not well understood. In this view, the present work investigated the role of PTPRO in LUAD. Analysis of 90 pairs of clinical LUAD specimens revealed significantly lower PTPRO levels in LUAD compared with adjacent non-tumor tissue, as well as a negative correlation of PTPRO expression with tumor size and TNM stage. Survival analyses demonstrated that PTPRO level can help stratify the prognosis of LUAD patients. Furthermore, PTPRO overexpression was found to suppress the progression of LUAD both in vitro and in vivo by inducing cell death via mitochondria-dependent apoptosis, downregulating protein expression of molecules (Bcl-2, Bax, caspase 3, cleaved-caspase 3/9, cleaved-PARP and Bid) essential in cell survival. Additionally, PTPRO decreased LUAD migration and invasion by regulating proteins involved in the epithelial-to-mesenchymal transition (E-cadherin, N-cadherin, and Snail). Moreover, PTPRO was shown to restrain JAK2/STAT3 signaling pathways. Expression of PTPRO was negatively correlated with p-JAK2, p-STAT3, Bcl-2, and Snail levels in LUAD tumor samples. Furthermore, the anti-tumor effect of PTPRO in LUAD was significant but compromised in STAT3-deficient cells. These data support the remarkable suppressive role of PTPRO in LUAD, which may represent a viable therapeutic target for LUAD patients.

Graphite Equivalent Evaluation of Anthracite-Associated Graphite by Raman Spectroscopy.

Anthracite-associated graphite is an important graphite resource with a wide range of applications besides being used as a fuel. This paper introduces a method for evaluating the graphite equivalent evaluation of anthracite-associated graphite. A series of graphite-anthracite standard samples with known graphite content were prepared, and their Raman spectra were obtained using a Raman spectrometer. By employing peak-fitting analysis to decipher the peak spectrum information of the D peak and G peak, trends in the peak position, peak intensity ratio, half-width, and peak area of the D peak and G peak in standard samples with different graphite contents were obtained. Subsequently, a standard curve and fitting equation were established using the peak area data. The goodness of fit for the equation (R2) was 0.9984. Then the equation was used to evaluate 100 natural anthracite-associated graphite samples with unknown graphite content, obtaining a corresponding graphite equivalent evaluation.

Quantitative analysis of Cd based on the stress effect of minerals in rice by laser-induced breakdown spectroscopy.

Cadmium (Cd) is a highly toxic heavy metal that can accumulate in the food chain, posing a significant threat to human health. One of the key food sources through which Cd is often observed is rice. Therefore, determining heavy metals in rice is essential to assess the risk status of rice. Laser-induced breakdown spectroscopy (LIBS) has the advantages of simple sample preparation and fast analysis, which is expected to achieve real-time and rapid detection of rice. In this work, 40 naturally matured rice samples growing from the area that is possibly contaminated with Cd were collected to determine the Cd reference content in rice by graphite furnace atomic absorption spectroscopy as recommended by the Chinese National Standard. LIBS spectral acquisition and analysis are adopted as well. The Cd characteristic spectral lines were selected to predict the Cd content directly using PCA, PLSR, and ELM models, and the coefficient of determination (R2) of the models' training and prediction sets was 0.9278, 0.8920; 0.9036, 0.9771; 0.7940, and 0.8409, respectively. Further, based on the Cd stress effect in rice, the spectra of elements Mn, Mg, K, and Na with highly significant and significant correlation with Cd were selected and coupled with the Cd characteristic spectra to form a new matrix of the same size for quantitative analysis. Based on the stress effect, R2 of models' training and prediction sets was improved to 0.9786, 0.9753; 0.9395, 0.9900; 0.9798, and 0.9927, respectively. It is demonstrated that combining the stress effect when using LIBS for quantitative analysis of Cd in rice reduces the overfitting and further improves the model's prediction accuracy. This work indicates that using LIBS combined with suitable mathematical models to predict the Cd content of naturally matured rice based on stress effects in rice is feasible. It is promising to evaluate the safety of rice by analyzing LIBS spectra.

Novel insecticidal proteins from ferns resemble insecticidal proteins from Bacillus thuringiensis.

Lepidopterans affect crop production worldwide. The use of transgenes encoding insecticidal proteins from Bacillus thuringiensis (Bt) in crop plants is a well-established technology that enhances protection against lepidopteran larvae. Concern about widespread field-evolved resistance to Bt proteins has highlighted an urgent need for new insecticidal proteins with different modes or sites of action. We discovered a new family of insecticidal proteins from ferns. The prototype protein from Pteris species (Order Polypodiales) and variants from two other orders of ferns, Schizaeales and Ophioglossales, were effective against important lepidopteran pests of maize and soybean in diet-based assays. Transgenic maize and soybean plants producing these proteins were more resistant to insect damage than controls. We report here the crystal structure of a variant of the prototype protein to 1.98 Å resolution. Remarkably, despite being derived from plants, the structure resembles the 3-domain Cry proteins from Bt but has only two out of three of their characteristic domains, lacking the C-terminal domain which is typically required for their activities. Two of the fern proteins were effective against strains of fall armyworm that were resistant to Bt 3-domain Cry proteins Cry1Fa or Cry2A.127. This therefore represents a novel family of insecticidal proteins that have the potential to provide future tools for pest control.

[Incidence and Risk Factors of Venous Thromboembolism in Patients 
with Lung Adenocarcinoma Receiving Anti-tumor Therapy].

BACKGROUND: Venous thromboembolism (VTE) as the most common cancer-associated complication has become the second death-causing reason among cancer patients. The management of VTE in patients with lung adenocarcinoma should focus on early and timely detection of risk factors. The aim of the study is to investigate the current situation of VTE in patients with lung adenocarcinoma treated with anti-tumor therapy and then explore the risk factors associated with the occurrence of VTE during anti-tumor therapy for early detection and screening of VTE. METHODS: The present study included patients diagnosed as lung adenocarcinoma undergoing anti-tumor therapy in First Affiliated Hospital of Nanjing Medical University between December 2019 and May 2021. The risk factors were identified via univariate and multivariate Cox analysis. The incidence of independent risk factors were investigated through Kaplan-Meier curves combined with Log-rank test. RESULTS: The results of univariate and multivariate Cox regression showed that history of VTE, targeted therapy and radiotherapy were risk factors for VTE in patients with lung adenocarcinoma treated with anti-tumor therapy (P<0.05). Furthermore, the results of Kaplan-Meier curves and Log-rank tests indicated the incidences of VTE in patients with history of VTE, targeted therapy and radiotherapy were higher (P<0.05). CONCLUSIONS: History of VTE, radiotherapy and targeted therapy are found as independent risk factors for the occurrence of VTE, which should be identified and monitored for reduction of VTE incidence.
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Inactivation of fungal spores by performic acid in water: Comparisons with peracetic acid.

Performic acid (PFA) has received increasing attention in water disinfection due to its high disinfection efficiency and fewer formation of disinfection by-products. However, the inactivation of fungal spores by PFA has not been investigated. In this study, the results showed that the log-linear regression plus tail model adequately described the inactivation kinetic of fungal spores with PFA. The k values of A. niger and A. flavus with PFA were 0.36 min-1 and 0.07 min-1, respectively. Compared to peracetic acid, PFA was more efficient in inactivating fungal spores and caused more serious damage on cell membrane. Compared to neutral and alkaline conditions, acidic environments demonstrated a greater inactivation efficiency for PFA. The increase of PFA dosage and temperature had a promoting effect on the inactivation efficiency of fungal spores. PFA could kill the fungal spores by damaging cell membrane and penetration of cell membranes. In real water, the inactivation efficiency declined as a result of the existence of background substances such as dissolved organic matter. Moreover, the regrowth potential of fungal spores in R2A medium were severely inhibited after inactivation. This study provides some information for PFA to control fungi pollution and explores the mechanism of PFA inactivation.

Clinicopathological characteristics and cancer-specific prognosis of primary pulmonary lymphoepithelioma-like carcinoma: a population study of the US SEER database and a Chinese hospital.

Introduction: Primary pulmonary lymphoepithelioma-like carcinoma (PPLELC) is a rare histological type of non-small cell lung cancer (NSCLC), which accounts for less than 1% of NSCLC. Currently, there is no well-recognized treatment guideline for PPLELC. Methods: We identified PPLELC patients from the Surveillance, Epidemiology, and End Results (SEER) dataset between 2000 and 2015 (n = 72) as well as from our medical center between 2014 and 2020 (n = 16). All diagnoses were confirmed by pathological testing, and the clinicopathological characteristics of patients were retrieved and summarized. Survival analyses were conducted using the Kaplan-Meier analysis and log-rank tests. Multivariate survival analysis was performed with the Cox regression hazards model. Results: The median age at diagnosis of the PPLELC cohort was 64 years, ranging from 15 to 86 years. The percentages of patients with TNM stages I, II, III, and IV were 52.3%, 10.2%, 20.5%, and 17.0%, respectively. Among the 88 cases, lesion resection was performed in 69 cases (78.4%), 16 cases (18.1%) received beam radiation, and 40 cases (45.5%) underwent chemotherapy. In the SEER dataset of lung cancer, the percentage of PPLELC in the Asian race (0.528‰) was almost 10 times higher than that in the white (0.065‰) and black (0.056‰) races. Patients with TNM stage III-IV exhibited a worse prognosis than those with TNM stage I-II (p = 0.008), with a 5-year cancer-specific survival (CSS) rate of 81.8% for TNM stage I-II and 56.2% for TNM stage III-IV. Specifically, the N stage and M stage were the leading prognostic factors, not the T stage and tumor size. Moreover, patients who underwent surgery had significantly better outcomes than those who did not (p = 0.014). Additional multivariate analysis indicated that the TNM stage was an independent prognosis factor for CSS (HR, 3.31; 95% CI, 1.08-10.14). Conclusion: PPLELC is a rare tumor with Asian susceptibility. Although the prognosis of PPLELC is better than that of other subtypes of NSCLC, it remains unsatisfactory for advanced-stage disease. The current treatment options for PPLELC include surgical resection, chemotherapy, radiotherapy, and immune therapy. Among these options, patients with surgical resection have better survival rates in this study. However, large-scale clinical research trials will be necessary to develop effective treatment guidelines for PPLELC.

Time to clinical improvement: an appropriate surrogate endpoint for pulmonary arterial hypertension medication trials.

Background: Many retrospective studies suggest that risk improvement may be a suitable efficacy surrogate endpoint for pulmonary arterial hypertension (PAH) medication trials. This prospective multicenter study assessed the efficacy of domestic ambrisentan in Chinese PAH patients and observed risk improvement and time to clinical improvement (TTCI) under ambrisentan treatment. Methods: Eligible patients with PAH were enrolled for a 24-week treatment with ambrisentan. The primary efficacy endpoint was 6-min walk distance (Δ6MWD). The exploratory endpoints were risk improvement and TTCI, defined as the time from initiation of treatment to the first occurrence of risk improvement. Results: A total of 83 subjects were enrolled. After ambrisentan treatment, Δ6MWD was significantly increased at week 12 (42.2 m, P < 0.0001) and week 24 (53.4 m, P < 0.0001). Within 24 weeks, risk improvement was observed in 53 (64.6%) subjects (P < 0.0001), which is higher than WHO-FC (30.5%) and TAPSE/PASP (32.9%). Kaplan-Meier analysis of TTCI showed a median improvement time of 131 days and a cumulative improvement rate of 75.1%. Also, TTCI is consistent across different baseline risk status populations (log-rank P = 0.51). The naive group had more risk improvement (P = 0.043) and shorter TTCI (log-rank P = 0.008) than the add-on group, while Δ6MWD did not show significant differences between the two groups. Conclusions: Domestic ambrisentan significantly improved the exercise capacity and risk status of Chinese PAH patients. TTCI has a relatively high positive event rate within 24-week treatment duration. Compared to Δ6MWD, TTCI is not affected by baseline risk status. Additionally, TTCI could identify better improvements in patients, which Δ6MWD does not detect. TTCI is an appropriate composite surrogate endpoint for PAH medication trials. Clinical Trial Registration: NCT No. [ClinicalTrials.gov], identifier [NCT05437224].

NLRP3 Inflammasome Mediates Silica-induced Lung Epithelial Injury and Aberrant Regeneration in Lung Stem/Progenitor Cell-derived Organotypic Models.

Silica-induced lung epithelial injury and fibrosis are vital pathogeneses of silicosis. Although the NOD-like receptor protein 3 (NLRP3) inflammasome contributes to silica-induced chronic lung inflammation, its role in epithelial injury and regeneration remains unclear. Here, using mouse lung stem/progenitor cell-derived organotypic systems, including 2D air-liquid interface and 3D organoid cultures, we investigated the effects of the NLRP3 inflammasome on airway epithelial phenotype and function, cellular injury and regeneration, and the potential mechanisms. Our data showed that silica-induced NLRP3 inflammasome activation disrupted the epithelial architecture, impaired mucociliary clearance, induced cellular hyperplasia and the epithelial-mesenchymal transition in 2D culture, and inhibited organoid development in 3D system. Moreover, abnormal expression of the stem/progenitor cell markers SOX2 and SOX9 was observed in the 2D and 3D organotypic models after sustained silica stimulation. Notably, these silica-induced structural and functional abnormalities were ameliorated by MCC950, a selective NLRP3 inflammasome inhibitor. Further studies indicated that the NF-κB, Shh-Gli and Wnt/ß-catenin pathways were involved in NLRP3 inflammasome-mediated abnormal differentiation and dysfunction of the airway epithelium. Thus, prolonged NLRP3 inflammasome activation caused injury and aberrant lung epithelial regeneration, suggesting that the NLRP3 inflammasome is a pivotal target for regulating tissue repair in chronic inflammatory lung diseases.

Bio-Inspired Electro-Thermal-Hygro Responsive Rewritable Systems with Temporal/Spatial Control for Environment-Interactive Information Display.

Utilization of rewritable luminescent materials for secure information storage and delivery has long been envisaged to reduce the cost and environmental wastes. However, it remains challenging to realize a temporally/spatially controlled display of the written information, which is crucial for secure information encryption. Here, inspired by bioelectricity-triggered skin pattern switching in cephalopods, an ideal rewritable system consisting of conductive graphene film and carbon dots (CDs) gel with blue-to-red fluorescence-color changes via water-triggered CDs aggregation and re-dispersion is presented. Its rewritability is guaranteed by using water ink to write on the CDs-gel and employing Joule heat of graphene film to evaporate water. Due to the highly controlled electrical stimulus, temporally/spatially controlled display is achieved, enabling on-demand delivery and duration time regulation of the written information. Furthermore, new-concept environment-interactive rewritable system is obtained by integrating sensitive acoustic/optical sensors and multichannel electronic time-delay devices. This work opens unprecedented avenues of rewritable systems and expands potential uses for information encryption/delivery.

Eupafolin regulates non-small-cell lung cancer cell proliferation,migration, and invasion by suppressing MMP9 and RhoA via FAK/PI3K/AKT signaling pathway.

Non-small-cell lung cancer (NSCLC) predominates lung cancer with a striking percentage of 85%. Eupafolin is documented to possess anti-tumor efficacy, which prompts efforts to uncover its impacts on the pathology of diseases including cancers. Focal adhesion kinase (FAK)-mediated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) has been found to be associated with several carcinomas. Nevertheless, how eupafolin exerts its effects in NSCLC and whether FAK/PI3K/AKT is related to the corresponding mechanism remain unclear. Thus, the relevant experiments were carried out with NSCLC cells treated with eupafolin and/or LY294002 at first. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, wound healing, and transwell assays were used to assess cell viability, proliferation, migration, and invasion, respectively. Western blot assay was performed to measure the relative protein expressions of phosphorylated (p)-FAK/FAK, p-PI3K/ PI3K, p-AKT/AKT, matrix metalloproteinase 9 (MMP9), and ras homolog gene family member A (RhoA), and to determine transfection efficiency. From experimental results, it was found that eupafolin inhibited the viability, proliferation, migration, and invasion of NSCLC cells, and inactivated the FAK/PI3K/AKT pathway by downregulating the ratios of p-FAK/FAK, p-PI3K/PI3K, and p-AKT/AKTand the expressions of MMP9 and RhoA. On the contrary, overexpressed FAK upregulated the expressions of FAK, MMP9, and RhoA and the ratios of p-PI3K/ PI3K and p-AKT/AKT, and promoted cell proliferation, migration, and invasion. LY294002, conversely, could partly reverse the effects of FAK on the aforementioned aspects of NSCLC cells. Collectively, it was verified in our study that eupafolin regulates the proliferation, migration, and invasion of NSCLC cells by downregulating MMP9 and RhoA expressions via the FAK/PI3K/AKT axis, which may provide a promising avenue for cancer therapy.

Regulating Aggregated Structures in Organohydrogels for On-Demand Information Encryption.

As one of the most promising candidates for dynamic information storage, intelligent gels with tunable optical properties under external stimuli have received great attention. The implementation of transparency variation for information display is a favorable and versatile strategy but still faces the challenge of on-demand encryption-decryption. Herein, an optical tunable organohydrogel is prepared, which has interpenetrating heterogeneous networks consisting of hydrophilic poly(N,N-dimethylacrylamide) (PDMA) and hydrophobic polyoctadecyl methacrylate (PSMA). The long alkane side chains of PSMA endow the organohydrogel with the capacity of crystallization-melting transitions under the stimulus of heat, accompanied by transparent-opaque switching. In addition, the variations of transparency can also be achieved by water-induced hydrophobic association and microphase separation, resulting from the unique heterogeneous networks of the organohydrogel. Based on the abovementioned two aggregated structures, various pieces of information can be loaded on the organohydrogel by light writing or water printing with the assistance of masks. The coded information can be encrypted and decrypted by solvent replacement and temperature switching. This elaborately designed organohydrogel can act as an effective communication platform with an improved security level and ignite the sparks of developing novel information storage materials.

EIF4A3 stabilizes the expression of lncRNA AGAP2-AS1 to activate cancer-associated fibroblasts via MyD88/NF-κb signaling.

BACKGROUND: Lung cancer (LC) is a fatal malignancy and often accompanied with converting normal fibroblasts to cancer-associated fibroblasts (CAFs). Exosomal lncRNA AGAP2-AS1 has been elucidated to be a potent prognostic factor for LC, while its role in activating CAFs is largely unknown. METHODS: We first extracted exosomes from LC patients and co-cultured them with MRC5 cells to observe the state of MRC5 cells, detect AGAP2-AS1 using real-time quantitative polymerase chain reaction, and then analyze the interaction between EIF4A3 and AGAP2-AS1 using RNA pull down experiments. CCK-8 assay was used to detect cell proliferation. Transwell experiments demonstrated the regulation of MRC5 cells and, finally, the role of MyD88/NF-κB in the downstream mechanism of EIF4A3/AGAP2-AS1 was explored by RNA interference technology and pyrrolidinedithiocarbamic acid inhibition. RESULTS: We demonstrated that exosomes from the LC patients (cancer-exo) notably increased the metastatic ability of MRC-5 cells, promoting the expressions of the CAF biomarkers and lncRNA AGAP2-AS1. Overexpression of lncRNA AGAP2-AS1 prominently activated MRC-5 cells. Moreover, EIF4A3 was upregulated in the cancer-exo-treated MRC-5 cells, and EIF4A3 was verified to bind with lncRNA AGAP2-AS1 to improve its stability. The MyD88/NF-κB signaling pathway was subsequently proved to be positively regulated by lncRNA AGAP2-AS1, and the promotive role of lncRNA AGAP2-AS1 in LC and activating CAFs was confirmed in vivo. CONCLUSIONS: The positive feedback of EIF4A3/AGAP2-AS1/MyD88/NF-κB signaling pathway contributed to the activation of CAFs and exacerbated LC in turn, revealing a novel regulatory axis underlying LC.

Causes of death and conditional survival estimates of long-term lung cancer survivors.

Introduction: Lung cancer ranks the leading cause of cancer-related death worldwide. This retrospective cohort study was designed to determine time-dependent death hazards of diverse causes and conditional survival of lung cancer. Methods: We collected 816,436 lung cancer cases during 2000-2015 in the SEER database, after exclusion, 612,100 cases were enrolled for data analyses. Cancer-specific survival, overall survival and dynamic death hazard were assessed in this study. Additionally, based on the FDA approval time of Nivolumab in 2015, we evaluated the effect of immunotherapy on metastatic patients' survival by comparing cases in 2016-2018 (immunotherapy era, n=7135) and those in 2013-2016 (non-immunotherapy era, n=42061). Results: Of the 612,100 patients, 285,705 were women, the mean (SD) age was 68.3 (11.0) years old. 252,558 patients were characterized as lung adenocarcinoma, 133,302 cases were lung squamous cell carcinoma, and only 78,700 cases were small cell lung carcinomas. TNM stage was I in 140,518 cases, II in 38,225 cases, III in 159,095 cases, and IV in 274,262 patients. 164,394 cases underwent surgical intervention. The 5-y overall survival and cancer-specific survival were 54.2% and 73.8%, respectively. The 5-y conditional survival rate of cancer-specific survival is improved in a time-dependent pattern, while conditional overall survival tends to be steady after 5-y follow-up. Except from age, hazard disparities of other risk factors (such as stage and surgery) diminished over time according to the conditional survival curves. After 8 years since diagnosis, mortality hazard from other causes became higher than that from lung cancer. This critical time point was earlier in elder patients while was postponed in patients with advanced stages. Moreover, both cancer-specific survival and overall survival of metastatic patients in immunotherapy era were significantly better than those in non-immunotherapy era (P<0.001), indicating that immunotherapeutic intervention indeed bring remarkable benefits to advanced lung cancer patients. Conclusions: Our findings expand on previous studies by demonstrating that non-lung-cancer related death risk becomes more and more predominant over the course of follow-up, and we establish a personalized web-based calculator to determine this critical time point for long-term survivors. We also confirmed the survival benefit of advanced lung cancer patients in immunotherapy era.

Inhibition of Bruton's Tyrosine Kinase Alleviates Monocrotaline-Induced Pulmonary Arterial Hypertension by Modulating Macrophage Polarization.

Macrophage accumulation and activation contribute to the development of pulmonary arterial hypertension (PAH), while Bruton's tyrosine kinase (BTK) is an important regulator for the activation and polarization of macrophage. However, the role of BTK in PAH remains unknown. In the present study, a selective BTK inhibitor (BTKi) BGB-3111 was applied to investigate the role of BTK in monocrotaline- (MCT-) induced PAH rat and phorbol myristate acetate- (PMA-) differentiated U937 macrophages. Our results showed that BTK was mainly distributed and upregulated in CD68+ macrophages in the lungs of PAH rats. Daily treated with BTKi BGB-3111 alleviated MCT-induced PAH, as indicated by the decrease in right ventricular systolic pressure (RVSP), attenuation in right ventricle hypertrophy and pulmonary vascular remodeling, reduction in perivascular collagen deposition, as well as inhibition of inflammation and endothelial-to-mesenchymal transition (EndMT) in the lung. Moreover, BTK inhibition suppressed MCT-induced recruitment of macrophages, especially the classical activated macrophages (M1) in the lung. In vitro, BGB-3111 significantly suppressed lipopolysaccharide- (LPS-) induced M1 polarization and proinflammatory cytokine production in U937-derived macrophages. The underlying mechanism is associated with the inhibition of NF-κB/MAPK pathways and nucleotide-binding oligomerization domain-like receptor with pyrin domain 3 (NLRP3) inflammasome activation. Furthermore, macrophage conditioned medium (CM) from LPS-induced M1 macrophages promoted migration and EndMT of HPAECs, while CM from BGB-3111-pretreated LPS-induced M1 macrophages failed to induce this response. These findings suggest that BTK inhibition alleviates PAH by regulating macrophage recruitment and polarization and may be a potential therapeutic strategy for the treatment of PAH.

Rhodotron and rotating target: A solution towards micro-spot for high energy and high dose rate bremsstrahlung sources.

High energy over MeV bremsstrahlung sources that employ normal conducting radio frequency linear accelerators have expanding applications in industrial computerized tomography (CT) for non-destructive inspection and evaluation. The X-ray spot size that mainly affects the imaging quality is yet limited by the electron beam width in the high resolution CT systems. In a short exposure time, high beam power is required to generate sufficient photons to improve the signal to noise ratio of imaging. However, with ∼kW level of average beam power these linear accelerators usually have a beam spot size over 1 mm since the temperature rising due to the beam energy deposition in the target should be far below its melting point. We propose a concept of using a Rhodotron-based accelerator to provide high power electron beams in a long duration pulse and a rotating target to mitigate the overheating issue, such that the gap between micro-spot and high dose rate can be bridged in the high energy bremsstrahlung sources. This article presents an in-depth simulation work to discuss and evaluate this scheme of X-ray source. The simulations of beam dynamics in the accelerator and bremsstrahlung process in the target predict the generated X-rays with a spot size as small as 68 µm at full-width half-maximum and a dose rate as high as 4700 cGy/min from a 9 MeV electron beam interacting with a 1 mm thickness tantalum target. Further thermal analysis in the rotating target indicates a significant improvement of beam power handling in comparison with the conventional stationary one.