RESUMO
High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HDC/ASCT) has been useful in relapsed or refractory classic Hodgkin lymphoma (RRcHL). Furthermore, a ranimustine, cytarabine, etoposide, and cyclophosphamide (MCVAC) conditioning regimen has been effective in diffuse large B-cell lymphoma. However, limited data are available regarding this conditioning regimen for cHL. In this study, we investigated the efficacy and toxicity of MCVAC for RRcHL. We retrospectively analyzed 10 patients with RRcHL who underwent ASCT preceded by the MCVAC conditioning regimen between January 2009 and December 2021 at our institution. A total of 10 patients (median [range] age, 36 [23-64] years), including 5 (50%) men and 5 (50%) women, were treated with the MCVAC regimen followed by ASCT. The median follow-up duration of the 10 patients was 25.0 months. The 36-month PFS and OS rates were 43.8% (95% CI, 11.9%-72.6%) and 64.0% (95% CI, 22.6%-87.5%), respectively. Two patients died because of treatment-related factors, and one patient died because of disease progression. Based on our findings, recognizing the risk factors for adverse events (AEs) associated with this treatment, MCVAC may be a valid treatment option for the management of RRcHL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Citarabina , Etoposídeo , Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin , Condicionamento Pré-Transplante , Transplante Autólogo , Humanos , Doença de Hodgkin/terapia , Doença de Hodgkin/mortalidade , Transplante de Células-Tronco Hematopoéticas/métodos , Adulto , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Condicionamento Pré-Transplante/métodos , Citarabina/administração & dosagem , Citarabina/uso terapêutico , Etoposídeo/administração & dosagem , Etoposídeo/uso terapêutico , Ciclofosfamida/uso terapêutico , Ciclofosfamida/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adulto Jovem , Compostos de Nitrosoureia/administração & dosagem , Compostos de Nitrosoureia/uso terapêutico , RecidivaRESUMO
The aim of this study was to analyze postsurgical outcomes for individuals with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) who underwent anterior temporal lobectomy, based on the presence of calcified neurocysticercosis (cNCC). A retrospective cross-sectional study was conducted on 89 patients with MTLE-HS who underwent anterior temporal lobectomy between January 2012 and December 2020 at a basic epilepsy surgery center located in Lima, Peru. We collected sociodemographic, clinical, and diagnostic information. The postsurgical results were analyzed using bivariate analysis according to the Engel classification. We included 89 individuals with a median age of 28 years (interquartile range [IQR]: 24-37), and more than half (55.1%) were male. Seventeen (19.1%) were diagnosed with cNCC. A greater number of patients with cNCC had lived in rural areas of Peru during their early life compared with those without cNCC (12 [70.6%] versus 26 [36.1%]; P = 0.010). Patients with cNCC exhibited a greater median frequency of focal to bilateral tonic-clonic seizures per month (1 [IQR: 0-2] versus 0 [0-0.5]; P = 0.009). Conversely, a lower proportion of patients with cNCC reported a history of an initial precipitating injury in comparison to the group without cNCC (4 [23.5%] versus 42 [58.3%]; P = 0.014). At the 1-year follow-up, most patients (82.4%) with cNCC were categorized as Engel IA. Similarly, at the 2-year follow-up, nine (75.0%) were classified as Engel IA. Our findings suggest that most patients diagnosed with cNCC exhibit favorable postsurgical outcomes, comparable to those without cNCC. Additionally, it can be postulated that cNCC may play a role as an initial precipitating injury.
Assuntos
Epilepsia do Lobo Temporal , Epilepsia , Esclerose Hipocampal , Neurocisticercose , Compostos de Nitrosoureia , Humanos , Masculino , Adulto , Feminino , Epilepsia do Lobo Temporal/complicações , Epilepsia do Lobo Temporal/cirurgia , Neurocisticercose/complicações , Neurocisticercose/cirurgia , Estudos Retrospectivos , Estudos Transversais , Resultado do Tratamento , Epilepsia/complicações , HipocampoRESUMO
Chloroethylnitrosoureas (CENUs) are important chemotherapies applied in the treatment of cancer. They exert anticancer activity by inducing DNA interstrand cross-links (ICLs) via the formation of two O6-alkylguanine intermediates, O6-chloroethylguanine (O6-ClEtG) and N1,O6-ethanoguanine (N1,O6-EtG). However, O6-alkylguanine-DNA alkyltransferase (AGT), a DNA-repair enzyme, can restore the O6-alkylguanine damages and thereby obstruct the formation of ICLs (dG-dC cross-link). In this study, the inhibitory mechanism of ICL formation was investigated to elucidate the drug resistance of CENUs mediated by AGT in detail. Based on the structures of the substrate-enzyme complexes obtained from docking and MD simulations, two ONIOM (QM/MM) models with different sizes of the QM region were constructed. The model with a larger QM region, which included the substrate (O6-ClEtG or N1,O6-EtG), a water molecule, and five residues (Tyr114, Cys145, His146, Lys165, and Glu172) in the active pocket of AGT, accurately described the repairing reaction and generated the results coinciding with the experimental outcomes. The repair process consists of two sequential steps: hydrogen transfer to form a thiolate anion on Cys145 and alkyl transfer from the O6 site of guanine (the rate-limiting step). The repair of N1,O6-EtG was more favorable than that of O6-ClEtG from both kinetics and thermodynamics aspects. Moreover, the comparison of the repairing process with the formation of dG-dC cross-link and the inhibition of AGT by O6-benzylguanine (O6-BG) showed that the presence of AGT could effectively interrupt the formation of ICLs leading to drug resistance, and the inhibition of AGT by O6-BG that was energetically more favorable than the repair of O6-ClEtG could not prevent the repair of N1,O6-EtG. Therefore, it is necessary to completely eliminate AGT activity before CENUs medication to enhance the chemotherapeutic effectiveness. This work provides reasonable explanations for the supposed mechanism of AGT-mediated drug resistance of CENUs and will assist in the development of novel CENU chemotherapies and their medication strategies.
Assuntos
Reparo do DNA , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , O(6)-Metilguanina-DNA Metiltransferase , O(6)-Metilguanina-DNA Metiltransferase/metabolismo , O(6)-Metilguanina-DNA Metiltransferase/química , O(6)-Metilguanina-DNA Metiltransferase/antagonistas & inibidores , Humanos , Teoria Quântica , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos de Nitrosoureia/química , Compostos de Nitrosoureia/farmacologia , Compostos de Nitrosoureia/metabolismoRESUMO
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/patologiaRESUMO
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 â benzaldehyde â 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 , CatáliseRESUMO
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 VidaRESUMO
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/químicaRESUMO
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 tissuesâ , 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/toxicidadeRESUMO
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 , HumanosRESUMO
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 terapêuticoRESUMO
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 , Retinose Pigmentar , Ratos , Animais , Retinose Pigmentar/tratamento farmacológico , Retinose Pigmentar/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/metabolismoRESUMO
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 NitrosoureiaRESUMO
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 , MetaisRESUMO
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 ModificadosRESUMO
Bacteria possess protective mechanisms against excess Mn(â ¡) to reduce its toxicity. Stenotrophomonas sp. MNB17 showed high Mn(â ¡) removal capacity (92.24-99.16 %) by forming Mn-precipitates (MnCO3 and Mn-oxides), whose Mn-oxides content increased with increasing Mn(â ¡) concentrations (10-50 mM). Compared with 0 mM Mn(â ¡)-stressed cells, transcriptomic analysis identified genes with the same transcriptional trends in 10 mM and 50 mM Mn(â ¡)-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(â ¡) 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(â ¡) 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(â ¡) as MnCO3. This study is the first to correlate histidine biosynthesis, reactive oxygen species, and Mn-oxides formation at high Mn(â ¡) concentrations, providing novel insights into the molecular regulatory mechanisms associated with Mn(â ¡) 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 , TranscriptomaRESUMO
Microorganism-mediated Mn(â ¡) 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(â ¡) removal efficiencies of 98.51-99.38% within 7 days and 92.24% within 20 days at Mn(â ¡) concentrations of 10-40 mM and 50 mM, respectively. On day 7, 80.44% of 50 mM Mn(â ¡) was oxidized to Mn(â ¢/â £), whereas only 2.11-2.86% of 10-40 mM Mn(â ¡) was oxidized. This difference in the proportion of Mn-oxides suggested that the strain MNB17 could remove soluble Mn(â ¡) via distinct mechanisms under different Mn(â ¡) concentrations. At 10 mM Mn(â ¡), indirect mechanisms were employed by strain MNB17 to remove Mn(â ¡). 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(â ¡), most of the soluble Mn(â ¡) was oxidized, and Mn-oxides dominated the Mn-precipitates (80.44%). Mn(â ¡) 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(â ¡) removal as MnCO3 at a concentration of 50 mM. Overall, this study reports a novel strain MNB17 with the biotechnological potential of Mn(â ¡) removal and elucidates the function of cellular energy metabolism during the Mn(â ¡) removal process. In addition, it demonstrates the potential of aerobic respiration-related substrates in accelerating the removal of high concentrations of Mn(â ¡) 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/metabolismoRESUMO
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 & dosagemRESUMO
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/genéticaRESUMO
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.