Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.799
Filtrar
1.
Int J Nanomedicine ; 19: 1699-1707, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38406602

RESUMO

Introduction: The presence of cancer stem cells (CSCs) significantly limits the therapeutic efficacy of radiotherapy (RT). Efficient elimination of potential CSCs is crucial for enhancing the effectiveness of RT. Methods: In this study, we developed a biomimetic hybrid nano-system (PMC) composed of MnCO3 as the inner core and platelet membrane (PM) as the outer shell. By exploiting the specific recognition properties of membrane surface proteins, PMC enables precise targeting of CSCs. Sonodynamic therapy (SDT) was employed using manganese carbonate nanoparticles (MnCO3 NPs), which generate abundant reactive oxygen species (ROS) upon ultrasound (US) irradiation, thereby impairing CSC self-renewal capacity and eradicating CSCs. Subsequent RT effectively eliminates common tumor cells. Results: Both in vitro cell experiments and in vivo animal studies demonstrate that SDT mediated by PMC synergistically enhances RT to selectively combat CSCs while inhibiting tumor growth without noticeable side effects. Discussion: Our findings offer novel insights for enhancing the efficacy and safety profiles of RT.


Assuntos
Carbonatos , Manganês , Nanopartículas , Neoplasias , Compostos de Nitrosoureia , Animais , Linhagem Celular Tumoral , Biomimética , Espécies Reativas de Oxigênio/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias/patologia
2.
Chemosphere ; 352: 141346, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38311035

RESUMO

Doping proves to be an efficacious method of establishing intermetallic interactions for enhancing toluene oxidation performance of bimetallic oxides. However, conventional bimetallic oxide catalysts are yet to overcome their inadequacy in establishing intermetallic interactions. In this work, the dispersion of Mn-Co bimetallic sites was improved by hydrolytic co-precipitation, strengthening the intermetallic interactions which improved the structural and physicochemical properties of the catalysts, thus significantly enhancing its catalytic behavior. MnCo-H catalysts fabricated by the hydrolytic co-precipitation method showed promising catalytic performance (T50 = 223 °C, T90 = 229 °C), robust stability (at least 100 h) and impressive water resistance (under 10 vol.% of water) for toluene elimination. Hydrolytic co-precipitation has been found to improve dispersion of MnCo elements and to enhance interaction between Co and Mn ions (Mn4+ + Co2+ = Mn3+ + Co3+), resulting in a lower reduction temperature (215 °C) and a weaker Mn-O bond strength, creating more lattice defects and oxygen vacancies, which are responsible for superior catalytic properties of MnCo-H samples. Furthermore, in situ DRIFTs showed that gaseous toluene molecules adsorbed on the surface of MnCo-H were continuously oxidized to benzyl alcohol → benzaldehyde → benzoate, followed by a ring-opening reaction with surface-activated oxygen to convert to maleic anhydride as the final intermediate, which further generates water and carbon dioxide. It was also revealed that the ring-opening reaction for the conversion of benzoic acid to maleic anhydride is the rate-controlling step. This study reveals that optimizing active sites and improving reactive oxygen species by altering the dispersion of bimetals to enhance bimetallic interactions is an effective strategy for the improvement of catalytic behavior, while the hydrolytic co-precipitation method fits well with this corollary.


Assuntos
Compostos de Manganês , Manganês , Compostos de Nitrosoureia , Tolueno , Manganês/química , Oxirredução , Tolueno/química , Anidridos Maleicos , Óxidos/química , Água , Cobalto/química , Oxigênio/química , Catálise
3.
Eur J Cancer ; 199: 113531, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38271746

RESUMO

BACKGROUND: The primary analysis of the phase III NIBIT-M2 study showed a 41% 4-year overall survival (OS) of melanoma patients with asymptomatic brain metastases treated with ipilimumab plus nivolumab. METHODS: Here, we report the 7-year efficacy outcomes and the Health-Related Quality of Life (HRQoL) analyses of the NIBIT-M2 study. RESULTS: As of May 1, 2023, at a median follow-up of 67 months (mo), the median OS was 8.5 (95% CI: 6.6-10.3), 8.2 (95% CI: 2.1-14.3) and 29.2 (95% CI: 0-69.9) mo for the fotemustine (F) Arm A, ipilimumab plus fotemustine Arm B, and ipilimumab plus nivolumab Arm C, respectively. The 7-year OS rate was 10.0% (95% CI: 0-22.5) in Arm A, 10.3% (95% CI: 0-22.6) in Arm B, and 42.8% (95% CI: 23.4-62.2) in Arm C. HRQoL was preserved in all treatment arms. Most functional scales evaluated from baseline to W12 were preserved, with a lower mean score decrease for EORTC Quality of Life Questionnaire (QLQ)-C30 and an increase for EORTC QLQ-Brain neoplasm (BN20) in patients receiving ipilimumab plus nivolumab. CONCLUSIONS: With the longest follow-up available to date in melanoma patients with asymptomatic brain metastases, the NIBIT-M2 study continues to show persistent therapeutic efficacy of I ipilimumab plus nivolumab while preserving HRQoL.


Assuntos
Neoplasias Encefálicas , Melanoma , Compostos de Nitrosoureia , Compostos Organofosforados , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Encefálicas/secundário , Ipilimumab/efeitos adversos , Melanoma/patologia , Nivolumabe/efeitos adversos , Qualidade de Vida
4.
Bioresour Technol ; 395: 130378, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38281546

RESUMO

A novel manganese cobalt metal-organic framework based carbon nanofiber electrode (MnCo/CNF) was prepared and used as microbial fuel cell (MFC) anode. Pyrite was introduced into the anode chamber (MnCoPy_MFC). Synergistic function between pyrite and MnCo/CNF facilitated the pollutants removal and energy generation in MnCoPy_MFC. MnCoPy_MFC showed the highest chemical oxygen demand removal efficiency (82 ± 1%) and the highest coulombic efficiency (35 ± 1%). MnCoPy_MFC achieved both efficient electricity generation (maximum voltage: 658 mV; maximum power density: 3.2 W/m3) and total antimony (Sb) removal efficiency (99%). The application of MnCo/CNF significantly enhanced the biocatalytic efficiency of MnCoPy_MFC, attributed to its large surface area and abundant porous structure that provided ample attachment sites for electroactive microorganisms. This study revealed the synergistic interaction between pyrite and MnCo/CNF anode, which provided a new strategy for the application of composite anode MFC in heavy metal removal and energy recovery.


Assuntos
Fontes de Energia Bioelétrica , Ferro , Nanofibras , Compostos de Nitrosoureia , Sulfetos , Carbono , Manganês , Antimônio , Cobalto , Fontes de Energia Bioelétrica/microbiologia , Eletricidade , Eletrodos , Bactérias/química
5.
Artigo em Inglês | MEDLINE | ID: mdl-37770135

RESUMO

Duplex sequencing (DS) is an error-corrected next-generation sequencing method in which molecular barcodes informatically link PCR-copies back to their source DNA strands, enabling computational removal of errors in consensus sequences. The resulting background of less than one artifactual mutation per 107 nucleotides allows for direct detection of somatic mutations. TwinStrand Biosciences, Inc. has developed a DS-based mutagenesis assay to sample the rat genome, which can be applied to genetic toxicity testing. To evaluate this assay for early detection of mutagenesis, a time-course study was conducted using male Hsd:Sprague Dawley SD rats (3 per group) administered a single dose of 40 mg/kg N-ethyl-N-nitrosourea (ENU) via gavage, with mutation frequency (MF) and spectrum analyzed in stomach, bone marrow, blood, and liver tissues at 3 h, 24 h, 7 d, and 28 d post-exposure. Significant increases in MF were observed in ENU-exposed rats as early as 24 h for stomach (site of contact) and bone marrow (a highly proliferative tissue) and at 7 d for liver and blood. The canonical, mutational signature of ENU was established by 7 d post-exposure in all four tissues. Interlaboratory analysis of a subset of samples from different tissues and time points demonstrated remarkable reproducibility for both MF and spectrum. These results demonstrate that MF and spectrum can be evaluated successfully by directly sequencing targeted regions of DNA obtained from various tissues⁠, a considerable advancement compared to currently used in vivo gene mutation assays.


Assuntos
Etilnitrosoureia , Compostos de Nitrosoureia , Ratos , Masculino , Animais , Etilnitrosoureia/toxicidade , Reprodutibilidade dos Testes , Ratos Sprague-Dawley , Mutagênese , Mutação , Mutagênicos/toxicidade
6.
J Mol Graph Model ; 123: 108517, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37235904

RESUMO

This study aimed to explore the potential of Host-Guest coupling with Nanocarrier graphyne (GPH) to enhance the bioavailability of the drug 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (LUM) for brain tumor therapy. The electronic, geometric, and excited-state properties of GPH, LUM, and the graphyne@1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea-complex (GPH@LUM-complex) were studied using DFT B3LYP/6-31G** level of theory. The results showed that the GPH@LUM-complex was stable with negative adsorption energy (-0.20 eV), and there was good interaction between GPH and LUM in the solvent phase. The weak interaction forces between the two indicated an easy release of the drug at the target site. The Frontier Molecular Orbitals (FMO), Charge Density Analysis (CDA), and Natural Bond Orbital (NBO) analysis supported LUM to GPH charge transfer during complex formation, and the Reduced Density Gradient (RDG) isosurfaces identified steric effects and non-bonded interactions. UV-visible examination showed the potential of the GPH@LUM-complex as a drug carrier with a blue shift of 23 nm wavelength in the electronic spectra. The PET process analysis revealed a fluorescence-quenching process, facilitating systematic drug delivery. The study concluded that GPH had potential as a carrier for delivering LUM, and different 2D nanomaterials could be explored for drug delivery applications. The theoretical study's findings may motivate researchers to investigate the practical applications of GPH@LUM-complex in oncology.


Assuntos
Neoplasias Encefálicas , Compostos de Nitrosoureia , Humanos
7.
Brain Nerve ; 75(5): 561-566, 2023 May.
Artigo em Japonês | MEDLINE | ID: mdl-37194532

RESUMO

Treatment of brain tumors, particularly malignant gliomas, is challenging using only surgical resection and radiation therapy, and medical treatment plays an important role in the management of these malignancies. Temozolomide has been mainly used for the treatment of malignant gliomas over a decade. However, novel therapeutic options, such as molecular-targeted drugs and oncolytic virus therapeutic agents have been introduced in recent years. Classical anticancer medications, such as nitrosoureas and platinum-based drugs, continue to be administered for treatment of some types of malignant brain tumors.


Assuntos
Antineoplásicos , Neoplasias Encefálicas , Glioma , Humanos , Neoplasias Encefálicas/tratamento farmacológico , Antineoplásicos/uso terapêutico , Glioma/tratamento farmacológico , Temozolomida/uso terapêutico , Compostos de Nitrosoureia/uso terapêutico
8.
Phytomedicine ; 115: 154828, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37116386

RESUMO

BACKGROUND: Retinitis pigmentosa (RP) refers to a group of progressive photoreceptor degenerative diseases. The activation of microglia has been reported to play an important role in the photoreceptor degeneration in RP retinal. Bujing Yishi tablets (BJYS), a Chinese herbal medicine, has been used to treat retinal diseases in China with desirable effect in improving visual function. However, the mechanisms underlying the efficacy of BJYS treatment in RP are not yet fully understood. PURPOSE: Based on the preliminary experiments, this study aimed to investigate the therapeutic mechanism involved in treating N-Methyl-N-Nitrosourea (MNU)-induced retinal degeneration of RP with BJYS. METHODS: To explore the efficacy of BJYS, a rat experimental RP model was established through intraperitoneal injection of MNU (50 mg/kg). Two experiment was carried out. After the treatment, we conducted H&E, TUNEL, retinal cytokine levels and IBA-1 expression in microglia to confirm the impact on RP model. The specific mechanism of action of BJYS tablet was assessed by western blot, real-time polymerase chain reaction (RT-PCR), and immunofluorescence to determine the mRNA and protein expression levels involved in clarifying the effectiveness of BJYS exerted through P2X7R/CX3CL1/CX3CR1 pathway. RESULTS: Significant alleviation of retinal morphological structure and photoreceptor degeneration by BJYS treatment was observed in the retinal of MNU-induced RP rats, BJYS prevented the reduction of ONL thickness and decreased the level of apoptotic cells in ONL. It also inhibited microglia overactivation and reduced retinal levels of IL-1ß, IL-6, TNF-α. In addition, BJYS decreased the protein expression and mRNA expression of P2X7, CX3CL1 and CX3CR1 and reduced the phosphorylation of p38 MAPK. CONCLUSION: In summary, this study suggested that BJYS treatment could alleviate photoreceptors degeneration of RP by inhibiting microglia overactivation and inflammation through the P2X7R/CX3CL1/CX3CR1 pathway. These effects suggest that BJYS tablets may serve as a promising oral therapeutic agent for RP.


Assuntos
Degeneração Retiniana , Retinite Pigmentosa , Ratos , Animais , Retinite Pigmentosa/tratamento farmacológico , Retinite Pigmentosa/metabolismo , Células Fotorreceptoras/metabolismo , Retina , Degeneração Retiniana/induzido quimicamente , Morte Celular , Compostos de Nitrosoureia/efeitos adversos , Compostos de Nitrosoureia/metabolismo , Apoptose , Modelos Animais de Doenças , Quimiocina CX3CL1/efeitos adversos , Quimiocina CX3CL1/metabolismo , Receptor 1 de Quimiocina CX3C/metabolismo
9.
J Mol Graph Model ; 122: 108469, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37068440

RESUMO

In this study, oxygenated triarylmethyl (oxTAM) is investigated by DFT calculations as a drug carrier framework for Nitrosourea (NU) and Fluorouracil (FU) drugs. Based on the adsorption analysis i.e., energies and distances between interacting atoms, it is found that oxTAM exhibits excellent carrier abilities for the delivery of FU (-1.53 eV & 2.00 Å) and NU (-1.33 eV & 2.12 Å) drugs. NCI and QTAIM results indicate the presence of hydrogen bonding in drug-carrier complexes. The values of dipole moment and global chemical descriptors show the significant reactivity of oxTAM for NU and FU drugs. Based on electronic property analysis, FU@oxTAM has a higher adsorption trend for complexation with oxTAM as compared to NU@oxTAM. Moreover, FU can easily release from the carrier due to the decreasing adsorption stability after protonation under an acidic environment as well as a short recovery time observed for the oxTAM carrier surface. Keeping in view all the above parameters, we inferred that oxTAM can serve as a potential drug delivery system for anticancer drugs including, Nitrosourea and Fluorouracil drugs.


Assuntos
Antineoplásicos , Antineoplásicos/farmacologia , Antineoplásicos/química , Fluoruracila/farmacologia , Fluoruracila/química , Sistemas de Liberação de Medicamentos , Portadores de Fármacos , Compostos de Nitrosoureia
10.
J Agric Food Chem ; 71(5): 2600-2609, 2023 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-36715487

RESUMO

Transition-metal oxides (TMOs) with a hollow multishelled structure have emerged as highly potential materials for high-performance electrochemical sensing, benefiting from their superior electronic conductivity, exceptionally large specific surface area, excellent stability, and electrochemistry properties. In particular, binary TMOs are expected to outperform unitary TMOs due to the synergistic effect of the different metals. Herein, MnCo2O4.5 hollow quadruple-shelled porous micropolyhedrons (MnCo2O4.5 HoQS-MPs) were prepared and employed to construct an ultrasensitive sensing platform for a multipesticide assay. Profiting from complex hollow interior structures and abundant active sites, the MnCo2O4.5 HoQS-MPs manifest outstanding electrochemical properties as electrode materials for the pesticide assay. The MnCo2O4.5 HoQS-MP-based biosensor demonstrated remarkable performance for monocrotophos, methamidophos, and carbaryl detection, with wide linear ranges, as well as low detection limits. This work unveils a new pathway for the ultrasensitive detection of pesticides and demonstrates tremendous potential for detecting other environmentally deleterious chemicals.


Assuntos
Óxidos , Praguicidas , Óxidos/química , Compostos de Nitrosoureia , Metais
11.
Birth Defects Res ; 115(3): 371-389, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36369674

RESUMO

Losses and malformations of cranial neural crest cell (cNCC) derivatives are a hallmark of several common brain and face malformations. Nevertheless, the etiology of these cNCC defects remains unknown for many cases, suggesting a complex basis involving interactions between genetic and/or environmental factors. However, the sheer number of possible factors (thousands of genes and hundreds of thousands of toxicants) has hindered identification of specific interactions. Here, we develop a high-throughput analysis that will enable faster identification of multifactorial interactions in the genesis of craniofacial defects. Zebrafish embryos expressing a fluorescent marker of cNCCs (fli1:EGFP) were exposed to a pathway inhibitor standard or environmental toxicant, and resulting changes in fluorescence were measured in high-throughput using a fluorescent microplate reader to approximate cNCC losses. Embryos exposed to the environmental Hedgehog pathway inhibitor piperonyl butoxide (PBO), a Hedgehog pathway inhibitor standard, or alcohol (ethanol) exhibited reduced fli1:EGFP fluorescence at one day post fertilization, which corresponded with craniofacial defects at five days post fertilization. Combining PBO and alcohol in a co-exposure paradigm synergistically reduced fluorescence, demonstrating a multifactorial interaction. Using pathway reporter transgenics, we show that the plate reader assay is sensitive at detecting alterations in Hedgehog signaling, a critical regulator of craniofacial development. We go on to demonstrate that this technique readily detects defects in other important cell types, namely neurons. Together, these findings demonstrate this novel in vivo platform can predict developmental abnormalities and multifactorial interactions in high-throughput.


Assuntos
Proteínas Hedgehog , Peixe-Zebra , Animais , Peixe-Zebra/genética , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Compostos de Nitrosoureia/metabolismo , Animais Geneticamente Modificados
12.
Ecotoxicol Environ Saf ; 244: 114056, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-36075124

RESUMO

Bacteria possess protective mechanisms against excess Mn(Ⅱ) to reduce its toxicity. Stenotrophomonas sp. MNB17 showed high Mn(Ⅱ) removal capacity (92.24-99.16 %) by forming Mn-precipitates (MnCO3 and Mn-oxides), whose Mn-oxides content increased with increasing Mn(Ⅱ) concentrations (10-50 mM). Compared with 0 mM Mn(Ⅱ)-stressed cells, transcriptomic analysis identified genes with the same transcriptional trends in 10 mM and 50 mM Mn(Ⅱ)-stressed cells, including genes involved in metal transport, cell envelope homeostasis, and histidine biosynthesis, as well as genes with different transcriptional trends, such as those involved in oxidative stress response, glyoxylate cycle, electron transport, and protein metabolism. The upregulation of histidine biosynthesis and oxidative stress responses were the most prominent features of these metabolisms under Mn(Ⅱ) stress. We confirmed that the increased level of reactive oxygen species was one of the reasons for the increased Mn-oxides formation at high Mn(Ⅱ) concentrations. Metabolite analysis indicated that the enhanced histidine biosynthesis rather than the tricarboxylic acid cycle resulted in an elevated level of α-ketoglutarate, which helped eliminate reactive oxygen species. Consistent with these results, the exogenous addition of histidine significantly reduced the production of reactive oxygen species and Mn-oxides and enhanced the removal of Mn(Ⅱ) as MnCO3. This study is the first to correlate histidine biosynthesis, reactive oxygen species, and Mn-oxides formation at high Mn(Ⅱ) concentrations, providing novel insights into the molecular regulatory mechanisms associated with Mn(Ⅱ) removal in bacteria.


Assuntos
Compostos de Manganês , Manganês , Bactérias/metabolismo , Glioxilatos/metabolismo , Histidina , Ácidos Cetoglutáricos , Manganês/metabolismo , Manganês/toxicidade , Compostos de Nitrosoureia , Oxirredução , Óxidos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Stenotrophomonas/metabolismo , Transcriptoma
13.
Chemosphere ; 308(Pt 2): 136435, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36113658

RESUMO

Microorganism-mediated Mn(Ⅱ) removal has gained increasing attention as a valuble bioremediation approach. In this study, a novel strain Stenotrophomonas sp. MNB17 - obtained from marine sediments - was found to show Mn(Ⅱ) removal efficiencies of 98.51-99.38% within 7 days and 92.24% within 20 days at Mn(Ⅱ) concentrations of 10-40 mM and 50 mM, respectively. On day 7, 80.44% of 50 mM Mn(Ⅱ) was oxidized to Mn(Ⅲ/Ⅳ), whereas only 2.11-2.86% of 10-40 mM Mn(Ⅱ) was oxidized. This difference in the proportion of Mn-oxides suggested that the strain MNB17 could remove soluble Mn(Ⅱ) via distinct mechanisms under different Mn(Ⅱ) concentrations. At 10 mM Mn(Ⅱ), indirect mechanisms were employed by strain MNB17 to remove Mn(Ⅱ). The sufficient energy generated by increased cellular respiration led to enhanced ammonification, and MnCO3 was the main component of the Mn-precipitates (97.27%). Meanwhile, intracellular fatty acids were degraded and served as an important carbon source for respiration. At 50 mM Mn(Ⅱ), most of the soluble Mn(Ⅱ) was oxidized, and Mn-oxides dominated the Mn-precipitates (80.44%). Mn(Ⅱ) oxidation likely contributed to electrons for energy production, as the down-regulation of respiratory pathways resulted in a deficit of electron supply, which warrants futher study. The exogenous addition of tricarboxylic acid cycle substrates (malate, α-ketoglutarate, oxaloacetate, succinate, and fumarate) was found to accelerate Mn(Ⅱ) removal as MnCO3 at a concentration of 50 mM. Overall, this study reports a novel strain MNB17 with the biotechnological potential of Mn(Ⅱ) removal and elucidates the function of cellular energy metabolism during the Mn(Ⅱ) removal process. In addition, it demonstrates the potential of aerobic respiration-related substrates in accelerating the removal of high concentrations of Mn(Ⅱ) for the first time.


Assuntos
Malatos , Stenotrophomonas , Bactérias/metabolismo , Carbono/metabolismo , Ácidos Graxos/metabolismo , Fumaratos/metabolismo , Ácidos Cetoglutáricos/metabolismo , Malatos/metabolismo , Manganês/metabolismo , Compostos de Manganês/metabolismo , Compostos de Nitrosoureia , Oxirredução , Óxidos/metabolismo , Succinatos/metabolismo
15.
Br J Haematol ; 195(4): 571-584, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34405395

RESUMO

Adult T-cell leukaemia/lymphoma (ATL) patients have a poor prognosis. Here, we investigated the impact of TP53 gene mutations on prognosis of ATL treated in different ways. Among 177 patients, we identified 47 single nucleotide variants or insertion-deletions (SNVs/indels) of the TP53 gene in 37 individuals. TP53 copy number variations (CNVs) were observed in 38 patients. Altogether, 67 of 177 patients harboured TP53 SNVs/indels or TP53 CNVs, and were categorized as having TP53 mutations. In the entire cohort, median survival of patients with and without TP53 mutations was 1·0 and 6·7 years respectively (P < 0·001). After allogeneic haematopoietic stem cell transplantation (HSCT), median survival of patients with (n = 16) and without (n = 29) TP53 mutations was 0·4 years and not reached respectively (P = 0·001). For patients receiving mogamulizumab without allogeneic HSCT, the median survival from the first dose of antibody in patients with TP53 mutations (n = 27) was only 0·9 years, but 5·1 years in those without (n = 42; P < 0·001). Thus, TP53 mutations are associated with unfavourable prognosis of ATL, regardless of treatment strategy. The establishment of alternative modalities to overcome the adverse impact of TP53 mutations in patients with ATL is required.


Assuntos
Genes p53 , Leucemia-Linfoma de Células T do Adulto/genética , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Aloenxertos , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígenos CD28/genética , Carboplatina/administração & dosagem , Ciclofosfamida/administração & dosagem , Variações do Número de Cópias de DNA , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Mutação INDEL , Estimativa de Kaplan-Meier , Lenalidomida/administração & dosagem , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Leucemia-Linfoma de Células T do Adulto/mortalidade , Leucemia-Linfoma de Células T do Adulto/terapia , Masculino , Pessoa de Meia-Idade , Compostos de Nitrosoureia/administração & dosagem , Polimorfismo de Nucleotídeo Único , Prednisolona/administração & dosagem , Prednisona/administração & dosagem , Prognóstico , Receptores CCR4/genética , Vincristina/administração & dosagem , Vindesina/administração & dosagem
16.
Int J Mol Sci ; 22(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206129

RESUMO

Endometriosis is a common disease. Its pathogenesis still remains uncertain, but it is clear that cell proliferation, apoptosis and chronic inflammation play an important role in its development. This paper aimed to investigate the anti-proliferative and anti-inflammatory effects of a combined therapy with fotemustine and dexamethasone. Endometriosis was induced by intraperitoneal injections of uterine fragments from donor animals to recipient animals. Next, the pathology was allowed to develop for 7 days. On the seventh day, fotemustine was administered once and dexamethasone was administered daily for the next 7 days. On Day 14, the animals were sacrificed, and peritoneal fluids and lesions were explanted. In order to evaluate the gastrointestinal side effects of the drugs, stomachs were harvested as well. The combined therapy of fotemustine and dexamethasone reduced the proinflammatory mediator levels in the peritoneal fluid and reduced the lesions' area and diameter. In particular, fotemustine and dexamethasone administration reduced the heterogeneous development of endometrial stroma and glands (histological analysis of lesions) and hyperproliferation of endometriotic cells (immunohistochemical analysis of Ki67 and Western blot analysis of PCNA) through the mitogen-activated protein kinase (MAPK) signaling pathway. Combined fotemustine and dexamethasone therapy showed anti-inflammatory effects by inducing the synthesis of anti-inflammatory mediators at the transcriptional and post-transcriptional levels (Western blot analysis of NFκB, COX-2 and PGE2 expression). Fotemustine and dexamethasone administration had anti-apoptotic activity, restoring the impaired mechanism (TUNEL assay and Western blot analysis of Bax and Bcl-2). Moreover, no gastric disfunction was detected (histological analysis of stomachs). Thus, our data showed that the combined therapy of fotemustine and dexamethasone reduced endometriosis-induced inflammation, hyperproliferation and apoptosis resistance.


Assuntos
Dexametasona/farmacologia , Endometriose/tratamento farmacológico , Inflamação/tratamento farmacológico , Compostos de Nitrosoureia/farmacologia , Compostos Organofosforados/farmacologia , Animais , Apoptose/efeitos dos fármacos , Líquido Ascítico/metabolismo , Proliferação de Células/efeitos dos fármacos , Endometriose/complicações , Endometriose/genética , Endometriose/patologia , Endométrio/efeitos dos fármacos , Endométrio/patologia , Feminino , Humanos , Inflamação/complicações , Inflamação/genética , Inflamação/patologia , NF-kappa B/genética , Antígeno Nuclear de Célula em Proliferação/genética , Ratos , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/genética
17.
Clin Cancer Res ; 27(17): 4737-4745, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34112708

RESUMO

PURPOSE: Phase II trials have shown encouraging activity with ipilimumab plus fotemustine and ipilimumab plus nivolumab in melanoma brain metastases. We report the primary analysis and 4-year follow-up of the NIBIT-M2 study, the first phase III trial comparing these regimens with fotemustine in patients with melanoma with brain metastases. PATIENTS AND METHODS: This phase III study recruited patients 18 years of age and older with BRAF wild-type or mutant melanoma, and active, untreated, asymptomatic brain metastases from nine centers, randomized (1:1:1) to fotemustine, ipilimumab plus fotemustine, or ipilimumab plus nivolumab. The primary endpoint was overall survival (OS). RESULTS: From January, 2013 to September, 2018, 27, 26, and 27 patients received fotemustine, ipilimumab plus fotemustine, and ipilimumab plus nivolumab. Median OS was 8.5 months [95% confidence interval (CI), 4.8-12.2] in the fotemustine arm, 8.2 months (95% CI, 2.2-14.3) in the ipilimumab plus fotemustine arm (HR vs. fotemustine, 1.09; 95% CI, 0.59-1.99; P = 0.78), and 29.2 months (95% CI, 0-65.1) in the ipilimumab plus nivolumab arm (HR vs. fotemustine, 0.44; 95% CI, 0.22-0.87; P = 0.017). Four-year survival rate was significantly higher for ipilimumab plus nivolumab than fotemustine [(41.0%; 95% CI, 20.6-61.4) vs. 10.9% (95% CI, 0-24.4; P = 0.015)], and was 10.3% (95% CI, 0-22.6) for ipilimumab plus fotemustine. In the fotemustine, ipilimumab plus fotemustine, and ipilimumab plus nivolumab arms, respectively, 11 (48%), 18 (69%), and eight (30%) patients had treatment-related grade 3 or 4 adverse events, without treatment-related deaths. CONCLUSIONS: Compared with fotemustine, ipilimumab plus nivolumab significantly improved overall and long-term survival of patients with melanoma with asymptomatic brain metastases.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Ipilimumab/administração & dosagem , Melanoma/tratamento farmacológico , Melanoma/secundário , Compostos de Nitrosoureia/administração & dosagem , Nivolumabe/administração & dosagem , Compostos Organofosforados/administração & dosagem , Neoplasias Cutâneas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/mortalidade , Feminino , Seguimentos , Humanos , Masculino , Melanoma/mortalidade , Pessoa de Meia-Idade , Neoplasias Cutâneas/mortalidade , Taxa de Sobrevida , Fatores de Tempo , Adulto Jovem
18.
Environ Mol Mutagen ; 62(6): 350-363, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34117657

RESUMO

We have used whole genome sequencing (WGS) to determine mutational signatures induced in the T-cells of rats treated in vivo with N-propyl-N-nitrosourea (PNU) or procarbazine (PCZ). The signatures from the treated rats were different from the signature of background mutations. The main component of the spontaneous T-cell mutational signature was C➔T transition with all other single base substitutions evenly distributed. The PNU-induced mutational signature showed relatively equal contributions from C➔T and T➔C transitions, and T➔A transversions. The PCZ-induced signature was characterized by T➔C transitions, T➔A and, to a smaller extent, T➔G transversions. C➔G transversions were infrequent in either the PNU or PCZ signatures. WGS not only allowed mutational signature detection, but also measured quantitative responses to mutagen treatment: 10-40× increases in the number of mutations per clone were detected in T-cell clones from treated rats. The overall strand specificity of induced mutations for annotated rat genes was comparable to the strand specificity of mutations determined previously for the endogenous X-linked Pig-a gene. Our results provide valuable reference data for future applications of WGS in safety research and risk assessment.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Mutação , Compostos de Nitrosoureia/toxicidade , Procarbazina/toxicidade , Linfócitos T/efeitos dos fármacos , Animais , Antineoplásicos/toxicidade , Masculino , Mutagênicos/toxicidade , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Linfócitos T/metabolismo , Linfócitos T/patologia , Sequenciamento Completo do Genoma
19.
Radiol Oncol ; 55(3): 347-353, 2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34051707

RESUMO

BACKGROUND: The aim of the study was to evaluate pretreatment inflammatory markers as prognostic factors in patients with unresectable uveal melanoma liver metastases treated with transarterial hepatic chemoperfusion. PATIENTS AND METHODS: 54 patients (44% male, median age: 61 years) were retrospectively assessed. A median of 3 (range: 1-11) treatment sessions were performed with melphalan (92%) or fotemustin (8%). Inflammatory indices were calculated as follows: neutrophils/nl to lymphocytes/nl ratio (NLR), systemic immune-inflammation index ([platelets/nl × neutrophils/nl]/[lymphocytes/nl]; SII), and platelets/nl to lymphocytes/nl ratio (PLR). The cut-off for dichotomization purposes was set at the median (inflammatory indices, hepatic tumor burden) or the upper level of normal. Kaplan Meier analysis was performed for median overall survival (OS) in months, and Cox proportional hazard model for uni(UVA) and multivariate (MVA) hazard ratio (HR, 95%CI) analyses were performed. RESULTS: Median OS of the study cohort was 7.7 (6.3-10.9) months. In UVA OS was prolonged for low C reactive protein (CRP) (13.5 vs. 5.2; p = 0.0005), low SII (10.8 vs. 5.6; p = 0.0005), low NLR (11.1 vs. 6.3; p = 0.0045), low aspartate aminotransferase (AST) (11.5 vs. 5.6; p = 0.015), alanine aminotransferases (ALT) (11.5 vs. 5.6; p = 0.01), and tumor burden ≦ 50% (8.2 vs. 4.8; p = 0.007). MVA confirmed low CRP (HR: 0.29, 0.11-0.7; p = 0.005), low SII (HR: 0.19, 0.11-0.7; p = 0.008), and low ALT (HR: 0.13, 0.02-0.63; p = 0.011) as independent predictors for prolonged OS. Patients with ≦ 1, 2, 3 elevated significant MVA-factors survived a median of 14.9, 7.7, and 3.9 months, respectively (p = 0.0001). CONCLUSIONS: Pretreatment inflammatory markers (CRP, SII) and AST were independent prognostic survival markers in patients with uveal melanoma liver metastases treated with transarterial hepatic chemoperfusion. A combination of factors may help to identify patients potentially benefitting from treatment.


Assuntos
Neoplasias Hepáticas/sangue , Melanoma/sangue , Neoplasias Uveais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/sangue , Antineoplásicos/uso terapêutico , Aspartato Aminotransferases/sangue , Biomarcadores Tumorais/sangue , Plaquetas/citologia , Proteína C-Reativa/análise , Quimioterapia do Câncer por Perfusão Regional/métodos , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Linfócitos/citologia , Masculino , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Melanoma/secundário , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Neutrófilos/citologia , Compostos de Nitrosoureia/uso terapêutico , Compostos Organofosforados/uso terapêutico , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Carga Tumoral , Neoplasias Uveais/sangue
20.
Inorg Chem ; 60(11): 7719-7731, 2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34004115

RESUMO

The non-heme iron-dependent enzyme SznF catalyzes a critical N-nitrosation step during the N-nitrosourea pharmacophore biosynthesis in streptozotocin. The intramolecular oxidative rearrangement process is known to proceed at the FeII-containing active site in the cupin domain of SznF, but its mechanism has not been elucidated to date. In this study, based on the density functional theory calculations, a unique mechanism was proposed for the N-nitrosation reaction catalyzed by SznF in which a four-electron oxidation process is accomplished through a series of complicated electron transferring between the iron center and substrate to bypass the high-valent FeIV═O species. In the catalytic reaction pathway, the O2 binds to the iron center and attacks on the substrate to form the peroxo bridge intermediate by obtaining two electrons from the substrate exclusively. Then, instead of cleaving the peroxo bridge, the Cε-Nω bond of the substrate is homolytically cleaved first to form a carbocation intermediate, which polarizes the peroxo bridge and promotes its heterolysis. After O-O bond cleavage, the following reaction steps proceed effortlessly so that the N-nitrosation is accomplished without NO exchange among reaction species.


Assuntos
Compostos de Nitrosoureia/metabolismo , Ferroproteínas não Heme/metabolismo , Biocatálise , Compostos Ferrosos/química , Compostos Ferrosos/metabolismo , Conformação Molecular , Nitrosação , Compostos de Nitrosoureia/química , Ferroproteínas não Heme/química , Oxirredução , Streptomyces/enzimologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...