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OBJECTIVE: Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), mostly characterised by HBV integrations, is prevalent worldwide. Previous HBV studies mainly focused on a few hotspot integrations. However, the oncogenic role of the other HBV integrations remains unclear. This study aimed to elucidate HBV integration-induced tumourigenesis further. DESIGN: Here, we illuminated the genomic structures encompassing HBV integrations in 124 HCCs across ages using whole genome sequencing and Nanopore long reads. We classified a repertoire of integration patterns featured by complex genomic rearrangement. We also conducted a clustered regularly interspaced short palindromic repeat (CRISPR)-based gain-of-function genetic screen in mouse hepatocytes. We individually activated each candidate gene in the mouse model to uncover HBV integration-mediated oncogenic aberration that elicits tumourigenesis in mice. RESULTS: These HBV-mediated rearrangements are significantly enriched in a bridge-fusion-bridge pattern and interchromosomal translocations, and frequently led to a wide range of aberrations including driver copy number variations in chr 4q, 5p (TERT), 6q, 8p, 16q, 9p (CDKN2A/B), 17p (TP53) and 13q (RB1), and particularly, ultra-early amplifications in chr8q. Integrated HBV frequently contains complex structures correlated with the translocation distance. Paired breakpoints within each integration event usually exhibit different microhomology, likely mediated by different DNA repair mechanisms. HBV-mediated rearrangements significantly correlated with young age, higher HBV DNA level and TP53 mutations but were less prevalent in the patients subjected to prior antiviral therapies. Finally, we recapitulated the TONSL and TMEM65 amplification in chr8q led by HBV integration using CRISPR/Cas9 editing and demonstrated their tumourigenic potentials. CONCLUSION: HBV integrations extensively reshape genomic structures and promote hepatocarcinogenesis (graphical abstract), which may occur early in a patient's life.
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Carcinoma Hepatocelular , Virus de la Hepatitis B , Neoplasias Hepáticas , Integración Viral , Carcinoma Hepatocelular/virología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/patología , Virus de la Hepatitis B/genética , Humanos , Integración Viral/genética , Animales , Ratones , Masculino , Persona de Mediana Edad , Femenino , Adulto , Secuenciación Completa del Genoma , Variaciones en el Número de Copia de ADN , AncianoRESUMEN
Ion mobility spectrometry (IMS) is a reliable and sensitive technique for the detection and analysis of compounds at the trace level. Depending on the chemical composition of the sample, compounds may be positively or negatively charged to form different polarity ions and detected in positive or negative polarity of the electric field. In order to detect multiple threats simultaneously with miniaturized devices, using a single detection unit to achieve high resolving power and high sensitivity is important. In this work, a miniaturized drift tube with fast polarity switching capabilities integrated with Fourier deconvolution multiplexing techniques is proposed for the first time as a means to improve the performance of ion mobility spectrometry. The sensitivity and resolving power are improved compared to traditional polarity switching signal averaging data acquisition methods. The displayed device had a high resolving power up to 52 at a drift length of 41 mm and a drift tube voltage of 2 kV. Trinitrotoluene (TNT), methamphetamine (MA), benzene, toluene, methyl tert-butyl ether (MTBE), acetic acid, and methylene chloride were evaluated using the proposed fast polarity switching multiplexing spectrometer and exhibited satisfied performance.
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High-power-density electronic devices under vibrations call for soft and damping thermal interface materials (TIMs) for efficient heat dissipation. However, integrating low hardness, high damping, and superior heat transfer capability into one TIM is highly challenging. Herein, soft, damping, and thermally conductive TIMs are designed and prepared by constructing a honeycomb-board-mimetic boron nitride nanosheet (BNNS) network in a dynamic polyimine via one-step horizontal centrifugal casting. The unique filler network makes the TIMs perform a high through-plane thermal conductivity (> 7.69 W m-1 K-1) and a uniform heat transfer process. Meanwhile, the hierarchical dynamic bonding of the polyimine endows the TIMs with low compressive strength (2.16 MPa at 20% strain) and excellent damping performance (tan δ > ≈0.3 at 10-2-102 Hz). The resulting TIMs also exhibit electrical insulation and remarkable recycling ability. Compared with the commercial ones, the TIMs provide better heat dissipation (4.1 °C) for a high-power 5G base station and less temperature fluctuation (1.8 °C) for an automotive insulated gate bipolar transistor (IGBT) under vibrations. This rational design offers a viable approach to prepare soft and damping TIMs for effective heat dissipation of high-power-density electronic devices under vibrations.
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Structured illumination microscopy (SIM) is a powerful technique for super-resolution (SR) image reconstruction. However, conventional SIM methods require high-contrast illumination patterns, which necessitate precision optics and highly stable light sources. To overcome these challenges, we propose a new method called contrast-robust structured illumination microscopy (CR-SIM). CR-SIM employs a deep residual neural network to enhance the quality of SIM imaging, particularly in scenarios involving low-contrast illumination stripes. The key contribution of this study is the achievement of reliable SR image reconstruction even in suboptimal illumination contrast conditions. The results of our study will benefit various scientific disciplines.
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High throughput has become an important research direction in the field of super-resolution (SR) microscopy, especially in improving the capability of dynamic observations. In this study, we present a hexagonal lattice structured illumination microscopy (hexSIM) system characterized by a large field of view (FOV), rapid imaging speed, and high power efficiency. Our approach employs spatial light interference to generate a two-dimensional hexagonal SIM pattern, and utilizes electro-optical modulators for high-speed phase shifting. This design enables the achievement of a 210-µm diameter SIM illumination FOV when using a 100×/1.49 objective lens, capturing 2048 × 2048 pixel images at an impressive 98 frames per second (fps) single frame rate. Notably, this method attains a near 100% full field-of-view and power efficiency, with the speed limited only by the camera's capabilities. Our hexSIM demonstrates a substantial 1.73-fold improvement in spatial resolution and necessitates only seven phase-shift images, thus enhancing the imaging speed compared to conventional 2D-SIM.
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The objective of this study was to analyze the correlation between skeletal muscle mass and the distribution of peripheral blood lymphocytes and natural killer (NK) cells, as well as their impact on prognosis in patients with acute myeloid leukemia (AML). A retrospective analysis was conducted on 211 newly diagnosed AML patients, evaluating skeletal muscle index (SMI), NK cell proportion, and absolute value, along with relevant clinical data. Linear regression and Spearman's correlation coefficient were used to assess the relationship between various indicators and SMI, followed by multiple linear regression for further modeling. Univariate and multivariate Cox proportional hazards regression models were used to identify independent predictors for overall survival (OS). Among the 211 AML patients, 38 cases (18.0%) were diagnosed with sarcopenia. Multiple linear regression analysis included weight, fat mass, ECOG score, body mass index, and peripheral blood NK cell proportion, constructing a correlation model for SMI (R2 = 0.745). Univariate analysis identified higher NK cell count (> 9.53 × 106/L) as a poor predictor for OS. Multivariate Cox proportional hazards regression model indicated that age ≥ 60 years, PLT < 100 × 109/L, ELN high risk, sarcopenia, and B cell count > 94.6 × 106/L were independent adverse prognostic factors for AML patients. Low skeletal muscle mass may negatively impact the count and function of NK cells, thereby affecting the prognosis of AML. However, further basic and clinical research is needed to explore the specific mechanisms underlying the relationship between NK cells and SMI in AML.
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Leucemia Mieloide Aguda , Sarcopenia , Humanos , Persona de Mediana Edad , Sarcopenia/patología , Estudios Retrospectivos , Pronóstico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/patología , Músculo Esquelético , Células Asesinas NaturalesRESUMEN
BACKGROUND: The SYNTAX score â ¡ 2020 (SSâ ¡-2020) was created as a customized decision-making tool for individuals diagnosed with complex coronary artery disease (CAD). Nevertheless, there has been a scarcity of research investigating the long-term predictive significance of SSâ ¡-2020 for patients with both CAD and chronic renal insufficiency (CRI) who undergo percutaneous coronary intervention (PCI). AIMS: We sought to showcase the prognostic capacity of SSII-2020 in evaluating long-term all-cause mortality (ACM) within this high-risk patient cohort. METHODS: A retrospective cohort comprising 1156 individuals diagnosed with CRI and exhibiting left main CAD, three-vessel CAD or both was included in this investigation. We categorized participants into three groups based on the optimal SSII-2020 threshold for predicting long-term ACM, determined using the X-tile software. RESULTS: At the median follow-up duration of 6.3 years, the ACM rates were determined to be 10% in the low, 17% in the moderate, and 28% in the high SSII-2020 groups (p < 0.001). Employing multivariate Cox regression analysis, it was observed that the high SSII-2020 group exhibited a 3.289-fold increased risk of ACM (95% confidence interval [CI]: 2.229-4.856, p < 0.001) compared with the low SSII-2020 group, whereas the high SSII-2020 group displayed a 1.757-fold (95% CI: 1.190-2.597, p = 0.005) in comparison to the median SSII-2020 groups. Compared with SSII, the SSII-2020 had an incremental value for predicting 7-year ACM (C-index: 0.662 vs. 0.534, p = 0.007; IDI: 0.016, p < 0.001). CONCLUSIONS: SSII-2020 enhances long-term ACM prediction, facilitates improved risk stratification, and improves clinical utility for PCI patients with complex CAD and CRI.
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Enfermedad de la Arteria Coronaria , Intervención Coronaria Percutánea , Insuficiencia Renal Crónica , Humanos , Intervención Coronaria Percutánea/efectos adversos , Estudios Retrospectivos , Resultado del Tratamiento , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/terapia , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/diagnóstico , Factores de Riesgo , Medición de RiesgoRESUMEN
A monolithic catalyst was fabricated through an emulsion-templating method, postpolymerization modification, and in situ loading of active constituents. To achieve a high specific surface area, divinylbenzene (DVB) was solely employed as the monomer, while the porous structure was adjusted with the porogen content and the types of initiators. Then, anchor points were introduced on the pore wall through nitration and amination of the polymeric scaffold. Using a controlled "silver mirror reaction", monolithic catalysts were obtained after loading of silver nanoparticles (Ag NPs), which was verified from morphological and crystallinity characteristics. The catalytic performance of the resultant monolithic catalyst was determined with the model reduction of 4-nitrophenol (4-NP). In static catalysis, the monolithic catalyst was proved to have a reactively high apparent rate constant and a good reusability. Furthermore, a flow reactor was fabricated with the monolithic catalyst, showing a high efficiency and long-term durability for the continuous reduction of 4-NP. This work broadened the adjustment of porous structures and the subsequent application for emulsion-templated monoliths.
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A method for the selective construction of S-N/C(sp2)-S bonds using N-substituted O-thiocarbamates and indoles as substrates is reported. This protocol features good atom utilization, mild conditions, short reaction time, and wide substrate scope, which can provide a convenient path for the functionalization of indoles. In addition, the reaction could be scaled up on gram scale, showing potential application value in industry synthesis.
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BACKGROUND: Accurate prediction of postoperative vault in implantable collamer lens (ICL) implantation is crucial; however, current formulas often fail to account for individual anatomical variations, leading to suboptimal visual outcomes and necessitating improved predictive models. We aimed to verify the prediction accuracy of our new predictive model for vaulting based on anterior and posterior chamber structural parameters. METHODS: This retrospective observational study included 137 patients (240 eyes) who previously underwent ICL surgery. Patients were randomly divided into the model establishment (192 eyes) or validation (48 eyes) groups. Preoperative measurements of the anterior and posterior chamber structures were obtained using Pentacam, CASIA2 anterior segment optical coherence tomography (AS-OCT), ultrasound biomicroscopy, and other devices. Stepwise multiple linear regression analysis was used to evaluate the relationship between the vault and each variable (WL formula). The Friedman test was performed for the vaulting prediction results of the WL, NK (Ver. 3), and KS formulas (Ver. 4) in CASIA2 AS-OCT, as well as the Zhu formula and vault measurements. The proportions of prediction error within ± 250 µm per formula were compared. RESULTS: The predicted vault values of the WL, NK, KS, and Zhu formulas and vault measurements were 668.74 ± 162.12, 650.85 ± 248.47, 546.56 ± 128.99, 486.56 ± 210.76, and 716.06 ± 233.84 µm, respectively, with a significant difference (χ2 = 69.883, P = 0.000). Significant differences were also found between the measured vault value and Zhu formula, measured vault value and KS formula, WL formula and Zhu formula, WL formula and KS formula, NK formula and KS formula, and NK formula and Zhu formula (P < 0.001) but not between other groups. The proportions of prediction error within ± 250 µm per formula were as follows: WL formula (81.3%) > NK formula (70.8%) > KS formula (66.7%) > Zhu formula (54.2%). CONCLUSIONS: The WL formula, which considers the complexity of the anterior and posterior chamber structures, demonstrates greater calculation accuracy, compared with the KS (Ver. 4) and Zhu formulas. The proportion of absolute prediction error ≤ 250 µm is higher with the WL formula than with the NK formula (ver. 3). This enhanced predictive capability can improve ICL sizing decisions, thereby increasing the safety and efficacy of ICL implantation surgeries.
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Implantación de Lentes Intraoculares , Tomografía de Coherencia Óptica , Humanos , Estudios Retrospectivos , Femenino , Masculino , Tomografía de Coherencia Óptica/métodos , Adulto , Implantación de Lentes Intraoculares/métodos , Cámara Anterior/diagnóstico por imagen , Lentes Intraoculares Fáquicas , Miopía/cirugía , Microscopía Acústica/métodos , Adulto Joven , Persona de Mediana Edad , Agudeza Visual , Biometría/métodos , Refracción Ocular/fisiologíaRESUMEN
Fueled by the concepts of topological insulators, analogous topological acoustics offer an alternative approach to manipulate sound. Theoretical proposals for subwavelength acoustic topological insulators are considered to be ideal effective parameters or utilizeing artificial coiling-space metamaterials. However, the corresponding realization using realistic soft metamaterials remains challenging. In this study, we present the design of an acoustic subwavelength second-order topological insulator using nanoscale porous solid material, silica aerogel, which supports pseudospin-dependent topological edge and corner states simultaneously. Through simulations and experiments, we demonstrate that silica aerogel can function as a soft acoustic metamaterial at the subwavelength scale. By embedding silica aerogel in an air matrix to construct a honeycomb lattice, a double Dirac cone is obtained. A topological phase transition is induced by expanding or contracting the supercell, resulting in band inversion. Additionally, we propose topologically robust acoustic transmission along the one-dimensional edge. Furthermore, we discover that the proposed sonic crystal sustains zero-dimensional corner states, which can efficiently confine energy at subwavelength corners. These findings offer potential for the realization of subwavelength topological acoustic devices using realistic soft metamaterials.
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Members of the C-X-C motif chemokine receptor (CXCR) superfamily play central roles in initiating the innate immune response in mammalian cells by orchestrating selective cell migration and immune cell activation. With its multilayered structure, the skin, which is the largest organ in the body, performs a crucial defense function, protecting the human body from harmful environmental threats and pathogens. CXCRs contribute to primary immunological defense; these receptors are differentially expressed by different types of skin cells and act as key players in initiating downstream innate immune responses. While the initiation of inflammatory responses by CXCRs is essential for pathogen elimination and tissue healing, overactivation of these receptors can enhance T-cell-mediated autoimmune responses, resulting in excessive inflammation and the development of several skin disorders, including psoriasis, atopic dermatitis, allergic contact dermatitis, vitiligo, autoimmune diseases, and skin cancers. In summary, CXCRs serve as critical links that connect innate immunity and adaptive immunity. In this article, we present the current knowledge about the functions of CXCRs in the homeostasis function of the skin and their contributions to the pathogenesis of allergic contact dermatitis and psoriasis. Furthermore, we will examine the research progress and efficacy of therapeutic approaches that target CXCRs.
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Dermatitis Alérgica por Contacto , Psoriasis , Humanos , Animales , Cisteína , Receptores de Quimiocina , Psoriasis/etiología , Dermatitis Alérgica por Contacto/etiología , Homeostasis , MamíferosRESUMEN
Surfactant pollution is escalatitheng in eutrophic waters, but the effect of surfactant charge properties on the physiological and biochemical properties of toxin-producing microalgae remains inadequately explored. To address this gap, this study explores the effects and mechanisms of three common surfactants-cetyltrimethylammonium bromide (CTAB, cationic), sodium dodecyl sulfate (SDS, anionic), and Triton X-100 (nonionic)-found in surface waters, on the agglomeration behavior, physiological indicators, and Microcystin-LR (MC-LR) release of Microcystis aeruginosa (M. aeruginosa) by using UV-visible spectroscope, Malvern Zetasizer, fluorescence spectrometer, etc. Results suggest that charge properties significantly affect cyanobacterial aggregation and cellular metabolism. The CTAB-treated group demonstrates a â¼5.74 and â¼9.74 times higher aggregation effect compared to Triton X-100 and SDS (300 mg/L for 180 min) due to strong electrostatic attraction. Triton X-100 outperforms CTAB and SDS in polysaccharide extraction, attributed to its higher water solubility and lower critical micelle concentration. CTAB stimulates cyanobacteria to secrete proteins, xanthohumic acid, and humic acids to maintain normal physiological cells. Additionally, the results of SEM and ion content showed that CTAB damages the cell membrane, resulting in a â¼90% increase in the release of intracellular MC-LR without cell disintegration. Ionic analyses confirm that all three surfactants alter cell membrane permeability and disrupt ionic metabolic pathways in microalgae. This study highlights the relationship between the surface charge properties of typical surfactants and the dispersion/agglomeration behavior of cyanobacteria. It provides insights into the impact mechanism of exogenous surfactants on toxic algae production in eutrophic water bodies, offering theoretical references for managing surfactant pollution and treating algae blooms.
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Microcistinas , Microcystis , Tensoactivos , Microcistinas/química , Microcistinas/metabolismo , Microcystis/efectos de los fármacos , Tensoactivos/química , Tensoactivos/farmacología , Octoxinol/química , Octoxinol/farmacología , Dodecil Sulfato de Sodio/química , Dodecil Sulfato de Sodio/farmacologíaRESUMEN
PURPOSE: Emergency resuscitative thoracotomy (ERT) is a final salvage procedure for critically injured trauma patients. Given its low success rate and ambiguous indications, its use in blunt trauma scenarios remains highly debated. Consequently, our study seeks to ascertain the overall survival rate of ERT in blunt trauma patients and determine which patients would benefit most from this procedure. METHODS: A retrospective case-control study was conducted for this research. Blunt trauma patients who underwent ERT between January 2020 and December 2023 in our trauma center were selected for analysis, with the endpoint outcome being in-hospital survival, divided into survival and non-survival groups. Inter-group comparisons were conducted using Chi-square and Fisher's exact tests, the Kruskal-Wallis test, Student's t-test, or the Mann-Whitney U test. Univariate and multivariate logistic regression analyses were conducted to assess potential predictors of survival. Then, the efficacy of the predictors was assessed through sensitivity and specificity analysis. RESULTS: A total of 33 patients were included in the study, with 4 survivors (12.12%). Multivariate logistic regression analysis indicated a significant association between cardiac tamponade and survival, with an adjusted odds ratio of 33.4 (95% CI: 1.31 - 850, p = 0.034). Additionally, an analysis of sensitivity and specificity, targeting cardiac tamponade as an indicator for survivor identification, showed a sensitivity rate of 75.0% and a specificity rate of 96.6%. CONCLUSION: The survival rate among blunt trauma patients undergoing ERT exceeds traditional expectations, suggesting that select individuals with blunt trauma can significantly benefit from the procedure. Notably, those presenting with cardiac tamponade are identified as the subgroup most likely to derive substantial benefits from ERT.
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This study aims to observe the effects of the traditional Chinese medicine prescription Dahuang Zhechong Pills(DHZCP on renal aging and explore its potential multi-target effects. Rats were assigned into the normal, model, DHZCP, and vitamin E(VE)groups. Firstly, the rat model of D-galactose(D-gal)-induced renal aging was established. During the modeling period, the rats in the 4 groups were administrated with double distilled water, double distilled water, DHZCP suspension, and VE suspension, respectively,by gavage every day. On day 60 of intervention, the indicators of renal aging and injury in rats were measured, including the function,histopathological characteristics, senescence-associated ß-galactosidase( SA-ß-gal) staining, and expression levels of Klotho and proteins associated with cell cycle arrest and senescence-associated secretory phenotype(SASP) in the renal tissue. Moreover, nontargeted metabolomic analysis of the renal tissue was performed for the 4 groups of rats to screen out the potential biomarkers and metabolic pathways. Finally, the signaling pathways of key targets were preliminarily validated. The results showed that DHZCP and VE significantly improved the renal function, histopathological features of renal tubular/interstitial tissue, and degree of SA-ß-gal staining, up-regulated the expression level of Klotho, and down-regulated the expression levels of proteins associated with cell cycle arrest and SASP in the renal tissue of the aging rats. In addition, DHZCP and VE regulated the metabolites in the renal tissue of the aging rats. There were 21 common differential metabolites. Among them, 5 differential metabolites were significantly increased in the aging rats and recovered after DHZCP or VE treatment, and they were involved in the lipid metabolism and energy metabolism pathways. The areas under the curves of the groups in comparison varied within the range of 0. 88-1. DHZCP regulated multiple signaling pathways, such as the adenosine monophosphate-activated protein kinase(AMPK), cyclic guanosine monophosphate-protein kinase G( c GMP-PKG), cyclic adenylic acid( c AMP), phosphatidylinositol-3-kinase-protein kinase B( PI3K-Akt), mammalian target of rapamycin(mTOR), and autophagy signaling pathways. In addition, it affected the multiple metabolic pathways, such as renin secretion, longevity regulation pathway, diabetic cardiomyopathy, and niacin and nicotinamide metabolism. DHZCP and VE significantly up-regulated the expression level of the key proteins in the AMPK signaling pathway in the renal tissue of the aging rats. In all, DHZCP and VE could mitigate renal aging and injury. DHZCP exerted multi-target effects via multiple signaling pathways and metabolic pathways in the kidney, in which the AMPK signaling pathway may be one of the key targets for action.
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Envejecimiento , Medicamentos Herbarios Chinos , Riñón , Metabolómica , Ratas Sprague-Dawley , Animales , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/farmacología , Ratas , Riñón/efectos de los fármacos , Riñón/metabolismo , Envejecimiento/efectos de los fármacos , Envejecimiento/metabolismo , Masculino , Transducción de Señal/efectos de los fármacosRESUMEN
Herein, we present a unified chemical synthesis of three subgroups of cephalotaxus diterpenoids. Key to the success lies in adopting a synthetic strategy that is inspired by biosynthesis but is opposite in nature. By employing selective one-carbon introduction and ring expansion operations, we have successfully converted cephalotane-type C18 dinorditerpenoids (using cephanolide B as a starting material) into troponoid-type C19 norditerpenoids and intact cephalotane-type C20 diterpenoids. This synthetic approach has enabled us to synthesize cephinoid H, 13-oxo-cephinoid H, 7-oxo-cephinoid H, fortalpinoid C, 7-epi-fortalpinoid C, cephanolide E, and 13-epi-cephanolide E. Furthermore, through the development of an intermolecular asymmetric Michael reaction between ß-oxo esters and ß-substituted enones, we have achieved the enantioselective synthesis of advanced intermediates within our synthetic sequence, thus formally realizing the asymmetric total synthesis of the cephalotaxus diterpenoids family.
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Cephalotaxus , Diterpenos , Diterpenos/síntesis química , Diterpenos/química , Cephalotaxus/química , Estructura Molecular , EstereoisomerismoRESUMEN
This study aims to investigate the effects of Blaps rynchopetera Fairmaire and/or cyclophosphamide on the proliferation and apoptosis of lung cancer cells and decipher the underlying mechanism. B. rynchopetera and cyclophosphamide-containing serum and blank serum were prepared from SD rats. Cell counting kit-8(CCK-8) assay was employed to examine the proliferation of lung cancer cell lines A549 and Lewis treated with corresponding agents. The Jin's formula method was used to evaluate the combined effect of the two drugs. According to the evaluation results, appropriate drug concentrations and lung cancer cell line were selected for subsequent experiments, which included control, B. rynchopetera, cyclophosphamide, B. rynchopetera + cyclophosphamide, and B. rynchopetera + Wnt/ß-catenin pathway agonist lithium chloride(LiCl) groups. Immunocytochemistry was employed to measure the expression of proliferation-related proteins in Lewis cells after drug interventions. Flow cytometry was employed to determine the cell cycle and apoptosis. The expression levels of proliferating cell nuclear antigen(PCNA), cyclinD1, B-cell lymphoma 2(Bcl-2), Bcl-2-assiocated X protein(Bax), Wnt1, and ß-catenin were determined by Western blot. The results showed that B. rynchopetera and/or cyclophosphamide significantly inhibited the proliferation of A549 and Lewis cells. Compared with B. rynchopetera alone, the combination increased the inhibition rate on cell proliferation. The combination of B. rynchopetera and cyclophosphamide demonstrated a synergistic effect according to Jin's formula-based evaluation. Compared with the control group, the B. rynchopetera, cyclophosphamide, and B. rynchopetera + cyclophosphamide groups showed increased proportion of Lewis cells in G_0/G_1 phase, increased apoptosis rate, up-regulated expression of Bax, and down-regulated expression of PCNA, cyclinD1, Bcl-2, Wnt1, and ß-catenin. Compared with the cyclophosphamide group, the combination group showed increased proportion of cells in G_0/G_1 phase, increased apoptosis rate, up-regulated expression of Bax, and down-regulated expression of PCNA, cyclinD1, Bcl-2, Wnt1, and ß-catenin. Compared with the B. rynchopetera group, the B. rynchopetera + LiCl group had deceased proportion of cells in G_0/G_1 phase, decreased apoptosis rate, down-regulated expression of Bax, and up-regulated expression of PCNA, cyclinD1, Bcl-2, Wnt1, and ß-catenin. The results indicated that B. rynchopetera could inhibit the proliferation, arrest the cell cycle, and induce the apoptosis of lung cancer cells by inhibiting the Wnt/ß-catenin signaling pathway. Moreover, B. rynchopetera had a synergistic effect with cyclophosphamide.
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Neoplasias Pulmonares , Vía de Señalización Wnt , Ratas , Animales , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , beta Catenina/genética , beta Catenina/metabolismo , Antígeno Nuclear de Célula en Proliferación , Proteína X Asociada a bcl-2/metabolismo , Ratas Endogámicas Lew , Ratas Sprague-Dawley , Apoptosis , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proliferación Celular , Ciclofosfamida , Línea Celular TumoralRESUMEN
Background: The ALTA-1 L trial and EXP-3B arm of NCT01970865 trial found that both brigatinib and lorlatinib showed durable and robust responses in treating ALK-positive non-small cell lung cancer (NSCLC) patients. However, brigatinib and lorlatinib treatments are costly and need indefinite administration until the disease progression. Thus, it remains uncertain whether using brigatinib followed by lorlatinib before chemotherapy is cost-effective compared to reserving these two drugs until progression after chemotherapy. Methods: We used a Markov model to assess clinical outcomes and healthcare costs of treating ALK-positive NSCLC individuals with brigatinib followed by lorlatinib before chemotherapy versus a strategy of reserving these drugs until progression after chemotherapy. Transition probabilities were estimated using parametric survival modeling based on multiple clinical trials. The drug acquisition costs, adverse events costs, administration costs were extracted from published studies before and publicly available data. We calculated lifetime direct healthcare costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios from the perspective of a United States payer. Results: Our base-case analysis indicated that the incremental cost-effectiveness ratios of using first-line brigatinib followed by lorlatinib compared with second-line brigatinib followed by lorlatinib is $-400,722.09/QALY which meant that second-line brigatinib followed by lorlatinib had less costs and better outcomes. Univariate sensitivity analysis indicated the results were most sensitive to the cost of brigatinib. Probability sensitivity analysis revealed that using brigatinib followed by lorlatinib before chemotherapy had a 0% probability of cost-effectiveness versus delaying these two drugs until progression after chemotherapy at a willingness-to-pay threshold of $150,000 per QALY. Sensitivity analyses conducted revealed the robustness of this result, as incremental cost-effectiveness ratios never exceeded the willingness-to-pay threshold. Conclusion: Using brigatinib as first-line treatment followed by lorlatinib for ALK-positive NSCLC may not be cost-effective given current pricing from the perspective of a United States payer. Delaying brigatinib followed by lorlatinib until subsequent lines of treatment may be a reasonable strategy that could limit healthcare costs without affecting clinical outcomes. More mature data are needed to better estimate cost-effectiveness in this setting.
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Aminopiridinas , Carcinoma de Pulmón de Células no Pequeñas , Lactamas , Neoplasias Pulmonares , Compuestos Organofosforados , Pirazoles , Pirimidinas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Análisis Costo-Beneficio , Neoplasias Pulmonares/tratamiento farmacológico , Lactamas Macrocíclicas , Proteínas Tirosina Quinasas ReceptorasRESUMEN
OBJECTIVE: To evaluate the cost-effectiveness of tisotumab vedotin to treat recurrent or metastatic cervical cancer in second- or third-line from the U.S. payer perspective. METHODS: A Markov model with three-state was employed to simulate recurrent or metastatic cervical cancer patients who were administered either tisotumab vedotin or investigator's choice of chemotherapy based on the phase II, open-labeled innovaTV 301 randomized clinical trial. The data on cost and health preferences were collected from the literature. RESULTS: Tisotumab vedotin generated an additional 0.25 quality-adjusted life-years (QALYs) compared to chemotherapy, but at an additional cost of $206,779. This results in incremental cost-effectiveness ratios of 839,107.88 per QALY. The results of the univariate sensitivity analysis indicated that cost of tisotumab vedotin, utility of progressive disease and progression-free survival had the greatest impacts on the outcomes. Probability sensitivity analysis showed that tisotumab vedotin had a 0% chance of being considered cost-effective. CONCLUSION: Tisotumab vedotin was unlikely cost-effective compared to chemotherapy for recurrent or metastatic cervical cancer patients at a willingness-to-pay threshold of $150,000/QALY from the perspective of a U.S. payer. Lowering the prices of tisotumab vedotin could potentially enhance its cost-effectiveness.
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Carbon emissions have become a global challenge, and China, as the world's largest developing country, has a serious emissions problem. Developing green buildings is an important way of reducing carbon emissions. China's low-carbon city pilot policy may be an effective way of promoting green building development and reducing these emissions. This study uses the low carbon city pilot policy as a quasi-natural experiment and employs the staggered difference-in-differences method to investigate its impact on green building development. The results show that the low-carbon city pilot policy promotes green building development, and this policy promotes it by enhancing regional green innovation capacity, improving green total factor productivity at the firm and regional levels, and reducing the financing constraints of firms in the construction and real estate sectors. In addition, the promotion effect of the policy on green building development is stronger in western and non-resource-based regions and large-scale cities in China. This study contributes to the literature related to environmental policy, green building, and carbon emissions and supports the promotion of green building development and the reduction of carbon emissions.