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2.
BMC Oral Health ; 22(1): 442, 2022 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-36229871

RESUMO

BACKGROUND: Temporary implant-retained restorations are required to support function and esthetics of the masticatory system until the final restoration is completed and delivered. Acrylic resins are commonly used in prosthetic dentistry and lately they have been used in three-dimensional (3D) printing technology. Since this technology it is fairly new, the number of studies on their susceptibility to microbial adhesion is low. Restorations placed even for a short period of time may become the reservoir for microorganisms that may affect the peri-implant tissues and trigger inflammation endangering further procedures. The aim of the study was to test the biofilm formation on acrylamide resins used to fabricate temporary restorations in 3D printing technology and to assess if the post-processing impacts microbial adhesion. METHODS: Disk-shaped samples were manufactured using the 3D printing technique from three commercially available UV-curable resins consisting of acrylate and methacrylate oligomers with various time and inhibitors of polymerization (NextDent MFH bleach, NextDent 3D Plus, MazicD Temp). The tested samples were raw, polished and glazed. The ability to create biofilm by oral streptococci (S. mutans, S. sanguinis, S. oralis, S. mitis) was tested, as well as species with higher pathogenic potential: Staphylococcus aureus, Staphylococcus epidermidis and Candida albicans. The roughness of the materials was measured by an atomic force microscope. Biofilm formation was assessed after 72 h of incubation by crystal violet staining with absorbance measurement, quantification of viable microorganisms, and imaging with a scanning electron microscope (SEM). RESULTS: Each tested species formed the biofilm on the samples of all three resins. Post-production processing resulted in reduced roughness parameters and biofilm abundance. Polishing and glazing reduced roughness parameters significantly in the NextDent resin group, while glazing alone caused significant surface smoothing in Mazic Temp. A thin layer of microbial biofilm covered glazed resin surfaces with a small number of microorganisms for all tested strains except S. oralis and S. epidermidis, while raw and polished surfaces were covered with a dense biofilm, rich in microorganisms. CONCLUSIONS: UV-curing acrylic resins used for fabricating temporary restorations in the 3D technology are the interim solution, but are susceptible to adhesion and biofilm formation by oral streptococci, staphylococci and Candida. Post-processing and particularly glazing process significantly reduce bacterial biofilm formation and the risk of failure of final restoration.


Assuntos
Resinas Acrílicas , Violeta Genciana , Acrilamidas , Acrilatos , Resinas Acrílicas/química , Biofilmes , Resinas Compostas , Humanos , Teste de Materiais , Metacrilatos , Impressão Tridimensional , Propriedades de Superfície
4.
Molecules ; 27(19)2022 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-36234890

RESUMO

Establishing the structure-property relationships of monomers and polymers via theoretical chemistry is vital for designing new polymer structures with a specific application. Developing bifunctional monomers with selective polymerizable sites is one of the strategies employed to obtain complex polymeric systems. In this work, a theoretical study on anilinium 2-acrylamide-2-methyl-1-propanesulfonate (ani-AMPS) and anilinium 4-styrenesulfonate (ani-SS) monomers and their respective doped polyaniline dimer (PAni-d AMPS or PAni-d SS) was performed. The study focused on understanding the susceptibility of the vinyl group to a radical attack and the conformation changes resulting from the coordinated covalent bond between sulfonate and aniliniun. Applying Density Functional Theory with the B3LYP functional and a basis set of 6 - 31 + G(d,p), the structures of the ani-AMPS, ani-SS, PAni-d AMPS, and PAni-d SS were optimized, and the different chemical descriptors were determined. The simulation showed that the reactivity of the vinyl group in the ani-AMPS is slightly higher. The sulfonate group undergoes a conformational change when bonding with PAni-d AMPS or PAni-d SS compared to its respective bifunctional monomer. Additionally, the electronegativity of PAni-d depends on the dopant's structure. Thus, the bonded spacer between the vinyl and sulfonate groups (dopant) plays a notable role in the final characteristics of ani-AMPS, ani-SS, PAni-d AMPS, and PAni-d SS.


Assuntos
Compostos de Anilina , Polímeros , Acrilamidas , Alcanossulfonatos , Compostos de Anilina/química , Modelos Teóricos , Polímeros/química , Cloreto de Polivinila
5.
J Mater Chem B ; 10(41): 8462-8477, 2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36197075

RESUMO

A new acrylamide monomer, N-isopropyl-N-(3-(isopropylamino)-3-oxopropyl)acrylamide (M3i), consisting of both isopropyl and isopropylamidopropyl moieties, has been synthesized from isopropylamine and N-isopropylacrylamide via an aza-Michael addition reaction followed by amidation with acryloyl chloride. The homopolymer of M3i (polyM3i) and a series of random copolymers of M3i and poly(ethylene glycol)methyl ether acrylate (PEGA: CH2CHCO2(CH2CH2O)nMe, Mn = 480, n = 9 on average) with varying compositions have been synthesized via reversible addition-fragmentation chain transfer polymerization using 2-(dodecylthiocarbonothioylthio)-2-methylpropionic acid (DDMAT) as well as 1-phenylethyl phenyl dithioacetate (PEPD) as a RAFT agent. These polymers have been characterized by 1H NMR, FTIR, GPC, UV-Vis, fluorescence, TGDTA, DSC, DLS, and TEM techniques. A lower critical solution temperature (LCST) and glass transition temperature (Tg) for polyM3i prepared using DDMAT were observed at 17 and 133 °C, respectively, while for a polymer formed using PEPD, no LCST was observed until 0 °C and its observed Tg was found at 127.3 °C. The polymers are thermally stable up to 300 °C. Upon an increase in the M3i content in the copolymers, LCST decreases, Tg increases, and the apparent hydrodynamic diameter decreases. Moreover, the effects of concentration and the addition of urea and sodium chloride on the LCST of the copolymer with an LCST close to body temperature were studied. Owing to the incorporation of PEGA, a higher critical micellar concentration and larger TEM particle size of this copolymer were observed with respect to those of polyM3i. The usefulness of the micelles of the copolymers as nano-carriers for the drug doxorubicin was explored. The in vitro tumoricidal activity of the micelles of the doxorubicin-loaded copolymers was also assessed against Dalton's lymphoma cells.


Assuntos
Antineoplásicos , Éteres Metílicos , Micelas , Acrilamida , Cloreto de Sódio , Polímeros/química , Acrilamidas/química , Doxorrubicina/farmacologia , Doxorrubicina/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Polietilenoglicóis/química , Ureia
6.
Anal Biochem ; 658: 114926, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36183795

RESUMO

Bacteriocins exhibited a wide spectrum of antibacterial activity against different pathogens. The aim of current study was to characterize the bacteriocins produced by Bifidobacterium spp. isolated from ruminants. The Bifidobacterium isolates were identified as B. longum, B. pseudolongum, B. bifidum, B. thermophilum, B. boum, B. merycicum and B. ruminantium. Bacteriocins were found to be pH stable, heat resistant, highly diffusible, NaCl tolerant and resistant to UV radiations. SDS, EDTA and urea induced 14%, 21% and 24% bacteriocins activity loss. Modified MRS broth (1% tryptone, 1% yeast extract and 2% glucose) was found to be the best nutrient medium for optimal production of bacteriocins. Minimum inhibitory concentration (MIC) values varied from 300 µl/ml to 500 µl/ml and minimum bactericidal concentration (MBC) values ranged from 500 µl/ml to >500 µl/ml for E. coli and S. aureus respectively. The highest protein concentration (29.0248 mg/ml) was recorded for Bifidobacteria bacteriocin produced by B. longum. Tricine-Sodium Dodecyl Sulfate-Poly Acrylamide Gel Electrophoresis (SDS-PAGE) revealed that molecular weight of isolated bifidobacterial bacteriocins was in the range of 3.6 kDa-30 kDa. Current study indicated that bifidobacterial bacteriocins have considerable potential to be used as biopreservative.


Assuntos
Bacteriocinas , Bifidobacterium , Ruminantes , Animais , Acrilamidas , Antibacterianos/farmacologia , Antibacterianos/química , Bacteriocinas/farmacologia , Bacteriocinas/química , Ácido Edético , Escherichia coli , Glucose , Concentração de Íons de Hidrogênio , Ruminantes/microbiologia , Cloreto de Sódio , Dodecilsulfato de Sódio , Staphylococcus aureus , Ureia
7.
Nanotechnology ; 34(4)2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36215962

RESUMO

The present work reports the antibacterial activity againstPseudomonasaeruginosaof a nanocomposite made of zinc oxide nanoparticles dispersed in a poly(acrylamide-co-hydroxyethylmethacrylate) matrix (PAAm-Hema-ZnONPs). Thein situsynthesis of ZnONPs inside of the PAAm-Hema crosslinked network is described. Moreover, the physicochemical properties of the PAAm-Hema-ZnONPs nanocomposite are analyzed. The results confirm that the PAAm-Hema hydrogel provides an excellent scaffold to generate ZnONPs. The presence of ZnONPs inside the hydrogel was confirmed by UV-visible (band at 320 nm), by Infrared spectroscopy (peak at 470 cm-1), SEM, and TEM images. The presence of NPs in PAAm-Hema diminish the swelling percentage by 70%, and the Young modulus by 33.7%, compared with pristine hydrogel. The 75% of ZnONPs are released from the nanocomposite after 48 h of spontaneous diffusion, allowing the use of the nanocomposite as an antibacterial agent.In vitro, the agar diffusion test presents an inhibition halo againstP. aeruginosabacteria 50% higher than the unloaded hydrogel. Also, the PAAm-Hema-ZnONPs live/dead test shows 54% of dead cells more than the hydrogel. These results suggest that the easy, one-step way generated composites can be used in biomedical applications as antimicrobial agents.


Assuntos
Nanocompostos , Nanopartículas , Óxido de Zinco , Óxidos , Nanocompostos/química , Óxido de Zinco/farmacologia , Óxido de Zinco/química , Antibacterianos/química , Hidrogéis/farmacologia , Hidrogéis/química , Acrilamidas
8.
Environ Monit Assess ; 194(12): 875, 2022 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-36227428

RESUMO

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.


Assuntos
Campos de Petróleo e Gás , Petróleo , Acrilamidas , Resinas Acrílicas/química , Resinas Acrílicas/metabolismo , Monitoramento Ambiental , Humanos , Poluição da Água
10.
Mol Cancer ; 21(1): 193, 2022 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-36203195

RESUMO

EGFR-TKI targeted therapy is one of the most effective treatments for lung cancer patients harboring EGFR activating mutations. However, inhibition response is easily attenuated by drug resistance, which is mainly due to bypass activation or downstream activation. Herein, we established osimertinib-resistant cells by stepwise dose-escalation in vitro and an osimertinib-resistant patient-derived xenograft model through persistent treatment in vivo. Phosphorylated proteomics identified that MEK1 and AKT1/2 were abnormally activated in resistant cells compared with parental cells. Likewise, EGFR inhibition by osimertinib induced activation of MEK1 and AKT1/2, which weakened osimertinib sensitivity in NSCLC cells. Consequently, this study aimed to identify a novel inhibitor which could suppress resistant cell growth by dual targeting of MEK1 and AKT1/2. Based on computational screening, we identified that costunolide could interact with MEK1 and AKT1/2. Further exploration using in vitro kinase assays validated that costunolide inhibited the kinase activity of MEK1 and AKT1/2, which restrained downstream ERK-RSK2 and GSK3ß signal transduction and significantly induced cell apoptosis. Remarkably, the combination of osimertinib and costunolide showed synergistic or additive inhibitory effects on tumor growth in osimertinib-resistant cell lines and PDX model. Hence, this study highlights a potential therapeutic strategy for osimertinib-resistant patients through targeting of MEK1 and AKT1/2 by costunolide.


Assuntos
Receptores ErbB , Neoplasias Pulmonares , Acrilamidas , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Glicogênio Sintase Quinase 3 beta/genética , Humanos , Indóis , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/genética , Pirimidinas , Sesquiterpenos
11.
Nan Fang Yi Ke Da Xue Xue Bao ; 42(9): 1403-1409, 2022 Sep 20.
Artigo em Chinês | MEDLINE | ID: mdl-36210715

RESUMO

OBJECTIVE: To investigate the effects of AZD9291 on the proliferation and migration of nasopharyngeal carcinoma cells. METHODS: Nasopharyngeal carcinoma HNE1 and CNE2Z cells were treated with AZD9291 at the doses of 0.5, 1, 2, 4, and 8 µmol/L and at the doses of 1, 2, 4, 8, and 16 µmol/L, respectively. Cell survival was measured using CCK8 assay, and proliferation inhibition of the cells after AZD9291 treatment was examined with colony-forming assay; the cell repair and migration abilities were determined using scratch assay and Transwell experiment. The expressions of EGFR-related signaling proteins and migration-related proteins were detected using Western blotting. RESULTS: The results of CCK8 assay and colonyforming assay showed that AZD9291 significantly inhibited the viability and proliferation of both HNE1 and CNE2Z cells (P < 0.01). AZD9291 treatment also attenuated the migration ability of HNE1 and CNE2Z cells (P < 0.01). Western blotting showed that, as the concentration of AZD9291 increased, the expression levels of the proteins involved in the PI3K-AKT-mTOR signaling pathway were lowered progressively (P < 0.01), resulting in inhibition of migration of HNE1 and CNE2Z cells (P < 0.01). CONCLUSION: AZD9291 suppresses proliferation and attenuates repair and migration capacities of nasopharyngeal carcinoma cells by inhibiting the EGFR/PI3K/AKT/mTOR signaling pathway, suggesting the potential value of AZD9291 in the treatment of nasopharyngeal carcinoma.


Assuntos
Neoplasias Nasofaríngeas , Fosfatidilinositol 3-Quinases , Acrilamidas , Compostos de Anilina , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Receptores ErbB , Humanos , Indóis , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas , Serina-Treonina Quinases TOR/metabolismo
12.
Cells ; 11(19)2022 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-36231025

RESUMO

Pyrotinib is an irreversible pan-ErbB receptor tyrosine kinase inhibitor, designed for the therapy of HER2-positive breast cancers. Inhibition of the epidermal growth factor receptor (EGFR, HER family) efficiently and selectively suppresses the proliferation of human TSC2-deficient smooth muscle cells and reverses lung changes in LAM/TSC. Our pilot study indicated that pyrotinib dramatically restrained the vitality of TSC2-deficient cells compared to its limited impact on TSC2-expression cells. Pyrotinib induced G1-phase arrest and triggered apoptosis by blocking abnormally activated CD24 in TSC2-deficient cells. CD24 is not only an important immune checkpoint, but is also involved in the regulation of signaling pathways. Pyrotinib inhibited the nuclear import of pEGFR and restrained the pEGFR/pSTAT3 signals, which directly boosted the transcriptional expression of CD24 by binding to its promoter region. In reverse, CD24 enhanced pEGFR function by directly binding. Pyrotinib specifically targeted TSC2-deficient cells, inhibited tumor cell viability and induced apoptosis through EGFR-STAT3/CD24 Loop in vivo and in vitro. Thus, pyrotinib may be a promising new therapeutic drug for TSC treatment.


Assuntos
Receptores ErbB , Inibidores de Proteínas Quinases , Acrilamidas , Aminoquinolinas , Antígeno CD24 , Carotenoides , Sobrevivência Celular , Humanos , Projetos Piloto , Fator de Transcrição STAT3 , Vitamina A/análogos & derivados
13.
PLoS One ; 17(10): e0268592, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36206263

RESUMO

Fetuin-A is a liver derived plasma protein showing highest serum concentrations in utero, preterm infants, and neonates. Fetuin-A is also present in cerebrospinal fluid (CSF). The origin of CSF fetuin-A, blood-derived via the blood-CSF barrier or synthesized intrathecally, is presently unclear. Fetuin-A prevents ectopic calcification by stabilizing calcium and phosphate as colloidal calciprotein particles mediating their transport and clearance. Thus, fetuin-A plays a suppressive role in inflammation. Fetuin-A is a negative acute-phase protein under investigation as a biomarker for multiple sclerosis (MS). Here we studied the association of pediatric inflammatory CNS diseases with fetuin-A glycosylation and phosphorylation. Paired blood and CSF samples from 66 children were included in the study. Concentration measurements were performed using a commercial human fetuin-A/AHSG ELISA. Of 60 pairs, 23 pairs were analyzed by SDS-PAGE following glycosidase digestion with PNGase-F and Sialidase-AU. Phosphorylation was analyzed in 43 pairs by Phos-TagTM acrylamide electrophoresis following alkaline phosphatase digestion. Mean serum and CSF fetuin-A levels were 0.30 ± 0.06 mg/ml and 0.644 ± 0.55 µg/ml, respectively. This study showed that serum fetuin-A levels decreased in inflammation corroborating its role as a negative acute-phase protein. Blood-CSF barrier disruption was associated with elevated fetuin-A in CSF. A strong positive correlation was found between the CSF fetuin-A/serum fetuin-A quotient and the CSF albumin/serum albumin quotient, suggesting predominantly transport across the blood-CSF barrier rather than intrathecal fetuin-A synthesis. Sialidase digestion showed increased asialofetuin-A levels in serum and CSF samples from children with neuroinflammatory diseases. Desialylation enhanced hepatic fetuin-A clearance via the asialoglycoprotein receptor thus rapidly reducing serum levels during inflammation. Phosphorylation of fetuin-A was more abundant in serum samples than in CSF, suggesting that phosphorylation may regulate fetuin-A influx into the CNS. These results may help establish Fetuin-A as a potential biomarker for neuroinflammatory diseases.


Assuntos
Cálcio , alfa-2-Glicoproteína-HS , Acrilamidas/metabolismo , Proteínas de Fase Aguda/metabolismo , Fosfatase Alcalina/metabolismo , Receptor de Asialoglicoproteína/metabolismo , Biomarcadores , Cálcio/metabolismo , Doenças do Sistema Nervoso Central , Criança , Glicosilação , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Inflamação/metabolismo , Fígado/metabolismo , Neuraminidase/metabolismo , Fosfatos/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional , Albumina Sérica/metabolismo , alfa-2-Glicoproteína-HS/metabolismo , alfa-Fetoproteínas/metabolismo
14.
Med Oncol ; 39(12): 195, 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36071367

RESUMO

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that is effective against the EGFR T790M mutation in patients with advanced non-small-cell lung cancer (NSCLC). However, acquired resistance appears invariably due to several mechanisms. The strategy of using EGF-targeted nanobodies (Nbs) to block the initial step of the EGFR pathway constitutes a new research area. Nbs offer several advantages compared to traditional mAbs, such as their reduced size, increased stability, and tissue penetration, which provide key advantages for targeting soluble tumoral growth factors. In this study we investigated the efficacy of anti-EGF Nbs to reduce Osimertinib resistance. Two anti-EGF Nbs, generated in our laboratory, were shown to inhibit cell viability and colony formation in PC9 and PC9-derived osimertinib-resistant cell lines. The combination of these Nbs with osimertinib improved the antitumor efficacy of this EGFR-TKI in cell viability and colony formation experiments. In a mechanistic study of the EGFR pathway, the combination treatment dampened the activation of downstream proteins such as Akt and Erk1/2 MAP kinases. In addition, it increased cellular apoptosis and decreased the expression of Hes1, a cancer stem cell marker involved in metastasis and osimertinib resistance. We conclude that the addition of anti-EGF nanobodies enhances the antitumor properties of osimertinib, thus representing a potentially effective strategy for NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Anticorpos de Domínio Único , Acrilamidas , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Humanos , Indóis , Neoplasias Pulmonares/patologia , Mutação , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas , Anticorpos de Domínio Único/genética , Anticorpos de Domínio Único/farmacologia
15.
Anticancer Drugs ; 33(9): 963-965, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-36136993

RESUMO

Heterogeneity in the acquired genetic cause of osimertinib resistance leads to difficulties in understanding and addressing molecular mechanisms of resistance in clinical practice. Recent studies and clinical cases established that altered BRAF could drive osimertinib resistance in an EGFR-independent manner. Herein, we present a case in which an EGFR-positive, MET-amplified nonsmall cell lung cancer (NSCLC) patient acquired BRAF p.D594N mutation on third-line osimertinib plus crizotinib and responded to seventh-line treatment with osimertinib plus MEK inhibitor trametinib. Disease control was maintained for 6 months. BRAF p.D594N is a kinase impaired mutation but leads to increased MEK/ERK signaling, which could activate the downstream signaling of EGFR and induce drug resistance. There has been preclinical evidence supporting dual inhibition of MEK and EGFR for overcoming this resistance. To the best of our knowledge, our case is the first to provide clinical evidence that trametinib plus osimertinib was effective for EGFR-mutant NSCLC patients with acquired BRAF p.D594N mutation. More supporting data and systematic validation studies are needed for comprehensive understanding of this therapy strategy and future applications.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Fibrossarcoma , Neoplasias Pulmonares , Acrilamidas , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Crizotinibe/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Fibrossarcoma/tratamento farmacológico , Humanos , Indóis , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Quinases de Proteína Quinase Ativadas por Mitógeno , Mutação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas , Pirimidinas , Pirimidinonas
16.
Curr Oncol ; 29(9): 6053-6067, 2022 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-36135045

RESUMO

BACKGROUND: The overexpression of the human epidermal growth factor receptor-2 (HER2) gene is present in 20~25% of breast cancer (BC) patients, contributing to an inferior prognosis. Recent clinical trials showed that pyrotinib has promising antitumor activities and acceptable tolerability for those patients (ClinicalTrials.gov, NCT03080805 and NCT02422199). Therefore, this study aims to assess the cost-effectiveness of pyrotinib plus capecitabine versus lapatinib plus capecitabine for patients with HER2-positive metastatic BC after prior trastuzumab. METHODS: A lifetime-partitioned survival model was established to evaluate health and economic outcomes with different treatment strategies. The primary outcome was the incremental cost-effectiveness ratio (ICER). Data were derived from the published literature, clinical trials, expert opinions, and other local charges. Sensitivity analyses were performed to assess the robustness of the findings. Scenario analyses were developed to make further evaluations. RESULTS: The pyrotinib regimen had significant advantages over the lapatinib regimen after enrolling in the National Reimbursement Drug List (NRDL), with cost savings of USD 15,599.27 and a gain of 0.53 QALYs. Meanwhile, before enrolling in NRDL, the pyrotinib regimen afforded the same QALYs at a higher incremental cost of USD 45,400.64 versus the lapatinib regimen, producing an ICER of USD 85,944.79 per QALY. Scenario analyses yielded similar results. Sensitivity analyses suggested stability in the cost-effectiveness findings. CONCLUSIONS: Compared to lapatinib plus capecitabine, the pyrotinib plus capecitabine enrolled in NRDL is a cost-effective alternative second-line treatment for patients with HER2-positive metastatic BC in China.


Assuntos
Neoplasias da Mama , Segunda Neoplasia Primária , Acrilamidas , Aminoquinolinas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Capecitabina/uso terapêutico , Ensaios Clínicos como Assunto , Análise Custo-Benefício , Feminino , Humanos , Cobertura do Seguro , Lapatinib/uso terapêutico , Trastuzumab/uso terapêutico
18.
Bioorg Med Chem Lett ; 75: 128970, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36064123

RESUMO

Based on EGFR-TKI Osimertinib as lead compound, a series of novel macrocyclic derivatives bearing aniline pyrimidine scaffolds were designed and synthesized by macrocyclization. Their structures were identified by 1H NMR, 13C NMR, 19F NMR and HRMS. The pharmacological activities of the target compounds were tested and the preliminary structure-activity relationship was discussed. Among them, 17-membered ring compound H1 displayed the best inhibitory activities against EGFRL858R/T790M and EGFRd746-750/T790M with IC50 value of 2.92 nM and 0.34 nM, respectively. Exhilaratingly, 17-membered ring compound H7 possessed the most potent antiproliferative activity against BaF3-EGFRdel19/T790M cell lines (IC50 = 0.035 µm), which rivaled that of Osimertinib (IC50 = 0.033 µm).


Assuntos
Antineoplásicos , Neoplasias Pulmonares , Acrilamidas , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Antineoplásicos/química , Proliferação de Células , Receptores ErbB , Humanos , Indóis , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Relação Estrutura-Atividade
19.
J Med Chem ; 65(19): 13052-13073, 2022 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-36178776

RESUMO

Addressing resistance to third-generation EGFR TKIs such as osimertinib via the EGFRC797S mutation remains a highly unmet need in EGFR-driven non-small-cell lung cancer (NSCLC). Herein, we present the discovery of the allosteric EGFR inhibitor 57, a novel fourth-generation inhibitor to overcome EGFRC797S-mediated resistance in patients harboring the activating EGFRL858R mutation. 57 exhibits an improved potency compared to previous allosteric EGFR inhibitors. To our knowledge, 57 is the first allosteric EGFR inhibitor that demonstrates robust tumor regression in a mutant EGFRL858R/C797S tumor model. Additionally, 57 is active in an H1975 EGFRL858R/T790M NSCLC xenograft model and shows superior efficacy in combination with osimertinib compared to the single agents. Our data highlight the potential of 57 as a single agent against EGFRL858R/C797S and EGFRL858R/T790M/C797S and as combination therapy for EGFRL858R- and EGFRL858R/T790M-driven NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Acrilamidas , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Humanos , Indóis , Neoplasias Pulmonares/patologia , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas
20.
J Org Chem ; 87(19): 13073-13088, 2022 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-36163013

RESUMO

A Co(III)-catalyzed redox-neutral [4 + 2] annulation of N-chlorobenzamides/acrylamides with substituted alkenes at ambient temperature is demonstrated. Using this protocol, pharmaceutically important 3,4-dihydroisoquinolinone derivatives were synthesized in good yields. Intriguingly, the synthetically useful functional group of allylic coupling partners such as sulfonyl, carbonate, acetate, phosphate, amide, nitrile, and silane were retained in the final cyclized product. The present annulation reaction was compatible with various substituted benzamides and allylic coupling partners. To support the proposed reaction mechanism, competition experiments, deuterium labeling studies, and kinetic isotope effect studies were performed.


Assuntos
Alcenos , Cobalto , Acetatos , Acrilamidas , Amidas , Benzamidas , Catálise , Deutério , Nitrilas , Fosfatos , Silanos , Estereoisomerismo
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