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BACKGROUND: Pancreatic cancer remains one of the most lethal malignancies, and has limited effective treatment. Gemcitabine (GEM), a chemotherapeutic agent, is commonly used for clinical treatment of pancreatic cancer, but it has characteristics of low drug delivery efficiency and significant side effects. The study tested the hypothesis that human bone marrow mesenchymal stem cell (MSC)-derived exosomes loaded with GEM (Exo-GEM) would have a higher cytotoxicity against human pancreatic cancer cells by enhancing their apoptosis. AIM: To investigate the cytotoxicity of MSC-derived Exo-GEM against pancreatic cancer cells in vitro. METHODS: Exosomes were isolated from MSCs and characterized by transmission electron microscopy and nanoparticle tracking analysis. Exo-GEM through electroporation, sonication, or incubation, and the loading efficiency was evaluated. The cytotoxicity of Exo-GEM or GEM alone against human pancreatic cancer Panc-1 and MiaPaca-2 cells was assessed by MTT and flow cytometry assays. RESULTS: The isolated exosomes had an average size of 76.7 nm. The encapsulation efficacy and loading efficiency of GEM by electroporation and sonication were similar and significantly better than incubation. The cytotoxicity of Exo-GEM against pancreatic cancer cells was stronger than free GEM and treatment with 0.02 µM Exo-GEM significantly reduced the viability of both Panc-1 and MiaPaca-2 cells. Moreover, Exo-GEM enhanced the frequency of GEM-induced apoptosis in both cell lines. CONCLUSION: Human bone marrow MSC-derived Exo-GEM have a potent cytotoxicity against human pancreatic cancer cells by enhancing their apoptosis, offering a promising drug delivery system for improving therapeutic outcomes.
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BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of subsequent radiotherapy (RT) following first-line treatment with durvalumab plus chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). METHODS: A total of 122 patients with ES-SCLC from three hospitals during July 2019 to December 2021 were retrospectively analyzed. Inverse probability of treatment weighting (IPTW) analysis was performed to address potential confounding factors. The primary focus of our evaluation was to assess the impact of RT on progression-free survival (PFS) and overall survival (OS). RESULTS: After IPTW analysis, 49 patients received durvalumab plus platinum-etoposide(EP) chemotherapy followed by RT (Durva + EP + RT) and 72 patients received immunochemotherapy (Durva + EP). The median OS was 17.2 months vs. 12.3 months (hazard ratio [HR]: 0.38, 95% CI: 0.17-0.85, P = 0.020), and the median PFS was 8.9 months vs. 5.9 months (HR: 0.56, 95% CI: 0.32-0.97, P = 0.030) in Durva + EP + RT and Durva + EP groups, respectively. Thoracic radiation therapy (TRT) resulted in longer OS (17.2 months vs. 14.7 months) and PFS (9.1 months vs. 7.2 months) compared to RT directed to other metastatic sites. Among patients with oligo-metastasis, RT also showed significant benefits, with a median OS of 17.4 months vs. 13.7 months and median PFS of 9.8 months vs. 5.9 months compared to no RT. Continuous durvalumab treatment beyond progression (TBP) prolonged OS compared to patients without TBP, in both the Durva + EP + RT (NA vs. 15.8 months, HR: 0.48, 95% CI: 0.14-1.63, P = 0.238) and Durva + EP groups (12.3 months vs. 4.3 months, HR: 0.29, 95% CI: 0.10-0.81, P = 0.018). Grade 3 or 4 adverse events occurred in 13 (26.5%) and 13 (18.1%) patients, respectively, in the two groups; pneumonitis was mostly low-grade. CONCLUSION: Addition of RT after first-line immunochemotherapy significantly improved survival outcomes with manageable toxicity in ES-SCLC.
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Fungal diseases not only reduce the yield of edible mushrooms but also pose potential threats to the preservation and quality of harvested mushrooms. Cobweb disease, caused primarily by fungal pathogens from the Hypocreaceae family, is one of the most significant diseases affecting edible mushrooms. Deciphering the genomes of these pathogens will help unravel the molecular basis of their evolution and identify genes responsible for pathogenicity. Here, we present high-quality genome sequences of three cobweb disease fungi: Hypomyces aurantius Cb-Fv, Cladobotryum mycophilum CB-Ab, and Cladobotryum protrusum CB-Mi, isolated from Flammulina velutipes, Agaricus bisporus, and Morchella importuna, respectively. The assembled genomes of H. aurantius, C. mycophilum, and C. protrusum are 33.19 Mb, 39.83 Mb, and 38.10 Mb, respectively. This is the first report of the genome of H. aurantius. Phylogenetic analysis revealed that cobweb disease pathogens are closely related and diverged approximately 17.51 million years ago. CAZymes (mainly chitinases, glucan endo-1,3-beta-glucosidases, and secondary metabolite synthases), proteases, KP3 killer proteins, lipases, and hydrophobins were found to be conserved and strongly associated with pathogenicity, virulence, and adaptation in the three cobweb pathogens. This study provides insights into the genome structure, genome organization, and pathogenicity of these three cobweb disease fungi, which will be a valuable resource for comparative genomics studies of cobweb pathogens and will help control this disease, thereby enhancing mushroom quality.
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It is an interesting research topic to study the interfacial interactions between hemicellulose and cellulose, specifically how hemicellulose's structure affects its binding to cellulose nanofibers. Our research proposes that dispersion interaction play an important role in this interfacial interaction, more so than electrostatic forces when considering the adherence of cellulose to xylan. To quantify these interactions, the Atomic Force Microscope (AFM) colloidal probe technique is applied to measure the intermolecular forces between cellulose nanofibers, which are attached to the probe and xylan. These measured forces are then analyzed in relation to the length, diameter and functional groups of the nanocellulose, as well as the molecular weight and side chains of the xylan. Moreover, the predominance of dispersion forces by contrasting the adhesive forces before and after the grafting of a large nonpolar group onto xylan. This modification significantly reduces contact between the cellulose and xylan backbone, thereby markedly diminishing the dispersion interactions. Parallel to the AFM experiments, molecular dynamics (MD) simulations corroborate the experimental results and support our hypotheses. Collectively, these findings contribute to a deeper understanding of polysaccharide interactions within lignocellulose.
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Celulose , Microfibrilas , Microscopia de Força Atômica , Simulação de Dinâmica Molecular , Polissacarídeos , Xilanos , Microscopia de Força Atômica/métodos , Polissacarídeos/química , Celulose/química , Xilanos/química , Microfibrilas/química , Microfibrilas/ultraestrutura , Coloides/química , Nanofibras/química , Nanofibras/ultraestruturaRESUMO
Tire wear particles (TWP), as an emerging type of microplastics, are a significant source of contaminants in roadside soils due to their high concentration of pollutants, including polycyclic aromatic hydrocarbons (PAHs). This study explored the impact of ultraviolet (UV) exposure and natural aging on the in vitro bioaccessibility of PAHs associated with TWP in soil on a China-wide scale. Our findings suggested that UV exposure amplified the negative charge of TWP by 75 % and increased the hydrophobic groups on the particle surface. The bioaccessibility of 3- and 4-ring PAHs in TWP was significantly (p < 0.05) heightened by UV exposure. After 20 types of soils containing 2 % UV-exposed TWP underwent natural aging, the bioaccessibility of PAHs saw a significant decrease (p < 0.05) to 16-48 %, compared to 28-96 % in the unaged group. Soil pH and electrical conductivity (EC) were the two primary soil properties positively influencing the reduction of in vitro PAHs concentration and PAHs bioaccessibility. According to the prediction results, soils in southern China presented the highest potential region for the release of bioaccessible PAHs from TWP, highlighting the regional specificity of environmental impact. Our study provides valuable insights into the biological impact of PAHs associated with TWP on a regional scale, and offers scientific evidence for targeted soil risk management strategies.
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Hidrocarbonetos Policíclicos Aromáticos , Poluentes do Solo , Solo , Raios Ultravioleta , Hidrocarbonetos Policíclicos Aromáticos/análise , Poluentes do Solo/análise , Solo/química , China , Monitoramento Ambiental , MicroplásticosRESUMO
Bacterial intestinal inflammation frequently occurs in cultured fish. Nevertheless, research on intestinal barrier dysfunction in the process of intestinal inflammation is deficient. In this study, we explored the changes of intestinal inflammation induced by Aeromonas hydrophila (A. hydrophila) in snakehead and the relationship between intestinal barrier and inflammation. Snakehead [(13.05 ± 2.39) g] were infected via anus with A. hydrophila. Specimens were collected for analysis at 0, 1, 3, 7 and 21 d post-injection. The results showed that with the increase of exposure time, the hindgut underwent stages of normal function, damage, damage deterioration, repair and recovery. Relative to 0 d, the levels of IL-1ß and TNF-α in serum, and the expression of nod1, tlr1, tlr5, nf-κb, tnf-α and il-1ß in intestine were significantly increased, and showed an upward then downward pattern over time. However, the expression of tlr2 and il-10 were markedly decreased, and showed the opposite trend. In addition, with the development of intestinal inflammation, the diversity and richness of species, and the levels of phylum and genus in intestine were obviously altered. The levels of trypsin, LPS, AMS, T-SOD, CAT, GPx, AKP, LZM and C3 in intestine were markedly reduced, and displayed a trend of first decreasing and then rebounding. The ultrastructure observation showed that the microvilli and tight junction structure of intestinal epithelial cells experienced normal function initially, then damage, and finally recovery over time. The expression of claudin-3 and zo-1 in intestine were significantly decreased, and showed a trend of first decreasing and then rebounding. Conversely, the expression of mhc-i, igm, igt and pigr in intestine were markedly increased, and displayed a trend of increasing first and then decreasing. The above results revealed the changes in intestinal barrier during the occurrence and development of intestinal inflammation, which provided a theoretical basis for explaining the relationship between the two.
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Aeromonas hydrophila , Doenças dos Peixes , Infecções por Bactérias Gram-Negativas , Intestinos , Animais , Aeromonas hydrophila/fisiologia , Doenças dos Peixes/imunologia , Doenças dos Peixes/microbiologia , Peixes/imunologia , Peixes/microbiologia , Microbioma Gastrointestinal , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/veterinária , Inflamação/imunologia , Inflamação/veterinária , Mucosa Intestinal/imunologia , Intestinos/imunologia , Intestinos/patologiaRESUMO
Background: Immune checkpoint inhibitors (ICIs) no longer are approved for second-line or later treatment of extensive-stage small cell lung cancer (ES-SCLC), and have not been studied in combination with chemotherapy. Exploring the efficacy and safety of second-line or later immunotherapy for ES-SCLC is an urgent clinical question that needs to be addressed, and combination therapies are an important research direction. This study intended to investigate the efficacy and safety of the sintilimab in combination with chemotherapy as a second-line and beyond treatment option for ES-SCLC. Methods: Medical records of patients who received treatment with sintilimab in combination with chemotherapy or chemotherapy alone as a second-line or beyond therapy were retrospectively analyzed. The study evaluated efficacy and safety. Indicators of efficacy included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Safety indicators included adverse events (AEs). Results: This cohort comprised of 46 patients: 24 in the sintilimab combination chemotherapy group and 22 in the chemotherapy group. Chemotherapy received by both groups was either albumin-bound paclitaxel or irinotecan. Compared with the chemotherapy group, the sintilimab combination chemotherapy group had higher ORR and DCR (ORR: 37.5% vs. 9.1%, P=0.04; DCR: 75.0% vs. 40.9%, P=0.04), and significantly prolonged PFS and OS [median PFS (mPFS): 5.07 vs. 2.45 months, P=0.006; median OS (mOS): 14.43 vs. 10.34 months, P=0.009]. Also, there was no significant increase in the incidence of AEs in the sintilimab combination chemotherapy group, which was well tolerated by patients. Conclusions: Sintilimab in combination with chemotherapy is superior to single-agent chemotherapeutic treatment as second-line or later therapy in ES-SCLC patients who have not received prior immunotherapy. These results need to be confirmed in future clinical trials.
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As a new type of high-performance material, gradient structural steel is widely used in engineering fields due to its unique microstructure and excellent mechanical properties. For the prevalent fatigue failure problem, the rate of change in the local grain size gradients along the structure (referred to as the gradient rate) is a key parameter in the design of gradient structures, which significantly affects the fatigue performance of gradient structural steel. In this study, a new method of 'Voronoi primary + secondary modeling' is adopted to successfully establish three typical high-strength steel models corresponding to the convex-, linear-, and concave-type gradient rates for gradient structures, focusing on the stress-strain response and crack propagation in structural steel with different gradient rates under cyclic loading. It was found that the concave gradient rate structural model is dominated by finer grains with larger volume fraction, which is conducive to hindering fatigue crack propagation and has the longest fatigue life, which is 16.16% longer than that of the linear gradient rate structure and 23.66% longer than that of the convex gradient rate structure. The simulation results in this study are consistent with the relevant experimental phenomena. Therefore, when regulating the gradient rate, priority should be given to increasing the volume fraction of fine grains and designing a gradient rate structure dominated by fine grains to improve the fatigue life of the material. This study presents a new strategy for designing engineering materials with better service performance.
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ABSTRACT: Clinical practice shows that a critical unmet need in the field of thrombosis prevention is the availability of anticoagulant therapy without bleeding risk. Inhibitors against FXIa or FXIIa have been extensively studied because of their low bleeding risk. However, whether these compounds produce synergistic effects has not yet been explored. In this study, analyses of activated partial thromboplastin time in combination with the FXIa inhibitor PN2KPI and the FXIIa inhibitor Infestin4 at different proportions were performed using the SynergyFinder tool identifying synergistic anticoagulation effects. Both an FeCl 3 -induced carotid artery thrombosis mouse model and a transient occlusion of the middle cerebral artery mouse model showed that the combination of PN2KPI and Infestin4, which are 28.57% and 6.25% of the effective dose, respectively, significantly prevents coagulation, and furthermore, dual inhibition does not cause bleeding risk.
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Anticoagulantes , Coagulação Sanguínea , Modelos Animais de Doenças , Sinergismo Farmacológico , Fator XIIa , Fator XIa , Animais , Fator XIa/antagonistas & inibidores , Fator XIa/metabolismo , Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Masculino , Fator XIIa/antagonistas & inibidores , Fator XIIa/metabolismo , Trombose das Artérias Carótidas/prevenção & controle , Trombose das Artérias Carótidas/induzido quimicamente , Trombose das Artérias Carótidas/tratamento farmacológico , Camundongos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Hemorragia/induzido quimicamente , Camundongos Endogâmicos C57BL , Tempo de Tromboplastina ParcialRESUMO
The incidence of non-alcoholic fatty liver disease (NAFLD) tends to be younger. And the role of theobromine in fatty liver disease remains unclear. The purpose of this study was to investigate the relationship between dietary theobromine intake and degree of hepatic steatosis in individuals aged 45 and below, using data from the 2017-2020 National Health and Nutrition Examination Survey (NHANES) and liver ultrasonography transient elastography. A total of 1796 participants aged below 45 years were included from NHANES 2017-2020 data after applying exclusion criteria. Multivariate regression and subgroup analyses were conducted to examine the associations between theobromine intake and controlled attenuation parameter (CAP), adjusting for potential confounders. Generalized additive models and two-piecewise linear regression were used to analyze nonlinear relationships. In the unadjusted Model 1 and preliminarily adjusted Model 2, there was no significant correlation between theobromine intake and CAP values. However, in Models 3 and 4, which accounted for confounding factors, a higher intake of theobromine was significantly associated with lower CAP values. Subgroup analyses in the fully adjusted Model 4 revealed a significant negative correlation among individuals aged 18-45, women, and white populations. Nonlinear analysis revealed a U-shaped relationship in black Americans, with the lowest CAP values at 44.5 mg/day theobromine. This study provides evidence that higher theobromine intake is correlated with lower degree of hepatic steatosis in young people, especially those aged 18-45 years, women, and whites. For black Americans, maintaining theobromine intake around 44.5 mg/day may help minimize liver steatosis. These findings may help personalize clinical nutritional guidance, prevent the degree of hepatic steatosis, and provide pharmacological approaches to reverse fatty liver disease in young people.
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Hepatopatia Gordurosa não Alcoólica , Inquéritos Nutricionais , Teobromina , Humanos , Teobromina/administração & dosagem , Feminino , Masculino , Adulto , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Fígado/diagnóstico por imagem , Fígado/patologia , Técnicas de Imagem por Elasticidade , Fígado Gorduroso/epidemiologia , Fígado Gorduroso/diagnóstico por imagemRESUMO
BACKGROUND: Low-dose chemotherapy is a promising treatment strategy that may be improved by controlled delivery. OBJECTIVE: This study aimed to design polyethylene glycol-stabilized bilayer-decorated magnetic Cationic Liposomes (CLs) as a drug delivery system for integrated functional studies of lung cancer cell therapy and imaging. METHODS: A novel multifunctional folic acid targeting magnetic CLs docetaxel drug-loading system (FA-CLs-Fe- DOC) was prepared and tested for its physical properties, encapsulation rate and drug release performance. The feasibility of FA-CLs-Fe-DOC ability to inhibit tumor cells and act as an MRI contrast agent was investigated in vitro, and the target recognition and therapeutic ability of FA-CLs-Fe-DOC was studied in vivo. RESULTS: FA-CLs-Fe-DOC had a particle size of 221.54 ± 6.42 nm and a potential of 28.64 ± 3.56 mv, with superparamagnetic properties and better stability. The encapsulation rate was 95.36 ± 1.63%, and the drug loading capacity was 9.52 ± 0.22%, which possessed the drug slow-release performance and low cytotoxicity and could effectively inhibit the proliferation of lung cancer cells, promoting apoptosis of lung cancer cells. MRI showed that it had the function of tracking and localization of lung cancer cells. In vivo experiments confirmed the targeted recognition property and therapeutic function of lung cancer cells. CONCLUSION: In this study, we successfully prepared an FA-CLs-Fe-DOC capable of specifically targeting lung cancer cells with integrated functions of efficient lung cancer cell killing and imaging localization. This targeted drug packaging technology may provide a new strategy for the design of integrated carriers for targeted cancer therapy and imaging.
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Antineoplásicos , Cátions , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Lipossomos , Neoplasias Pulmonares , Lipossomos/química , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Cátions/química , Proliferação de Células/efeitos dos fármacos , Animais , Camundongos , Apoptose/efeitos dos fármacos , Docetaxel/química , Docetaxel/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/síntese química , Tamanho da Partícula , Sistemas de Liberação de Medicamentos , Estrutura Molecular , Ácido Fólico/química , Relação Dose-Resposta a Droga , Relação Estrutura-Atividade , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Liberação Controlada de FármacosRESUMO
The number of people suffering from scrub typhus, which is not of concern, is increasing year by year, especially in Yunnan Province, China. From June 1, 2021 to August 15, 2022, a total of 505 mammalian samples were collected from farm, forest, and residential habitats with high incidence of scrub typhus in Yunnan, China, for nPCR (nested PCR) and qPCR (quantitative real-time PCR) detection of Orientia tsutsugamushi. A total of 4 orders of murine-like animals, Rodentia (87.52%, n = 442), Insectivora (10.29%, n = 52), Lagomorpha (1.79%, n = 9) and Scandentia (0.40%, n = 2) were trapped. Comparing the qPCR infection rates in the three habitats, it was no significant difference that the infection rate of residential habitat (44.44%) and that of the farm habitat (45.05%, P>0.05), which is much larger than that of the forest habitat (3.08%) (P<0.001). Three genotypes (Karp-like, Kato-like and TA763-like) of O. tsutsugamushi were found from Yunnan, China in this study.
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Orientia tsutsugamushi , Tifo por Ácaros , Humanos , Animais , Camundongos , Tifo por Ácaros/diagnóstico , Fazendas , China/epidemiologia , Orientia tsutsugamushi/genética , Roedores/genética , Reação em Cadeia da Polimerase em Tempo Real , Estudos Epidemiológicos , Florestas , Eulipotyphla/genéticaRESUMO
OBJECTIVES: Given the modest efficacy of docetaxel in advanced non-small cell lung cancer (NSCLC), this study assesses the therapeutic potential and safety profile of anlotinib in combination with docetaxel compared to docetaxel monotherapy as a second-line therapy for patients with advanced NSCLC. MATERIALS AND METHODS: In this phase II study, patients with advanced NSCLC experiencing failure with first-line platinum-based regimens were randomized in a 1:1 ratio to receive either anlotinib plus docetaxel or docetaxel alone. Primary endpoint was progression-free survival (PFS), with overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety as secondary endpoints. RESULTS: A total of 83 patients were randomized. The combination of anlotinib and docetaxel significantly extended median PFS to 4.4 months compared to 1.6 months for docetaxel alone (hazard ratio [HR] = 0.38, 95 % confidence interval [CI]: 0.23-0.63, P = 0.0002), and also demonstrated superior ORR (32.5 % vs. 9.3 %, P = 0.0089) and DCR (87.5 % vs. 53.5 %, P = 0.0007). Median OS was observed at 12.0 months in the combination group vs. 10.9 months in the monotherapy group (HR = 0.82, 95 % CI: 0.47-1.43, P = 0.4803). For patients previously treated with immunotherapy, the median PFS was notably longer at 7.8 vs. 1.7 months (HR = 0.22, 95 % CI: 0.09-0.51, P = 0.0290). The incidence of grade ≥ 3 treatment-related adverse events, predominantly leukopenia (15.0 % vs. 7.0 %) and neutropenia (10.0 % vs. 5.0 %), was manageable across both groups. CONCLUSION: Anlotinib plus docetaxel offers a viable therapeutic alternative for patients with advanced NSCLC who failed first-line platinum-based treatments.
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Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Docetaxel , Indóis , Neoplasias Pulmonares , Quinolinas , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Docetaxel/administração & dosagem , Docetaxel/uso terapêutico , Masculino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Feminino , Pessoa de Meia-Idade , Idoso , Indóis/administração & dosagem , Indóis/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/uso terapêutico , Quinolinas/efeitos adversos , Adulto , Estadiamento de Neoplasias , Resultado do Tratamento , Idoso de 80 Anos ou maisRESUMO
Hypertrophic scar formation is influenced by the intricate interplay between fibroblasts and endothelial cells. In this study, we investigated this relationship using in vitro and in vivo models. Clinical observations revealed distinct morphological changes and increased vascularity at pathological scar sites. Further analysis using OCTA, immunohistochemistry, and immunofluorescence confirmed the involvement of angiogenesis in scar formation. Our indirect co-culture systems demonstrated that endothelial cells enhance the proliferation and migration of fibroblasts through the secretion of cytokines including VEGF, PDGF, bFGF, and TGF-ß. Additionally, a suspended co-culture multicellular spheroid model revealed molecular-level changes associated with extracellular matrix remodeling, cellular behaviors, inflammatory response, and pro-angiogenic activity. Furthermore, KEGG pathway analysis identified the involvement of TGF-ß, IL-17, Wnt, Notch, PI3K-Akt, and MAPK pathways in regulating fibroblasts activity. These findings underscore the critical role of fibroblasts-endothelial cells crosstalk in scar formation and provide potential targets for therapeutic intervention. Understanding the molecular mechanisms underlying this interplay holds promise for the development of innovative approaches to treat tissue injuries and diseases.
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Patients with arterial embolic disease have benefited greatly from antiplatelet therapy. However, hemorrhage risk of antiplatelet agents cannot be ignored. Herein, we describe the discovery of 2,3-dihydro[1,4]dioxino[2,3-g]benzofuran compounds as novel PAR4 antagonists. Notably, the isomers 36 and 37 with the chemotype of phenoxyl methylene substituted on the 2,3-dihydro-1,4-dioxine ring exhibited potent in vitro antiplatelet activity (IC50 = 26.13 nM for 36 and 14.26 nM for 37) and significantly improved metabolic stability in human liver microsomes (T1/2 = 97.6 min for 36 and 11.1 min for BMS-986120). 36 also displayed good oral PK profiles (mice: T1/2 = 7.32 h and F = 45.11%). Both of them showed overall potent ex vivo antiplatelet activity at concentrations of 6 and 12 mg/kg, with no impact on the coagulation system and low bleeding liability. Our work will facilitate development of novel PAR4 antagonists as a safer therapeutic option for arterial embolism.
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Benzofuranos , Trombose , Humanos , Camundongos , Animais , Receptores de Trombina , Inibidores da Agregação Plaquetária/metabolismo , Hemorragia/induzido quimicamente , Hemorragia/tratamento farmacológico , Hemorragia/metabolismo , Coagulação Sanguínea , Trombose/tratamento farmacológico , Benzofuranos/uso terapêutico , Agregação Plaquetária , Receptor PAR-1/metabolismo , Receptor PAR-1/uso terapêutico , Plaquetas/metabolismoRESUMO
Background: Platinum-doublet chemotherapy plus immunotherapy has been the standard of care for the first-line treatment of advanced non-small cell lung cancer lacking actional driver mutations. However, optimization of drug combinations is still needed to find a better balance between therapeutic efficacy and safety in the immunotherapy era. We aimed to investigate the efficacy and safety of platinum-free albumin bound paclitaxel (nab-paclitaxel) combined with camrelizumab and apatinib as first-line treatment for patients with advanced lung adenocarcinoma. Methods: In this multicenter open-label, single-arm phase II trial, patients with systemic treatment-naïve advanced lung adenocarcinoma without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations received a rational-based combination of camrelizumab (200 mg intravenously, day one), apatinib (250 mg, q.d., five continuous days per week), and nab-paclitaxel (135 mg/m2 intravenously, days one and eight) every three weeks for four to six cycles in China. Patients with controlled disease were maintained with camrelizumab and apatinib. The primary end point was progression-free survival (PFS). This trial is registered with ClinicalTrials.gov (No. NCT04459078). Findings: Between August 26, 2020 and May 20, 2022, 64 patients were enrolled. The median PFS was 14.3 (95% CI: 9.9, not reached) months. The confirmed objective response rate was 64.1% (95% CI: 51.1, 75.7). The grade 3-4 hematologic treatment-related adverse events (TRAEs) were decreased neutrophil count (14.1%), decreased white blood cell count (7.8%), and anemia (3.1%). The most common non-hematologic TRAEs of grade 3-4 were increased alanine transaminase (18.8%) and aspartate transaminase (15.6%). No treatment-related death occurred. The quality of life was on average not clinically meaningful worse through treatment cycle 14. Interpretation: Nab-paclitaxel plus camrelizumab and apatinib showed clinically meaningful anti-tumor activity and manageable safety, with few hematologic toxicities, and might be a potential treatment option in patients with advanced lung adenocarcinoma lacking EGFR/ALK mutations. Funding: Heath Research Foundation of Chinese Society of Clinical Oncology, Hunan Provincial Natural Science Foundation of China, Hunan Cancer Hospital Climb Plan, Sister Institution Network Fund of The University of Texas MD Anderson Cancer Center, The Science and Technology Innovation Program of Hunan Province, and Suzhou Sheng Diya Biomedical Co., Ltd, a subsidiary of Jiangsu Hengrui Pharmaceuticals Co., Ltd. (Shanghai, China).