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1.
Mol Cell ; 73(6): 1282-1291.e8, 2019 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-30792174

RESUMO

Toxin-antitoxin (TA) systems regulate fundamental cellular processes in bacteria and represent potential therapeutic targets. We report a new RES-Xre TA system in multiple human pathogens, including Mycobacterium tuberculosis. The toxin, MbcT, is bactericidal unless neutralized by its antitoxin MbcA. To investigate the mechanism, we solved the 1.8 Å-resolution crystal structure of the MbcTA complex. We found that MbcT resembles secreted NAD+-dependent bacterial exotoxins, such as diphtheria toxin. Indeed, MbcT catalyzes NAD+ degradation in vitro and in vivo. Unexpectedly, the reaction is stimulated by inorganic phosphate, and our data reveal that MbcT is a NAD+ phosphorylase. In the absence of MbcA, MbcT triggers rapid M. tuberculosis cell death, which reduces mycobacterial survival in macrophages and prolongs the survival of infected mice. Our study expands the molecular activities employed by bacterial TA modules and uncovers a new class of enzymes that could be exploited to treat tuberculosis and other infectious diseases.


Assuntos
Antitoxinas/metabolismo , Proteínas de Bactérias/metabolismo , Toxinas Bacterianas/metabolismo , Macrófagos/microbiologia , Mycobacterium tuberculosis/enzimologia , Fosforilases/metabolismo , Sistemas Toxina-Antitoxina , Tuberculose/microbiologia , Animais , Antibióticos Antituberculose/farmacologia , Antitoxinas/química , Antitoxinas/genética , Carga Bacteriana , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Toxinas Bacterianas/química , Toxinas Bacterianas/genética , Células Cultivadas , Modelos Animais de Doenças , Feminino , Interações Hospedeiro-Patógeno , Humanos , Cinética , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos SCID , Camundongos Transgênicos , Viabilidade Microbiana , Modelos Moleculares , Mycobacterium smegmatis/enzimologia , Mycobacterium smegmatis/genética , Mycobacterium smegmatis/patogenicidade , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/patogenicidade , NAD/metabolismo , Fosforilases/química , Fosforilases/genética , Conformação Proteica , Sistemas Toxina-Antitoxina/genética , Tuberculose/tratamento farmacológico
2.
Pharmacol Rev ; 74(4): 1136-1145, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36180110

RESUMO

The number of cancer drugs is increasing as new chemical entities are developed to target molecules, often protein kinases, driving cancer progression. In 2009, Fedorov et al. identified that of the protein kinases in the human kinome, most of the focus has been on a small subset. They highlighted that many poorly investigated protein kinases were cancer drivers, but there was no relationship between publications and involvement in cancer development or progression. Since 2009, there has been a doubling in the number of publications, patents, and drugs targeting the kinome. To determine whether this was an expansion in knowledge of well-studied targets-searching in the light under the lamppost-or an explosion of investigations into previously poorly investigated targets, we searched the literature for publications on each kinase, updating Federov et al.'s assessment of the druggable kinome. The proportion of papers focusing on the 50 most-studied kinases had not changed, and the makeup of those 50 had barely changed. The majority of new drugs (80%) were against the same group of 50 kinases identified as targets 10 years ago, and the proportion of studies investigating previously poorly investigated kinases (<1%) was unchanged. With three exceptions [p38 mitogenactivated protein kinase (p38a), AMP-activated protein kinase catalytic α-subunit 1,2, and B-Raf proto-oncogene (BRAF) serine/threonine kinase], >95% of publications addressing kinases still focused on a relatively small proportion (<50%) of the human kinome independently of their involvement as cancer drivers. There is, therefore, still extensive scope for discovery of therapeutics targeting different protein kinases in cancer and still a bias toward well-characterized targets over the innovative searchlight into the unknown. SIGNIFICANCE STATEMENT: This study presents evidence that drug discovery efforts in cancer are still to some extent focused on a narrow group of well-studied kinases 10 years after the identification of multiple novel cancer targets in the human kinome. This suggests that there is still room for researchers in academia, industry, and the not-for-profit sector to develop new and diverse therapies targeting kinases for cancer.


Assuntos
Antineoplásicos , Neoplasias , Proteínas Quinases Ativadas por AMP , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas B-raf , Serina
3.
J Cogn Neurosci ; 36(5): 936-961, 2024 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-38319886

RESUMO

Changes in error processing are observable in a range of anxiety-related disorders. Numerous studies, however, have reported contradictory and nonreplicating findings, thus the exact mapping of brain response to errors (i.e., error-related negativity [ERN]; error-related positivity [Pe]) onto specific anxiety symptoms remains unclear. In this study, we collected 16 self-reported scores of anxiety dimensions and obtained spatial features of EEG recordings from 171 individuals. We then used machine learning to (1) identify symptoms that are central for elevated ERN/Pe and (2) estimate the generalizability of traditional statistical approaches. ERN was associated with rumination, threat overestimation, and inhibitory intolerance of uncertainty. Pe was associated with rumination, prospective intolerance of uncertainty, and behavioral inhibition. Our findings emphasize that not only the amplitude of ERN but also other sources of brain signal variance encode information relevant to individual differences in error processing. The results of the generalizability check reveal the need for a change in result-validation methods to move toward robust findings that reflect stable individual differences and clinically useful biomarkers. Our study benefits from the use of machine learning to improve the generalizability of results.


Assuntos
Eletroencefalografia , Potenciais Evocados , Humanos , Potenciais Evocados/fisiologia , Eletroencefalografia/métodos , Estudos Prospectivos , Ansiedade , Encéfalo , Tempo de Reação/fisiologia
4.
Int J Mol Sci ; 25(14)2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-39062768

RESUMO

Diabetes mellitus (DM) is the most common metabolic disease in humans, and its prevalence is increasing worldwide in parallel with the obesity pandemic. A lack of insulin or insulin resistance, and consequently hyperglycemia, leads to many systemic disorders, among which diabetic encephalopathy (DE) is a long-term complication of the central nervous system (CNS), characterized by cognitive impairment and motor dysfunctions. The role of oxidative stress and neuroinflammation in the pathomechanism of DE has been proven. Fractalkine (CX3CL1) has unique properties as an adhesion molecule and chemoattractant, and by acting on its only receptor, CX3CR1, it regulates the activity of microglia in physiological states and neuroinflammation. Depending on the clinical context, CX3CL1-CX3CR1 signaling may have neuroprotective effects by inhibiting the inflammatory process in microglia or, conversely, maintaining/intensifying inflammation and neurotoxicity. This review discusses the evidence supporting that the CX3CL1-CX3CR1 pair is neuroprotective and other evidence that it is neurotoxic. Therefore, interrupting the vicious cycle within neuron-microglia interactions by promoting neuroprotective effects or inhibiting the neurotoxic effects of the CX3CL1-CX3CR1 signaling axis may be a therapeutic goal in DE by limiting the inflammatory response. However, the optimal approach to prevent DE is simply tight glycemic control, because the elimination of dysglycemic states in the CNS abolishes the fundamental mechanisms that induce this vicious cycle.


Assuntos
Quimiocina CX3CL1 , Microglia , Transdução de Sinais , Humanos , Quimiocina CX3CL1/metabolismo , Animais , Microglia/metabolismo , Microglia/patologia , Receptor 1 de Quimiocina CX3C/metabolismo
5.
Int J Mol Sci ; 25(6)2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38542084

RESUMO

Unbalanced blood glucose levels may cause inflammation within the central nervous system (CNS). This effect can be reversed by the action of a natural neuroprotective compound, resveratrol (RSV). The study aimed to investigate the anti-inflammatory effect of RSV on astrocyte cytokine profiles within an in vitro model of the blood-brain barrier (BBB) under varying glucose concentrations (2.2, 5.0, and 25.0 mmol/L), corresponding to hypo-, normo-, and hyperglycemia. The model included co-cultures of astrocytes (brain compartment, BC) and endothelial cells (microvascular compartment, MC), separated by 0.4 µm wide pores. Subsequent exposure to 0.2 µM LPS in the brain compartment (BC) and 50 µM RSV in the microvascular compartment (MC) of each well was carried out. Cytokine levels (IL-1 α, IL-1 ß, IL-2, IL-4, IL-6, IL-8) in the BC were assessed using a Multi-Analyte ELISArray Kit before and after the addition of LPS and RSV. Statistical analysis was performed to determine significance levels. The results demonstrated that RSV reduced the concentration of all studied cytokines in the BC, regardless of glucose levels, with the most substantial decrease observed under normoglycemic conditions. Additionally, the concentration of RSV in the BC was highest under normoglycemic conditions compared to hypo- and hyperglycemia. These findings confirm that administration of RSV in the MC exerts anti-inflammatory effects within the BC, particularly under normoglycemia-simulating conditions. Further in vivo studies, including animal and human research, are warranted to elucidate the bioavailability of RSV within the central nervous system (CNS).


Assuntos
Barreira Hematoencefálica , Hiperglicemia , Animais , Humanos , Resveratrol/farmacologia , Barreira Hematoencefálica/metabolismo , Células Endoteliais/metabolismo , Lipopolissacarídeos/toxicidade , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Glucose/farmacologia , Hiperglicemia/tratamento farmacológico
6.
Small ; 19(12): e2205961, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36587987

RESUMO

Improving the tumor reoxygenation to sensitize the tumor to radiation therapy is a cornerstone in radiation oncology. Here, the pre-clinical development of a clinically transferable liposomal formulation encapsulating trans sodium crocetinate (NP TSC) is reported to improve oxygen diffusion through the tumor environment. Early pharmacokinetic analysis of the clinical trial of this molecule performed on 37 patients orient to define the optimal fixed dosage to use in a triple-negative breast cancer model to validate the therapeutic combination of radiation therapy and NP TSC. Notably, it is reported that this formulation is non-toxic in both humans and mice at the defined fixed concentration, provides a normalization of the tumor vasculature within 72 h window after systemic injection, leads to a transient increase (50% improvement) in the tumor oxygenation, and significantly improves the efficacy of both mono-fractionated and fractionated radiation therapy treatment. Together, these findings support the introduction of a first-in-class therapeutic construct capable of tumor-specific reoxygenation without associated toxicities.


Assuntos
Neoplasias , Hipóxia Tumoral , Humanos , Camundongos , Animais , Carotenoides , Neoplasias/terapia , Vitamina A/uso terapêutico
7.
Med Sci Monit ; 29: e941044, 2023 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-37817396

RESUMO

BACKGROUND The prevalence of type 2 diabetes mellitus is rising, presumably because of a coexisting pandemic of obesity. Since diabetic neuropathy and neuroinflammation are frequent and significant complications of both prolonged hyperglycemia and iatrogenic hypoglycemia, the effect of glucose concentration and resveratrol (RSV) supplementation on cytokine profile was assessed in an in vitro model of the blood-brain barrier (BBB). MATERIAL AND METHODS The in vitro model of BBB was formed of endothelial cells and astrocytes, which represented the microvascular and brain compartments (MC and BC, respectively). The BC concentrations of selected cytokines - IL-10, IL-12, IL-17A, TNF-alpha, IFN-γ, GM-CSF in response to different glucose concentrations in the MC were studied. The influence of LPS in the BC and RSV in the MC on the cytokine profile in the BC was examined. RESULTS Low glucose concentration (40 mg/dL) in the MC resulted in increased concentration of all the cytokines in the BC except TNF-alpha, compared to normoglycemia-imitating conditions (90 mg/dL) (P<0.05). High glucose concentration (450 mg/dL) in the MC elevated the concentration of all the cytokines in the BC (P<0.05). RSV decreased the level of all cytokines in the BC after 24 h following its administration for all glucose concentrations in the MC (P<0.02). The greatest decline was observed in normoglycemic conditions (P<0.05). CONCLUSIONS Both hypo- and hyperglycemia-simulating conditions impair the cytokine profile in BC, while RSV can normalize it, despite relatively poor penetration through the BBB. RSV exhibits anti-neuroinflammatory effects, especially in the group with normoglycemia-simulating conditions.


Assuntos
Diabetes Mellitus Tipo 2 , Hiperglicemia , Humanos , Citocinas/metabolismo , Barreira Hematoencefálica , Resveratrol/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Doenças Neuroinflamatórias , Células Endoteliais/metabolismo , Hiperglicemia/tratamento farmacológico , Glucose/farmacologia
8.
Acta Neurochir (Wien) ; 165(7): 1955-1962, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37284837

RESUMO

BACKGROUND: Trigeminal neuralgia (TN), a severe type of facial pain, is mainly caused by a neurovascular conflict (NVC). The severity of the NVC seems associated with the outcome following microvascular decompression (MVD) surgery. This study aimed to investigate the outcome after MVD and whether it is affected by NVC severity and sex. METHODS: TN patients (n = 109) were followed for 5 to 10 years after MVD. Barrow Neurology Index (BNI), Patients Global Impression of Change (PGIC), complications, and time to relapse were evaluated. The NVC severity was retrospectively reviewed from presurgical MRI. Demographic and clinical factors and NVC severity were analyzed for potential association with outcome after MVD. RESULTS: The success rate (BNI ≤ 2) was 80% after 5 to 10 years follow-up for TN patients with severe NVC (grade 2-3) and 56% for TN patients with mild NVC (grade 0-1, P = 0.003). No sex difference was observed in outcome for patients with both mild (P = 0.924) and severe NVC (P = 0.883) respectively. Three patients (2.8%) during the hospital stay, and two patients (1.8%) at 6 weeks, experienced a complication requiring invasive treatment. At long-term 52/109 patients (47.7%) reported some type of persistent adverse event, of which the majority were mild and required no treatment. CONCLUSIONS: MVD offers an 80% probability of long-term pain relief in TN patients with severe NVC, with low frequency of serious complications. NVC severity significantly affects outcome after MVD, while no sex differences in outcome were found. In consistency with previous work, the results stress the importance of adequate neuroradiological assessment of the NVC for preoperative patient selection.


Assuntos
Cirurgia de Descompressão Microvascular , Neuralgia do Trigêmeo , Humanos , Neuralgia do Trigêmeo/diagnóstico por imagem , Neuralgia do Trigêmeo/cirurgia , Neuralgia do Trigêmeo/complicações , Cirurgia de Descompressão Microvascular/efeitos adversos , Estudos Retrospectivos , Dor Facial/etiologia , Manejo da Dor/efeitos adversos , Resultado do Tratamento
9.
Int J Mol Sci ; 24(12)2023 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-37373216

RESUMO

Diabetes mellitus is one of the most common metabolic diseases worldwide, and its long-term complications include neuropathy, referring both to the peripheral and to the central nervous system. Detrimental effects of dysglycemia, especially hyperglycemia, on the structure and function of the blood-brain barrier (BBB), seem to be a significant backgrounds of diabetic neuropathy pertaining to the central nervous system (CNS). Effects of hyperglycemia, including excessive glucose influx to insulin-independent cells, may induce oxidative stress and secondary innate immunity dependent inflammatory response, which can damage cells within the CNS, thus promoting neurodegeneration and dementia. Advanced glycation end products (AGE) may exert similar, pro-inflammatory effects through activating receptors for advanced glycation end products (RAGE), as well as some pattern-recognition receptors (PRR). Moreover, long-term hyperglycemia can promote brain insulin resistance, which may in turn promote Aß aggregate accumulation and tau hyperphosphorylation. This review is focused on a detailed analysis of the effects mentioned above towards the CNS, with special regard to mechanisms taking part in the pathogenesis of central long-term complications of diabetes mellitus initiated by the loss of BBB integrity.


Assuntos
Demência , Diabetes Mellitus , Neuropatias Diabéticas , Hiperglicemia , Humanos , Barreira Hematoencefálica/metabolismo , Hiperglicemia/complicações , Hiperglicemia/metabolismo , Neuropatias Diabéticas/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Demência/etiologia , Demência/metabolismo , Diabetes Mellitus/metabolismo
10.
Int J Mol Sci ; 24(14)2023 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-37511397

RESUMO

The flow of substances between the blood and the central nervous system is precisely regulated by the blood-brain barrier (BBB). Its disruption due to unbalanced blood glucose levels (hyper- and hypoglycemia) occurring in metabolic disorders, such as type 2 diabetes, can lead to neuroinflammation, and increase the risk of developing neurodegenerative diseases. One of the most studied natural anti-diabetic, anti-inflammatory, and neuroprotective compounds is resveratrol (RSV). It activates sirtuin 1 (SIRT1), a key metabolism regulator dependent on cell energy status. The aim of this study was to assess the astrocyte SIRT1 response to neuroinflammation and subsequent RSV treatment, depending on systemic glycemia. For this purpose, we used an optimized in vitro model of the BBB consisting of endothelial cells and astrocytes, representing microvascular and brain compartments (MC and BC), in different glycemic backgrounds. Astrocyte-secreted SIRT1 reached the highest concentration in hypo-, the lowest in normo-, and the lowest in hyperglycemic backgrounds. Lipopolysaccharide (LPS)-induced neuroinflammation caused a substantial decrease in SIRT1 in all glycemic backgrounds, as observed earliest in hyperglycemia. RSV partially counterbalanced the effect of LPS on SIRT1 secretion, most remarkably in normoglycemia. Our results suggest that abnormal glycemic states have a worse prognosis for RSV-therapy effectiveness compared to normoglycemia.


Assuntos
Astrócitos , Diabetes Mellitus Tipo 2 , Humanos , Resveratrol/farmacologia , Astrócitos/metabolismo , Sirtuína 1/metabolismo , Doenças Neuroinflamatórias , Células Endoteliais/metabolismo , Lipopolissacarídeos
11.
Int J Mol Sci ; 24(13)2023 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-37446144

RESUMO

The MRE11 nuclease is essential during DNA damage recognition, homologous recombination, and replication. BRCA2 plays important roles during homologous recombination and replication. Here, we show that effecting an MRE11 blockade using a prototypical inhibitor (Mirin) induces synthetic lethality (SL) in BRCA2-deficient ovarian cancer cells, HeLa cells, and 3D spheroids compared to BRCA2-proficient controls. Increased cytotoxicity was associated with double-strand break accumulation, S-phase cell cycle arrest, and increased apoptosis. An in silico analysis revealed Mirin docking onto the active site of MRE11. While Mirin sensitises DT40 MRE11+/- cells to the Top1 poison SN-38, it does not sensitise nuclease-dead MRE11 cells to this compound confirming that Mirin specifically inhibits Mre11 nuclease activity. MRE11 knockdown reduced cell viability in BRCA2-deficient PEO1 cells but not in BRCA2-proficient PEO4 cells. In a Mirin-resistant model, we show the downregulation of 53BP1 and DNA repair upregulation, leading to resistance, including in in vivo xenograft models. In a clinical cohort of human ovarian tumours, low levels of BRCA2 expression with high levels of MRE11 co-expression were linked with worse progression-free survival (PFS) (p = 0.005) and overall survival (OS) (p = 0.001). We conclude that MRE11 is an attractive SL target, and the pharmaceutical development of MRE11 inhibitors for precision oncology therapeutics may be of clinical benefit.


Assuntos
Proteínas de Ligação a DNA , Neoplasias Ovarianas , Humanos , Feminino , Proteínas de Ligação a DNA/metabolismo , Proteína Homóloga a MRE11/genética , Proteína Homóloga a MRE11/metabolismo , Células HeLa , Medicina de Precisão , Proteína BRCA2/metabolismo , Reparo do DNA , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Linhagem Celular Tumoral
12.
Neuroimage ; 251: 118889, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35065268

RESUMO

Current models of episodic memory posit that retrieval involves the reenactment of encoding processes. Recent evidence has shown that this reinstatement process - indexed by subsequent encoding-retrieval similarity of brain activity patterns - is related to the activity in the hippocampus during encoding. However, we tend to re-experience emotional events in memory more richly than dull events. The role of amygdala - a critical hub of emotion processing - in reinstatement of emotional events was poorly understood. To investigate it, we leveraged a previously overlooked divergence in the role of amygdala in memory modulation by distinct emotions - disgust and fear. Here we used a novel paradigm in which participants encoded complex events (word pairs) and their memory was tested after 3 weeks, both phases during fMRI scanning. Using representational similarity analysis and univariate analyses, we show that the strength of amygdala activation during encoding was correlated with memory reinstatement of individual event representations in emotion-specific regions. Critically, amygdala modulated reinstatement more for disgust than fear. This was in line with other differences observed at the level of memory performance and neural mechanisms of encoding. Specifically, amygdala and perirhinal cortex were more involved during encoding of disgust-related events, whereas hippocampus and parahippocampal gyrus during encoding of fear-related events. Together, these findings shed a new light on the role of the amygdala and medial temporal lobe regions in encoding and reinstatement of specific emotional memories.


Assuntos
Asco , Tonsila do Cerebelo/diagnóstico por imagem , Mapeamento Encefálico , Medo , Hipocampo/diagnóstico por imagem , Hipocampo/fisiologia , Humanos , Imageamento por Ressonância Magnética , Lobo Temporal/fisiologia
13.
Cancer Control ; 29: 10732748221140696, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36447439

RESUMO

BACKGROUND: Abiraterone acetate (AA) is a drug used in advanced prostate cancer. However, known clinical factors with predictive and prognostic value are scarce. This study evaluated cardiovascular (CV) factors and geriatric scales as potential markers of superior response during AA therapy. METHODS: This is a prospective observational study. Serum levels of high sensitivity troponin T (hsTnT), D-dimer, NT-proBNP and left ventricle ejection fraction (LVEF) were used for CV evaluation. Questionnaires of G8, VES-13, Activities of Daily Living (ADL), Instrumental Activities of Daily Living (iADL), and Geriatric Depression Scale (GDS) were included in the geriatric screening assessment. All measures were taken before AA initiation. Survival curves and Cox proportional hazard models (univariate and multivariate) were used to determine the predictors for a longer time to treatment failure (TTF). RESULTS: Forty nine patients were included in the study. Overall median TTF was 7.9 months (95% CI: 5.9-12.4). In univariate analysis, factors associated with inferior TTF were (P-value < .05): visceral metastases - HR 2.34; 95% CI: 1.24-4.45, history of coronary artery disease - HR 3.02; 95% CI: 1.19-7.66; LVEF < 50% - HR 2.53; 95% CI: 1.03-6.17; P = .041; age-adjusted D-dimer > upper reference limit (URL) - HR 3.53; 95% CI: 1.81-6.85; P < .001; hsTnT > URL - HR 2.17; 95% CI: 1.13-4.16; P = .016; NT-proBNP ≥ 300 pg/mL - HR 2.3; 95% CI: 1.22-4.34; P = .01; G8 score ≤14 points - HR 2.47; 95% CI: 1.29-4.74; P = .007. In multivariate analysis, age-adjusted D-dimer > URL, G8 score ≤ 14 points and visceral metastases remained statistically significant in prediction of inferior TTF. The number of these factors was associated with shorter median TTF: 0-1 factor - 14.1 months; 2 factors - 5.9 months; 3 factors - 2.7 months; P < .001, log-rank). CONCLUSIONS: Age-adjusted D-dimer, and geriatric G8 scores may predict TTF in men with metastatic castration-resistant prostate cancer during AA therapy. These observations require further study in a larger population.


Assuntos
Acetato de Abiraterona , Neoplasias da Próstata , Masculino , Idoso , Humanos , Acetato de Abiraterona/uso terapêutico , Avaliação Geriátrica , Atividades Cotidianas , Oncologia
14.
J Pathol ; 253(3): 326-338, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33206391

RESUMO

Medulloblastoma (MB) is the most common malignant brain tumour in children and is subdivided into four subgroups: WNT, SHH, Group 3, and Group 4. These molecular subgroups differ in their metastasis patterns and related prognosis rates. Conventional 2D cell culture methods fail to recapitulate these clinical differences. Realistic 3D models of the cerebellum are therefore necessary to investigate subgroup-specific functional differences and their role in metastasis and chemoresistance. A major component of the brain extracellular matrix (ECM) is the glycosaminoglycan hyaluronan. MB cell lines encapsulated in hyaluronan hydrogels grew as tumour nodules, with Group 3 and Group 4 cell lines displaying clinically characteristic laminar metastatic patterns and levels of chemoresistance. The glycoproteins, laminin and vitronectin, were identified as subgroup-specific, tumour-secreted ECM factors. Gels of higher complexity, formed by incorporation of laminin or vitronectin, revealed subgroup-specific adhesion and growth patterns closely mimicking clinical phenotypes. ECM subtypes, defined by relative levels of laminin and vitronectin expression in patient tissue microarrays and gene expression data sets, were able to identify novel high-risk MB patient subgroups and predict overall survival. Our hyaluronan model system has therefore allowed us to functionally characterize the interaction between different MB subtypes and their environment. It highlights the prognostic and pathological role of specific ECM factors and enables preclinical development of subgroup-specific therapies. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.


Assuntos
Neoplasias Cerebelares/patologia , Matriz Extracelular/patologia , Hidrogéis , Meduloblastoma/patologia , Modelos Anatômicos , Linhagem Celular Tumoral , Humanos
15.
Dev Sci ; 25(2): e13173, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34448328

RESUMO

This study focuses on the role of numerous cognitive skills such as phonological awareness (PA), rapid automatized naming (RAN), visual and selective attention, auditory skills, and implicit learning in developmental dyslexia. We examined the (co)existence of cognitive deficits in dyslexia and assessed cognitive skills' predictive value for reading. First, we compared school-aged children with severe reading impairment (n = 51) to typical readers (n = 71) to explore the individual patterns of deficits in dyslexia. Children with dyslexia, as a group, presented low PA and RAN scores, as well as limited implicit learning skills. However, we found no differences in the other domains. We found a phonological deficit in 51% and a RAN deficit in 26% of children with dyslexia. These deficits coexisted in 14% of the children. Deficits in other cognitive domains were uncommon and most often coexisted with phonological or RAN deficits. Despite having a severe reading impairment, 26% of children with dyslexia did not present any of the tested deficits. Second, in a group of children presenting a wide range of reading abilities (N = 211), we analysed the relationship between cognitive skills and reading level. PA and RAN were independently related to reading abilities. Other skills did not explain any additional variance. The impact of PA and RAN on reading skills differed. While RAN was a consistent predictor of reading, PA predicted reading abilities particularly well in average and good readers with a smaller impact in poorer readers.


Assuntos
Dislexia , Fonética , Aptidão , Conscientização , Criança , Cognição , Dislexia/psicologia , Humanos
16.
BMC Vet Res ; 18(1): 414, 2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36414934

RESUMO

BACKGROUND: Progesterone plays a crucial role in the maintenance of pregnancy from conception to about 100-120 days of gestation when placenta becomes the main source of gestagens. The aim of the study was to test progesterone concentration 14 days after ovulation in pregnant mares and relate it to peak estral endometrial edema and the presence of intrauterine fluid (IUF) after artificial insemination (AI), the number of treatments against IUF, and the time from AI to the day when the uterus was found free of fluid. RESULTS: Mares were divided into two groups: group A (n = 13; age 10.8 ± 4.5 years) in which a normal embryonic vesicle with a diameter ≥ 14 mm and a corpus luteum with a diameter ≥ 15 mm were found 14 days after ovulation, and group B (n = 22; age 9.4 ± 4 .0 years) in which 14 days after ovulation, a small (< 15 mm) corpus luteum and/or a small embryonic vesicle was observed (diameter < 14 mm). Mares from group A had a significantly higher progesterone concentrations at 14 days after ovulation compared with group B mares. The presence of IUF, the number of treatments against IUF, and the time from AI to the day when uterus was found free of fluid did not affect progesterone concentration measured 14 days after ovulation. In group B, a significant correlation was found between progesterone concentration measured 14 days after ovulation and endometrial edema evaluated during estrus. CONCLUSIONS: In some cases poor development of endometrial edema during estrus can be associated with lower progesterone production 14 days after ovulation. Nevertheless, scientific explanation for this finding cannot be given based on our study.


Assuntos
Estro , Progesterona , Gravidez , Cavalos , Feminino , Animais , Ovulação , Inseminação Artificial/veterinária , Edema/veterinária
17.
Macromol Rapid Commun ; 42(6): e2000321, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33249682

RESUMO

The versatility of the Passerini three component reaction (Passerini-3CR) is herein exploited for the synthesis of an amphiphilic diblock copolymer, which self-assembles into polymersomes. Carboxy-functionalized poly(ethylene glycol) methyl ether is reacted with AB-type bifunctional monomers and tert-butyl isocyanide in a single process via Passerini-3CR. The resultant diblock copolymer (P1) is obtained in good yield and molar mass dispersity and is well tolerated in model cell lines. The Passerini-3CR versatility and reproducibility are shown by the synthesis of P2, P3, and P4 copolymers. The ability of the Passerini P1 polymersomes to incorporate hydrophilic molecules is verified by loading doxorubicin hydrochloride in P1DOX polymersomes. The flexibility of the synthesis is further demonstrated by simple post-functionalization with a dye, Cyanine-5 (Cy5). The obtained P1-Cy5 polymersomes rapidly internalize in 2D cell monolayers and penetrate deep into 3D spheroids of MDA-MB-231 triple-negative breast cancer cells. P1-Cy5 polymersomes injected systemically in healthy mice are well tolerated and no visible adverse effects are seen under the conditions tested. These data demonstrate that new, biodegradable, biocompatible polymersomes having properties suitable for future use in drug delivery can be easily synthesized by the Passerini-3CR.


Assuntos
Sistemas de Liberação de Medicamentos , Polímeros , Animais , Doxorrubicina/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Reprodutibilidade dos Testes
18.
Childs Nerv Syst ; 37(12): 3891-3895, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34136944

RESUMO

Acute disseminated encephalomyelitis (ADEM) is an immune-mediated demyelinating central nervous system disorder with predilection for early childhood. Delayed onset of ADEM is rare, and herein we present a previously healthy 5-year-old boy, with an unusual clinical course of ADEM with high intracranial pressure (ICP) and acute visual loss that was at first diagnosed as idiopathic intracranial hypertension without papilledema (IIHWOP). The boy underwent acute neurosurgical intervention with ventriculoperitoneal (VP) shunt using Miethke valve and sensor reservoir system and received high-dose steroid treatment with symptom relieve within days. This is the first case report using this system in such a young child, and we find it feasible and valuable also in younger children when VP shunt with ICP measurement is indicated.


Assuntos
Encefalomielite Aguda Disseminada , Pseudotumor Cerebral , Criança , Pré-Escolar , Encefalomielite Aguda Disseminada/diagnóstico por imagem , Estudos de Viabilidade , Humanos , Pressão Intracraniana , Masculino , Derivação Ventriculoperitoneal
19.
Nucleic Acids Res ; 46(14): 6950-6961, 2018 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-29947784

RESUMO

Protein synthesis is a fundamental requirement of all cells for survival and replication. To date, vast numbers of genetic and biochemical studies have been performed to address the mechanisms of translation and its regulation in Escherichia coli, but only a limited number of studies have investigated these processes in other bacteria, particularly in slow growing bacteria like Mycobacterium tuberculosis, the causative agent of human tuberculosis. In this Review, we highlight important differences in the translational machinery of M. tuberculosis compared with E. coli, specifically the presence of two additional proteins and subunit stabilizing elements such as the B9 bridge. We also consider the role of leaderless translation in the ability of M. tuberculosis to establish latent infection and look at the experimental evidence that translational regulatory mechanisms operate in mycobacteria during stress adaptation, particularly focussing on differences in toxin-antitoxin systems between E. coli and M. tuberculosis and on the role of tuneable translational fidelity in conferring phenotypic antibiotic resistance. Finally, we consider the implications of these differences in the context of the biological adaptation of M. tuberculosis and discuss how these regulatory mechanisms could aid in the development of novel therapeutics for tuberculosis.


Assuntos
Regulação Bacteriana da Expressão Gênica , Mycobacterium tuberculosis/genética , Biossíntese de Proteínas , Escherichia coli/genética , Iniciação Traducional da Cadeia Peptídica , Ribossomos/química , Estresse Fisiológico/genética , Sistemas Toxina-Antitoxina/genética
20.
J Fish Biol ; 96(1): 261-273, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31755097

RESUMO

This study was conducted to describe the major and the minor rDNA chromosome distribution in the spined loach Cobitis taenia (2n = 48) and the Danubian loach Cobitis elongatoides (2n = 50), and their laboratory-produced diploid reciprocal F1 hybrid progeny. It was tested by fluorescence in situ hybridisation (FISH) whether the number of 28s and 5s rDNA sites in the karyotypes of diploid hybrids corresponds to the expectations resulting from Mendelian ratio and if nucleolar organiser regions (NOR)were inherited from both parents or nucleolar dominance can be observed in the induced F1 hybrid progeny. Ten (females) or twelve (males) 28s rDNA loci were located in nine uniarm chromosomes of C. taenia. Two of such loci terminally bounded on one acrocentric chromosome were unique and indicated as specific for this species. Large 5s rDNA clusters were located on two acrocentric chromosomes. In C. elongatoides of both sexes, six NOR sites in terminal regions on six meta-submetacentric chromosomes and two 5s rDNA sites on large submetacentrics were detected. The F1 hybrid progeny (2n = 49) was characterised by the intermediate karyotype with the sites of ribosome synthesis on chromosomes inherited from both parents without showing nucleolar dominance. 5s rDNA sites were detected on large submetacentric and two acrocentric chromosomes. The observed number of both 28s and 5s rDNAs signals in F1 diploid Cobitis hybrids was disproportionally inherited from the two parental species, showing inconsistency with the Mendelian ratios. The presented rDNA patterns indicate some marker chromosomes that allow the species of the parental male and female to be recognised in hybrid progeny. The 5s rDNA was found to be a particularly effective diagnostic marker of C. elongatoides to partially discern genomic composition of diploid Cobitis hybrids and presumably allopolyploids resulting from their backcrossing with one of the parental species. Thus, the current study provides insight into the extent of rDNA heredity in Cobitis chromosomes and their cytotaxonomic character.


Assuntos
Cipriniformes/genética , Hereditariedade/genética , RNA Ribossômico 28S/genética , RNA Ribossômico 5S/genética , Animais , Biomarcadores , Quimera , Cromossomos , DNA Ribossômico , Diploide , Feminino , Hibridização in Situ Fluorescente , Cariótipo , Masculino
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