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Glycosylation processes are under high natural selection pressure, presumably because these can modulate resistance to infection. Here, we asked whether inactivation of the UDP-galactose:ß-galactoside-α1-3-galactosyltransferase (α1,3GT) gene, which ablated the expression of the Galα1-3Galß1-4GlcNAc-R (α-gal) glycan and allowed for the production of anti-α-gal antibodies (Abs) in humans, confers protection against Plasmodium spp. infection, the causative agent of malaria and a major driving force in human evolution. We demonstrate that both Plasmodium spp. and the human gut pathobiont E. coli O86:B7 express α-gal and that anti-α-gal Abs are associated with protection against malaria transmission in humans as well as in α1,3GT-deficient mice, which produce protective anti-α-gal Abs when colonized by E. coli O86:B7. Anti-α-gal Abs target Plasmodium sporozoites for complement-mediated cytotoxicity in the skin, immediately after inoculation by Anopheles mosquitoes. Vaccination against α-gal confers sterile protection against malaria in mice, suggesting that a similar approach may reduce malaria transmission in humans.
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Escherichia coli/fisiología , Inmunoglobulina M/inmunología , Malaria Falciparum/inmunología , Malaria Falciparum/transmisión , Plasmodium/fisiología , Polisacáridos/inmunología , Adulto , Animales , Anopheles/parasitología , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Anticuerpos Antiprotozoarios/sangre , Anticuerpos Antiprotozoarios/inmunología , Autoantígenos/inmunología , Línea Celular Tumoral , Niño , Escherichia coli/clasificación , Escherichia coli/inmunología , Femenino , Galactosiltransferasas/genética , Galactosiltransferasas/metabolismo , Tracto Gastrointestinal/microbiología , Vida Libre de Gérmenes , Humanos , Inmunoglobulina M/sangre , Malaria Falciparum/microbiología , Malaria Falciparum/parasitología , Ratones , Plasmodium/clasificación , Plasmodium/crecimiento & desarrollo , Plasmodium/inmunología , Plasmodium falciparum/inmunología , Plasmodium falciparum/fisiología , Esporozoítos/inmunología , Receptor Toll-Like 9/agonistasRESUMEN
The endoplasmic reticulum (ER) is crucial for protein quality control, and disruptions in its function can lead to various diseases. ER stress triggers an adaptive response called the unfolded protein response (UPR), which can either restore cellular homeostasis or induce cell death. Melatonin, a safe and multifunctional compound, shows promise in controlling ER stress and could be a valuable therapeutic agent for managing the UPR. By regulating ER and mitochondrial functions, melatonin helps maintain cellular homeostasis via reduction of oxidative stress, inflammation, and apoptosis. Melatonin can directly or indirectly interfere with ER-associated sensors and downstream targets of the UPR, impacting cell death, autophagy, inflammation, molecular repair, among others. Crucially, this review explores the mechanistic role of melatonin on ER stress in various diseases including liver damage, neurodegeneration, reproductive disorders, pulmonary disease, cardiomyopathy, insulin resistance, renal dysfunction, and cancer. Interestingly, while it alleviates the burden of ER stress in most pathological contexts, it can paradoxically stimulate ER stress in cancer cells, highlighting its intricate involvement in cellular homeostasis. With numerous successful studies using in vivo and in vitro models, the continuation of clinical trials is imperative to fully explore melatonin's therapeutic potential in these conditions.
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The use of pesticides is often regarded as a fundamental aspect of conventional agriculture. However, these compounds have gained recognition as some of the oldest and most widely employed xenobiotic contaminants, necessitating effective strategies for human biomonitoring. In this context, a method was developed for the determination of 16 legacy organochlorine pesticides, 6 metabolites of current pesticides (2,4-D, malathion, parathion, fipronil, pyraclostrobin, cypermethrin, permethrin, cyfluthrin), and 1 triazine herbicide (atrazine) in serum. Samples were prepared with water, formic acid, acetonitrile, and ultrasound irradiation, followed by solid-phase extraction with Oasis Prime HLB. Subsequently, metabolites from current pesticides underwent derivatization using MTBSTFA with 1% TBDMSCl for analysis via gas chromatography-tandem mass spectrometry (GC-MS/MS), employing an SLB-5MS fused silica capillary column. Analytical curves were generated with limits of quantification from 0.3 to 4.0 ng.mL-1. Accuracy ranged from 69 to 124%, and the coefficient of variation from 2 to 28%. Moreover, determining 1-(4-chlorophenyl)-1H-pyrazol-3-ol was suggested as a biomarker for pyraclostrobin biomonitoring. This analytical approach facilitated the determination of both legacy and metabolites of current pesticides in the same serum sample, presenting an interesting and cost-effective option for large cohorts, and multi-omics studies that evaluate time-dependent biomarkers in blood samples, thereby enabling biomonitoring within the same matrix. Furthermore, a proof-of-concept involving 10 volunteers demonstrated exposure to 9 pesticides at mean concentrations measured in ng mL-1, consistent with findings from various biomonitoring initiatives.
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OBJECTIVE: To describe clinical, epidemiological and management information on cases of acute Chagas disease (ACD) by oral transmission in the state of Amazonas in western Amazon. METHODS: Manual and electronic medical records of patients diagnosed with ACD at the Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD) were included. RESULTS: There were 147 cases of acute CD registered from 10 outbreaks that occurred in the state of Amazonas between 2004 and 2022. The transmission pathway was through oral route, with probable contaminated palm fruit juice (açaí and/or papatuá), and involved people from the same family, friends or neighbours. Of 147 identified cases, 87 (59%) were males; cases were aged 10 months to 82 years. The most common symptom was the febrile syndrome (123/147; 91.8%); cardiac alterations were present in 33/100 (33%), (2/147; 1.4%) had severe ACD with meningoencephalitis, and 12 (8.2%) were asymptomatic. Most cases were diagnosed through thick blood smear (132/147; 89.8%), a few (14/147; 9.5%) were diagnosed by serology and (1/147; 0.7%) by polymerase chain reaction (PCR) and blood culture. In all these outbreaks, 74.1% of the patients were analysed by PCR, and Trypanosoma cruzi TcIV was detected in all of them. No deaths were recorded. The incidence of these foci coincided with the fruit harvest period in the state of Amazonas. CONCLUSION: The occurrence of ACD outbreaks in the Amazon affected individuals of both sexes, young adults, living in rural and peri-urban areas and related to the consumption of regional foods. Early diagnosis is an important factor in surveillance. There was a low frequency of cardiac alterations. Continuous follow-up of most patients was not carried out due to difficulty in getting to specialised centres; therefore, little is known about post-treatment.
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Enfermedad de Chagas , Trypanosoma cruzi , Masculino , Femenino , Adulto Joven , Humanos , Brasil/epidemiología , Enfermedad de Chagas/epidemiología , Brotes de Enfermedades , Ingestión de AlimentosRESUMEN
The use of pesticide use has been linked to the higher production of reactive oxygen species, resulting in oxidative stress, which in turn can cause genomic instability. A marker for instability is the copy number variation of the mitochondrial genome (mtDNAcn), which has been found to be altered in diverse human diseases, including tumors. This research aimed to examine the variation of mtDNAcn in individuals occupationally exposed to pesticides. Real-time PCR assays were conducted on 154 individuals (78 exposed and 76 non-exposed). Pesticide-exposed ndividuals exhibited a significant reduction in mtDNAcn (1.11 ± 0.37mtDNAcn/genome) compared to non-exposed individuals (1.30 ± 0.33mtDNAcn/genome; p = 0.001). The multivariate analysis indicated that individuals who reported using haloxyfop and copper sulfate demonstrated an increase (ß = 0.200, p = 0.053) and a decrease (ß=-0.2, p = 0.021), respectively, in mtDNAcn. In conclusion, our findings suggest that chronic exposure to pesticides results in changes in mtDNAcn.
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Construction environment is composed of various substances classified as carcinogens. Thus, workers exposed in this environment can be susceptible to genomic instability that can be evaluated by absolute telomere length (TL). In this work, we evaluated TL in construction workers compared to a non-exposed group performed by qPCR assay. The TL was evaluated in 59 men exposed to the construction environment (10 years of exposure) and 49 men non-exposed. Our data showed that individuals exposed to the construction environment exhibited a significantly lower TL in relation to non-exposed group (p = 0.009). Also, on the multiple linear regression model, we observed that TL was significantly influenced by the construction environment exposure (p ≤ 0.001). Additionally, the arsenic exposure is associated to a shortening telomere (p ≤ 0.001), and the lead exposure caused an increase in TL (p ≤ 0.001). Thus, our findings suggest a modulation in TL by construction environment exposure, mainly by arsenic and lead exposure.
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Arsénico , Masculino , Humanos , Arsénico/toxicidad , Plomo/toxicidad , Exposición a Riesgos Ambientales , Linfocitos , TelómeroRESUMEN
Dunbar syndrome is diagnosed by excluding other possible causes of abdominal pains. Surgical treatment comprises complete dissection of the ligament and the surrounding nerve ganglion. This report describes the case of a previously healthy 45-year-old male patient who presented with epigastric abdominal pain irradiating to the back and weakness. Initially, abdominal computed tomography was ordered, showing arteriopathy of the celiac trunk and mesenteric artery with stenosis. The patient underwent surgical treatment because of the refractory pain, but findings were nonspecific. It was necessary to continue workup with serial angiotomography to follow the case. After around 6 months, thickening of the arcuate ligament was found, with compression of the proximal third of the celiac trunk and 80% stenosis. The patient therefore underwent laparoscopy to relieve celiac trunk compression, with satisfactory postoperative recovery.
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Ovarian cancer (OC) is the most lethal gynecologic malignancy, and melatonin has shown various antitumor properties. Herein, we investigated the influence of melatonin therapy on energy metabolism and mitochondrial integrity in SKOV-3 cells and tested whether its effects depended on MT1 receptor activation. SKOV-3 cells were exposed to different melatonin concentrations, and experimental groups were divided as to the presence of MT1 receptors (melatonin groups) or receptor absence by RNAi silencing (siRNA MT1+melatonin). Intracellular melatonin levels increased after treatment with melatonin independent of the MT1. The mitochondrial membrane potential of SKOV-3 cells decreased in the group treated with the highest melatonin concentration. Melatonin reduced cellular glucose consumption, while MT1 knockdown increased its consumption. Interconversion of lactate to pyruvate increased after treatment with melatonin and was remarkable in siRNA MT1 groups. Moreover, lactate dehydrogenase activity decreased with melatonin and increased after MT1 silencing at all concentrations. The UCSC XenaBrowser tool showed a positive correlation between the human ASMTL gene and the ATP synthase genes, succinate dehydrogenase gene (SDHD), and pyruvate dehydrogenase genes (PDHA and PDHB). We conclude that melatonin changes the glycolytic phenotype and mitochondrial integrity of SKOV-3 cells independent of the MT1 receptor, thus decreasing the survival advantage of OC cells.
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Melatonina , Neoplasias Ováricas , Receptor de Melatonina MT1 , Carcinoma Epitelial de Ovario , Femenino , Humanos , Melatonina/metabolismo , Melatonina/farmacología , Potencial de la Membrana Mitocondrial , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Piruvatos , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Receptor de Melatonina MT1/genética , Receptor de Melatonina MT1/metabolismoRESUMEN
In a large part of the population inefficient ingestion of proteins, whether for cultural, aesthetic or economic reasons, is a global concern. Low-protein diets can cause severe functional complications, mainly during the development and maturation of organs and systems, including the female reproductive system. The present study investigated the effect of nutritional protein restriction during puberty on the oestrous cycle and expression of sex steroid receptors (AR, ERα e ERß) in ovarian and uterine tissues of adult rats. Protein restriction promoted lower body weight gain, feed efficiency and higher caloric intake. There was an increase in the oestrus phase arrest without changing the total length of the oestrous cycle. The consumption of low-protein diet also reduced the thickness of the uterine endometrium (uterine epithelium and endometrial stroma) in addition to increasing the number of primary and atretic follicles in the ovaries. Furthermore, the low-protein diet reduced the levels of androgen receptor (AR) and increased the oestrogen receptor ß (ERß) in the ovary, while no significant changes were observed in the uterus. Our study reinforces the importance of adequate protein intake during puberty, since physiological changes in this developmental period interfere with the histomorphometry of the ovaries and uteri, possibly resulting in impaired folliculogenesis and fertility in the reproductive period.
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Ciclo Estral/fisiología , Ovario/patología , Deficiencia de Proteína/fisiopatología , Maduración Sexual/fisiología , Útero/patología , Animales , Femenino , Ovario/metabolismo , Deficiencia de Proteína/metabolismo , Deficiencia de Proteína/patología , Ratas , Ratas Endogámicas F344 , Útero/metabolismoRESUMEN
BACKGROUND: Cape Verde is an archipelago located off the West African coast and is in a pre-elimination phase of malaria control. Since 2010, fewer than 20 Plasmodium falciparum malaria cases have been reported annually, except in 2017, when an outbreak in Praia before the rainy season led to 423 autochthonous cases. It is important to understand the genetic diversity of circulating P. falciparum to inform on drug resistance, potential transmission networks and sources of infection, including parasite importation. METHODS: Enrolled subjects involved malaria patients admitted to Dr Agostinho Neto Hospital at Praia city, Santiago island, Cape Verde, between July and October 2017. Neighbours and family members of enrolled cases were assessed for the presence of anti-P. falciparum antibodies. Sanger sequencing and real-time PCR was used to identify SNPs in genes associated with drug resistance (e.g., pfdhfr, pfdhps, pfmdr1, pfk13, pfcrt), and whole genome sequencing data were generated to investigate the population structure of P. falciparum parasites. RESULTS: The study analysed 190 parasite samples, 187 indigenous and 3 from imported infections. Malaria cases were distributed throughout Praia city. There were no cases of severe malaria and all patients had an adequate clinical and parasitological response after treatment. Anti-P. falciparum antibodies were not detected in the 137 neighbours and family members tested. No mutations were detected in pfdhps. The triple mutation S108N/N51I/C59R in pfdhfr and the chloroquine-resistant CVIET haplotype in the pfcrt gene were detected in almost all samples. Variations in pfk13 were identified in only one sample (R645T, E668K). The haplotype NFD for pfmdr1 was detected in the majority of samples (89.7%). CONCLUSIONS: Polymorphisms in pfk13 associated with artemisinin-based combination therapy (ACT) tolerance in Southeast Asia were not detected, but the majority of the tested samples carried the pfmdr1 haplotype NFD and anti-malarial-associated mutations in the the pfcrt and pfdhfr genes. The first whole genome sequencing (WGS) was performed for Cape Verdean parasites that showed that the samples cluster together, have a very high level of similarity and are close to other parasites populations from West Africa.
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Resistencia a Medicamentos/genética , Malaria Falciparum/prevención & control , Plasmodium falciparum/genética , Polimorfismo Genético , Proteínas Protozoarias/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antimaláricos/uso terapéutico , Cabo Verde/epidemiología , Niño , Preescolar , Brotes de Enfermedades , Femenino , Humanos , Malaria Falciparum/epidemiología , Masculino , Persona de Mediana Edad , Plasmodium falciparum/efectos de los fármacos , Adulto JovenRESUMEN
Somatic copy number aberrations (CNAs) have been associated with clear-cell renal carcinoma (ccRCC) pathogenesis and are a potential source of new diagnostic, prognostic and therapeutic biomarkers. Recurrent CNAs include loss of chromosome arms 3p, 14q, 9p, and gains of 5q and 8q. Some of these regional CNAs are suspected of altering gene expression and could influence clinical outcomes. Despite many studies of CNAs in RCC, there are currently no descriptions of genomic copy number alterations in a Brazilian ccRCC cohort. This study was designed to evaluate the chromosomal profile of CNAs in Brazilian ccRCC tumors and explore clinical associations. A total of 92 ccRCC Brazilian patients that underwent nephrectomy at Barretos Cancer Hospital were analyzed for CNAs by array comparative genomic hybridization. Most patients in the cohort had early-stage localized disease. The most significant alterations were loss of 3p (87.3%), 14q (35.8%), 6q (29.3%), 9p (28.6%) and 10q (25.0%), and gains of 5q (59.7%), 7p (29.3%) and 16q (20.6%). Bioinformatics analysis revealed 19 genes mapping to CNA significant regions, including SETD2, BAP1, FLT4, PTEN, FGFR4 and NSD1. Moreover, gain of 5q34-q35.3 (FLT4 and NSD1) and loss of 6q23.2-q23.3 (MYB) and 9p21.3 (MLLT3) had gene expression levels that correlated with TCGA data and was also associated with advanced disease features, such as larger tumors, Fuhrman 3, metastasis at diagnosis and death. The loss of region 14q22.1 which encompasses the NIN gene was associated with poor overall survival. Overall, this study provides the first CNA landscape of Brazilian patients and pinpoints genomic regions and specific genes worthy of more detailed investigations. Our results highlight important genes that are associated with copy number changes involving large chromosomal regions that are potentially related to ccRCC tumorigenesis and disease biology for future clinical investigations.
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Carcinoma de Células Renales/genética , Variaciones en el Número de Copia de ADN/genética , Neoplasias Renales/genética , Adulto , Anciano , Anciano de 80 o más Años , Brasil , Cromosomas Humanos Par 14/genética , Simulación por Computador , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Análisis de Supervivencia , Transcriptoma/genética , Adulto JovenRESUMEN
PURPOSE: Construction workers are exposed to a mixture of substances in the workplace considered carcinogenic. This study aimed to characterise gene-specific changes in DNA methylation over the workweek in this population as this type of environmental exposure has not been studied extensively. MATERIALS AND METHODS: We evaluated their DNA methylation in 4 gene-promoter regions (CDKN2A, RASSF1A, MLH1 and APC) and 2 repeat elements (ALU and LINE-1) in blood samples obtained on the first and fifth day of the same workweek of a group of 39 male construction workers. DNA methylation was measured by bisulphite-PCR-Pyrosequencing. We also measured the levels of trace elements in the whole blood by ICP-MS. RESULTS: Only the CDKN2A gene had significant differences in the average methylation level between the first and fifth day of the workweek. We also observed that the levels of Cu, Pb, Se, Mn, and Ti decreased during the fifth day of exposure, and only lead, titanium and copper showed a low significant correlation with the methylation level mean for three specific CpG sites of the CDKN2A. CONCLUSIONS: In summary, the data suggest that altered levels of CDKN2A methylation in construction workers may be a potential biomarker of recent exposure in this environment.
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Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Metilación de ADN/genética , Epigénesis Genética , Exposición Profesional/efectos adversos , Adulto , Elementos Alu/genética , Biomarcadores/sangre , Industria de la Construcción , Humanos , Elementos de Nucleótido Esparcido Largo/genética , Masculino , Homólogo 1 de la Proteína MutL/genética , Regiones Promotoras Genéticas/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
BACKGROUND: Malignant pleural mesothelioma (MPM) is a highly lethal disease comprising a heterogeneous group of tumors with challenging to predict biological behavior. The diagnosis is complex, and the histologic classification includes 2 major subtypes of MPM: epithelioid (â¼60% of cases) and sarcomatous (â¼20%). Its identification depends upon pathological investigation supported by clinical and radiological evidence and more recently ancillary molecular testing. Treatment options are currently limited, with no known targeted therapies available. OBJECTIVES: To elucidate the mutation profile of driver tumor suppressor and oncogenic genes in a cohort of Brazilian patients. METHODS: We sequenced 16 driver genes in a series of 43 Brazilian malignant mesothelioma (MM) patients from 3 distinct Brazilian centers. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor tissue blocks, and the TERT promoter region was amplified by PCR followed by direct capillary sequencing. The Illumina TruSight Tumor 15 was used to evaluate 250 amplicons from 15 genes associated with solid tumors (AKT1, GNA11, NRAS, BRAF, GNAQ, PDGFRA, EGFR, KIT, PIK3CA, ERBB2, KRAS, RET, FOXL2, MET,and TP53). Library preparation with the TruSight Tumor 15 was performed before sequencing at the MiSeq platform. Data analysis was performed using Sophia DDM software. RESULTS: Out of 43 MPM patients, 38 (88.4%) were epithelioid subtype and 5 (11.6%) were sarcomatoid histotype. Asbestos exposure was present in 15 (39.5%) patients with epithelioid MPM and 3 (60%) patients with sarcomatoid MPM. We found a TERT promoter mutation in 11.6% of MM, and the c.-146C>T mutation was the most common event. The next-generation sequencing was successful in 33 cases. A total of 18 samples showed at least 1 pathogenic, with a median of 1.8 variants, ranging from 1 to 6. The most mutated genes were TP53 and ERBB2 with 7 variants each, followed by NRAS BRAF, PI3KCA, EGFR and PDGFRA with 2 variants each. KIT, AKT1, and FOXL2 genes exhibited 1 variant each. Interestingly, 2 variants observed in the PDGFRA gene are classic imatinib-sensitive therapy. CONCLUSIONS: We concluded that Brazilian MPM harbor mutation in classic tumor suppressor and oncogenic genes, which might help in the guidance of personalized treatment of MPM.
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Genes Supresores de Tumor , Neoplasias Pulmonares/genética , Mesotelioma Maligno/genética , Mutación , Oncogenes , Carcinogénesis , Estudios de Cohortes , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Adhesión en ParafinaRESUMEN
Cancers of the reproductive organs have a strong association with mitochondrial defects, and a deeper understanding of the role of this organelle in preneoplastic-neoplastic changes is important to determine the appropriate therapeutic intervention. Mitochondria are involved in events during cancer development, including metabolic and oxidative status, acquisition of metastatic potential, resistance to chemotherapy, apoptosis, and others. Because of their origin from melatonin-producing bacteria, mitochondria are speculated to produce melatonin and its derivatives at high levels; in addition, exogenously administered melatonin accumulates in the mitochondria against a concentration gradient. Melatonin is transported into tumor cell by GLUT/SLC2A and/or by the PEPT1/2 transporters, and plays beneficial roles in mitochondrial homeostasis, such as influencing oxidative phosphorylation and electron flux, ATP synthesis, bioenergetics, calcium influx, and mitochondrial permeability transition pore. Moreover, melatonin promotes mitochondrial homeostasis by regulating nuclear DNA and mtDNA transcriptional activities. This review focuses on the main functions of melatonin on mitochondrial processes, and reviews from a mechanistic standpoint, how mitochondrial crosstalk evolved in ovarian, endometrial, cervical, breast, and prostate cancers relative to melatonin's known actions. We put emphasis on signaling pathways whereby melatonin interferes within cancer-cell mitochondria after its administration. Depending on subtype and intratumor metabolic heterogeneity, melatonin seems to be helpful in promoting apoptosis, anti-proliferation, pro-oxidation, metabolic shifting, inhibiting neovasculogenesis and controlling inflammation, and restoration of chemosensitivity. This results in attenuation of development, progression, and metastatic potential of reproductive cancers, in addition to lowering the risk of recurrence and improving the life quality of patients.
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Neoplasias de los Genitales Femeninos/patología , Melatonina/fisiología , Mitocondrias/fisiología , Neoplasias de la Próstata/patología , Animales , Neoplasias de la Mama/patología , Neoplasias Endometriales/patología , Femenino , Humanos , Masculino , Neoplasias Ováricas/patología , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Neoplasias del Cuello Uterino/patologíaRESUMEN
In the Brazilian Amazon, the suspected source of infection in an outbreak of acute Chagas disease involving 10 patients was Euterpe oleracea (açaí berry) juice. Patient blood and juice samples contained Trypanosoma cruzi TcIV, indicating oral transmission of the Chagas disease agent.
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Enfermedad de Chagas/transmisión , Brotes de Enfermedades , Euterpe , Jugos de Frutas y Vegetales/parasitología , Trypanosoma cruzi/fisiología , Adolescente , Adulto , Anciano , Brasil/epidemiología , Enfermedad de Chagas/parasitología , Femenino , Inocuidad de los Alimentos , Humanos , Lactante , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
The development of the endometrium is a cyclic event tightly regulated by hormones and growth factors to coordinate the menstrual cycle while promoting a suitable microenvironment for embryo implantation during the "receptivity window". Many women experience uterine failures that hamper the success of conception, such as endometrium thickness, endometriosis, luteal phase defects, endometrial polyps, adenomyosis, viral infection, and even endometrial cancer; most of these disturbances involve changes in endocrine components or cell damage. The emerging evidence has proven that circadian rhythm deregulation followed by low circulating melatonin is associated with low implantation rates and difficulties to maintain pregnancy. Given that melatonin is a circadian-regulating hormone also involved in the maintenance of uterine homeostasis through regulation of numerous pathways associated with uterine receptivity and gestation, the success of female reproduction may be dependent on the levels and activity of uterine and placental melatonin. Based on the fact that irregular production of maternal and placental melatonin is related to recurrent spontaneous abortion and maternal/fetal disturbances, melatonin replacement may offer an excellent opportunity to restore normal physiological function of the affected tissues. By alleviating oxidative damage in the placenta, melatonin favors nutrient transfer and improves vascular dynamics at the uterine-placental interface. This review focuses on the main in vivo and in vitro functions of melatonin on uterine physiological processes, such as decidualization and implantation, and also on the feto-maternal tissues, and reviews how exogenous melatonin functions from a mechanistic standpoint to preserve the organ health. New insights on the potential signaling pathways whereby melatonin resists preeclampsia and endometriosis are further emphasized in this review.
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Aborto Habitual , Endometriosis , Endometrio/metabolismo , Melatonina/metabolismo , Placenta , Preeclampsia , Aborto Habitual/metabolismo , Aborto Habitual/patología , Ritmo Circadiano , Endometriosis/metabolismo , Endometriosis/patología , Femenino , Humanos , Ciclo Menstrual , Placenta/metabolismo , Placenta/patología , Preeclampsia/metabolismo , Preeclampsia/patología , EmbarazoRESUMEN
OBJECTIVES: The methylation profile of genes in precursor lesions in cervical cancer was characterized to improve screening techniques for high-grade intraepithelial neoplasia. METHODS: A total of 447 cervical cytology samples obtained from women who underwent colposcopy were examined. The cases were distributed as follows: (1) cervices without cervical intraepithelial neoplasia (CIN; nâ¯=â¯152); (2) cervices with a CIN grade of 1 (CIN 1; nâ¯=â¯147); and (3) cervices with a CIN grade of 2 or 3 (CIN 2/3; nâ¯=â¯148). The methylation pattern for a panel of 15 genes was analysed by quantitative methylation-specific PCR (qMSP) and compared between the groups (≤CIN 1 vs. CIN 2+). RESULTS: In the validation set, seven genes presented significantly different methylation profiles according to diagnosis, namely, DAPK1 (pâ¯=â¯0.001), EPB41L3 (pâ¯=â¯0.001), HIC1 (pâ¯=â¯0.028), hsa-miR-124-2 (pâ¯=â¯0.001), LMX1A (pâ¯=â¯0.001), SOX1 (pâ¯=â¯0.001), and TERT (pâ¯=â¯0.001). Six genes showed a significant increase in the frequency of methylation in the presence of hr-HPV, namely, DAPK1 (pâ¯=â¯0.001), EPB41L3 (pâ¯=â¯0.001), hsa-miR-124-2 (pâ¯=â¯0.001), LMX1A (pâ¯=â¯0.001), SOX1 (pâ¯=â¯0.001), and TERT (pâ¯=â¯0.001). The methylation of the hsa-miR-124 gene showed sensitivity and specificity (86.7% and 61.3%, respectively) similar to that of the HPV test (91.3% and 50.0%, respectively). The independent factors associated with the diagnosis of CIN 2+ and the methylation of the hsa-miR-124-2 (ORâ¯=â¯5.1), SOX1 (ORâ¯=â¯2.8), TERT (ORâ¯=â¯2.2), and LMX1A (ORâ¯=â¯2.0) genes were a positive test for hr-HPV (odds ratio [OR]â¯=â¯5.5). CONCLUSIONS: Hypermethylation of the hsa-miR-124-2, SOX1, TERT, and LMX1A genes may be a promising biomarker for precursor lesions in cervical cancer regardless of the hr-HPV status.
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Metilación de ADN , Displasia del Cuello del Útero/diagnóstico , Displasia del Cuello del Útero/genética , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/genética , Adulto , Biomarcadores de Tumor/genética , Detección Precoz del Cáncer , Femenino , Humanos , Proteínas con Homeodominio LIM/genética , MicroARNs/genética , Persona de Mediana Edad , Papillomaviridae , Infecciones por Papillomavirus/complicaciones , Regiones Promotoras Genéticas , Factores de Transcripción SOXB1/genética , Sensibilidad y Especificidad , Telomerasa/genética , Factores de Transcripción/genética , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virología , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/virologíaRESUMEN
BACKGROUND: In Brazil, most medical schools do not offer trauma surgery in their undergraduate curriculum. The Trauma Leagues arose in Brazil as an important promoter of trauma education and stimulated activities related to surgical skills and practices. In recent decades, studies have demonstrated that the number of surgical residency applicants has decreased worldwide. Strategies to motivate medical students to choose surgery are needed. OBJECTIVE: To evaluate the impact of participation in the Unicamp Trauma League (UTL) during a 20-year period in the choice for a surgical career. METHODS: The study included 276 students in a Brazilian university hospital who were part of the Trauma League. Research of records in universities and medical societies about the specialties chosen during residency were evaluated. A Likert questionnaire was sent to participants to evaluate the impact of participating in the Trauma League in the student's professional career. RESULTS: The questionnaire was answered by 76% of the participants. Of those, 38.4% chose general surgery. About 55.1% did not know what medical career to choose when joined the league. Participation in the league had an influence on specialty choice in 79.1% of the students. Of those choosing surgery, 93.2% believed that participating in the league had positively influenced their career choice. Overall, 93.1% believed that participating in the league provided knowledge and information that the medical school curriculum was not able to provide. CONCLUSION: Participation in Trauma League has been an effective strategy to encourage medical students to choose a career in general surgery in Campinas, Brazil.
Asunto(s)
Selección de Profesión , Sociedades Médicas , Estudiantes de Medicina/psicología , Traumatología , Adulto , Brasil , Estudios Transversales , Curriculum , Femenino , Hospitales Universitarios , Humanos , Internado y Residencia/estadística & datos numéricos , Masculino , Encuestas y CuestionariosRESUMEN
BACKGROUND: Strategies designed to advance towards malaria elimination rely on the detection and treatment of infections, rather than fever, and the interruption of malaria transmission between mosquitoes and humans. Mass drug administration with anti-malarials directed at eliminating parasites in blood, either to entire populations or targeting only those with malaria infections, are considered useful strategies to progress towards malaria elimination, but may be insufficient if applied on their own. These strategies assume a closer contact with populations, so incorporating a vector control intervention tool to those approaches could significantly enhance their efficacy. Ivermectin, an endectocide drug efficacious against a range of Anopheles species, could be added to other drug-based interventions. Interestingly, ivermectin could also be useful to target outdoor feeding and resting vectors, something not possible with current vector control tools, such as impregnated bed nets or indoor residual spraying (IRS). RESULTS: Anopheles aquasalis susceptibility to ivermectin was assessed. In vivo assessments were performed in six volunteers, being three men and three women. The effect of ivermectin on reproductive fitness and mosquito survivorship using membrane feeding assay (MFA) and direct feeding assay (DFA) was assessed and compared. The ivermectin lethal concentration (LC) values were LC50 = 47.03 ng/ml [44.68-49.40], LC25 = 31.92 ng/ml [28.60-34.57] and LC5 = 18.28 ng/ml [14.51-21.45]. Ivermectin significantly reduced the survivorship of An. aquasalis blood-fed 4 h post-ingestion (X 2 [N = 880] = 328.16, p < 0.001), 2 days post-ingestion (DPI 2) (X 2 [N = 983] = 156.75, p < 0.001), DPI 7 (X 2 [N = 935] = 31.17, p < 0.001) and DPI 14 (X 2 [N = 898] = 38.63, p < 0.001) compared to the blood fed on the untreated control. The average number of oviposited eggs per female was significantly lower in LC5 group (22.44 [SD = 3.38]) than in control (34.70 [SD = 12.09]) (X 2 [N = 199] = 10.52, p < 0.001) as well as the egg hatch rate (LC5 = 74.76 [SD = 5.48]) (Control = 81.91 [SD = 5.92]) (X 2 [N = 124] = 64.24, p < 0.001). However, no differences were observed on the number of pupae that developed from larvae (Control = 34.19 [SD = 10.42) and group (LC5 = 33.33 [SD = 11.97]) (X 2 [N = 124] = 0.96, p > 0.05). CONCLUSIONS: Ivermectin drug reduces mosquito survivorship when blood fed on volunteer blood from 4 h to 14 days post-ingestion controlling for volunteers' gender. Ivermectin at mosquito sub-lethal concentrations (LC5) reduces fecundity and egg hatch rate but not the number of pupae that developed from larvae. DFA had significantly higher effects on mosquito survival compared to MFA. The findings are presented and discussed through the prism of malaria elimination in the Amazon region.
RESUMEN
Data on chloroquine (CQ)-resistant Plasmodium vivax in Latin America is limited, even with the current research efforts to sustain an efficient malaria control program in all these countries where P. vivax is endemic and where malaria still is a major public health issue. This study estimated in vivo CQ resistance in patients with uncomplicated P. vivax malaria, with use of CQ and primaquine simultaneously, in the Brazilian Amazon. Of a total of 135 enrolled subjects who accomplished the 28-day follow-up, parasitological failure was observed in 7 (5.2%) patients, in whom plasma CQ and desethylchloroquine (DCQ) concentrations were above 100 ng/dl. Univariate analysis showed that previous exposure to malaria and a higher initial mean parasitemia were associated with resistance but not with age or gender. In the multivariate analysis, only high initial parasitemia remained significant. Hemoglobin levels were similar at the beginning of the follow-up and were not associated with parasitemia. However, at day 3 and day 7, hemoglobin levels were significantly lower in patients presenting CQ resistance. The P. vivax dhfr (pvdhfr), pvmrp1, pvmdr1, and pvdhps gene mutations were not related to resistance in this small sample. P. vivax CQ resistance is already a problem in the Brazilian Amazon, which could be to some extent associated with the simultaneous report of anemia triggered by this parasite, a common complication of the disease in most of the areas of endemicity.