RESUMEN
Breast cancer remains the leading cause of cancer deaths for women. Long-term estrogen exposure is considered carcinogenic due to semiquinone production and to compromised detoxification. Metabolic regulator polymorphisms, such as KEAP1 (rs1048290) and NRF2 (rs35652124, rs6721961, rs6706649), can be valuable in understanding the individual cytoprotection profile. Thus, we aim to genotype these polymorphisms in blood, tumours and surrounding tissue, to identify somatic mutations and correlate it to prognoses. A total of 23 controls and 69 women with histological confirmed breast cancer were recruited, and DNA from blood/surrounding/tumour tissue was genotyped. Genotyping and clinicopathological data were correlated. We verified that rs35652124 presents different genotype distribution between the blood/surrounding tissue (p-value = 0.023) and tumour/surrounding tissues (p-value = 0.041). Apart from rs35652124 and considering the histological grade, the other four polymorphisms have different distributions among different tissues. There is a tendency towards the loss of heterozygosity in the surrounding tissue when compared to blood and tumour tissues, and higher genotype variability in histologic grade 2. These somatic mutations and different distribution patterns may indicate a heterogeneous and active microenvironment, influencing breast cancer outcome. Additionally, it would be pertinent to evaluate the predictive value of the histologic grade 2 considering somatic mutation profiles and distributions.
RESUMEN
Human skin is the first line of photoprotection against UV radiation. However, despite having its defence mechanisms, the photoprotection that the skin exerts is not enough. To protect human skin, the inclusion of UV filters in the cosmetic industry has grown significantly as a photoprotection strategy. Octylmethoxycinnamate, also designated by octinoxate, or 2-ethylhexyl-4-methoxycinnamate (CAS number: 5466-77-3) is one of the most widely used UV-B filter in the cosmetic industry. The toxic effects of OMC have alarmed the public, but there is still no consensus in the scientific community about its use. This article aims to provide an overview of the UV filters' photoprotection, emphasizing the OMC and the possible negative effects it may have on the public health. Moreover, the current legislation will be addressed. In summary, the recommendations should be rethought to assess their risk-benefit, since the existing literature warns us to endocrine-disrupting effects of OMC. Further studies should be focus on the toxicity of OMC alone, in mixture and should consider its degradation products, to improve the knowledge of its risk assessment as EDC.
Asunto(s)
Cinamatos , Disruptores Endocrinos , Protectores Solares , Rayos Ultravioleta , Cinamatos/química , Cinamatos/toxicidad , Humanos , Protectores Solares/toxicidad , Disruptores Endocrinos/toxicidad , Medición de Riesgo , Piel/efectos de los fármacos , Piel/efectos de la radiación , Cosméticos/toxicidadRESUMEN
Humulus lupulus extracts have in their composition different molecules, such as polyphenols, α-acids, ß-acids, and hydrocarbons, which contribute to the plant's medicinal properties. These molecules are associated with antimicrobial, antioxidant and anti-inflammatory activities. OBJECTIVE: This work focuses on the evaluation of H. lupulus biological activities, with the aim of evaluating its potential for inclusion in cosmetic formulations. METHODS: Two distinct aqueous extracts and two hydrolates obtained via hydrodistillation were evaluated. These include the flower parts (FE, FH) and the mix of aboveground parts (ME, MH). The chemical profiles for both aqueous extracts and hydrolates were identified by high performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS). Antimicrobial, antioxidant, cytotoxicity, and anti-inflammatory activity were tested in vitro using standard methods. RESULTS: Rutin was the major compound found in FE (40.041 µg mg-1 of extract) and ME (2.909 µg mg-1 of extract), while humulenol II was the most abundant compound in hydrolates (FH: 20.83%; MH: 46.80%). Furthermore, FE was able to inhibit the growth of Staphylococcus aureus and Staphylococcus epidermis with MIC values of 50% and 25% (v/v), respectively. FH showed the same effect in Staphylococcus aureus (50% v/v). FH evidenced poor antioxidant potential in DPPH scavenging test and demonstrated significant antioxidant and anti-inflammatory effects by reducing (***p < 0.001) intracellular reactive oxygen species (ROS), NO (nitric oxide) levels (***p < 0.001) and cyclooxygenase-2 (COX-2) protein expression (***p < 0.001) in lipopolysaccharide (LPS)-stimulated macrophages. Nevertheless, it is important to note that FH exhibited cytotoxicity at high concentrations in 3T3 fibroblasts and RAW 264.7 macrophages. CONCLUSION: The studied H. lupulus aqueous extracts and hydrolates revealed that FH stands out as the most promising bioactive source for cosmetic formulations. However, future research addressing antimicrobial activity is necessary to confirm its potential incorporation into dermatological and cosmetic formulations.
Asunto(s)
Antiinflamatorios , Antioxidantes , Cosméticos , Humulus , Extractos Vegetales , Humulus/química , Extractos Vegetales/farmacología , Extractos Vegetales/química , Antioxidantes/farmacología , Antiinflamatorios/farmacología , Ratones , Animales , Células RAW 264.7 , Flores/química , Antiinfecciosos/farmacología , Antiinfecciosos/química , Fitoquímicos/farmacología , Fitoquímicos/aislamiento & purificación , Macrófagos/efectos de los fármacos , Pruebas de Sensibilidad MicrobianaRESUMEN
Given the increasing concern surrounding ultraviolet (UV) radiation-induced skin damage, there has been a rise in demand for UV filters. Currently, UV-filters are considered emerging contaminants. The extensive production and use of UV filters have led to their widespread release into the aquatic environment. Thus, there is growing concern that UV filters may bioaccumulate and exhibit persistent properties within the environment, raising several safety health concerns. Octyl-methoxycinnamate (OMC) is extensively employed as a UV-B filter in the cosmetic industry. While initially designed to mitigate the adverse photobiological effects attributed to UV radiation, the safety of OMC has been questioned with some studies reporting toxic effects on environment. The aim of this review to provide an overview of the scientific information regarding the most widely used organic UV-filter (OMC), and its effects on biodiversity and aquatic environment.
Asunto(s)
Cosméticos , Protectores Solares , Protectores Solares/toxicidad , Protectores Solares/efectos de la radiación , Cinamatos/toxicidad , Rayos Ultravioleta/efectos adversosRESUMEN
BACKGROUND: Clinical Pathways in Oncology can benefit patients using organized interventions to standardize and increase care efficiency. Healthcare systems should have tools to identify their oncological clinical pathways for a better institutional organization to reduce mortality rates and contain costs without compromising quality. Our objective is to determine the regional Oncology Clinical Pathway from a first basic hypothesis using questionnaires directed to healthcare professionals considered key deciders within the Pathway. METHODS: Study design consisted of data analysis of two structured region-wide questionnaires; built using available literature on Oncology Clinical Pathways, in a Portuguese Healthcare context and pre-tested in a focus group of key deciders (Physicians and nurses with management functions) from which a design was created. Queries analyzed the patients: tumor staging at service arrival; time intervals on tumor suspicion/diagnosis confirmation and diagnosis/first treatment; referral pathway; diagnostic networks and patient Follow-up. One questionnaire was sent to key deciders directly involved with Oncology patients at a Regional Hospital. 15 physicians and 18 nurses of this sample answered the questionnaire (approx. response rate = 67%). Another questionnaire sent to healthcare professionals in Primary Healthcare Centers yielded response rate 19.2%, N = 29 physicians and 46 nurses. Finally, we performed a descriptive analysis and a Cronbach Alpha reliability analysis. RESULTS: Our findings reveal: different appreciations of tumor staging at arrival in Primary Healthcare Centers and Regional Hospitals (the latter receiving more metastatic cases); approximately 4 weeks between tumor suspicion-diagnostic and divided opinions regarding diagnostic-treatment time intervals. Primary Healthcare Centers depend on private laboratories for diagnostics confirmation, while the Hospitals resolve this locally. Referral pathways indicate almost half of the patients being sent from primary healthcare centers to National Reference Hospitals instead of a Regional Hospital. Patient follow-up is developed throughout the institutions, however, is more established at Regional Hospitals. As patients advance through the Oncology Clinical Pathway and toward treatment stages the number of healthcare professionals involved reduce. CONCLUSION: Our questionnaires enable us to understand the real pathway between the different institutions involved and the main entry points of the patients into the Oncology Clinical Pathway.
Asunto(s)
Vías Clínicas , Neoplasias , Humanos , Reproducibilidad de los Resultados , Neoplasias/diagnóstico , Neoplasias/terapia , Oncología Médica , Personal de SaludRESUMEN
Oxidative stress has a fundamental role in the pathophysiology of various conditions, like infertility. This case-control study was performed to assess the potential role of CYP19A1, GSTM1, and GSTT1 in modifying individual predisposition to female infertility. Genotyping of 201 women with established infertility and 161 fertile female controls was performed, and statistical associations were analyzed. For carriers of GSTM1 null genotype along with CYP19A1 C allele, there is a significant association with female infertility risk (OR 7.023; 95% CI (3.627-13.601; p < 0.001), and, also for carriers of GSTT1 null genotype along with the CYP19A1 TC/CC genotype (OR 24.150; 95% CI (11.148-52.317; p < 0.001). A positive association with female infertility risk for carriers of the C allele in CYP19A1 and null genotypes in GTSM1 (OR 11.979; 95% CI (4.570-31.400; p < 0.001) or GSTT1 (OR 13.169; 95% CI (4.518-38.380; p < 0.001) was found. When both GSTs are deleted, the risk of developing female infertility is significant, independently of the CYP19A1 genotype; when all the presumed high-risk genotypes are present, we found a significant association with female infertility risk (OR 47,914; 95% CI (14,051-163,393; p < 0.001).
RESUMEN
Cell-free DNA fragments detected in blood and in other biological fluids are released from apoptotic/necrotic cells. In this study, we analyzed cfDNA levels in follicular fluid (FF) samples from patients with infertility. Samples were collected from 178 infertile women and cfDNA was extracted and quantified by qPCR, using ALU115 and ALU247 primers, and statistical correlations were performed. We found that cfDNA concentration was significantly higher in FF pools from women aged 35 and over than in women under 35 years of age (p = 0.017). We also found that q247 cfDNA levels were significantly higher in women with an associated female factor, such as endometriosis, PCOS and POF, compared with women with no specific cause of infertility (p = 0.033). The concentration of cfDNA did not vary significantly in each group of women with an associated female factor. The concentration of cfDNA was significantly higher in the FF of women that obtained embryos with a high fragmentation rate, compared to embryos with a low fragmentation rate (p = 0.007). Finally, we found that women who did not become pregnant during IVF treatments had higher q247 cfDNA levels (p = 0.043). The quantification of cfDNA could be an important biomarker of follicular micro-environment quality to predict embryo quality and the success of IVF, making them more specific and effective.
RESUMEN
Due to its high prevalence, infertility has become a prominent public health issue, posing a significant challenge to modern reproductive medicine. Some clinical conditions that lead to female infertility include polycystic ovary syndrome (PCOS), endometriosis, and premature ovarian failure (POF). Follicular fluid (FF) is the biological matrix that has the most contact with the oocyte and can, therefore, be used as a predictor of its quality. Volatilomics has emerged as a non-invasive, straightforward, affordable, and simple method for characterizing various diseases and determining the effectiveness of their current therapies. In order to find potential biomarkers of infertility, this study set out to determine the volatomic pattern of the follicular fluid from patients with PCOS, endometriosis, and POF. The chromatographic data integration was performed through solid-phase microextraction (SPME), followed by gas chromatography-mass spectrometry (GC-MS). The findings pointed to specific metabolite patterns as potential biomarkers for the studied diseases. These open the door for further research into the relevant metabolomic pathways to enhance infertility knowledge and diagnostic tools. An extended investigation may, however, produce a new mechanistic understanding of the pathophysiology of the diseases.
RESUMEN
The COVID-19 pandemic has changed the way cancer patients should be managed. Using published literature on best practices on oncology patient management, we developed checklists to establish which recommendations were followed and differences between healthcare staff and institutions in a local health unit (overseeing two regional hospitals and 14 primary Healthcare Centers) in an interior region in Portugal. Checklists were delivered and completed by 15 physicians, 18 nurses and 5 pharmacists working at the Hospitals, and 29 physicians and 46 nurses from primary healthcare centers. Hospital staff do not show statistically significant differences regarding most proposed recommendations for the oncology clinical pathway, human resources, treatments, patient management and service management. Primary healthcare centers seem to follow a similar trend. As a local health unit, general recommendations for Oncology Patient Management show statistically significantly different values on education of suspected cases, identification, isolation procedures and samples collection; extension of work schedules; and education on cancer patient and COVID-19 positive referral procedures. All the checklists indicated good-to-high internal consistency. Our analysis showed cohesive work between groups regarding control and prevention of sources of infection; therefore, it is considered the highest priority to ensure that all other services, including oncology, continue functioning. Patient management measures such as adjustments in treatments, analysis, patient care, referrals and emergencies were not ranked higher by responders.
Asunto(s)
COVID-19 , Neoplasias , COVID-19/epidemiología , Humanos , Oncología Médica , Neoplasias/epidemiología , Neoplasias/terapia , Pandemias , FarmacéuticosRESUMEN
Polycystic ovary syndrome (PCOS) represents one of the leading causes of anovulatory infertility and affects 5% to 20% of women worldwide. Until today, both the subsequent etiology and pathophysiology of PCOS remain unclear, and patients with PCOS that undergo assisted reproductive techniques (ART) might present a poor to exaggerated response, low oocyte quality, ovarian hyperstimulation syndrome, as well as changes in the follicular fluid metabolites pattern. These abnormalities originate a decrease of Metaphase II (MII) oocytes and decreased rates for fertilization, cleavage, implantation, blastocyst conversion, poor egg to follicle ratio, and increased miscarriages. Focus on obtaining high-quality embryos has been taken into more consideration over the years. Nowadays, the use of metabolomic analysis in the quantification of proteins and peptides in biological matrices might predict, with more accuracy, the success in assisted reproductive technology. In this article, we review the use of human follicular fluid as the matrix in metabolomic analysis for diagnostic and ART predictor of success for PCOS patients.
RESUMEN
Every day, people use personal care products containing UV filters. Although their use initially showed a protective role, toxicity is a concern for human health as several UV filters are endocrine-disrupting chemicals (EDCs). Exposure to EDCs may induce cardiovascular diseases and can affect the health of sensitive people, such as pregnant women. Currently, the world's most widely used UV-B filter is octylmethoxycinnamate (OMC), an EDC. However, the disruptive effects on pregnant women are little known. The present work proposed to understand how long-term exposure to OMC affects vascular homeostasis. Endothelium-denuded human umbilical artery (HUA) rings were incubated in an organ bath system. Long-term effects of exposure to OMC (0.001-50 µmol/L) were evaluated on the contractile responses of HUA to the application of the contractile agents, serotonin (5-HT) and histamine (Hist). To investigate in more detail the vascular mode of action of OMC, through which it impairs the vascular homeostasis of HUA, the activity and expression of different 5-HT and Hist-receptors involved in contractility processes were studied. Our findings pointed out an increase in the reactivity of HUA to 5-HT and Hist due to OMC exposure. These alterations in reactivity may be precursors of preeclampsia development and/or gestational hypertension.
RESUMEN
Personal care products (PCPs) are a group of diverse substances widely used daily for health, beauty, and cleanliness. More than 90% of all PCPs contain the UV-B filter octylmethoxycinnamate (OMC) as a protective function, however, their safety has recently been questioned. The purpose of the present work was to understand how the long-term exposure of UV-filter OMC, used daily by pregnant women, disrupts their vascular homeostasis, altering vascular responses of proteins and channels involved in contractile processes. The long-term effects of 24 h of exposure to OMC (1, 10, and 50 µmol/L) were evaluated on contractile responses of human umbilical arteries (HUA) to serotonin and potassium chloride. Since OMC altered vascular homeostasis of arteries, its vascular mode of action was explored in more detail through the analysis of the activity of cGMP and Ca2+-channels, two pathways involved in their relaxation and contraction, respectively. Our findings showed that long-term exposure of UV-filter OMC impaired the main vasorelaxant mechanism of HUA, once OMC altered the vasorelaxant response pattern of sodium nitroprusside and nifedipine. Results also showed that long-term exposure to OMC induced a decreased vasorelaxation response on HUA due to an interference with the NO/sGC/cGMP/PKG pathway. Moreover, OMC seems to modulate the L-type Ca2+ channels, the BKCa 1.1 α-subunit channels, and the PKG. Overall, since OMC compromises the vascular homeostasis of pregnant women it can be an inductor of pregnancy hypertensive disorders.
Asunto(s)
Arterias Umbilicales , Vasodilatadores , Cinamatos/toxicidad , Femenino , Humanos , Óxido Nítrico/farmacología , Embarazo , Vasodilatación , Vasodilatadores/toxicidadRESUMEN
Increasing evidence relating the exposure and/or bioaccumulation of endocrine-disrupting compounds (EDCs) with cardiovascular system are arising. Octylmethoxycinnamate (OMC) is the most widely used UV-B filter and as EDC interacts with TH receptors. However, their effects on thyroid diseases during pregnancy remain unknown. The purpose of this work was to assess the short- and long-term effects of OMC on arterial tonus of pregnant women with hypothyroidism. To elucidate this, human umbilical artery (HUA) rings without endothelium were used to explore the vascular effects of OMC by arterial and cellular experiments. The binding energy and the modes of interaction of the OMC into the active center of the TSHR and THRα were analyzed by molecular docking studies. Our results indicated that OMC altered the contractility patterns of HUA contracted with serotonin, histamine and KCl, possibly due to an interference with serotonin and histamine receptors or an involvement of the Ca2+ channels. The molecular docking analysis show that OMC compete with T3 for the binding center of THRα. Taken together, these findings pointed out to alterations in HUA reactivity as result of OMC-exposure, which may be involved in the development and increased risk of cardiovascular diseases.
RESUMEN
Estrogen metabolism plays an important role in tumor initiation and development. Lifetime exposure to high estrogens levels and deregulation of enzymes involved in estrogen biosynthetic and metabolic pathway are considered risk factors for breast cancer. The present study aimed to evaluate the impact of mutations acquisition during the lifetime in low penetrance genes that codify enzymes responsible for estrogen detoxification. Genotype analysis of GSTM1 and GSTT1 null polymorphisms, CYP1B1 Val432Leu and MTHFR C677T polymorphisms was performed in 157 samples of women with hormone-dependent breast cancer and correlated with the age at diagnosis. The majority of patients with GSTT1 null genotype and with both GSTM1 and GSTT1 null genotypes were 50 years old or more at the diagnosis (p-value = 0.021 and 0.018, respectively). Older women with GSTM1 null genotype were also carriers of the CYP1B1Val allele (p-value = 0.012). As well, GSTT1 null and CYP1B1Val genotypes were correlated with diagnosis at later ages (p-value = 0.022). Similar results were found associating MTHFR C677T and GSTT1 null polymorphism (p-value = 0.034). Our results suggest that estrogen metabolic pathway polymorphisms constitute a factor to be considered simultaneously with models for breast cancer risk assessment.
RESUMEN
Thermal therapy has gained popularity over the years, and Portugal is one of the richest European countries in mineral therapeutic waters. The interest in the use of these natural mineral waters (NMW) for dermatologic purposes is continuously growing but there is a lack of scientific studies supporting its health benefits. The study aims to investigate the effect of a silica-rich NMW in skin cell homeostasis using two representative cell lines of the epidermis and dermis, keratinocytes and fibroblasts, respectively, in addition to a macrophage cell line. Mouse skin fibroblasts, macrophages and human keratinocytes were exposed to culture medium prepared with NMW. Cell metabolism (MTT or resazurin assays) and cell proliferation (trypan blue exclusion dye assay) were investigated. Migration (scratch-wound assay) and senescence (ß-galactosidase activity assay) of fibroblasts were also studied. Exposure to NMW compromised the cell metabolic state of all the cell lines tested. This impairment was more pronounced in skin keratinocytes (60% reduction) relatively to skin fibroblasts (45% reduction) or macrophages (25% reduction). Proliferation of macrophages was reduced threefold upon exposure to thermal water, compared to controls. No differences were observed in migration between fibroblasts exposed to NMW and controls, while a potentiation of senescence of these cells was observed. Our results shed light in the bioactive effects of a silica-rich NMW supporting its therapeutic use. A reduction in both cell metabolism and proliferation of keratinocytes and macrophages supports the empirical clinical benefits of this NMW in hyperkeratotic conditions, such as psoriasis and atopic dermatitis.
Asunto(s)
Queratinocitos , Dióxido de Silicio , Animales , Proliferación Celular , Células Cultivadas , Europa (Continente) , Humanos , Ratones , Portugal , PielRESUMEN
RESEARCH QUESTION: Is GSTM1 and GSTT1 deletion associated with the development of polycystic ovary syndrome (PCOS)? DESIGN: A case-control study was designed to investigate the association between GSTM1 and GSTT1 gene polymorphisms with PCOS. Blood samples from 201 women diagnosed with infertility were taken, of which 69 women were diagnosed with PCOS. Genomic DNA was extracted, and genotyping analyses were conducted by polymerase chain reaction-based methods. Odds ratios and 95% confidence intervals were calculated by unconditional logistic regression. RESULTS: An increased risk of PCOS was found to be associated with GSTT1 null genotype (OR 4.890, 95% CI 2.261 to 9.122; P < 0.001). A strong association between GSTT1 null genotype was found with female infertility, regardless of the associated cause (OR 5.300, 95% CI 3.238 to 8.675; P < 0.001) as well as with the GSTM1 null genotype (OR 1.620, 95% CI 1.067 to 2.459; Pâ¯=â¯0.026). A statistically significant association with the development of infertility was also found when carriers of the combined genotype GSTT1+/GSTM1+ was compared with carriers of the combined genotype GSTT1-/ GSTM1+ (OR 3.600 95% CI 1.864 to 6.956; P < 0.001). The two-way combination of GSTT1 and GSTM1 null genotypes resulted in an increased susceptibility to infertility development (OR 11.136; 95% CI 5.035 to 24.629; P < 0.001). CONCLUSIONS: Carriers of GSTT1 null genotype seem to have higher susceptibility to developing PCOS and infertility from other causes. Also, GSTT1 null genotype, alone or in association, are related with increased susceptibility to infertility development, independently of its cause. GSTM1 null genotype is only associated with all cause of infertility when the GSTT1 is null.
Asunto(s)
Glutatión Transferasa/genética , Infertilidad Femenina/genética , Síndrome del Ovario Poliquístico/genética , Adulto , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Mutación , Polimorfismo de Nucleótido Simple , Adulto JovenRESUMEN
The common therapeutic indications of Portuguese Natural Mineral Waters (NMWs) are primarily for respiratory, rheumatic and musculoskeletal systems. However, these NMWs have been increasingly sought for dermatologic purposes. Opposing to what is observed in the major European Thermal Centres, there are few scientific evidences supporting the use of Portuguese NMWs for clinical applications. The aim of this study was to characterize the antimicrobial profile of individual NMWs from the central region of Portugal and correlate the results with their physicochemical characterization. An extensive multivariate analysis (principal component analysis) was also performed to further investigate this possible correlation. Six collection strains representing skin microbiota, namely Staphylococcus aureus, Escherichia coli, Corynebacterium amycolatum, Candida albicans, Staphylococcus epidermidis and Cutibacterium acnes, were analysed, and their antimicrobial profile was determined using Clinical and Laboratory Standards Institute M07-A10, M45-A2, M11-A6 and M27-A3 microdilution methods. Different NMWs presented different antimicrobial profiles against the strains used; the physicochemical composition of NMWs seemed to be correlated with the different susceptibility profiles. Cutibacterium acnes showed a particularly high susceptibility to all NMWs belonging sulphurous/bicarbonated/sodic ionic profile, exhibiting microbial reductions up to 65%. However, due to the complex physicochemical composition of each water an overall conclusion regarding the effect of a specific ion on the growth of different microorganisms is yet to be known.
Asunto(s)
Antiinfecciosos/farmacología , Aguas Minerales/análisis , Aguas Minerales/uso terapéutico , Piel/microbiología , Corynebacterium/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Microbiota , Portugal , Análisis de Componente Principal , Propionibacterium acnes/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Staphylococcus epidermidis/efectos de los fármacosRESUMEN
PURPOSE: Nuclear factor E2-related factor 2 (NRF2) is a transcription factor that plays a major role in the regulation of intracellular antioxidant response. The effect of NRF2 overexpression in many malignancies is still unclear and recent meta-analysis correlated NRF2 overexpression with poor prognosis in a variety of human cancers. However, the effect of NRF2 overexpression in breast cancer is still unclear. Thus, the main goal of this work was to clarify the role of NRF2 expression in survival and relapse of breast cancer patients by performing a systematic review according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) statement, followed by a meta-analysis. METHODS: The electronic search was conducted in PubMed, Scopus, SciELO, Web of Science and Embase between November of 2017 and September of 2018. To be included, studies should evaluate NRF2 expression in breast cancer tissue, through immunohistochemistry and/or mRNA and had to report one or more of the following outcomes: overall survival (OS), disease-free survival (DFS), mean survival and median survival. RESULTS: For the meta-analysis, seven studies were included and NRF2 expression was correlated with OS and DFS. It was observed that compared to patients with low NRF2 expression, patients with NRF2 overexpression had poorer OS with a hazard ratio of 1.82 (95% CI 1.32-2.50; p value < 0.0001), and poorer DFS, with a hazard ratio of 1.79 (95% CI 1.07-3.01; p value = 0.03). CONCLUSIONS: These results suggest that tumours that overexpress NRF2 have a worse clinical outcome. Thus, NRF2 expression could be a marker for the prognostic of breast cancer patients and, in the future, it would be pertinent to focus on improving treatment efficacy for patients with NRF2 overexpression.
Asunto(s)
Biomarcadores de Tumor , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Factor 2 Relacionado con NF-E2/metabolismo , Neoplasias de la Mama/genética , Femenino , Expresión Génica , Humanos , Inmunohistoquímica , Factor 2 Relacionado con NF-E2/genética , Pronóstico , Sesgo de PublicaciónRESUMEN
Preclinical safety assessment of vaginal products includes cytotoxicity assays upon cell lines. Furthermore, tissue explants have been considered for application on ex vivo models. In this study, traditional and renewed methods were studied for toxicity assessment of vaginal semisolids upon products currently used in clinical practice as antimicrobials (Gino-Canesten®, Sertopic®, Dermofix®, Gyno-Pevaryl®, Lomexin®, Gino Travogen®, Dalacin V®), containing estrogens (Ovestin®, Blissel®, Colpotrophine®), and reference formulations (Replens®, Universal Placebo). Two in vitro cytotoxicity tests were performed: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and neutral red uptake upon uterine (HEC-1A), cervical (HeLa) and vaginal (VK2 E6/E7) cells, according to ISO/EN 10993-5 (in vitro evaluation of medical devices). Similarly, a strategy to determine tissue viability on ex vivo porcine vaginal model (through MTT reduction assay and histological analysis) was developed and optimized. The vaginal cell line VK2 E6/E7 conducted to the most accurate calculation of half-maximal toxic concentration among all cells on the MTT assay. However, it was shown not be sensitive to the neutral red uptake assay. Tissues from the porcine model were collected with approx. 15% variability in thickness and variation coefficients lower than 25% when testing negative and positive controls were achieved. These models can improve cost-efficiency in early steps of product development.
Asunto(s)
Antiinfecciosos/administración & dosificación , Antiinfecciosos/química , Vagina/efectos de los fármacos , Administración Intravaginal , Animales , Bioensayo/métodos , Línea Celular Tumoral , Composición de Medicamentos/métodos , Femenino , Células HeLa , Humanos , PorcinosRESUMEN
Influence of Glutathione S-transferase Mu1 (GSTM1) has long been studied in breast cancer and GSTM1 null genotype was correlated with breast cancer risk. Nuclear factor-erythroid 2-related factor-2 (NRF2) is a transcription factor that forms a complex with Kelch-like ECH-associated protein-1 (KEAP1). Recent studies have demonstrated that expression of these proteins is deregulated in several malignancies. Thus, in the present study we aim to distinguish GSTM1 heterozygous from wild type genotype in breast cancer patients and evaluate the presence and clinical significance of NRF2 and KEAP1 polymorphisms, alone or in association, with breast cancer prognosis, in cases confirmed to have GSTM1-present genotype. Study population consisted in 52 patients with breast cancer. Genomic DNA was extracted, GSTM1 was genotyped through multiplex PCR and gene dose was evaluated through real-time PCR. All cases were sequenced, through Sanger sequencing, for specific regions of NRF2 and KEAP1. Genotyping and clinicopathological data were correlated and statistical analysis was performed. GSTM1 wild type was identified in 1 case and 26 cases were identified as heterozygous, these data were correlated with Human Epidermal growth factor Receptor 2 (HER2) status (p value = 0.017). We also verified that most cancers diagnosed at younger ages had the presence of KEAP1 and/or NRF2 polymorphisms. The association of GSTM1 heterozygous genotype with rs1048290 and rs35652124 seems to be associated with HER2+ (p < 0.05). Our results suggest that GSTM1 * 1/0 genotype and the cumulative presence of at least one allele mutated in KEAP1 and/or NRF2 polymorphisms might be associated with worse prognosis for breast cancer patients.