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The COVID-19 pandemic has resulted in millions of fatalities worldwide. The case of pediatric cancer patients stands out since, despite being considered a population at risk, few studies have been carried out concerning symptom detection or the description of the mechanisms capable of modifying the course of the COVID-19 disease, such as the interaction and response between the virus and the treatment given to cancer patients. By synthesizing existing studies, this paper aims to expose the treatment challenges for pediatric patients with COVID-19 in an oncology context. Additionally, this updated review includes studies that utilized the antiviral agents Remdesivir and PaxlovidTM in pediatric cancer patients. There is no specific treatment designed exclusively for pediatric cancer patients dealing with COVID-19, and it is advisable to avoid self-medication to prevent potential side effects. Managing COVID-19 in pediatric cancer patients is indeed a substantial challenge. New strategies, such as chemotherapy application rooms, have been implemented for children with cancer who were positive for COVID-19 but asymptomatic since the risk of disease progression is greater than the risk of complications from SARS-CoV-2.
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Alanina , Antivirales , COVID-19 , Neoplasias , SARS-CoV-2 , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Neoplasias/complicaciones , COVID-19/epidemiología , Niño , Antivirales/uso terapéutico , SARS-CoV-2/efectos de los fármacos , Alanina/análogos & derivados , Alanina/uso terapéutico , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/uso terapéutico , Tratamiento Farmacológico de COVID-19 , PandemiasRESUMEN
Multidrug resistance (MDR) commonly leads to cancer treatment failure because cancer cells often expel chemotherapeutic drugs using ATP-binding cassette (ABC) transporters, which reduce drug levels within the cells. This study investigated the clinical characteristics and single nucleotide variant (SNV) in ABCB1, ABCC1, ABCC2, ABCC4, and ABCG2, and their association with mortality in pediatric patients with central nervous system tumors (CNST). Using TaqMan probes, a real-time polymerase chain reaction genotyped 15 SNPs in 111 samples. Patients were followed up until death or the last follow-up day using the Cox proportional hazards model. An association was found between the rs1045642 (ABCB1) in the recessive model (HR = 2.433, 95% CI 1.098-5.392, p = 0.029), and the ICE scheme in the codominant model (HR = 9.810, 95% CI 2.74-35.06, p ≤ 0.001), dominant model (HR = 6.807, 95% CI 2.87-16.103, p ≤ 0.001), and recessive model (HR = 6.903, 95% CI 2.915-16.544, p = 0.038) significantly increased mortality in this cohort of patients. An association was also observed between the variant rs3114020 (ABCG2) and mortality in the codominant model (HR = 5.35, 95% CI 1.83-15.39, p = 0.002) and the dominant model (HR = 4.421, 95% CI 1.747-11.185, p = 0.002). A significant association between the ICE treatment schedule and increased mortality risk in the codominant model (HR = 6.351, 95% CI 1.831-22.02, p = 0.004, HR = 9.571, 95% CI 2.856-32.07, p ≤ 0.001), dominant model (HR = 6.592, 95% CI 2.669-16.280, p ≤ 0.001), and recessive model (HR = 5.798, 95% CI 2.411-13.940, p ≤ 0.001). The genetic variants rs3114020 in the ABCG2 gene and rs1045642 in the ABCB1 gene and the ICE chemotherapy schedule were associated with an increased mortality risk in this cohort of pediatric patients with CNST.
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Neoplasias del Sistema Nervioso Central , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Polimorfismo de Nucleótido Simple , Humanos , Masculino , Femenino , Niño , Preescolar , Lactante , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/mortalidad , Neoplasias del Sistema Nervioso Central/patología , Estudios de Cohortes , Adolescente , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Marcadores Genéticos/genética , Proteínas de Neoplasias/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Biomarcadores de Tumor/genéticaRESUMEN
N-acetylcysteine (NAC) is a membrane-permeable cysteine precursor capable of enhancing the intracellular cysteine pool, enhancing cellular glutathione (GSH) synthesis, and thus potentiating the endogenous antioxidant mechanism. Late administration of NAC after cisplatin has been shown in different in vivo studies to reduce the side effects caused by various toxicities at different levels without affecting the antitumor efficacy of platinum, improving total and enzymatic antioxidant capacity and decreasing oxidative stress markers. These characteristics provide NAC with a rationale as a potentially effective chemo protectant in cisplatin-based therapeutic cycles. NAC represents a potential candidate as a chemoprotective agent to decrease toxicities secondary to cisplatin treatment. It suggests that it could be used in clinical trials, whereby the effective dose, timing, and route should be adjusted to optimize chemoprotection. This review provides an overview of the effect of NAC on cisplatin toxicity, a drug widely used in the clinic in adults and children.
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The function of the circadian cycle is to determine the natural 24 h biological rhythm, which includes physiological, metabolic, and hormonal changes that occur daily in the body. This cycle is controlled by an internal biological clock that is present in the body's tissues and helps regulate various processes such as sleeping, eating, and others. Interestingly, animal models have provided enough evidence to assume that the alteration in the circadian system leads to the appearance of numerous diseases. Alterations in breathing patterns in lung diseases can modify oxygenation and the circadian cycles; however, the response mechanisms to hypoxia and their relationship with the clock genes are not fully understood. Hypoxia is a condition in which the lack of adequate oxygenation promotes adaptation mechanisms and is related to several genes that regulate the circadian cycles, the latter because hypoxia alters the production of melatonin and brain physiology. Additionally, the lack of oxygen alters the expression of clock genes, leading to an alteration in the regularity and precision of the circadian cycle. In this sense, hypoxia is a hallmark of a wide variety of lung diseases. In the present work, we intended to review the functional repercussions of hypoxia in the presence of asthma, chronic obstructive sleep apnea, lung cancer, idiopathic pulmonary fibrosis, obstructive sleep apnea, influenza, and COVID-19 and its repercussions on the circadian cycles.
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Enfermedades Pulmonares , Apnea Obstructiva del Sueño , Animales , Humanos , Ritmo Circadiano/genética , Hipoxia , Relojes Biológicos/fisiologíaRESUMEN
The adverse events related to sodium colistimethate have had variability regarding the prevalence of nephrotoxicity, neurotoxicity, and less frequent respiratory depression. In recent years, its use has been relevant due to the increase of multidrug-resistant bacteria since it is considered the last-line drug, being its main adverse event and reason for discrepancies between authors' nephrotoxicity. The indiscriminate use of antibiotic therapy has generated multiple mechanisms of resistance, the most common being related to Colistin, the bactericidal escape effect. Based on the search criteria, no randomized clinical trials were identified showing safety and efficacy with the use of Colistin, inferring that the application of the appropriate dose is governed by expert opinion and retrospective and prospective observational studies, which confounding factors such as the severity of the patient and the predisposition to develop acute renal failure are constant. In this review, we focus on identifying the mechanism of nephrotoxicity and bacterial resistance, where much remains to be known.
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Midazolam is a drug that is metabolized by cytochrome P450 (CYP450) enzymes, particularly CYP3A4 and CYP3A5. The present study aimed to determine the sex and age influence on association of CYP450 polymorphism with midazolam levels in critically ill children. Seventy-two DNA samples were genotyped by real-time PCR. Children ≤ five years of age who carry the rs776746 (T) allele in CYP3A5 gene were associated with lower plasma midazolam levels. The concentration median in patients was 0.0 ng/mL, while in patients with the normal (C) allele, it was 438.17 ng/mL (Q25 135.75-Q75 580.24), p = 0.005. The midazolam plasmatic concentration in female patients with the minor (T) allele was 0.0 ng/mL (Q250.00-Q75204.3), while in patients with the normal (C) allele median it was 459.0 ng/mL (Q25296.9-Q75789.7), p = 0.002. Analysis of the dominant model for the rs2740574 variant in CYP3A4 revealed a median of 0.38 L/kg (Q250.02-Q751.5) for the volume of distribution parameter in female patients with the normal T allele, while female patients with the minor C allele showed a median of 18.1 L/kg (Q257.5-Q7528.7) p = 0.02. Our results suggest an altered midazolam metabolism due to the presence the allelic rs2740574 variants of CYP3A4 and rs776746 of CYP3A5, and also the strong influence of age and sex.
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Hypoxia and hypoxia-inducible factors (HIFs) are essential in regulating several cellular processes, such as survival, differentiation, and the cell cycle; this adaptation is orchestrated in a complex way. In this review, we focused on the impact of hypoxia in the physiopathology of idiopathic pulmonary fibrosis (IPF) related to lung development, regeneration, and repair. There is robust evidence that the responses of HIF-1α and -2α differ; HIF-1α participates mainly in the acute phase of the response to hypoxia, and HIF-2α in the chronic phase. The analysis of their structure and of different studies showed a high specificity according to the tissue and the process involved. We propose that hypoxia-inducible transcription factor 2a (HIF-2α) is part of the persistent aberrant regeneration associated with developing IPF.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Fibrosis Pulmonar Idiopática , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Diferenciación Celular , Hipoxia de la Célula , Humanos , HipoxiaRESUMEN
Idiopathic pulmonary fibrosis (IPF) is an aging-associated disease characterized by exacerbated extracellular matrix deposition that disrupts oxygen exchange. Hypoxia and its transcription factors (HIF-1α and 2α) influence numerous circuits that could perpetuate fibrosis by increasing myofibroblasts differentiation and by promoting extracellular matrix accumulation. Therefore, this work aimed to elucidate the signature of hypoxia in the transcriptomic circuitry of IPF-derived fibroblasts. To determine this transcriptomic signature, a gene expression analysis with six lines of lung fibroblasts under normoxia or hypoxia was performed: three cell lines were derived from patients with IPF, and three were from healthy donors, a total of 36 replicates. We used the Clariom D platform, which allows us to evaluate a huge number of transcripts, to analyze the response to hypoxia in both controls and IPF. The control's response is greater by the number of genes and complexity. In the search for specific genes responsible for the IPF fibroblast phenotype, nineteen dysregulated genes were found in lung fibroblasts from IPF patients in hypoxia (nine upregulated and ten downregulated). In this sense, the signaling pathways revealed to be affected in the pulmonary fibroblasts of patients with IPF may represent an adaptation to chronic hypoxia.
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Fibrosis Pulmonar Idiopática , Fibroblastos/metabolismo , Humanos , Hipoxia/genética , Hipoxia/metabolismo , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/metabolismo , Pulmón/metabolismo , Oxígeno/metabolismo , Factores de Transcripción/metabolismo , Transcriptoma/genéticaRESUMEN
Background: Infection by SARS-CoV-2 has been associated with multiple symptoms; however, still, little is known about persistent symptoms and their probable association with the risk of developing pulmonary fibrosis in patients post-COVID-19. Methods: A longitudinal prospective study on health workers infected by SARS-CoV-2 was conducted. In this work, signs and symptoms were recorded of 149 health workers with a positive PCR test for SARS-CoV-2 at the beginning of the diagnosis, during the active infection, and during post-COVID-19 follow-up. The McNemar chi-square test was used to compare the proportions and percentages of symptoms between the baseline and each follow-up period. Results: The signs and symptoms after follow-up were cardiorespiratory, neurological, and inflammatory. Gastrointestinal symptoms were unusual at the disease onset, but unexpectedly, their frequency was higher in the post-infection stage. The multivariate analysis showed that pneumonia (HR 2.4, IC95%: 1.5−3.8, p < 0.001) and positive PCR tests still after four weeks (HR 5.3, IC95%: 2.3-12.3, p < 0.001) were factors associated with the diagnosis of post-COVID-19 pulmonary fibrosis in this study group. Conclusions: Our results showed that pneumonia and virus infection persistence were risk factors for developing pulmonary fibrosis post-COVID-19, after months of initial infection.
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COVID-19 , Fibrosis Pulmonar , COVID-19/complicaciones , Humanos , Pacientes Ambulatorios , Estudios Prospectivos , Fibrosis Pulmonar/epidemiología , SARS-CoV-2RESUMEN
The SARS-CoV-2 pandemic has confirmed the apocalyptic predictions that virologists have been making for several decades. The challenge the world is facing is that of trying to find a possible treatment, and a viable and expedient option for addressing this challenge is the repurposing of drugs. However, in some cases, although these drugs are approved for use in humans, the mechanisms of action involved are unknown. In this sense, to justify its therapeutic application to a new disease, it is ideal, but not necessary, to know the basic mechanisms of action involved in a drug's biological effects. This review compiled the available information regarding the various effects attributed to Ivermectin. The controversy over its use for the treatment of COVID-19 is demonstrated by this report that considers the proposal unfeasible because the therapeutic doses proposed to achieve this effect cannot be achieved. However, due to the urgent need to find a treatment, an exhaustive and impartial review is necessary in order to integrate the knowledge that exists, to date, of the possible mechanisms through which the treatment may be helpful in defining safe doses and schedules of Ivermectin.
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Background: More than 135 million COVID-19 cases (coronavirus disease 2019) have been reported worldwide until today, with over 2.9 million deaths. Several studies have demonstrated that disease severity is lower in the pediatric population than in adults; however, differences are described in patients with chronic diseases, including oncological patients. Current world literature suggests patients with comorbidities, including cancer, have an increased risk of unfortunate outcomes. Therefore, our objective was to describe the clinical characteristics and epidemiological factors associated with mortality in a cohort of pediatric cancer patients hospitalized for COVID-19. Methods: This is a retrospective, descriptive study of the cases of patients with cancer hospitalized for COVID-19. A total of 40 pediatrics were included in the analysis. Data from pediatric patients with COVID-19 included clinical and epidemiological records, laboratory, imaging studies, COVID-19 diagnostic methods, and medical treatment. Results: Of the 40 pediatric patients admitted with cancer with a confirmed diagnosis of COVID-19, 42.5% were solid tumors, 40% leukemias, and 17.5% lymphomas. The clinical parameters associated with mortality were stage IV tumor (p = 0.029) and intubation (p < 0.001). The biochemical factors associated with lower survival were thrombocytopenia under 25,000 cells/mm3 (p < 0.001), D-dimer over 1 µg/ml (p = 0.003), clinical malnutrition (p = 0.023), and disseminated intravascular coagulation (p = 0.03). Conclusion: Our findings showed that the fever was the most frequent symptom, and the clinical parameters associated with mortality were stage IV tumor, intubation, saturation percentage, RDW, platelets, creatinine, ALT, D-dimer, ferritin, and FiO2 percentage. The thrombocytopenia, D-dimer, nutritional status, and disseminated intravascular coagulation were significantly associated with lower survival.
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BACKGROUND: Changes in neutrophil to lymphocyte ratio (ΔNLR) have been used as a clinical tool for stratification and prognosis of patients with solid tumors, there is scarce evidence of their clinical relevance in patients with tumors of the central nervous system who have also undergone surgical resection. OBJECTIVE: Determine if (ΔNLR) are associated with poor response to treatment and worse prognosis in pediatric patients with central nervous system tumors (CNST) who underwent surgical resection. METHODS: We performed a retrospective cohort study; demographic, clinical, and hematological variables were evaluated, Kaplan-Meier survival curves and Cox proportional hazards regression model were performed to evaluate prognosis. RESULTS: The ΔNLR cutoff value obtained through the third interquartile range was 4.30; The probability of survival and complete response to treatment was different between patients with high ΔNLR when compared to patients with low ΔNLR (p= 0.013, p=⪠0.001, respectively). A high ΔNLR behaved as an independent predictor of worse Overall Survival (HR 2,297; 95% CI: 1,075-4.908, p= 0.032). CONCLUSION: An elevated ΔNLR was a predictor of poor response to treatment and a prognostic factor for worse Overall Survival in pediatric patients with CNST undergoing surgical resection.
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Neoplasias del Sistema Nervioso Central , Neutrófilos , Neoplasias del Sistema Nervioso Central/cirugía , Niño , Humanos , Estimación de Kaplan-Meier , Linfocitos/patología , Neutrófilos/patología , Pronóstico , Estudios RetrospectivosRESUMEN
Metformin pharmacokinetics in a liquid extemporaneous formulation from commercial tablets was determined in paediatric patients. A randomized, transversal clinical trial was conducted in 34 children and adolescents between 7 and 17 years of age. 17 children were randomized to take metformin in the liquid formulation and, after a 1-week wash period, a 500 mg metformin tablet was administered to them. Blood samples were obtained in Whatman 903® cards at 0, 1, 2, 4, 8, 12 and 24 hours. Extraction was made by direct precipitation with acetonitrile (ACN) and methanol, detection by UPLC and tandem mass spectrometry. The method was accurate, precise, selective and linear from 50 to 1000 ng/mL (r = .9982). Comparative pharmacokinetics, tablet vs formulation, were as follows: Cmax 1503.2 ng/mL vs 1521.4, Tmax 1.5 h vs 2.3, and half-life 8.2 vs 7.5 h. The liquid formulation of metformin showed similar pharmacokinetics to the tablet, and the ratios (90% CI) of geometric mean for metformin were 100.63% (89.13-113.6), 98.08% (88.04-109.2), and 97.52% (84.9-112.01), for Cmax, AUC0-t, and AUC 0-∞, respectively. Pharmacokinetics was determined using WinNonlin Pro 3.1 software. The liquid formulation of metformin showed similar pharmacokinetics to the tablet, allowing a more precise dose adjustment and ease of administration.
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WHAT IS KNOWN AND OBJECTIVE: Midazolam is a drug that is metabolized by cytochrome P450 (CYP450) enzymes, particularly CYP3A4 and CYP3A5. The presence of single-nucleotide polymorphisms (SNPs) in the genes encoding these enzymes, such as CYP3A4*1B which is associated with low enzyme expression and activity and CYP3A5*3, has been associated with decrease in enzymatic activity and reduced drug clearance, with potential effects on drug levels and/or toxicity. The present study was conducted to determine the frequencies of the allelic variants of the CYP3A4 (rs2740574) and CYP3A5 (rs776746) genes and their effects on the plasma levels and clearance of intravenous midazolam in critically ill Mexican paediatric patients. METHODS: Seventy-two DNA samples were genotyped by real-time PCR with TaqMan probes. Plasma midazolam levels were determined at 3 and 24 h post infusion by high-performance liquid chromatography. RESULTS AND DISCUSSION: The allelic variant rs776746 (CYP3A5*3) was associated with high midazolam plasma levels; the median concentration in patients with the normal genotype (CC) <0.01 ng/ml (Q25 0.01-Q75 196.09), whereas patients with the allelic variant (TT+TC) had a median midazolam concentration of 320.3 ng/ml (Q25 37.51-Q75 529.51), p = 0.001. The median pharmacokinetic clearance rates were 0.10 L/kg/h (Q25 0.01-Q75 0.34) in patients with the allelic variant (TT+TC) and 0.03 L/kg/h (Q25 0.002-Q75 0.13) in patients with the normal genotype (CC), p = 0.042. WHAT IS NEW AND CONCLUSION: This is the first study that reports the frequency of the rs776746 polymorphism in critically ill paediatric patients, which is relevant, since carriers of the *1 allele synthesizing a functional enzyme may need higher doses to achieve adequate sedation. Our results show that compared with carriers of the normal allele, patients with the CYP3A5*3 allelic variant (rs776746) had increased plasma midazolam levels at 3 h after infusion discontinuation (320.3 ng/ml) and greater clearance (0.10 L/kg/h) of the drug.
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Citocromo P-450 CYP3A/genética , Hipnóticos y Sedantes/farmacocinética , Midazolam/farmacocinética , Adolescente , Niño , Preescolar , Enfermedad Crítica , Femenino , Genotipo , Semivida , Humanos , Lactante , Masculino , Tasa de Depuración Metabólica , México , Fenotipo , Polimorfismo de Nucleótido SimpleRESUMEN
A hypoxic microenvironment is a hallmark in different types of tumors; this phenomenon participates in a metabolic alteration that confers resistance to treatments. Because of this, it was proposed that a combination of 2-methoxyestradiol (2-ME) and sodium dichloroacetate (DCA) could reduce this alteration, preventing proliferation through the reactivation of aerobic metabolism in lung adenocarcinoma cell line (A549). A549 cells were cultured in a hypoxic chamber at 1% O2 for 72 hours to determine the effect of this combination on growth, migration, and expression of hypoxia-inducible factors (HIFs) by immunofluorescence. The effect in the metabolism was evaluated by the determination of glucose/glutamine consumption and the lactate/glutamate production. The treatment of 2-ME (10 µM) in combination with DCA (40 mM) under hypoxic conditions showed an inhibitory effect on growth and migration. Notably, this reduction could be attributed to 2-ME, while DCA had a predominant effect on metabolic activity. Moreover, this combination decreases the signaling of HIF-3α and partially HIF-1α but not HIF-2α. The results of this study highlight the antitumor activity of the combination of 2-ME 10 µl/DCA 40 mM, even in hypoxic conditions.
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2-Metoxiestradiol/uso terapéutico , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Ácido Dicloroacético/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Hipoxia Tumoral , Microambiente Tumoral , 2-Metoxiestradiol/farmacología , Células A549 , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Proteínas Reguladoras de la Apoptosis/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ácido Dicloroacético/farmacología , Glucosa/metabolismo , Ácido Glutámico/metabolismo , Glutamina/metabolismo , Glucólisis/efectos de los fármacos , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ácido Láctico/metabolismo , Neoplasias Pulmonares/patología , Proteínas Represoras/metabolismo , Transducción de Señal/efectos de los fármacos , Hipoxia Tumoral/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacosRESUMEN
Context: Ifosfamide (IFA) is an effective antineoplastic for solid tumours in children, although it is associated with high levels of systemic toxicity and causes death in some cases. Objective: The aim of this study was to determine whether the presence of certain allelic variants of genes CYP2B6, CYP2C9, CYP3A4 and CYP3A5 increases the risk of toxicity in children with solid tumours treated with ifosfamide.Materials and methods: A total of 131 DNA samples were genotyped by real-time polymerase chain reaction (RT-PCR) using TaqMan probes. Toxicity was assessed using WHO criteria, and survival analysis was performed using Kaplan-Meier curves.Results: The rs3745274 allelic variant in CYP2B6 was associated with haematological toxicity, affecting neutrophils; CYP3A4 variant rs2740574 was also associated with toxicity, affecting both leukocytes and neutrophils. Additionally, the CYP3A5 gene variant rs776746 was found to affect haemoglobin.Conclusions: Our results show that allelic variants rs3745274 (CYP2B6), rs2740574 (CYP34) and rs776746 (CYP3A5) increase the risk for high haematological toxicity.Clinical trial registration: 068/2013.
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Citocromo P-450 CYP2B6/genética , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP3A/genética , Neoplasias/tratamiento farmacológico , Adolescente , Alelos , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Ifosfamida/administración & dosificación , Ifosfamida/efectos adversos , Lactante , Estimación de Kaplan-Meier , Masculino , Neoplasias/genética , Neoplasias/patologíaRESUMEN
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an age-related, progressive and lethal disease, whose pathogenesis is associated with fibroblasts/myofibroblasts foci that produce excessive extracellular matrix accumulation in lung parenchyma. Hypoxia has been described as a determinant factor in its development and progression. However, the role of distinct members of this pathway is not completely described. METHODS: By western blot, quantitative PCR, Immunohistochemistry and Immunocitochemistry were evaluated, the expression HIF alpha subunit isoforms 1, 2 & 3 as well, as their role in myofibroblast differentiation in lung tissue and fibroblast cell lines derived from IPF patients. RESULTS: Hypoxia signaling pathway was found very active in lungs and fibroblasts from IPF patients, as demonstrated by the abundance of alpha subunits 1 and 2, which further correlated with the increased expression of myofibroblast marker αSMA. In contrast, HIF-3α showed reduced expression associated with its promoter hypermethylation. CONCLUSIONS: This study lends further support to the involvement of hypoxia in the pathogenesis of IPF, and poses HIF-3α expression as a potential negative regulator of these phenomena.
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Proteínas Reguladoras de la Apoptosis/biosíntesis , Fibrosis Pulmonar Idiopática/metabolismo , Miofibroblastos/metabolismo , Proteínas Represoras/biosíntesis , Proteínas Reguladoras de la Apoptosis/genética , Línea Celular , Expresión Génica , Humanos , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/patología , Miofibroblastos/patología , Proteínas Represoras/genéticaRESUMEN
Purpose: The objective of this study was to determine whether a comorbidity index could be used to predict mortality in pediatric patients with chemotherapy-treated solid tumors. Methods: Pediatric patients who underwent chemotherapy treatment for solid tumors were included, and demographic, clinical, and comorbidity data were obtained from patient electronic records. Results: A total of 196 pediatric patients with embryonic solid tumors were included. Metastatic tumors were the most frequently observed (n = 103, 52.6%). The most common comorbidities encountered for the Charlson comorbidity index (CCI) were cellulitis (n = 24, 12.2%) and acute renal failure (n = 15, 7.7%). For the Pediatric Comorbidity Index (PCI), the most frequent comorbidities were pneumonia and sepsis, with n = 64 (32.7%) for each. We evaluated established the prognostic values for both indexes using Kaplan-Meier curves, finding that the CCI and PCI could predict mortality with p < 0.0001. Conclusion: Using the PCI, we observed 100% survival in patients without comorbidities, 70% survival in patients with a low degree of comorbidity, and 20% survival in patients with a high degree of comorbidity. Greater discrimination of probability of survival could be achieved using degrees of comorbidity on the PCI than using degrees of comorbidity on the CCI. The application of the PCI for assessing the hospitalized pediatric population may be of importance for improving clinical evaluation.
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Dexmedetomidine is an imidazole derivative, with high affinity for α2 adrenergic receptors, used for sedation, analgesia and adjuvant anaesthesia. In this study, an analytical method for the quantification of dexmedetomidine in dried blood spots was developed, validated and applied. The drug was extracted from dried blood spot by liquid extraction; the separation was carried out by ultra high-resolution liquid chromatography in reverse phase coupled to tandem mass spectrometry method. An X Select cyano 5 µm HSS column (2.1 X 150 mm, Waters) and a mobile phase composed of 0.1% formic acid: acetonitrile [50:50 v/v], were used. The test was linear over the concentration range of 50 to 2000 pg/mL. The coefficients of variation for the intra and interday trials were less than 15%. The drug was stable under the conditions tested. The method was successfully applied for the quantification of 6 patients, aged 0 to 2 years, with classification ASA I, who underwent ambulatory surgeries, receiving a dose of 1 µg/Kg dexmedetomidine IV. The drug concentrations in the different sampling times were in the range of 76 to 868 pg/mL.
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Agonistas de Receptores Adrenérgicos alfa 2/sangre , Dexmedetomidina/sangre , Pruebas con Sangre Seca/métodos , Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Agonistas de Receptores Adrenérgicos alfa 2/normas , Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/sangre , Analgésicos no Narcóticos/normas , Preescolar , Cromatografía Líquida de Alta Presión/métodos , Dexmedetomidina/administración & dosificación , Dexmedetomidina/normas , Pruebas con Sangre Seca/normas , Pruebas con Sangre Seca/estadística & datos numéricos , Hematócrito , Humanos , Hipnóticos y Sedantes/administración & dosificación , Hipnóticos y Sedantes/sangre , Hipnóticos y Sedantes/normas , Lactante , Recién Nacido , Estándares de Referencia , Espectrometría de Masas en Tándem/métodosRESUMEN
Kainic acid (KA) has been used to study the neurotoxicity induced after status epilepticus (SE) due to activation of excitatory amino acids with neuronal damage. Medicinal plants can protect against damage caused by KA-induced SE; in particular, organic extracts of Heterotheca inuloides and its metabolite quercetin display antioxidant activity and act as hepatoprotective agents. However, it is unknown whether these properties can protect against the hyperexcitability underlying the damage caused by KA-induced SE. Our aim was to study the protective effects (with regard to behavior and antioxidant activity) of administration of natural products methanolic (ME) and acetonic (AE) extracts and quercetin (Q) from H. inuloides at doses of 30 mg/kg (ME30, AE30, and Q30 groups), 100 mg/kg (ME100, AE100, and Q100 groups), and 300 mg/kg (ME300, AE300, and Q300 groups) against damage in brain regions of male Wistar rats treated with KA. We found dose-dependent effects on behavioral and biochemical studies in the all-natural product groups vs. the control group, with decreases in seizure severity (Racine's scale) and increases in seizure latency (p < 0.05 in the ME100, AE100, Q100, and Q300 groups and p < 0.01 in the AE300 and ME300 groups); on lipid peroxidation and carbonylated proteins in all brain tissues (p < 0.0001); and on GPx, GR, CAT, and SOD activities with all the treatments vs. KA (p ≤ 0.001). In addition, there were strong negative correlations between carbonyl levels and latency in the group treated with KA and in the group treated with methanolic extract in the presence of KA (r = -0.9919, p = 0.0084). This evidence suggests that organic extracts and quercetin from H. inuloides exert anticonvulsant effects via direct scavenging of reactive oxygen species (ROS) and modulation of antioxidant enzyme activity.