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BACKGROUND: Osimertinib is regarded as a promising third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for advanced non-squamous non-small cell lung cancer (NSCLC) patients who developed T790M. However the adverse effects, primarily fatigue, remain an overwhelming deficiency of Osimertinib, hindering it from achieving adequate clinical efficacy for such NSCLC. Ganoderma lucidum has been used for thousands of years in China to combat fatigue, while Ganoderma Lucidum spores powder (GLSP) is the main active ingredient. The aim of this study is to investigate whether GLSP is sufficiently effective and safe in improving fatigue and synergizing with Osimertinib in non-squamous NSCLC patients with EGFR mutant. METHOD/DESIGN: A total of 140 participants will be randomly assigned to receive either de-walled GSLP or placebo for a duration of 56 days. The primary outcome measure is the fatigue score associated with EGFR-TKI adverse reactions at week 8, evaluated by the Chinese version of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Patients (QLQ-C30). Secondary outcomes include evaluation of treatment effectiveness, assessment of quality of life (QoL), and exploration of immune indicators and gut microbiota relationships. Following enrollment, visits are scheduled biweekly until week 12. TRIAL REGISTRATION: China Clinical Trial Registry ChiCTR2300072786. Registrated on June 25, 2023.
Assuntos
Acrilamidas , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas , Indóis , Neoplasias Pulmonares , Pirimidinas , Reishi , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Qualidade de Vida , Pós/uso terapêutico , Receptores ErbB/genética , Inibidores de Proteínas Quinases/efeitos adversos , Mutação , Esporos Fúngicos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Three-dimensional liver bioprinting is an emerging technology in the field of regenerative medicine that aids in the creation of functional tissue constructs that can be used as transplantable organ substitutes. During transplantation, the bioprinted donor liver must be protected from the oxidative stress environment created by various factors during the transplantation procedure, as well as from drug-induced damage from medications taken as part of the post-surgery medication regimen following the procedure. In this study, Silymarin, a flavonoid with the hepatoprotective properties were introduced into the GelMA bioink formulation to protect the bioprinted liver against hepatotoxicity. The concentration of silymarin to be added in GelMA was optimised, bioink properties were evaluated, and HepG2 cells were used to bioprint liver tissue. Carbon tetrachloride (CCl4) was used to induce hepatotoxicity in bioprinted liver, and the effect of this chemical on the metabolic activities of HepG2 cells was studied. The results showed that Silymarin helps with albumin synthesis and shields liver tissue from the damaging effects of CCl4. According to gene expression analysis, CCl4 treatment increased TNF-α and the antioxidant enzyme SOD expression in HepG2 cells while the presence of silymarin protected the bioprinted construct from CCl4-induced damage. Thus, the outcomes demonstrate that the addition of silymarin in GelMA formulation protects liver function in toxic environments.
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Acrilamidas , Doença Hepática Induzida por Substâncias e Drogas , Transplante de Fígado , Silimarina , Humanos , Silimarina/metabolismo , Silimarina/farmacologia , Tetracloreto de Carbono , Gelatina , Extratos Vegetais/química , Doadores Vivos , Fígado , Antioxidantes/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismoRESUMO
This study looked at the toxic impacts of water-born acrylamide (ACR) on Nile tilapia (Oreochromis niloticus) in terms of behaviors, growth, immune/antioxidant parameters and their regulating genes, biochemical indices, tissue architecture, and resistance to Aeromonas hydrophila. As well as the probable ameliorative effect of Chlorella vulgaris (CV) microalgae as a feed additive against ACR exposure was studied. The 96-h lethal concentration 50 of ACR was investigated and found to be 34.67 mg/L for O. niloticus. For the chronic exposure study, a total of 180 healthy O. niloticus (24.33 ± 0.03 g) were allocated into four groups in tri-replicates (15 fish/replicate), C (control) and ACR groups were fed a basal diet and exposed to 0 and 1/10 of 96-h LC50 of ACR (3.46 mg/L), respectively. ACR+ CV5 and ACR+ CV10 groups were fed basal diets with 5 % and 10 % CV supplements, respectively and exposed to 1/10 of 96-h LC50 of ACR for 60 days. After the exposure trial (60 days) the experimental groups were challenged with A. hydrophila. The findings demonstrated that ACR exposure induced growth retardation (PË0.01) (lower final body weight, body weight gain, specific growth rate, feed intake, protein efficiency ratio, final body length, and condition factor as well as higher feed conversion ratio). A substantial decrease in the immune/antioxidant parameters (PË0.05) (lysozyme, serum bactericidal activity %, superoxide dismutase, and reduced glutathione) and neurotransmitter (acetylcholine esterase) (PË0.01) was noticed with ACR exposure. A substantial increase (PË0.01) in the serum levels of hepato-renal indicators, lipid peroxidation biomarker, and cortisol was noticed as a result of ACR exposure. ACR exposure resulted in up-regulation (PË0.05) of the pro-inflammatory cytokines and down-regulation (PË0.05) of the antioxidant-related gene expression. Furthermore, the hepatic, renal, brain, and splenic tissues were badly affected by ACR exposure. ACR-exposed fish were more sensitive to A. hydrophila infection and recorded the lowest survival rate (PË0.01). Feeding the ACR-exposed fish with CV diets significantly improved the growth and immune/antioxidant status, as well as modulating the hepatorenal functions, stress, and neurotransmitter level compared to the exposed-non fed fish. In addition, modulation of the pro-inflammatory and antioxidant-related gene expression was noticed by CV supplementation. Dietary CV improved the tissue architecture and increased the resistance to A. hydrophila challenge in the ACR-exposed fish. Noteworthy, the inclusion of 10 % CV produced better results than 5 %. Overall, CV diets could be added as a feed supplement in the O. niloticus diet to boost the fish's health, productivity, and resistance to A. hydrophila challenge during ACR exposure.
Assuntos
Chlorella vulgaris , Ciclídeos , Doenças dos Peixes , Infecções por Bactérias Gram-Negativas , Animais , Antioxidantes/metabolismo , Resistência à Doença , Dieta/veterinária , Suplementos Nutricionais , Neurotransmissores/metabolismo , Peso Corporal , Transtornos do Crescimento , Acrilamidas , Ração Animal/análise , Doenças dos Peixes/induzido quimicamente , Infecções por Bactérias Gram-Negativas/veterináriaRESUMO
Present investigation deals with the synthesis of psyllium based copolymeric hydrogels and evaluation of their physiochemical and biomedical properties. These copolymers have been prepared by grafting of poly(vinyl phosphonic acid) (poly (VPA)) and poly(acrylamide) (poly(AAm)) onto psyllium in the presence of crosslinker N,N-methylene bis acrylamide (NNMBA). These copolymers [psyllium-poly(VPA-co-AAm)-cl-NNMBA] were characterized by field emission-scanning electron micrographs (FE-SEM), electron dispersion X-ray analysis (EDAX), Atomic force microscopy (AFM), Fourier transform infrared spectroscopy (FTIR), 13C-nuclear magnetic resonance (NMR), X-ray diffraction (XRD), and thermogravimetric analysis (TGA)- differential thermal analysis (DTG). FESEM, AFM and XRD demonstrated heterogeneous morphology with a rough surface and an amorphous nature. Diffusion of ornidazole occurred with a non-Fickian diffusion mechanism, and the release profile data was fitted in the Korsemeyer-Peppas kinetic model. Biochemical analysis of hydrogel properties confirmed the blood-compatible nature during blood-polymer interactions and revealed haemolysis value 3.95 ± 0.05 %. The hydrogels exhibited mucoadhesive character during biomembrane-polymer interactions and demonstrated detachment force = 99.0 ± 0.016 mN. During 2,2-diphenyl-1-picrylhydrazyl reagent (DPPH) assay, free radical scavenging was observed 37.83 ± 3.64 % which illustrated antioxidant properties of hydrogels. Physiological and biomedical properties revealed that these hydrogels could be explored for drug delivery uses.
Assuntos
Acrilamida , Ácidos Fosforosos , Psyllium , Acrilamida/química , Psyllium/química , Hidrogéis/química , Acrilamidas/química , Polímeros/química , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Concentração de Íons de HidrogênioRESUMO
Priority water pollutants comprising six plasticizers, 18 volatile organic compounds (VOCs), total petroleum hydrocarbon (TPH), 1,4-dioxane, epichlorohydrin, formaldehyde, acrylamide, and cyanides were determined in surface river sediments to assess their distribution patterns and ecological risks. Among these, di (2-ethylhexyl) phthalate (DEHP), toluene, TPH, and acrylamide were frequently found in sediments. The industrial sites had higher concentrations of ∑plasticizers (median 628 ng/g dry weight (dw)), ∑VOCs (median 3.35 ng/g dw), acrylamide (median 0.966 ng/g dw), and TPH (median 152 µg/g dw) in sediments than the mixed and non-industrial areas. The other pollutants did not show the significant differences in levels according to site types because of their relatively low detection frequencies. Volatile and soluble substances as well as hydrophobic pollutants were predominantly detected in surface sediments from industrial areas. Sediment contamination patterns were affected by the size and composition of the industrial zones around the sampling sites. The ecological risks determined using the sediment quality guidelines (DEHP, VOCs, and TPH) and the mean probable effect level quotients (DEHP) were mostly acceptable. However, the two most representative industrial regions (the largest industrial area and the first industrial city) showed risks of concern for DEHP and TPH.
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Dietilexilftalato , Poluentes Ambientais , Petróleo , Ácidos Ftálicos , Poluentes Químicos da Água , Poluentes da Água , Rios/química , Poluentes Químicos da Água/análise , Medição de Risco , Plastificantes , Sedimentos Geológicos/química , Acrilamidas , China , Monitoramento AmbientalRESUMO
INTRODUCTION: Amivantamab-vmjw (amivantamab) is a bispecific EGFR/MET antibody approved for patients with advanced NSCLC with EGFR exon 20 insertion mutations, after prior therapy. Nevertheless, the benefits and safety of amivantamab in other EGFR-mutant lung cancer, with or without osimertinib, and with concurrent radiation therapy, are less known. METHODS: We queried the MD Anderson Lung Cancer GEMINI, Fred Hutchinson Cancer Research Center, University of California Davis Comprehensive Cancer Center, and Stanford Cancer Center's database for patients with EGFR-mutant NSCLC treated with amivantamab, not on a clinical trial. The data analyzed included initial response, duration of treatment, and concomitant radiation safety in overall population and prespecified subgroups. RESULTS: A total of 61 patients received amivantamab. Median age was 65 (31-81) years old; 72.1% were female; and 77% were patients with never smoking history. Median number of prior lines of therapies was four. On the basis of tumor's EGFR mutation, 39 patients were in the classical mutation cohort, 15 patients in the exon 20 cohort, and seven patients in the atypical cohort. There were 37 patients (58.7%) who received amivantamab concomitantly with osimertinib and 25 patients (39.1%) who received concomitant radiation. Furthermore, 54 patients were assessable for response in the overall population; 19 patients (45.2%) had clinical response and disease control rate (DCR) was 64.3%. In the classical mutation cohort of the 33 assessable patients, 12 (36.4%) had clinical response and DCR was 48.5%. In the atypical mutation cohort, six of the seven patients (85.7%) had clinical response and DCR was 100%. Of the 13 assessable patients in the exon 20 cohort, five patients (35.7%) had clinical response and DCR was 64.3%. Adverse events reported with amivantamab use were similar as previously described in product labeling. No additional toxicities were noted when amivantamab was given with radiation with or without osimertinib. CONCLUSIONS: Our real-world multicenter analysis revealed that amivantamab is a potentially effective treatment option for patients with EGFR mutations outside of exon 20 insertion mutations. The combination of osimertinib with amivantamab is safe and feasible. Radiation therapy also seems safe when administered sequentially or concurrently with amivantamab.
Assuntos
Acrilamidas , Anticorpos Biespecíficos , Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Indóis , Neoplasias Pulmonares , Pirimidinas , Humanos , Feminino , Idoso , Adulto , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Masculino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/induzido quimicamente , Antineoplásicos/uso terapêutico , Receptores ErbB/genética , Receptores ErbB/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/induzido quimicamente , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Mutação , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
The rational design of methodologies to control the neoformed compounds occurrence (NFCs), such as acrylamide and hydroxymethylfurfural (HMF) in roasted coffee, must consider the preservation of the bioactive compounds contained in this beverage. The aim of this work was to evaluate the integrated effect of yeast inoculation during the fermentation stage and the modification of roasting parameters on the final concentrations of NFCs and bioactive compounds of roasted coffee. A completely randomized factorial design was used to evaluate the effect of yeast inoculation (with and without inoculation), roasting temperature (150, 180 and 210 °C) and roast degree (medium, dark) on the (i) physicochemical characteristics (volume change, mass loss, water activity, non-enzymatic browning index, antioxidant capacity, total polyphenols, chlorogenic acid and caffeine) as well as HMF and acrylamide levels of roasted coffee. Response variables were analyzed separately by ANOVA and clustering of treatments was explored by PCA. Yeast inoculation did not significantly (p > 0.05) affect volume change, mass loss, antioxidant capacity, total polyphenols content, and caffeine contents. The interaction of evaluated factors significantly decreased (p < 0.05) the acrylamide and HMF contents of roasted coffee (43 % and 56.0 %, respectively). Based on PCA grouping the best treatments were medium roast at 210 °C (inoculated and uninoculated) and at 180 °C (inoculated). Under these conditions it is possible to produce a roasted coffee mitigated in neo formed contaminants that present the physicochemical properties of original product.
Assuntos
Coffea , Café , Café/química , Coffea/química , Saccharomyces cerevisiae , Cafeína , Antioxidantes/análise , Colômbia , Polifenóis/análise , AcrilamidasRESUMO
Acrylamide (AA) a widely used industrial chemical is also formed during food processing by the Maillard reaction, which makes its exposure to humans almost unavoidable. In this study, we used Schizosaccharomyces pombe as a model organism to investigate AA toxicity (10 or 20 mM concentration) in eukaryotes. In S. pombe, AA delays cell growth causes oxidative stress by enhancement of ROS production and triggers excitement of the antioxidant defence system resulting in the division arrest. Aronia fruit contains a variety of health-promoting substances with considerable antioxidant potential. Therefore, Aronia juice supplementation was tested to evaluate its protective effect against AA-derived perturbations of the organism. Cell treatment with several Aronia juice concentrations ranging from 0 to 2% revealed the best protective effect of 1 or 2% Aronia juice solutions. Both chosen Aronia juice concentrations alleviated AA toxicity through the improvement of the antioxidant cell capacity and metabolic activity by their strong ROS scavenging property. Efficiency of Aronia juice cell protection is dose dependent as the 2% solution led to significantly higher cellular defence compared with 1%. Due to the high similarity of biological processes of S. pombe with higher eukaryotes, the protective effect of Aronia juice against AA toxicity might also apply to higher organisms.
Assuntos
Photinia , Humanos , Photinia/química , Photinia/metabolismo , Antioxidantes/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Estresse Oxidativo , Extratos Vegetais/química , Acrilamidas/farmacologiaRESUMO
In this study, a composite hydrogel with a low swelling ratio, excellent mechanical properties, and good U (VI) adsorption capacity was developed by incorporating a metal-organic framework (MOF) with a poly (acrylamide-co-acrylic acid)/chitosan (P(AM-co-AA)/CS) composite. The CS chain, which contains NH2, reduces the swelling ratio of the hydrogel to 4.17 after 5 h of immersion in water. The coordinate bond between the MOF and carboxyl group on the surface of P(AM-co-AA)/CS improves the mechanical properties and stability of P(AM-co-AA)/CS. The U(VI) adsorption capacity of P(AM-co-AA)/CS/MOF-808 is 159.56 mg g-1 at C0 = 99.47 mg L-1 and pH = 8.0. The adsorption process is well fitted by the Langmuir isotherm and pseudo-second-order model. The P(AM-co-AA)/CS/MOF-808 also exhibits good repeatability and stability after five adsorption-desorption cycles. The uranium adsorption capacity of the developed adsorbent after one month in natural seawater is 6.2 mg g-1, and the rate of uranium adsorption on the hydrogel is 0.21 mg g-1 day-1.
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Quitosana , Estruturas Metalorgânicas , Urânio , Urânio/química , Quitosana/química , Hidrogéis/química , Concentração de Íons de Hidrogênio , Cinética , Água do Mar/química , Acrilamidas/química , AdsorçãoRESUMO
In this paper, a kind of superabsorbent resin (SAR) with superior quality for hygiene products was developed using Fructus Aurantii Immaturus pectin (FAIP) from Citrus aurantium L.. FAIP-g-AM/AMPS SAR was established by free radical graft co-polymerization with FAIP as skeleton structure, N, N'-Methylene-bis (acrylamide) (MBA) as the cross-linker. Meanwhile, the functional monomers of acrylamide (AM) and 2-acrylamido-2-methylpropane sulfonic acid (AMPS) were introduced. The structure and morphology of FAIP-g-AM/AMPS were characterized by FTIR, 13C NMR, XRD, SEM and TG-DSC analysis. The results confirmed that the AFIP-g-AM/AMPS SAR was successfully prepared, which exhibited a three-dimensional (3D) network structure and an excellent thermal stability. The absorption and retention capacity of FAIP-g-AM/AMPS was comparable to or even better than commercial diapers and sanitary napkins. Significantly, FAIP-g-AM/AMPS itself exhibited excellent antibacterial and safety. FAIP-g-AM/AMPS has an inhibition ratio of 97.1 % for Escherichia coli (E. coli) and 98.5 % for Staphylococcus aureus (S. aureus), and was non-irritating and non-allergic to the skin. In addition, FAIP-g-AM/AMPS presented amazing biodegradability and a weight loss reached 37.1 % after 30 days by soil burial test. The research provides a safe and high-performance SAR, which expected to be used in hygiene products such as baby diapers, adult incontinence pads and sanitary napkins.
Assuntos
Pectinas , Staphylococcus aureus , Pectinas/farmacologia , Escherichia coli , Antibacterianos/farmacologia , Antibacterianos/química , Acrilamidas/química , Cloreto de Sódio , AcrilamidaRESUMO
Using ionizing radiation in treating waste sludge from a drinking water treatment plant is a well-known technique. Sludge treated with ionizing radiation can be used as fertilizer in agriculture. In this paper, the effects of aging on the physicochemical characteristics, the content of microorganisms, molds, acrylamide, heavy metal concentration, and total nutrient content in waste sludge treated with e-beam and gamma irradiation were investigated. The possibility of using treated sludge as a fertilizer in agriculture was evaluated. It has been shown that the content of acrylamide in treated sludge after 15 months of storage does not exceed the limits for sludge to be used as fertilizer. If the sludge is stored in closed bags in a dark place, aging does not increase total microorganisms and molds. The research also showed that the sludge's physicochemical characteristics treated in this way do not decrease under the influence of aging. Finally, it has been shown that aging does not change the concentration of heavy metals and total nutrients in sludge treated by ionizing irradiation.
Assuntos
Água Potável , Metais Pesados , Esgotos/química , Solo/química , Fertilizantes/análise , Agricultura/métodos , Metais Pesados/análise , Radiação Ionizante , AcrilamidasRESUMO
Polymers, such as partially hydrolyzed polyacrylamide (HPAM), are widely used in oil fields to enhance or improve the recovery of crude oil from the reservoirs. It works by increasing the viscosity of the injected water, thus improving its mobility and oil recovery. However, during such enhanced oil recovery (EOR) operations, it also produces a huge quantity of water alongside oil. Depending on the age and the stage of the oil reserve, the oil field produces ~ 7-10 times more water than oil. Such water contains various types of toxic components, such as traces of crude oil, heavy metals, and different types of chemicals (used during EOR operations such as HPAM). Thus, a huge quantity of HPAM containing produced water generated worldwide requires proper treatment and usage. The possible toxicity of HPAM is still ambiguous, but its natural decomposition product, acrylamide, threatens humans' health and ecological environments. Therefore, the main challenge is the removal or degradation of HPAM in an environmentally safe manner from the produced water before proper disposal. Several chemical and thermal techniques are employed for the removal of HPAM, but they are not so environmentally friendly and somewhat expensive. Among different types of treatments, biodegradation with the aid of individual or mixed microbes (as biofilms) is touted to be an efficient and environmentally friendly way to solve the problem without harmful side effects. Many researchers have explored and reported the potential of such bioremediation technology with a variable removal efficiency of HPAM from the oil field produced water, both in lab scale and field scale studies. The current review is in line with United Nations Sustainability Goals, related to water security-UNSDG 6. It highlights the scale of such HPAM-based EOR applications, the challenge of produced water treatment, current possible solutions, and future possibilities to reuse such treated water sources for other applications.
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Campos de Petróleo e Gás , Petróleo , Acrilamidas , Resinas Acrílicas/química , Resinas Acrílicas/metabolismo , Monitoramento Ambiental , Humanos , Poluição da ÁguaRESUMO
Injectable, self-healing hydrogels with enhanced solubilization of hydrophobic drugs are urgently needed for antimicrobial intravaginal therapies. Here, we report the first hydrogel systems constructed of dynamic boronic esters cross-linking unimolecular micelles, which are a reservoir of antifungal hydrophobic drug molecules. The selective hydrophobization of hyperbranched polyglycidol with phenyl units in the core via ester or urethane bonds enabled the solubilization of clotrimazole, a water-insoluble drug of broad antifungal properties. The encapsulation efficiency of clotrimazole increases with the degree of the HbPGL core modification; however, the encapsulation is more favorable in the case of urethane derivatives. In addition, the rate of clotrimazole release was lower from HbPGL hydrophobized via urethane bonds than with ester linkages. In this work, we also revealed that the hydrophobization degree of HbPGL significantly influences the rheological properties of its hydrogels with poly(acrylamide-ran-2-acrylamidephenylboronic acid). The elastic strength of networks (GN) and the thermal stability of hydrogels increased along with the degree of HbPGL core hydrophobization. The degradation of the hydrogel constructed of the neat HbPGL was observed at approx. 40 °C, whereas the hydrogels constructed on HbPGL, where the monohydroxyl units were modified above 30 mol %, were stable above 50 °C. Moreover, the flow and self-healing ability of hydrogels were gradually decreased due to the reduced dynamics of macromolecules in the network as an effect of increased hydrophobicity. The changes in the rheological properties of hydrogels resulted from the engagement of phenyl units into the intermolecular hydrophobic interactions, which besides boronic esters constituted additional cross-links. This study demonstrates that the HbPGL core hydrophobized with phenyl units at 30 mol % degrees via urethane linkages is optimal in respect of the drug encapsulation efficiency and rheological properties including both self-healable and injectable behavior. This work is important because of a proper selection of a building component for the construction of a therapeutic hydrogel platform dedicated to the intravaginal delivery of hydrophobic drugs.
Assuntos
Ginecologia , Hidrogéis , Acrilamidas , Antifúngicos/farmacologia , Clotrimazol/farmacologia , Ésteres/química , Hidrogéis/química , Micelas , Uretana , ÁguaRESUMO
Injectability and self-setting properties are important factors to increase the efficiency of bone regeneration and reconstruction, thereby reducing the invasiveness of hard tissue engineering procedures. In this study, 63S bioactive glass (BG), nano-hydroxyapatite (n-HAp), alumina, titanium dioxide, and methylene bis-acrylamide (MBAM)-mediated polymeric crosslinking composites were prepared for the formulation of an efficient self-setting bone cement. According to the cytocompatibility and physicochemical analyses, all the samples qualified the standard of the bio-composite materials. They revealed high thermal stability, injectability, and self-setting ability supported by ~ 10.73% (maximum) mass loss, ~ 92-93% injectability and 24 ± 5 min of initial setting time. Moreover, a cellular adhesion and proliferation study was additionally performed with osteoblasts like MG-63 cells, which facilitate pseudopod-like cellular extensions on the BG/n-HAp composite scaffold surface. The SAM study was employed to non-invasively assess the self-setting properties of the composite bio-cement using the post injected distribution and physical properties of the phantom. These results validate the significant potential characteristics of the BG/n-HAp self-setting bio-cement (16:4:2:1) for promising minimal-invasive bone tissue engineering applications.
Assuntos
Cimentos Ósseos , Engenharia Tecidual , Acústica , Acrilamidas , Óxido de Alumínio , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Cimentos Ósseos/química , Materiais Dentários , Durapatita/química , Teste de Materiais/métodos , Engenharia Tecidual/métodosRESUMO
Osimertinib, as a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), targeting EGFR exon 19 deletions, L858R, and T790M, has shown robust clinical efficacy and promising survival advantages in a subset of non-small cell lung cancer (NSCLC) patients. However, osimertinib-treated patients ultimately develop secondary resistance. Besides EGFR C797S mutation and EGFR amplification, a rare EGFR mutation, L718V, has been reported to confer osimertinib resistance in the literature, which is developed in about 8.0% of osimertinib-resistant NSCLC patients. Although the National Comprehensive Cancer Network or Chinese Society of Clinical Oncology NSCLC guidelines recommend radiotherapy, anti-angiogenesis therapy, chemotherapy and or immunotherapy for the treatment of NSCLC patients who acquire resistance to osimertinib, the feasible treatment options for patients harboring EGFR L718V remain elusive. There is an unmet need to develop effective strategies to treat EGFR L718X-positive NSCLC patients. Herein, we report that a lung adenocarcinoma patient with acquired EGFR L718V mutation-mediated resistance towards osimertinib derived durable response to the second-generation EGFR-TKI afatinib with a progression-free survival of 18 months and counting. Our work provides clinical evidence to administer afatinib in metastatic NSCLC patients who develop EGFR L718V at progression to osimertinib and paves the way for its potential clinical utilization.
Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Acrilamidas , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Afatinib/uso terapêutico , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Berberine is a natural product that has long been used in traditional Chinese medicine due to its antimicrobial, anti-inflammatory and metabolism-regulatory properties. Osimertinib is the first third-generation EGFR-tyrosine kinase inhibitor (TKI) approved for the treatment of non-small cell lung cancer (NSCLC) with activating EGFR mutations and those resistant to earlier generation EGFR-TKIs due to a T790M mutation. However, emergence of acquired resistance to osimertinib limits its long-term efficacy in the clinic. One known mechanism of acquired resistance to osimertinib and other EGFR-TKIs is MET (c-MET) gene amplification. Here, we report that berberine, when combined with osimertinib, synergistically and selectively decreased the survival of several MET-amplified osimertinib-resistant EGFR mutant NSCLC cell lines with enhanced induction of apoptosis likely through Bim elevation and Mcl-1 reduction. Importantly, this combination effectively enhanced suppressive effect on the growth of MET-amplified osimertinib-resistant xenografts in nude mice and was well tolerated. Molecular modeling showed that berberine was able to bind to the kinase domain of non-phosphorylated MET, occupy the front of the binding pocket, and interact with the activation loop, in a similar way as other known MET inhibitors do. MET kinase assay showed clear concentration-dependent inhibitory effects of berberine against MET activity, confirming its kinase inhibitory activity. These findings collectively suggest that berberine can act as a naturally-existing MET inhibitor to synergize with osimertinib in overcoming osimertinib acquired resistance caused by MET amplification.
Assuntos
Acrilamidas/administração & dosagem , Compostos de Anilina/administração & dosagem , Antineoplásicos/administração & dosagem , Berberina/administração & dosagem , Produtos Biológicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos Nus , Proteínas Proto-Oncogênicas c-met/metabolismoRESUMO
Bacterial keratitis (BK) is a leading cause of visual impairment. The fluoroquinolone antibiotic moxifloxacin (Mox), being highly water-soluble, suffers from poor corneal penetration leading to unsatisfactory therapeutic outcomes in BK. Here, we prepared Mox-loaded co-polymeric nanoparticles (NPs) by entrapping the drug in co-polymeric NPs constituted by the self-assembly of a water-soluble copolymer, poly(ethylene glycol)-b-p(hydroxypropyl) methacrylamide (mPH). The polymer (mPH) was prepared using a radical polymerization technique at different mPEG: HPMA ratios of 1:70/100/150. The polymer/nanoparticles were characterized by GPC, CAC, DLS, SEM, XRD, DSC, FTIR, % DL, % EE, and release studies. The ex vivo muco-adhesiveness and corneal permeation ability were judged using a texture analyzer and Franz Diffusion Cells. In vitro cellular uptake, cytotoxicity, and safety assessment were performed using HCE cells in monolayers, spheroids, and multilayers in transwells. The DOE-optimized colloidal solution of Mox-mPH NPs (1:150) displayed a particle size of ~116 nm, superior drug loading (8.3%), entrapment (83.2%), robust mucoadhesion ex vivo, and ocular retention in vivo (~6 h) (judged by in vivo image analysis). The non-irritant formulation, Mox-mPH NPs (1:150) (proven by HET-CAM test) exhibited intense antimicrobial activity against P. aeruginosa, S. pneumoniae, and S. aureus in vitro analyzed by live-dead cells assay, zone of inhibition studies, and by determining the minimum inhibitory and bactericidal concentrations. The polymeric nanoparticles, mPH (1:150), decreased the opacity and the bacterial load compared to the other treatment groups. The studies warrant the safe and effective topical application of the Mox-mPH NPs solution in bacterial keratitis.
Assuntos
Ceratite , Nanopartículas , Acrilamidas , Córnea , Humanos , Moxifloxacina , Nanomedicina , Soluções Oftálmicas , Polímeros , Staphylococcus aureusRESUMO
The objective of this paper was to develop a preparative method for the separation and purification of phaseoloidin, entadamide A, and entadamide A-ß-D-glucopyranoside from the crude extract of Entada phaseoloides by high-speed countercurrent chromatography (HSCCC) for the first time. Optimized by orthogonal experiments, the extraction conditions were extraction temperature of 65°C, solid-to-liquid ratio of 1:15 (g/mL), ethanol concentration of 40%, and extraction time of 2.5 h. Using n-butanol-acetic acid-water (4:1:5, v/v/v) as the two-phase solvent system, 38.79 mg phaseoloidin (the purity was 99.3% with a recovery of 98.1%), 34.85 mg entadamide A (the purity was 96.4% with a recovery of 98.5%), and 33.97 mg entadamide A-ß-D-glucopyranoside (the purity was 98.6% with a recovery of 97.7%) were obtained from 500 mg crude extract by HSCCC in head-to-tail elution mode. The retention ratio of stationary phase was 51.0%. According to the antioxidant activity assays, phaseoloidin, entadamide A, and entadamide A-ß-D-glucopyranoside had certain scavenging abilities on 1,1-diphenyl-2-picrylhydrazyl free radicals and hydroxyl free radicals.
Assuntos
Acrilamidas , Distribuição Contracorrente/métodos , Fabaceae/química , Glucosídeos , Extratos Vegetais/química , Acrilamidas/análise , Acrilamidas/química , Acrilamidas/isolamento & purificação , Antioxidantes/análise , Antioxidantes/química , Antioxidantes/isolamento & purificação , Compostos de Bifenilo , Cromatografia Líquida de Alta Pressão , Glucosídeos/análise , Glucosídeos/química , Glucosídeos/isolamento & purificação , PicratosRESUMO
EGFR tyrosine kinase inhibitors (TKIs) are mainly used to treat non-small cell lung cancer; however, adverse effects such as severe diarrhea represent a major obstacle towards the continuation of EGFR-TKIs therapy. Chloride channels, which control the fluid flow in the intestinal lumen, are proposed as an important target to remediate EGFR-TKIs-induced diarrhea, but the mechanism remains unclear. The aim of this study was to clarify the mechanism underlying EGFR-TKIs-induced diarrhea with a particular focus on the role of intestinal chloride channels. Here, we show that osimertinib-treated rats exhibit diarrhea and an increase in fecal water content without showing any severe histopathological changes. This diarrhea was attenuated by intraperitoneal treatment with the calcium-activated chloride channel (CaCC) inhibitor CaCCinh-A01. These findings were confirmed in afatinib-treated rats with diarrhea. Moreover, treatment with the Japanese traditional herbal medicine, hangeshashinto (HST), decreased fecal water content and improved fecal appearance in rats treated with EGFR-TKIs. HST inhibited the ionomycin-induced CaCC activation in HEK293 cells in patch-clamp current experiments and its active ingredients were identified. In conclusion, secretory diarrhea induced by treatment with EGFR-TKIs might be partially mediated by the activation of CaCC. Therefore, blocking the CaCC could be a potential new treatment for EGFR-TKI-induced diarrhea.
Assuntos
Canais de Cloreto/antagonistas & inibidores , Canais de Cloreto/metabolismo , Diarreia/induzido quimicamente , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/toxicidade , Acrilamidas/toxicidade , Afatinib/toxicidade , Compostos de Anilina/toxicidade , Animais , Diarreia/patologia , Fezes/química , Células HEK293 , Humanos , Masculino , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Tiofenos/farmacologia , Água/químicaRESUMO
Despite the clinical success of the third-generation EGFR inhibitor osimertinib as a first-line treatment of EGFR-mutant non-small cell lung cancer (NSCLC), resistance arises due to the acquisition of EGFR second-site mutations and other mechanisms, which necessitates alternative therapies. Dacomitinib, a pan-HER inhibitor, is approved for first-line treatment and results in different acquired EGFR mutations than osimertinib that mediate on-target resistance. A combination of osimertinib and dacomitinib could therefore induce more durable responses by preventing the emergence of resistance. Here we present an integrated computational modeling and experimental approach to identify an optimal dosing schedule for osimertinib and dacomitinib combination therapy. We developed a predictive model that encompasses tumor heterogeneity and inter-subject pharmacokinetic variability to predict tumor evolution under different dosing schedules, parameterized using in vitro dose-response data. This model was validated using cell line data and used to identify an optimal combination dosing schedule. Our schedule was subsequently confirmed tolerable in an ongoing dose-escalation phase I clinical trial (NCT03810807), with some dose modifications, demonstrating that our rational modeling approach can be used to identify appropriate dosing for combination therapy in the clinical setting.