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This study outlines the development of a low line density, small blaze angle grating, optimized for a visible to short-wave infrared hyperspectral camera. An analysis of grating specifications was conducted to meet the precise requirements of this application, particularly focusing on the stringent tolerance limits for the blaze angle. A specialized ruling tool adjustment device was designed to adhere to these exacting blaze angle tolerances. The grating groove shape was examined using atomic force microscopy (AFM), and the theoretical diffraction efficiency of the grating was calculated based on these observations. Additionally, laser-based methods were employed to measure the actual diffraction efficiency of the grating, while interferometry was used to assess the grating's diffraction wavefront. The test results demonstrate our capability to fabricate high-quality gratings with a low line density and small blaze angles that are suitable for advanced hyperspectral imaging applications.
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A 300â mm×500â mm large-area echelle grating with groove density of 79 grooves/mm is fabricated for the spectrometer of the fiber array solar optical telescope (FASOT). This paper focusses on measurement methods of the grating performance. We present a method to evaluate the grating's stray light intensity, which is measured to a level of 10-4. The directly measured grating efficiency is approximately 90% of the designed value, and an indirect measurement method based on the grating groove profile is proposed. Based on the Rayleigh criterion and the grating diffraction wavefront, a physical optics method and a geometric grating method are proposed and are used to calculate the actual grating resolving power; the calculated results exceed 95% of the grating's theoretical resolving power. These results show that the CIOMP-6 ruling engine has sufficient precision to fabricate high-quality, large-area echelle gratings.
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BACKGROUND: ClpP is important for bacterial growth and plays an indispensable role in cellular protein quality control systems by refolding or degrading damaged proteins, but the physiological significance of ClpP in Enterococcus faecalis remains obscure. A clpP deletion mutant (â³clpP) was constructed using the E. faecalis OG1RF strain to clarify the effect of ClpP on E. faecalis. The global abundance of proteins was determined by a mass spectrometer with tandem mass tag labeling. RESULTS: The ΔclpP mutant strain showed impaired growth at 20 °C or 45 °C at 5% NaCl or 2 mM H2O2. The number of surviving ΔclpP mutants decreased after exposure to the high concentration (50× minimal inhibitory concentration) of linezolid or minocycline for 96 h. The ΔclpP mutant strain also demonstrated decreased biofilm formation but increased virulence in a Galleria mellonella model. The mass spectrometry proteomics data indicated that the abundances of 135 proteins changed (111 increased, 24 decreased) in the ΔclpP mutant strain. Among those, the abundances of stress response or virulence relating proteins: FsrA response regulator, gelatinase GelE, regulatory protein Spx (spxA), heat-inducible transcription repressor HrcA, transcriptional regulator CtsR, ATPase/chaperone ClpC, acetyl esterase/lipase, and chaperonin GroEL increased in the ΔclpP mutant strain; however, the abundances of ribosomal protein L4/L1 family protein (rplD), ribosomal protein L7/L12 (rplL2), 50S ribosomal protein L13 (rplM), L18 (rplR), L20 (rplT), 30S ribosomal protein S14 (rpsN2) and S18 (rpsR) all decreased. The abundances of biofilm formation-related adapter protein MecA increased, while the abundances of dihydroorotase (pyrC), orotate phosphoribosyltransferase (pyrE), and orotidine-5'-phosphate decarboxylase (pyrF) all decreased in the ΔclpP mutant strain. CONCLUSION: The present study demonstrates that ClpP participates in stress tolerance, biofilm formation, antimicrobial tolerance, and virulence of E. faecalis.
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Antibacterianos/farmacologia , Endopeptidase Clp/genética , Enterococcus faecalis/patogenicidade , Deleção de Genes , Proteômica/métodos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Biofilmes , Farmacorresistência Bacteriana , Endopeptidase Clp/metabolismo , Enterococcus faecalis/fisiologia , Linezolida/farmacologia , Minociclina/farmacologia , Estresse Fisiológico , Espectrometria de Massas em Tandem , VirulênciaRESUMO
Measuring mirror requirements and their impact on groove errors are related to the error compensation strategy for a ruling engine. We analyze why the measuring mirror of the CIOMP-6 engine affects the groove straightness and the grating diffraction wavefront. We study a theoretical model of the relationship between the measuring mirror's surface shape error and the grating wavefront, propose a requirement for the measuring mirror surface shape error, and reprocess the measuring mirror. Comparative ruling experiments prove that the grating's wavefront quality at the diffraction order along the groove direction improved significantly after reprocessing of the measuring mirror.
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Cytochrome P450 2E1 (CYP2E1) plays a vital role in drug-induced hepatotoxicity and cancers (e.g. lung and bladder cancer), since it is responsible for metabolizing a number of medications and environmental toxins to reactive intermediate metabolites. CYP2E1 was recently found to be the highest expressed CYP enzyme in human livers using a proteomics approach, and CYP2E1-related toxicity is strongly associated with its protein level that shows significant inter-individual variability related to ethnicity, age, and sex. Furthermore, the expression of CYP2E1 demonstrates regulation by extensive genetic polymorphism, endogenous hormones, cytokines, xenobiotics, and varying pathological states. Over the past decade, the knowledge of pharmacology, toxicology, and biology about CYP2E1 has grown remarkably, but the research progress has yet to be summarized. This study presents a timely systematic review on CYP2E1's xenobiotic metabolism, genetic polymorphism, and inhibitors, with the focus on their clinical relevance for the efficacy and toxicity of various CYP2E1 substrates. Moreover, several knowledge gaps have been identified towards fully understanding the potential interactions among different CYP2E1 substrates in clinical settings. Through in-depth analyses of these knowns and unknowns, we expect this review will aid in future drug development and improve management of CYP2E1 related clinical toxicity.
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Citocromo P-450 CYP2E1/metabolismo , Xenobióticos/metabolismo , Animais , HumanosRESUMO
PURPOSE: To investigate the feasibility of exploiting amorphous calcium phosphate (ACP) formed in situ from chitosan calcium microspheres and phosphate ions in water during brushing for caries control. METHODS: A prototype toothpaste, namely Chi-ACP paste, was specially formulated containing CaCl2/chitosan microspheres. The efficiency of Chi-ACP paste for remineralization on human tooth enamel was evaluated via an in vitro pH cycling approach. After 15 demineralization/remineralization cycles, the treated teeth were analyzed using scanning electron microscope (SEM) /energy dispersive X-ray spectroscopy (EDX), and polarized light microscope (PLM). RESULTS: EDX analysis showed the treated enamel in the Chi-ACP paste group had statistically significantly higher calcium content and Ca/P weight ratios than those in the negative control group, while the MI plus group had a slightly higher Ca content and a slightly higher Ca/P weight ratio. PLM analysis revealed that the Chi-ACP paste group had a larger remineralization band in treated enamel than the negative control group, although there was no statistically significant difference on the demineralization depths in the enamel among the three groups. CLINICAL SIGNIFICANCE: Antibacterial chitosan could be used to encapsulate CaCl2 and then formulated into toothpaste for caries control through in-situ formed amorphous calcium phosphate (ACP) during brushing.
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Anti-Infecciosos , Quitosana , Microesferas , Remineralização Dentária , Cremes Dentais , Anti-Infecciosos/administração & dosagem , Caseínas , Quitosana/uso terapêutico , Esmalte Dentário/efeitos dos fármacos , HumanosRESUMO
2-Selenouridine ((Se)U) is one of the naturally occurring modifications of Se-tRNAs ((Se)U-RNA) at the wobble position of the anticodon loop. Its role in the RNA-RNA interaction, especially during the mRNA decoding, is elusive. To assist the research exploration, herein we report the enzymatic synthesis of the (Se)U-RNA via 2-selenouridine triphosphate ((Se)UTP) synthesis and RNA transcription. Moreover, we have demonstrated that the synthesized (Se)UTP is stable and recognizable by T7 RNA polymerase. Under the optimized conditions, the transcription yield of (Se)U-RNA can reach up to 85% of the corresponding native RNA. Furthermore, the transcribed (Se)U-hammerhead ribozyme has the similar activity as the corresponding native, which suggests usefulness of (Se)U-RNAs in function and structure studies of noncoding RNAs, including the Se-tRNAs.
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Compostos Organosselênicos/síntese química , RNA/genética , Transcrição Gênica , Uridina Trifosfato/análogos & derivados , Anticódon , Catálise , RNA Polimerases Dirigidas por DNA/química , RNA Polimerases Dirigidas por DNA/genética , Modelos Moleculares , Conformação de Ácido Nucleico , Compostos Organosselênicos/química , RNA/química , RNA Catalítico/química , RNA Catalítico/genética , RNA Mensageiro/química , RNA Mensageiro/genética , Uridina Trifosfato/síntese química , Uridina Trifosfato/química , Proteínas Virais/química , Proteínas Virais/genéticaRESUMO
Recent studies have implied that aberration of miR-24 is linked to various human cancers. However, its role in non-small cell lung cancer (NSCLC) remains obscure. Here, we found that miR-24 was significantly upregulated in NSCLC tissues and patients' serum. High expression of miR-24 in patients' serum was independently correlated with a shorter overall survival of NSCLC patients. Depletion of miR-24 inhibited cell proliferation and anchorage-independent survival ability in lung cancer cell lines and reduced tumor formation ability in nude mice. Nuclear apoptosis-inducing factor 1 (NAIF1) was identified to be a functional target of miR-24 in the human lung. Next, we observed that the NAIF1 mRNA expression level in NSCLC tissues was suppressed in comparison to that in adjacent normal tissues. Restoration of NAIF1 in lung cancer cell inhibited cell proliferation and anchorage-independent survival ability, which were found to be similar with those from transfecting a miR-24 inhibitor into lung cancer cells. In conclusion, our study demonstrated that miR-24 was upregulated in NSCLC, and suppressing the expression of miR-24 inhibited tumor characteristics. MiR-24 acted as an oncomir, at least partially through regulation of its functional target NAIF1 in NSCLC. MiR-24 may serve as a novel potential biomarker for NSCLC diagnosis and prognosis.
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Proteínas Reguladoras de Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células , Neoplasias Pulmonares/patologia , MicroRNAs/fisiologia , Proteínas Nucleares/genética , Adulto , Idoso , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Camundongos , MicroRNAs/sangue , Pessoa de Meia-Idade , Regulação para CimaRESUMO
Specificity of nucleobase pairing provides essential foundation for genetic information storage, replication, transcription and translation in all living organisms. However, the wobble base pairs, where U in RNA (or T in DNA) pairs with G instead of A, might compromise the high specificity of the base pairing. The U/G wobble pairing is ubiquitous in RNA, especially in non-coding RNA. In order to increase U/A pairing specificity, we have hypothesized to discriminate against U/G wobble pair by tailoring the steric and electronic effects at the 2-exo position of uridine and replacing the 2-exo oxygen with a selenium atom. We report here the first synthesis of the 2-Se-U-RNAs as well as the 2-Se-uridine ((Se)U) phosphoramidite. Our biophysical and structural studies of the (Se)U-RNAs indicate that this single atom replacement can indeed create a novel U/A base pair with higher specificity than the natural one. We reveal that the (Se)U/A pair maintains a structure virtually identical to the native U/A base pair, while discriminating against U/G wobble pair. This oxygen replacement with selenium offers a unique chemical strategy to enhance the base pairing specificity at the atomic level.
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Compostos Organosselênicos/química , RNA/química , Uridina/análogos & derivados , Pareamento Incorreto de Bases , Pareamento de Bases , Cristalografia , Modelos Moleculares , Desnaturação de Ácido Nucleico , Compostos Organofosforados/síntese química , Uridina/síntese química , Uridina/químicaRESUMO
Human embryonic germ cells (hEGCs) are a valuable and underutilized source of pluripotent stem cells. Unlike embryonic stem cells, which have been extensively studied, little is known about the factors that regulate hEGC derivation and maintenance. This study demonstrates for the first time a central role for selective activation of PDGFR signaling in the derivation and maintenance of pluripotency in hEGCs. In the study, hEGCs were found to express PDGF receptor α at high levels compared to human embryonic stem cells (hESCs). PDGF significantly improved formation of alkaline phosphatase (AP) positive hEGC colonies. We subsequently determined that PDGF activates the phosphatidylinositol-3-kinase (PI3K) pathway as phosphorylation of AKT was up-regulated in response to PDGF. Furthermore, inhibition of PI3K signaling using small molecular inhibitor LY294002 led to significantly decreased AP positive hEGC colony formation whereas inhibition of MAPK pathway using U0126 had a negligible effect. We established a primary mechanism for PDGF mediated derivation and maintenance of hEGCs by demonstrating that OCT4 was upregulated and PTEN was suppressed in a dose dependent manner in response to PDGF.
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Células-Tronco Embrionárias/citologia , Células Germinativas/citologia , Fosfatidilinositol 3-Quinases/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Fosfatase Alcalina/metabolismo , Células Germinativas/metabolismo , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Células-Tronco Pluripotentes/citologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Transdução de SinaisRESUMO
Multiple myeloma (MM) is a plasma cell malignancy expressing B cell maturation antigen (BCMA). Elranatamab, a bispecific antibody, engages BCMA on MM and CD3 on T cells. The MagnetisMM-1 trial evaluated its safety, pharmacokinetics and efficacy. Primary endpoints, including the incidence of dose-limiting toxicities as well as objective response rate (ORR) and duration of response (DOR), were met. Secondary efficacy endpoints included progression-free survival (PFS) and overall survival (OS). Eighty-eight patients with relapsed or refractory MM received elranatamab monotherapy, and 55 patients received elranatamab at efficacious doses. Patients had received a median of five prior regimens; 90.9% were triple-class refractory, 29.1% had high cytogenetic risk and 23.6% received prior BCMA-directed therapy. No dose-limiting toxicities were observed during dose escalation. Adverse events included cytopenias and cytokine release syndrome. Exposure was dose proportional. With a median follow-up of 12.0 months, the ORR was 63.6% and 38.2% of patients achieving complete response or better. For responders, the median DOR was 17.1 months. All 13 patients evaluable for minimal residual disease achieved negativity. Even after prior BCMA-directed therapy, 53.8% achieved response. For all 55 patients, median PFS was 11.8 months, and median OS was 21.2 months. Elranatamab achieved durable responses, manageable safety and promising survival for patients with MM. ClinicalTrials.gov Identifier: NCT03269136 .
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Anemia , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/patologia , Antígeno de Maturação de Linfócitos B , Linfócitos T/patologia , Intervalo Livre de Progressão , Anemia/etiologia , Imunoterapia Adotiva/efeitos adversosRESUMO
Currently, the regulation of Lactobacillus on intestinal stem cells (ISCs) attracts broad attention, but their active ingredients and the underlying mechanism are worthy of further study. Previously, host intestinal commensal bacteria were verified to drive the differentiation of ISCs. In this study, the strong bacteriostatic activity of Lactobacillus salivarius and Lactobacillus agilis were illustrated, and the components (supernatant, precipitation) of L. salivarius or L. agilis were further demonstrated to decrease the differentiation of ISCs in vivo. Interestingly, antibiotics feeding decreased ISCs differentiation in vivo as well. However, the administration of L. salivarius supernatant following antibiotics feeding was shown to promote ISCs differentiation dramatically when compared with the antibiotics feeding group, indicating that some active ingredients existed in its supernatant to promote ISCs activity. Strikingly, in vitro, the treatment of L. salivarius supernatant was further confirmed to promote the intestinal organoids' size, budding, and LGR5 expression. Next, the metabolomics analysis of Lactobacilli' supernatants suggested that succinate might be a crucial metabolite to promote ISCs activity. Further, the succinate treatment in vitro (1000 µM) and in vivo (50 mM) was confirmed to enhance the expression of LGR5 and PCNA. SLC13A3 (a sodium/dicarboxylate cotransporter) was detected in the intestinal organoids and demonstrated to transport succinate into ISCs, as confirmed by the contact of FITC-succinate with ISCs nucleus. Subsequently, high mitochondrial membrane potential and reactive oxygen species levels appeared in the intestinal organoids upon succinate treatment. Collectively, the promotion of L. salivarius on ISCs activity is associated with succinate-induced mitochondrial energy metabolism. IMPORTANCE In our previous study, Lactobacillus salivarius and Lactobacillus agilis were demonstrated to regulate intestinal stem cell activity in hens, but their active ingredients and the underlying mechanism remain unclear. In this study, L. salivarius supernatant was shown to directly promote intestinal stem cell activity. Furthermore, the succinate (a critical metabolite of L. salivarius) was screened out to promote intestinal stem cell activity. Moreover, the succinate was confirmed to enter intestinal stem cells and induce high mitochondrial energy metabolism, finally promoting intestinal stem cell activity. These findings will advance uncovering the mechanism by which Lactobacillus regulate intestinal stem cell activity in chickens.
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Ligilactobacillus salivarius , Animais , Feminino , Mucosa Intestinal , Ácido Succínico/metabolismo , Galinhas/microbiologia , Células-Tronco/metabolismo , Antibacterianos/metabolismo , Metabolismo EnergéticoRESUMO
Ischemic cardiomyopathy (ICM) caused by coronary artery disease always leads to myocardial infarction and heart failure. Identification of novel transcriptional regulators in ICM is an effective method to establish new diagnostic and therapeutic strategies. In this study, we used two RNA-seq datasets and one microarray dataset from different studies, including 25 ICM and 21 non-failing control (NF) samples of human left ventricle tissues for further analysis. In total, 208 differentially expressed genes (DEGs) were found by combining two RNA-seq datasets with batch effects removed. GO and KEGG analyses of DEGs indicated that the response to wounding, positive regulation of smooth muscle contraction, chromatin, PI3K-Akt signaling pathway, and transporters pathways are involved in ICM. Simple Enrichment Analysis found that NFIC-binding motifs are enriched in promoter regions of downregulated genes. The Gene Importance Calculator further proved that NFIC is vital. NFIC and its downstream genes were verified in the validating microarray dataset. Meanwhile, in rat cardiomyocyte cell line H9C2 cells, two genes (Tspan1 and Hopx) were confirmed, which decreased significantly along with knocking down Nfic expression. In conclusion, NFIC participates in the ICM process by regulating TSPAN1 and HOPX. NFIC and its downstream genes may be marker genes and potential diagnostic and therapeutic targets for ICM.
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Cardiomiopatias , Proteínas de Homeodomínio , Isquemia Miocárdica , Fatores de Transcrição NFI , Tetraspaninas , Proteínas Supressoras de Tumor , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Biologia Computacional , Proteínas de Homeodomínio/genética , Humanos , Isquemia Miocárdica/genética , Isquemia Miocárdica/metabolismo , Fatores de Transcrição NFI/genética , RNA-Seq , Tetraspaninas/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
Pulmonary arterial hypertension (PAH) is a rare cardiovascular disease with very high mortality rate. The currently available therapeutic strategies, which improve symptoms, cannot fundamentally reverse the condition. Thus, new therapeutic strategies need to be established. Our research analyzed three microarray datasets of lung tissues from human PAH samples retrieved from the Gene Expression Omnibus (GEO) database. We combined two datasets for subsequent analyses, with the batch effects removed. In the merged dataset, 542 DEGs were identified and the key module relevant to PAH was selected using WGCNA. GO and KEGG analyses of DEGs and the key module indicated that the pre-ribosome, ribosome biogenesis, centriole, ATPase activity, helicase activity, hypertrophic cardiomyopathy, melanoma, and dilated cardiomyopathy pathways are involved in PAH. With the filtering standard (|MM| > 0.95 and |GS| > 0.90), 70 hub genes were identified. Subsequently, five candidate marker genes (CDC5L, AP3B1, ZFYVE16, DDX46, and PHAX) in the key module were found through overlapping with the top thirty genes calculated by two different methods in CytoHubb. Two of them (CDC5L and DDX46) were found to be significantly upregulated both in the merged dataset and the validating dataset in PAH patients. Meanwhile, expression of the selected genes in lung from PAH chicken measured by qRT-PCR and the ROC curve analyses further verified the potential marker genes' predictive value for PAH. In conclusion, CDC5L and DDX46 may be marker genes and potential therapeutic targets for PAH.
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Proteínas de Ciclo Celular/genética , RNA Helicases DEAD-box/genética , Hipertensão Arterial Pulmonar/diagnóstico , Proteínas de Ligação a RNA/genética , Ribonucleoproteína Nuclear Pequena U2/genética , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Galinhas , Biologia Computacional , RNA Helicases DEAD-box/antagonistas & inibidores , RNA Helicases DEAD-box/metabolismo , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Pulmão/patologia , Análise em Microsséries , Terapia de Alvo Molecular/métodos , Valor Preditivo dos Testes , Mapas de Interação de Proteínas/efeitos dos fármacos , Mapas de Interação de Proteínas/genética , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/genética , Hipertensão Arterial Pulmonar/patologia , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/metabolismo , Curva ROC , Ribonucleoproteína Nuclear Pequena U2/antagonistas & inibidores , Ribonucleoproteína Nuclear Pequena U2/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
The exposure-response relationship of direct acting oral anti-coagulants (DOACs) for bleeding risk is steep relative to ischemic stroke reduction. As a result, small changes in exposure may lead to bleeding events. The overall goal of this project was to determine the effect of critical formulation parameters on the pharmacokinetics (PKs) and thus safety and efficacy of generic DOACs. In this first installment of our overall finding, we developed and verified a physiologically-based PK (PBPK) model for dabigatran etexilate (DABE) and its metabolites. The model was developed following a middle out approach leveraging available in vitro and in vivo data. External validity of the model was confirmed by overlapping predicted and observed PK profiles for DABE as well as free and total dabigatran for a dataset not used during model development. The verified model was applied to interrogate the impact of modulating the microenvironment pH on DABE systemic exposure. The PBPK exploratory analyses highlighted the high sensitivity of DABE exposure to supersaturation ratio and precipitation kinetics.
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Antitrombinas/farmacocinética , Dabigatrana/farmacocinética , Composição de Medicamentos/métodos , Substituição de Medicamentos/métodos , AVC Isquêmico/prevenção & controle , Antitrombinas/efeitos adversos , Antitrombinas/química , Disponibilidade Biológica , Precipitação Química , Dabigatrana/efeitos adversos , Dabigatrana/química , Desenvolvimento de Medicamentos , Substituição de Medicamentos/estatística & dados numéricos , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/química , Inibidores do Fator Xa/farmacocinética , Hemorragia/induzido quimicamente , Humanos , Farmacocinética , Segurança , Resultado do TratamentoRESUMO
Acetaminophen protein adducts (adducts) are a well-established biomarker to diagnose acetaminophen toxicity. To date, the quantitative relationship between acetaminophen exposure, which drives adduct formation, and adduct exposure remains to be established. Our study characterized the adduct formation and disposition in adults using the approach of population parent-metabolite modeling. It demonstrated formation-limited pharmacokinetics (PK) for adducts in healthy subjects. This finding expands the existing knowledge on adduct PK that showed an apparent long elimination half-life. We then allometrically scaled the adduct PK model to children, simulated the adduct profiles, and compared these simulated profiles with those observed in an independent cohort of children. The scaled model significantly overpredicted the adduct concentrations in children early on in treatment and underpredicted concentrations following repeated acetaminophen doses. These results suggest that children demonstrate different adduct PK behavior from that of adults, most likely because of increased reactive metabolite detoxification in children. In summary, we described the first PK model linking acetaminophen and acetaminophen protein adduct concentrations, which provides a semimechanistic understanding of varying profiles of adduct exposure in adults and children.
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Previous reports have questioned the safety of multiple doses of acetaminophen administered to ill children. Acetaminophen protein adducts (adducts) are a biomarker of acetaminophen-induced liver injury and reflect the oxidative metabolism of acetaminophen, a known mechanism in acetaminophen toxicity. In this prospective observational study, we analyzed adduct concentrations in 1034 blood samples obtained from 181 hospitalized children (1 to 18 years inclusive) who received 2 or more doses of acetaminophen. Linear regression analysis showed that serum adduct concentrations increased as a function of the cumulative acetaminophen dose, which could be attributed, in part, to a long half-life of adducts (2.17 ± 1.04 days [mean ± standard deviation]) in children. However, few patients (2%) were found to have adduct concentrations higher than 1.0 nmol/mL, a previously identified toxicity cut point for the diagnosis of acetaminophen-induced liver injury in patients with alanine aminotransferase values exceeding 1000 IU/L. A small cohort of patients with suspected infection was noted to show higher adduct concentrations. In addition, adduct concentrations showed a stronger correlation with cumulative acetaminophen doses in adolescents compared with children (R2 = 0.41 vs 0.26). No other covariates (body weight, body mass index z score, sex, race, or surgery) remarkably correlated with adduct elevation. In summary, low levels of adducts can be detected in hospitalized children receiving multiple doses of acetaminophen, and adduct levels correlate with cumulative acetaminophen dose.
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Acetaminofen/efeitos adversos , Acetaminofen/sangue , Analgésicos não Narcóticos/efeitos adversos , Analgésicos não Narcóticos/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Overdose de Drogas/sangue , Acetaminofen/administração & dosagem , Adolescente , Alanina Transaminase/metabolismo , Analgésicos não Narcóticos/administração & dosagem , Biomarcadores/sangue , Criança , Criança Hospitalizada , Pré-Escolar , Overdose de Drogas/etiologia , Overdose de Drogas/metabolismo , Feminino , Meia-Vida , Humanos , Lactente , Fígado/metabolismo , Masculino , Estudos ProspectivosRESUMO
PURPOSE: This study aimed to explore daptomycin combined with fosfomycin or rifampin against the planktonic and adherent linezolid-resistant isolates of Enterococcus faecalis. METHODOLOGY: Four linezolid-resistant and four linezolid-sensitive isolates of E. faecalis which formed biofilms were collected for this study. Biofilm biomasses were detected by crystal violet staining and the adherent cells in the mature biofilms were quantified by c.f.u. determination. RESULTS: Daptomycin alone, or combined with fosfomycin or rifampin (4×MIC) demonstrated bactericidal activities on the planktonic cells, and daptomycin combined with fosfomycin killed more planktonic cells (at least 1-log10 c.f.u. ml-1) than daptomycin or fosfomycin alone. Daptomycin alone (16×MIC) showed anti-biofilm activities against the mature biofilms and bactericidal activities on the adherent cells, while daptomycin combined with fosfomycin (16×MIC) demonstrated significantly more anti-biofilm activities than daptomycin or fosfomycin alone and effectively killed the adherent cells in the mature biofilms. The high concentration of daptomycin (512 mg l-1 ) combined with fosfomycin indicated more bactericidal activities on the adherent cells and more anti-biofilm activities against the mature biofilms than daptomycin 64 mg l-1 (16×MIC) combined with fosfomycin. The addition of rifampin increased the anti-biofilm and bactericidal activities of daptomycin against the mature biofilms and the adherent cells of two isolates, however, which was not observed in other isolates. CONCLUSIONS: Daptomycin combined with fosfomycin demonstrated better effect on the planktonic and adherent linezolid-resistant isolates of E. faecalis than daptomycin or fosfomycin alone. The role of rifampin in the treatment of E. faecalis isolates is discrepant and needs more studies.
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Antibacterianos/farmacologia , Aderência Bacteriana/efeitos dos fármacos , Daptomicina/farmacologia , Enterococcus faecalis/efeitos dos fármacos , Fosfomicina/farmacologia , Linezolida/farmacologia , Rifampina/farmacologia , Biofilmes/efeitos dos fármacos , Linhagem Celular , Farmacorresistência Bacteriana , Enterococcus faecalis/fisiologia , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Plâncton/efeitos dos fármacos , Plâncton/fisiologiaRESUMO
Retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy (DR) are the leading causes of blindness in adults over the age of 50 years in the US. While most of those conditions do not have a cure, currently available treatment options attempt to prevent further vision loss. For many ophthalmic drugs, an efficient delivery system to provide maximum therapeutic efficacy and promote patient compliance remains an unmet medical need. An exploration of literature via PubMed spanning from 2007 to 2017 was conducted to identify studies that have evaluated nanotechnology as platforms for delivering therapeutic agents to the posterior segment of the eye where the retina is located. Until now, four routes that have been utilized for retinal drug delivery are the intravitreal, periocular, subretinal, and systemic routes. Intravitreal injections are now widely used in clinical practice due to their ability to directly target the back of the eye but are highly invasive procedures that may cause several complications, particularly with repeated uses over a short timespan. Nanotechnology shows great promise to revolutionize retinal drug delivery, offering many advantages such as a targeted delivery system towards the specific site of the retina as well as sustained delivery of therapeutic agents. In this review, specific eye anatomy and constraints on ocular drug administration are illustrated. Further, we list and highlight several examples of nanosystems, such as hydrogels, liposomes, dendrimers, and micelles, used via different drug delivery routes to treat various retinal diseases.
RESUMO
Microtubules (composed of α- and ß-tubulin heterodimers) play a pivotal role in mitosis and cell division, and are regarded as an excellent target for chemotherapeutic agents to treat cancer. There are four unique binding sites in tubulin to which taxanes, vinca alkaloids, laulimalide and colchicine bind respectively. While several tubulin inhibitors that bind to the taxane or vinca alkaloid binding sites have been approved by FDA, currently there are no FDA approved tubulin inhibitors targeting the colchicine binding site. Tubulin inhibitors that bind to the colchicine binding site have therapeutic advantages over taxanes and vinca alkaloids, for example, they can be administered orally, have less drug-drug interaction potential, and are less prone to develop multi-drug resistance. Typically, tubulin inhibitors that bind to the colchicine binding site bear the trimethoxyphenyl (TMP) moiety which is essential for interaction with tubulin. Over the last decade, a variety of molecules bearing the TMP moiety have been designed and synthesized as tubulin inhibitors for cancer treatment. In this review, we focus on the TMP analogs that are designed based on CA-4, indole, chalcone, colchicine and natural product scaffolds which are known to interact with the colchicine binding site in tubulin. The challenges and future direction of the TMP based tubulin inhibitors are also discussed in detail.