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Ataxia-telangiectasia (A-T) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene. Children with A-T are predisposed to hematological malignancies. We aimed to investigate their characteristics and outcomes in order to generate data-based treatment recommendations. In this multinational, observational study we report 202 patients aged ≤25 years with A-T and hematological malignancies from 25 countries. Ninety-one patients (45%) presented with mature B-cell lymphomas, 82 (41%) with acute lymphoblastic leukemia/lymphoma, 21(10%) with Hodgkin lymphoma and eight (4%) with other hematological malignancies. Four-year overall survival and event-free survival (EFS) were 50.8% (95% CI 43.6-59.1) and 47.9% (95% CI 40.8-56.2), respectively. Cure rates have not significantly improved over the last four decades (p=.76). The major cause of treatment failure was treatment-related mortality (TRM) with a four-year cumulative incidence of 25.9% (95% CI 19.5-32.4). Germline ATM PVs were categorized as null or hypomorphic and patients with available genetic data (n=110) were classified as having absent (n=81) or residual (n=29) ATM kinase activity. Four-year EFS was 39.4% (95% CI 29-53.3) vs 78.7% (95% CI 63.7-97.2), (p<.001), and TRM rates were 37.6% (95% CI 26.4-48.7) vs 4.0% (95% CI 0-11.8), (p=.017), for those with absent and residual ATM kinase activity, respectively. Absence of ATM kinase activity was independently associated with decreased EFS (HR=0.362, 95% CI 0.16-0.82; p=.009) and increased TRM (HR=14.11, 95% CI 1.36-146.31; p=.029). Patients with A-T and leukemia/lymphoma may benefit from de-escalated therapy for patients with absent ATM kinase activity and near-standard therapy regimens for those with residual kinase activity.
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The negative environmental and social impacts of food waste accumulation can be mitigated by utilizing bio-refineries' approach where food waste is revalorized into high-value products, such as prodigiosin (PG), using microbial bioprocesses. The diverse biological activities of PG position it as a promising compound, but its high production cost and promiscuous bioactivity hinder its wide application. Metal ions can modulate the electronic properties of organic molecules, leading to novel mechanisms of action and increased target potency, while metal complex formation can improve the stability, solubility and bioavailability of the parent compound. The objectives of this study were optimizing PG production through bacterial fermentation using food waste, allowing good quantities of the pure natural product for further synthesizing and evaluating copper(II) and zinc(II) complexes with it. Their antimicrobial and anticancer activities were assessed, and their binding affinity toward biologically important molecules, bovine serum albumin (BSA) and DNA was investigated by fluorescence emission spectroscopy and molecular docking. The yield of 83.1 mg/L of pure PG was obtained when processed meat waste at 18 g/L was utilized as the sole fermentation substrate. The obtained complexes CuPG and ZnPG showed high binding affinity towards target site III of BSA, and molecular docking simulations highlighted the affinity of the compounds for DNA minor grooves.
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Complejos de Coordinación , Cobre , ADN , Simulación del Acoplamiento Molecular , Prodigiosina , Albúmina Sérica Bovina , Zinc , Prodigiosina/química , Prodigiosina/metabolismo , Prodigiosina/farmacología , Cobre/química , Cobre/metabolismo , Zinc/metabolismo , Zinc/química , Albúmina Sérica Bovina/química , Albúmina Sérica Bovina/metabolismo , ADN/metabolismo , ADN/química , Animales , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Humanos , Bovinos , Antineoplásicos/farmacología , Antineoplásicos/química , Sitios de UniónRESUMEN
The European Union-funded COST Action (LEukaemia GENe Discovery by data sharing, mining, and collaboration) LEGEND was an international and multidisciplinary collaboration between clinicians and researchers that covered a range of aspects of genetic predisposition in childhood leukemia. Within this framework, we explored the perception and handling of genetic predisposition in the daily practice of European treatment centers. Herein, we present the results of our questionnaire-based survey. We found that the overall awareness is quite high, and respondents remarked that identification and treatment of the most common predisposition syndromes were present. Nevertheless, high demand for continuous education and routinely updated resources remains.
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Predisposición Genética a la Enfermedad , Neoplasias , Niño , Humanos , Neoplasias/genética , Neoplasias/terapia , Encuestas y Cuestionarios , Síndrome , PercepciónRESUMEN
The quest for sustainable biomaterials with excellent biocompatibility and tailorable properties has put polyhydroxyalkanoates (PHAs) into the research spotlight. However, high production costs and the lack of bioactivity limit their market penetration. To address this, poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) was combined with a bacterial pigment with strong anticancer activity, prodigiosin (PG), to obtain functionally enhanced PHBV-based biomaterials. The samples were produced in the form of films 115.6-118.8 µm in thickness using the solvent casting method. The effects of PG incorporation on the physical properties (morphology, biopolymer crystallinity and thermal stability) and functionality of the obtained biomaterials were investigated. PG has acted as a nucleating agent, in turn affecting the degree of crystallinity, thermal stability and morphology of the films. All samples with PG had a more organized internal structure and higher melting and degradation temperatures. The calculated degree of crystallinity of the PHBV copolymer was 53%, while the PG1, PG3 and PG3 films had values of 64.0%, 63.9% and 69.2%, respectively. Cytotoxicity studies have shown the excellent anticancer activity of films against HCT116 (colon cancer) cells, thus advancing PHBV biomedical application potential.
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Poliésteres , Polihidroxialcanoatos , Poliésteres/química , Prodigiosina/farmacología , Materiales Biocompatibles/farmacología , Materiales Biocompatibles/químicaRESUMEN
Prodigiosins (prodiginines) are a class of bacterial secondary metabolites with remarkable biological activities and color. In this study, optimized production, purification, and characterization of prodigiosin (PG) from easily accessible Serratia marcescens ATCC 27117 strain has been achieved to levels of 14 mg/L of culture within 24 h. Furthermore, environmentally friendly bromination of produced PG was used to afford both novel mono- and dibrominated derivatives of PG. PG and its Br derivatives showed anticancer potential with IC50 values range 0.62-17.00 µg/mL for all tested cancer cell lines and induction of apoptosis but low selectivity against healthy cell lines. All compounds did not affect Caenorhabditiselegans at concentrations up to 50 µg/mL. However, an improved toxicity profile of Br derivatives in comparison to parent PG was observed in vivo using zebrafish (Danio rerio) model system, when 10 µg/mL applied at 6 h post fertilization caused death rate of 100%, 30% and 0% by PG, PG-Br, and PG-Br2, respectively, which is a significant finding for further structural optimizations of bacterial prodigiosins. The drug-likeness of PG and its Br derivatives was examined, and the novel Br derivatives obey the Lipinski's "rule of five", with an exemption of being more lipophilic than PG, which still makes them good targets for further structural optimization.
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Neoplasias , Prodigiosina , Animales , Apoptosis , Prodigiosina/metabolismo , Prodigiosina/farmacología , Serratia marcescens/metabolismo , Pez Cebra/metabolismoRESUMEN
Primary central nervous system (CNS) post-transplant lymphoproliferative disorder (PTLD) in childhood is rare. Twenty-five patients were retrieved from nine European Intergroup for Childhood Non-Hodgkin's Lymphoma and/or international Berlin-Frankfurt-Münster Study Group members. Types of allografts included kidney (n = 11), liver (n = 4), heart (n = 5), bowel (n = 1) and haematopoietic stem cells (n = 4). Eighteen were male, 16 ≥ 10 years old, 21 had monomorphic disease and 24 solid intracranial tumour masses. Four-year event-free and overall survival rates were 50% ± 10% and 74% ± 9% respectively. This report represents the largest paediatric series of CNS PTLD reported to date, showing favourable survival odds following systemic and intrathecal chemotherapy and rituximab administration.
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Neoplasias Encefálicas , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trastornos Linfoproliferativos , Trasplante de Órganos/efectos adversos , Rituximab/administración & dosificación , Adolescente , Adulto , Aloinjertos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/etiología , Neoplasias Encefálicas/mortalidad , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Inyecciones Espinales , Trastornos Linfoproliferativos/tratamiento farmacológico , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/mortalidad , Masculino , Tasa de SupervivenciaRESUMEN
OBJECTIVE: We sought to investigate functional capacity, heart rate variability (HRV), as well as their relationship in the patients with uncomplicated type 2 diabetes. METHODS: This cross-sectional observational study included 62 controls and 53 uncomplicated diabetic patients. Included subjects underwent laboratory analysis, 24-h ECG Holter monitoring and cardiopulmonary exercise testing. RESULTS: All parameters of time and frequency domain of HRV were decreased in the diabetic patients. Oxygen uptake at ventilatory threshold (18.3 ± 3.9 vs. 14.6 ± 3.6 mL/kg/min, p < .001), peak oxygen uptake (peak VO2) (27.8 ± 4.1 vs. 19.5 ± 4.3, mL/kg/min, p < .001) and oxygen pulse were significantly lower in the diabetic group, whereas ventilation/carbon dioxide ratio and ventilation/carbon dioxide slope (25.4 ± 2.5 vs. 28.6 ± 3.9, p < .001) were significantly higher in this group. Furthermore, heart rate recovery in the first minute was significantly lower in the diabetic group (26 ± 5 vs. 23 ± 5 beats/min, p = .003). In the whole study population HbA1c and SDNN were independently of other clinical and HRV parameters associated with peak VO2, ventilation/carbon dioxide slope and heart rate recovery in the first minute. CONCLUSIONS: Our investigation showed that both functional capacity and HRV were significantly impaired in uncomplicated diabetic patients. HbA1c, an important parameter of glucose regulation, was independently associated with HRV parameters and functional capacity in the whole study population. This reveals a potentially important role of determination of functional capacity and cardiac autonomic function as important markers of preclinical damage in diabetic population.
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Diabetes Mellitus Tipo 2/fisiopatología , Pruebas de Función Cardíaca , Frecuencia Cardíaca , Anciano , Estudios de Casos y Controles , Estudios Transversales , Diabetes Mellitus Tipo 2/complicaciones , Electrocardiografía , Prueba de Esfuerzo , Femenino , Hemoglobina Glucada , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Data on management of pediatric marginal zone lymphoma (MZL) are scarce. This retrospective study assessed characteristics and outcome in 66 patients who were <18 years old. Forty-four (67%) had an extranodal MZL (EMZL), 21 (32%) a nodal MZL (NMZL), and one patient a splenic MZL. Thirty-three patients (50%) received a variable combination of adjuvant chemotherapy/immunotherapy/radiotherapy, while the remainder, including 20 of 21 with NMZL, entered an active observation period. Overall survival was excellent (98 ± 2%), although 11 patients relapsed (17%; NMZL, n = 1; EMZL, n = 10), seven after any therapy and four after complete resection only. In conclusion, outcome of NZML, in particular, seems to be excellent after (in)complete resection and observation only.
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Linfoma de Células B de la Zona Marginal/mortalidad , Linfoma de Células B de la Zona Marginal/fisiopatología , Linfoma de Células B de la Zona Marginal/terapia , Adolescente , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Candida spp. are leading causes of opportunistic mycoses, including life-threatening hospital-borne infections, and novel antifungals, preferably aiming targets that have not been used before, are constantly needed. Hydrazone- and guanidine-containing molecules have shown a wide range of biological activities, including recently described excellent antifungal properties. In this study, four bis-guanylhydrazone derivatives (BG1-4) were generated following a previously developed synthetic route. Anti-Candida (two C. albicans, C. glabrata, and C. parapsilosis) minimal inhibitory concentrations (MICs) of bis-guanylhydrazones were between 2 and 15.6 µg/mL. They were also effective against preformed 48-h-old C. albicans biofilms. In vitro DNA interaction, circular dichroism, and molecular docking analysis showed the great ability of these compounds to bind fungal DNA. Competition with DNA-binding stain, exposure of phosphatidylserine at the outer layer of the cytoplasmic membrane, and activation of metacaspases were shown for BG3. This pro-apoptotic effect of BG3 was only partially due to the accumulation of reactive oxygen species in C. albicans, as only twofold MIC and higher concentrations of BG3 caused depolarization of mitochondrial membrane which was accompanied by the decrease of the activity of fungal mitochondrial dehydrogenases, while the activity of oxidative stress response enzymes glutathione reductase and catalase was not significantly affected. BG3 showed synergistic activity with amphotericin B with a fractional inhibitory concentration index of 0.5. It also exerted low cytotoxicity and the ability to inhibit epithelial cell (TR146) invasion and damage by virulent C. albicans SC5314. With further developments, BG3 may further progress in the antifungal pipeline as a DNA-targeting agent.
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Antifúngicos/farmacología , Candida/efectos de los fármacos , ADN de Hongos/efectos de los fármacos , Guanidinas/farmacología , Hidrazonas/farmacología , Antifúngicos/síntesis química , Apoptosis , Candida/fisiología , Dicroismo Circular , Sinergismo Farmacológico , Guanidinas/síntesis química , Hidrazonas/síntesis química , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento MolecularRESUMEN
We present here the improved design and development of optical sensor for non-invasive measurements of arterial blood flow waveform. The sensor is based on a physical principle of reflective photoplethysmography (PPG). As the light source we used serially connected infrared diodes whereas NPN silicon phototransistors were used as light detectors. The electronic components were molded into square package and poured with silicone. Such preparation produced an elastic superficies that allowed excellent attachment of the sensor on the skin's surface. Moreover, a serial connection of infrared diodes and phototransistors completely eliminated signal artifacts caused by minor muscle contractions. The sensor recording performances were examined at the photoplethysmographic sites on three different arteries; the commune carotid, femoral and radial and, on each site the sensor demonstrated remarkable capability to make a consistent, reproducible measurements. Because of the advantageous physical and electrical properties, the new sensor is suitable for various cardiovascular diagnostics procedures, especially when long-term measurements of arterial blood flow waveform are required, for monitoring of different parameters in cardiovascular units and for research.
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Arterias/fisiología , Circulación Sanguínea , Dispositivos Ópticos , Fotopletismografía/instrumentación , Procesamiento de Señales Asistido por Computador , Calibración , Diseño de Equipo , HumanosRESUMEN
Children and adolescents with pre-existing conditions such as DNA repair defects or other primary immunodeficiencies have an increased risk of non-Hodgkin lymphoma. However, large-scale data on patients with non-Hodgkin lymphoma and their entire spectrum of pre-existing conditions are scarce. A retrospective multinational study was conducted by means of questionnaires sent out to the national study groups or centers, by the two largest consortia in childhood non-Hodgkin lymphoma, the European Intergroup for Childhood non-Hodgkin Lymphoma, and the international Berlin-Frankfurt-Münster Study Group. The study identified 213 patients with non-Hodgkin lymphoma and a pre-existing condition. Four subcategories were established: a) cancer predisposition syndromes (n=124, 58%); b) primary immunodeficiencies not further specified (n=27, 13%); c) genetic diseases with no increased cancer risk (n=40, 19%); and d) non-classifiable conditions (n=22, 10%). Seventy-nine of 124 (64%) cancer predispositions were reported in groups with more than 20 patients: ataxia telangiectasia (n=32), Nijmegen breakage syndrome (n=26), constitutional mismatch repair deficiency (n=21). For the 151 patients with a known cancer risk, 5-year event-free survival and overall survival rates were 40%±4% and 51%±4%, respectively. Five-year cumulative incidences of progression/relapse and treatment-related death as a first event were 22%±4% and 24%±4%, respectively. Ten-year incidence of second malignancy was 24%±5% and 7-year overall survival of the 21 patients with a second malignancy was 41%±11%. Patients with non-Hodgkin lymphoma and pre-existing conditions have an inferior survival rate with a large proportion of therapy-related deaths compared to patients with non-Hodgkin lymphoma and no pre-existing conditions. They may require special vigilance when receiving standard or modified/reduced-intensity chemotherapy or when undergoing allogeneic stem cell transplantation.
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Comorbilidad , Susceptibilidad a Enfermedades , Linfoma no Hodgkin/epidemiología , Vigilancia en Salud Pública , Adolescente , Niño , Preescolar , Terapia Combinada , Progresión de la Enfermedad , Femenino , Humanos , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Linfoma no Hodgkin/diagnóstico , Linfoma no Hodgkin/mortalidad , Linfoma no Hodgkin/terapia , Masculino , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Primarias Secundarias/etiología , Recurrencia , Resultado del TratamientoRESUMEN
Despite previous research efforts in the fields of histology and cell physiology, the relationship between chromatin structural organization and nuclear shape remains unclear. The aim of this research was to test the existence and strength of correlations between mathematical parameters of chromatin microarchitecture and roundness of the nuclear envelope. On a sample of 240 nuclei of adrenal zona fasciculata cells stained using the DNA-specific Feulgen method, we quantified fractal parameters such as fractal dimension and lacunarity, as well as textural parameters such as angular second moment (ASM), entropy, inverse difference moment, contrast, and variance. Circularity of the nuclear envelope was determined from the nuclear area and perimeter. The results indicate that there is a statistically significant negative correlation between chromatin ASM and circularity. Moreover, there was a statistically significant positive correlation between chromatin fractal dimension and envelope circularity. This is the first study to demonstrate these relationships in adrenal tissue, and also one of the first studies to test the connection between circularity and fractal and gray-level co-occurrence matrix parameters in DNA-specific Feulgen stain. The results could be useful both as an addition to the current knowledge on chromatin/nuclear envelope interactions, and for design of future computer-assisted research software for evaluation of nuclear morphology.
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Núcleo Celular/ultraestructura , Cromatina/química , Membrana Nuclear/ultraestructura , Zona Fascicular/citología , Animales , Fractales , Procesamiento de Imagen Asistido por Computador , Masculino , Ratas , Zona Fascicular/químicaRESUMEN
BACKGROUND: The physiological role of fig latex is to protect the plant from pathogens. Latex is a rich source of proteases, predominantly ficin. Fig latex also contains collagenolytic protease and chitinolytic enzymes. Our aim was to investigate changes in protein composition, enzyme and antifungal activities of fig latex during fruit ripening. RESULTS: Comparison of latex samples in different time periods showed a uniform increase of protein concentration in chronological order. The content of collagenolytic protease did not differ significantly in the latex samples, while the content of ficin decreased. Ficin-specific activity towards casein was the highest at the beginning of fruit development (about 80 U mg(-1)). Specific milk clotting activity increased as well as the abundance of casein band in the clots. Specific chitinolytic activity at the beginning of flowering was 6.5 times higher than the activity in the period when fruits are ripe. Antifungal activity is the most extensive in spring. CONCLUSION: Ficin forms with different casein specificities are present in different proportions during fruit ripening, which is of importance for applications in the dairy industry. The protection mechanism against insects and fungi, which relies on chitinolytic activity, is the most important in the early phases of flowering and is replaced with other strategies over time.
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Ficaína/análisis , Ficus/química , Frutas/crecimiento & desarrollo , Fungicidas Industriales/análisis , Látex/química , Péptido Hidrolasas/análisis , Animales , Caseínas/metabolismo , Quitina/metabolismo , Ficaína/metabolismo , Frutas/química , Insecticidas , Látex/farmacología , Leche/química , Leche/metabolismo , Proteínas de Plantas/análisis , Saccharomyces cerevisiae/efectos de los fármacos , Especificidad por SustratoRESUMEN
UNLABELLED: The interaction between the heart and the arterial system (ventricular-arterial coupling - VA) is an important determinant of cardiovascular performance. Vascular stiffness (Ea) and left ventricular (LV) endsystolic stiffness (Elv) augment with age and in heart failure (HF). Beta blockers (BB) are recommended therapy for patients with HF. However, data about the effects of BB on VA coupling are scarce. AIMS OF THE STUDY: TO ASSESS: 1) changes in VA after BB therapy; 2) interactions between VA and LV functions, 3) predictive factors influencing VA change. METHODS: Eight hundred seventy-seven elderly patients with HF (aged ≥ 65, NYHA ≥ II, LV ejection fraction (LVEF) ≤ 45%), treated with BB according to the CIBIS-ELD protocol of up-titration, underwent Doppler echocardiography with clinical and laboratory assessment before and after 12 weeks of BB. VA coupling was calculated as Ea/Elv ratio. RESULTS: Ventriculo-arterial interaction improved after 12 weeks of BB in elderly patients with HF. Values of Ea significantly decreased from 2.73 ± 1.16 to 2.40 ± 1.01, p < 0.001, resulting in a VA level close to the optimal range i.e. from 1.70 ± 1.05 (1.46) to 1.50 ± 0.94 (1.29), p < 0.001. A similar degree of VA change was found in the patients with ischemic and non-ischemic HF after the treatment. Improvement in the clinical stage of HF closely correlated with VA coupling change after BB (p = 0.006). The strongest predictor of VA coupling alteration during BB was the improvement in global LVEF (p < 0.001) followed by the age of patients (p = 0.014). CONCLUSIONS: The beneficial effect of BB in elderly patients with HF was achieved by optimizing VA coupling close to recommended range, associated with an improvement in LVEF and contractility.
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Antagonistas Adrenérgicos beta/farmacología , Antagonistas Adrenérgicos beta/uso terapéutico , Arterias/efectos de los fármacos , Bisoprolol/farmacología , Bisoprolol/uso terapéutico , Volumen Sistólico/efectos de los fármacos , Función Ventricular Izquierda/efectos de los fármacos , Anciano , Método Doble Ciego , Ecocardiografía Doppler/efectos de los fármacos , Femenino , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Función Ventricular Izquierda/fisiologíaRESUMEN
Bacterial natural products (BNPs) are very important sources of leads for drug development and chemical novelty. The possibility to perform late-stage diversification of BNPs using biocatalysis is an attractive alternative route other than total chemical synthesis or metal complexation reactions. Although biocatalysis is gaining popularity as a green chemistry methodology, a vast majority of orphan sequenced genomic data related to metabolic pathways for BNP biosynthesis and its tailoring enzymes are underexplored. In this review, we report a systematic overview of biotransformations of 21 molecules, which include derivatization by halogenation, esterification, reduction, oxidation, alkylation and nitration reactions, as well as degradation products as their sub-derivatives. These BNPs were grouped based on their biological activities into antibacterial (5), antifungal (5), anticancer (5), immunosuppressive (2) and quorum sensing modulating (4) compounds. This study summarized 73 derivatives and 16 degradation sub-derivatives originating from 12 BNPs. The highest number of biocatalytic reactions was observed for drugs that are already in clinical use: 28 reactions for the antibacterial drug vancomycin, followed by 18 reactions reported for the immunosuppressive drug rapamycin. The most common biocatalysts include oxidoreductases, transferases, lipases, isomerases and haloperoxidases. This review highlights biocatalytic routes for the late-stage diversification reactions of BNPs, which potentially help to recognize the structural optimizations of bioactive scaffolds for the generation of new biomolecules, eventually leading to drug development.
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Synthetic materials alternatives are crucial for reaching sustainable development goals and waste reduction. Biomaterials and biomolecules obtained through bacterial fermentation offer a viable solution. Double-layer active UV-blocking material composed of bacterial nanocellulose as an inner layer and poly(hydroxyoctanoic acid) containing prodigiosin as an active compound was produced by layer-by-layer deposition. This study referred the new material consisted of the three components produced in sustainable manner, by bacterial activity: bacterial bio-pigment prodigiosin, bacterial nanocellulose and poly(hydroytoctanoate) - biopolymer obtained by microbial fermentations. Prior the final double layer film was produced, PHO films containing different PG concentrations as a layer in charge of the bioactivity (0.2, 0.5 and 1 wt%) was casted and systematically characterized (FTIR, DSC, XRD, wettability, SEM, transparency, mechanical tests) to optimize their properties. The formulation with the best UV-blocking properties and less toxicity effect tested using MRC5 cells was chosen as an outer layer in double-layer films production. Water contact angle measurements confirmed that hydrophilic - hydrophobic double layer film was obtained with the improved mechanical properties in comparison to the native BNC. Migration test indicated release of PG in all tested media as a consequence of bilayer formulation, while the PG release from PHO in 10 % ethanol was not detected. All findings from the study suggested this activated, UV-blocking material as a candidate with excellent potential in packaging industry.
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Recognizing that metal ions play an important role in modifying the pharmacological properties of known organic-based drugs, the present manuscript addresses the complexation of the antifungal agent voriconazole (vcz) with the biologically relevant silver(I) ion as a strategy for the development of new antimycotics. The synthesized silver(I) complexes with vcz were characterized by mass spectrometry, IR, UV-Vis and NMR spectroscopy and single-crystal X-ray diffraction analysis. The crystallographic results showed that complexes {[Ag(vcz)(H2O)]CH3SO3}n (1), {[Ag(vcz)2]BF4}n (2) and {[Ag(vcz)2]PF6}n (3) have polymeric structures in the solid state, in which silver(I) ions have a distorted tetrahedral geometry. On the other hand, DFT calculations revealed that the investigated silver(I) complexes 1-3 in DMSO exist as linear [Ag(vcz-N2)(vcz-N19)]+ (1a), [Ag(vcz-N2)(vcz-N4)]+ (2a) and [Ag(vcz-N4)2]+ (3a) species, respectively. The evaluated complexes showed an enhanced anti-Candida activity compared to the parent drug with minimal inhibitory concentration (MIC) values in the range of 0.02-1.05 µM. In comparison with vcz, the corresponding silver(I) complexes showed better activity in prevention hyphae and biofilm formation of C. albicans, indicating that they could be considered as promising agents against Candida that significantly inhibit its virulence. Also, these complexes are much better inhibitors of ergosterol synthesis in the cell membrane of C. albicans at the concentration of 0.5 × MIC. This is also confirmed by a molecular docking, which revealed that complexes 1a - 3a showed better inhibitory activity than vcz against the sterol 14α-demethylase enzyme cytochrome P450 (CYP51B), which plays a crucial role in the formation of ergosterol.
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Antifúngicos , Complejos de Coordinación , Pruebas de Sensibilidad Microbiana , Plata , Voriconazol , Antifúngicos/farmacología , Antifúngicos/química , Antifúngicos/síntesis química , Voriconazol/farmacología , Voriconazol/química , Plata/química , Plata/farmacología , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Candida albicans/efectos de los fármacos , Candida/efectos de los fármacos , Cristalografía por Rayos XRESUMEN
Inspired by the emergence of resistance to currently available antifungal therapy and by the great potential of metal complexes for the treatment of various diseases, we synthesized three new silver(I) complexes containing clinically used antifungal azoles as ligands, [Ag(ecz)2]SbF6 (1, ecz is econazole), {[Ag(vcz)2]SbF6}n (2, vcz is voriconazole), and [Ag(ctz)2]SbF6 (3, ctz is clotrimazole), and investigated their antimicrobial properties. The synthesized complexes were characterized by mass spectrometry, IR, UV-vis and 1H NMR spectroscopy, cyclic voltammetry, and single-crystal X-ray diffraction analysis. In the mononuclear complexes 1 and 3 with ecz and ctz, respectively, the silver(I) ion has the expected linear geometry, in which the azoles are monodentately coordinated to this metal center through the N3 imidazole nitrogen atom. In contrast, the vcz-containing complex 2 has a polymeric structure in the solid state in which the silver(I) ions are coordinated by four nitrogen atoms in a distorted tetrahedral geometry. DFT calculations were done to predict the most favorable structures of the studied complexes in DMSO solution. All the studied silver(I) complexes have shown excellent antifungal and good to moderate antibacterial activities with minimal inhibitory concentration (MIC) values in the ranges of 0.01-27.1 and 2.61-47.9 µM on the selected panel of fungi and bacteria, respectively. Importantly, the complexes 1-3 have exhibited a significantly improved antifungal activity compared to the free azoles, with the most pronounced effect observed in the case of complex 2 compared to the parent vcz against Candida glabrata with an increase of activity by five orders of magnitude. Moreover, the silver(I)-azole complexes 2 and 3 significantly inhibited the formation of C. albicans hyphae and biofilms at the subinhibitory concentration of 50% MIC. To investigate the impact of the complex 3 more thoroughly on Candida pathogenesis, its effect on the adherence of C. albicans to A549 cells (human adenocarcinoma alveolar basal epithelial cells), as an initial step of the invasion of host cells, was studied.
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Complejos de Coordinación , Plata , Humanos , Plata/farmacología , Plata/química , Candida , Antifúngicos/farmacología , Antifúngicos/química , Azoles/farmacología , Candida albicans , Pruebas de Sensibilidad Microbiana , Iones/farmacología , Nitrógeno , Complejos de Coordinación/farmacología , Complejos de Coordinación/químicaRESUMEN
Acute myeloid leukemia (AML) is a very heterogeneous hematological malignancy that accounts for approximately 20% of all pediatric leukemia cases. The outcome of pediatric AML has improved over the last decades, with overall survival rates reaching up to 70%. Still, AML is among the leading types of pediatric cancers by its high mortality rate. Modulation of standard therapy, like chemotherapy intensification, hematopoietic stem cell transplantation and optimized supportive care, could only get this far, but for the significant improvement of the outcome in pediatric AML, development of novel targeted therapy approaches is necessary. In recent years the advances in genomic techniques have greatly expanded our knowledge of the AML biology, revealing molecular landscape and complexity of the disease, which in turn have led to the identification of novel therapeutic targets. This review provides a brief overview of the genetic landscape of pediatric AML, and how it's used for precise molecular characterization and risk stratification of the patients, and also for the development of effective targeted therapy. Furthermore, this review presents recent advances in molecular targeted therapy and immunotherapy with an emphasis on the therapeutic approaches with significant clinical benefits for pediatric AML.
Asunto(s)
Leucemia Mieloide Aguda , Niño , Humanos , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/tratamiento farmacológico , Inmunoterapia , Terapia Molecular DirigidaRESUMEN
Phenazines, including pyocyanin (PYO) and 1-hydroxyphenazine (1-HP) are extracellular secondary metabolites and multifunctional pigments of Pseudomonas aeruginosa responsible for its blue-green color. These versatile molecules are electrochemically active, involved in significant biological activities giving fitness to the host, but also recognized as antimicrobial and anticancer agents. Their wider application is still limited partly due to the cost of carbon substrate for production, which can be solved by the utilization of carbon from food waste within the biorefinery concept. In this study, a variety of food waste streams (banana peel, potato peel, potato washing, stale bread, yoghurt, processed meat, boiled eggs and mixed canteen waste) was used as sole nutrient source in submerged cultures of P. aeruginosa BK25H. Stale bread was identified as the most suitable substrate to support phenazine biopigments production and bacterial growth. This was further increased in 5-liter fermenter when on average 5.2 mg L-1 of PYO and 4.4 mg L-1 of 1-HP were purified after 24 h batch cultivations from the fermentation medium consisting of homogenized stale bread in tap water. Purified biopigments showed moderate antimicrobial activity, and showed different toxicity profiles, with PYO not being toxic against Caenorhabditis elegans, a free-living soil nematode up to 300 µg mL-1 and 1-HP showing lethal effects at 75 µg mL-1. Therefore, stale bread waste stream with minimal pretreatment should be considered as suitable biorefinery feedstock, as it can support the production of valuable biopigments such as phenazines.