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1.
Chembiochem ; 18(15): 1502-1509, 2017 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-28440961

RESUMO

Zinc-complexing ligands are prospective anti-biofilm agents because of the pivotal role of zinc in the formation of Staphylococcus aureus biofilm. Accordingly, the potential of a thiosemicarbazone (compound C1) and a benzothiazole-based ligand (compound C4) in the prevention of S. aureus biofilm formation was assessed. Compound C1 displayed a bimodal activity, hindering biofilm formation only at low concentrations and promoting biofilm growth at higher concentrations. In the case of C4, a dose-dependent inhibition of S. aureus biofilm growth was observed. Atomic force microscopy analysis suggested that at higher concentrations C1 formed globular aggregates, which perhaps formed a substratum that favored adhesion of cells and biofilm formation. In the case of C4, zinc supplementation experiments validated zinc complexation as a plausible mechanism of inhibition of S. aureus biofilm. Interestingly, C4 was nontoxic to cultured HeLa cells and thus has promise as a therapeutic anti-biofilm agent. The essential understanding of the structure-driven implications of zinc-complexing ligands acquired in this study might assist future screening regimes for identification of potent anti-biofilm agents.


Assuntos
Benzotiazóis/farmacologia , Biofilmes/efeitos dos fármacos , Quelantes/farmacologia , Semicarbazonas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Zinco/química , Benzotiazóis/síntese química , Benzotiazóis/toxicidade , Quelantes/síntese química , Quelantes/toxicidade , Ácido Edético/farmacologia , Ácido Edético/toxicidade , Células HeLa , Humanos , Microscopia de Fluorescência , Semicarbazonas/síntese química , Semicarbazonas/toxicidade
2.
J Phys Chem Lett ; 15(22): 5964-5977, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38814078

RESUMO

Perovskites are hybrid materials containing templating organic linkers and inorganic halides with efficiencies that have superseded the efficiency of silicon-based photovoltaic devices (PVs) in a very short period of 10 years. Nevertheless, low ambient stability due to traps and ion migration caused hysteresis to remain the bottlenecks on the way to achieving higher operational stability with bulk perovskite-based PVs. In this context, herein we highlight the prospects of in situ cross-linking of linkers within the perovskite lattice either mediated by thermal means or attained photochemically that can maneuver the ambient as well as operational stability for enhanced power conversion efficiency for PV applications or could improve the conductivity of this hybrid semiconductor. Additionally, some important studies of additive engineering via in situ cross-linking that can affect the structure of perovskite in addition to defect passivation to endow ambient environment stability are highlighted herein.

3.
Nat Med ; 30(3): 690-698, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38454124

RESUMO

Survivors of childhood cancer are at increased risk for subsequent cancers attributable to the late effects of radiotherapy and other treatment exposures; thus, further understanding of the impact of genetic predisposition on risk is needed. Combining genotype data for 11,220 5-year survivors from the Childhood Cancer Survivor Study and the St Jude Lifetime Cohort, we found that cancer-specific polygenic risk scores (PRSs) derived from general population, genome-wide association study, cancer loci identified survivors of European ancestry at increased risk of subsequent basal cell carcinoma (odds ratio per s.d. of the PRS: OR = 1.37, 95% confidence interval (CI) = 1.29-1.46), female breast cancer (OR = 1.42, 95% CI = 1.27-1.58), thyroid cancer (OR = 1.48, 95% CI = 1.31-1.67), squamous cell carcinoma (OR = 1.20, 95% CI = 1.00-1.44) and melanoma (OR = 1.60, 95% CI = 1.31-1.96); however, the association for colorectal cancer was not significant (OR = 1.19, 95% CI = 0.94-1.52). An investigation of joint associations between PRSs and radiotherapy found more than additive increased risks of basal cell carcinoma, and breast and thyroid cancers. For survivors with radiotherapy exposure, the cumulative incidence of subsequent cancer by age 50 years was increased for those with high versus low PRS. These findings suggest a degree of shared genetic etiology for these malignancy types in the general population and survivors, which remains evident in the context of strong radiotherapy-related risk.


Assuntos
Neoplasias da Mama , Sobreviventes de Câncer , Carcinoma Basocelular , Neoplasias , Neoplasias Cutâneas , Neoplasias da Glândula Tireoide , Humanos , Criança , Feminino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/genética , Neoplasias/radioterapia , Estratificação de Risco Genético , Estudo de Associação Genômica Ampla , Fatores de Risco , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama/radioterapia , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/genética
4.
Science ; 372(6543)2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33888599

RESUMO

The 1986 Chernobyl nuclear power plant accident increased papillary thyroid carcinoma (PTC) incidence in surrounding regions, particularly for radioactive iodine (131I)-exposed children. We analyzed genomic, transcriptomic, and epigenomic characteristics of 440 PTCs from Ukraine (from 359 individuals with estimated childhood 131I exposure and 81 unexposed children born after 1986). PTCs displayed radiation dose-dependent enrichment of fusion drivers, nearly all in the mitogen-activated protein kinase pathway, and increases in small deletions and simple/balanced structural variants that were clonal and bore hallmarks of nonhomologous end-joining repair. Radiation-related genomic alterations were more pronounced for individuals who were younger at exposure. Transcriptomic and epigenomic features were strongly associated with driver events but not radiation dose. Our results point to DNA double-strand breaks as early carcinogenic events that subsequently enable PTC growth after environmental radiation exposure.


Assuntos
Acidente Nuclear de Chernobyl , Mutação , Neoplasias Induzidas por Radiação/genética , Câncer Papilífero da Tireoide/etiologia , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/etiologia , Neoplasias da Glândula Tireoide/genética , Adolescente , Adulto , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Epigenoma , Feminino , Perfilação da Expressão Gênica , Genes ras , Variação Genética , Humanos , Lactente , Radioisótopos do Iodo , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/genética , RNA-Seq , Doses de Radiação , Glândula Tireoide/fisiologia , Glândula Tireoide/efeitos da radiação , Translocação Genética , Ucrânia , Sequenciamento Completo do Genoma , Adulto Jovem
5.
iScience ; 23(6): 101229, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32554190

RESUMO

Ex vivo human tumor models have emerged as promising, yet complex tools to study cancer immunotherapy response dynamics. Here, we present a strategy that integrates empirical data from an ex vivo human system with computational models to interpret the response dynamics of a clinically prescribed PD-1 inhibitor, nivolumab, in head and neck squamous cell carcinoma (HNSCC) biopsies (N = 50). Using biological assays, we show that drug-induced variance stratifies samples by T helper type 1 (Th1)-related pathways. We then built a systems biology network and mathematical framework of local and global sensitivity analyses to simulate and estimate antitumor phenotypes, which implicate a dynamic role for the induction of Th1-related cytokines and T cell proliferation patterns. Together, we describe a multi-disciplinary strategy to analyze and interpret the response dynamics of PD-1 blockade using heterogeneous ex vivo data and in silico simulations, which could provide researchers a powerful toolset to interrogate immune checkpoint inhibitors.

6.
Clin Cancer Res ; 25(7): 2254-2263, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30617129

RESUMO

PURPOSE: We developed a method to monitor copy number variations (CNV) in plasma cell-free DNA (cfDNA) from patients with metastatic squamous non-small cell lung cancer (NSCLC). We aimed to explore the association between tumor-derived cfDNA and clinical outcomes, and sought CNVs that may suggest potential resistance mechanisms. EXPERIMENTAL DESIGN: Sensitivity and specificity of low-pass whole-genome sequencing (LP-WGS) were first determined using cell line DNA and cfDNA. LP-WGS was performed on baseline and longitudinal cfDNA of 152 patients with squamous NSCLC treated with chemotherapy, or in combination with pictilisib, a pan-PI3K inhibitor. cfDNA tumor fraction and detected CNVs were analyzed in association with clinical outcomes. RESULTS: LP-WGS successfully detected CNVs in cfDNA with tumor fraction ≥10%, which represented approximately 30% of the first-line NSCLC patients in this study. The most frequent CNVs were gains in chromosome 3q, which harbors the PIK3CA and SOX2 oncogenes. The CNV landscape in cfDNA with a high tumor fraction generally matched that of corresponding tumor tissue. Tumor fraction in cfDNA was dynamic during treatment, and increases in tumor fraction and corresponding CNVs could be detected before radiographic progression in 7 of 12 patients. Recurrent CNVs, such as MYC amplification, were enriched in cfDNA from posttreatment samples compared with the baseline, suggesting a potential resistance mechanism to pictilisib. CONCLUSIONS: LP-WGS offers an unbiased and high-throughput way to investigate CNVs and tumor fraction in cfDNA of patients with cancer. It may also be valuable for monitoring treatment response, detecting disease progression early, and identifying emergent clones associated with therapeutic resistance.


Assuntos
Biomarcadores Tumorais , Carcinoma de Células Escamosas/genética , DNA Tumoral Circulante , Genoma Humano , Genômica , Neoplasias Pulmonares/genética , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/mortalidade , Linhagem Celular Tumoral , Estudos de Coortes , Variações do Número de Cópias de DNA , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Terapia de Alvo Molecular , Polimorfismo de Nucleotídeo Único , Prognóstico , Análise de Sequência de DNA , Sequenciamento Completo do Genoma
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