Role of NRF2 in Lung Cancer Sánchez-Ortega, Miriam; Carrera, Ana Clara; Garrido, Antonio
Cells (Basel, Switzerland),
07/2021, Letnik:
10, Številka:
8
Journal Article
Recenzirano
Odprti dostop
The gene expression program induced by NRF2 transcription factor plays a critical role in cell defense responses against a broad variety of cellular stresses, most importantly oxidative stress. NRF2 ...stability is fine-tuned regulated by KEAP1, which drives its degradation in the absence of oxidative stress. In the context of cancer, NRF2 cytoprotective functions were initially linked to anti-oncogenic properties. However, in the last few decades, growing evidence indicates that NRF2 acts as a tumor driver, inducing metastasis and resistance to chemotherapy. Constitutive activation of NRF2 has been found to be frequent in several tumors, including some lung cancer sub-types and it has been associated to the maintenance of a malignant cell phenotype. This apparently contradictory effect of the NRF2/KEAP1 signaling pathway in cancer (cell protection against cancer versus pro-tumoral properties) has generated a great controversy about its functions in this disease. In this review, we will describe the molecular mechanism regulating this signaling pathway in physiological conditions and summarize the most important findings related to the role of NRF2/KEAP1 in lung cancer. The focus will be placed on NRF2 activation mechanisms, the implication of those in lung cancer progression and current therapeutic strategies directed at blocking NRF2 action.
Osteosarcoma represents a rare cause of cancer in the general population, accounting for <1% of malignant neoplasms globally. Nonetheless, it represents the main cause of malignant bone neoplasm in ...children, adolescents and young adults under 20 years of age. It also presents another peak of incidence in people over 50 years of age and is associated with rheumatic diseases. Numerous environmental risk factors, such as bone diseases, genetics and a history of previous neoplasms, have been widely described in the literature, which allows monitoring a certain group of patients. Diagnosis requires numerous imaging tests that make it possible to stratify both the local involvement of the disease and its distant spread, which ominously determines the prognosis. Thanks to various clinical trials, the usefulness of different chemotherapy regimens, radiotherapy and surgical techniques with radical intent has now been demonstrated; these represent improvements in both prognosis and therapeutic approaches. Osteosarcoma patients should be evaluated in reference centres by multidisciplinary committees with extensive experience in proper management. Although numerous genetic and rheumatological diseases and risk factors have been described, the use of serological, genetic or other biomarkers has been limited in clinical practice compared to other neoplasms. This limits both the initial follow-up of these patients and screening in populations at risk. In addition, we cannot forget that the diagnosis is mainly based on the direct biopsy of the lesion and imaging tests, which illustrates the need to study new diagnostic alternatives. Therefore, the purpose of this study is to review the natural history of the disease and describe the main biomarkers, explaining their clinical uses, prognosis and limitations.
Global mechanisms defining the gene expression programs specific for hematopoiesis are still not fully understood. Here, we show that promoter DNA demethylation is associated with the activation of ...hematopoietic-specific genes. Using genome-wide promoter methylation arrays, we identified 694 hematopoietic-specific genes repressed by promoter DNA methylation in human embryonic stem cells and whose loss of methylation in hematopoietic can be associated with gene expression. The association between promoter methylation and gene expression was studied for many hematopoietic-specific genes including CD45, CD34, CD28, CD19, the T cell receptor (TCR), the MHC class II gene HLA-DR, perforin 1 and the phosphoinositide 3-kinase (PI3K) and results indicated that DNA demethylation was not always sufficient for gene activation. Promoter demethylation occurred either early during embryonic development or later on during hematopoietic differentiation. Analysis of the genome-wide promoter methylation status of induced pluripotent stem cells (iPSCs) generated from somatic CD34+ HSPCs and differentiated derivatives from CD34+ HSPCs confirmed the role of DNA methylation in regulating the expression of genes of the hemato-immune system, and indicated that promoter methylation of these genes may be associated to stemness. Together, these data suggest that promoter DNA demethylation might play a role in the tissue/cell-specific genome-wide gene regulation within the hematopoietic compartment.
The importance of counter electrodes in Dye Sensitized Solar Cells (DSSCs) cannot be neglected as they enable the transfer of electrons across the outer circuit, thereby facilitating the reduction ...reaction of the I3−/I− redox electrolyte. However, the dissolution and deposition of the usual platinum layer on the counter electrode has resulted in contamination concerns. To address this issue, metal-free counter electrodes made of reduced graphene oxide (rGO) aerogels were developed and their catalytic performance towards I3− reduction was evaluated. The reduced graphene materials were characterized, and the fitting analysis of XPS revealed the presence of various nitrogen species, with the primary peaks attributed to pyridinic and pyrrolic nitrogen. The hydrothermal treatment of graphene oxide (GO) resulted in a higher graphitic character and the intensification of the contacts between graphene nanosheets, which should entail higher electrical conductivity, both in-plane and between rGO sheets. Additionally, the presence of nitrogen-provided active sites promoted the catalytic reduction of the electrolyte. Encouragingly, good charge transfer rates were observed between the counter electrode and the electrolyte in the assembled DSSCs, resulting in good photocurrents and exceptional stability over the course of nearly 1200 h after cell assembly. The results obtained suggest that these GO-based systems are promising candidates for developing metal-free counter electrodes for DSSC, supporting the interest of further study.
Oncogenic mutations in the PI3K/AKT pathway are present in nearly half of human tumors. Nonetheless, inhibitory compounds of the pathway often induce pathway rebound and tumor resistance. We find ...that lung squamous cell carcinoma (SQCC), which accounts for ~20% of lung cancer, exhibits increased expression of the PI3K subunit PIK3R2, which is at low expression levels in normal tissues. We tested a new approach to interfere with PI3K/AKT pathway activation in lung SQCC. We generated tumor xenografts of SQCC cell lines and examined the consequences of targeting PIK3R2 expression. In tumors with high PIK3R2 expression, and independently of PIK3CA, KRAS, or PTEN mutations, PIK3R2 depletion induced lung SQCC xenograft regression without triggering PI3K/AKT pathway rebound. These results validate the use PIK3R2 interfering tools for the treatment of lung squamous cell carcinoma.
Object
To identify the perception of barriers to the comprehensive management of cleft lip and palate (CLP) by parents/caregivers of Colombian children with this condition.
Setting and Sample ...Population
Fifty parents/caregivers of children with CLP under 12 years attending a center specialized in the management of craniofacial congenital conditions in Bogota, Colombia.
Materials and Methods
This study consisted of 2 phases: a quantitative phase (descriptive cross-sectional) and a qualitative phase (focus group FG). Chi-square and Fisher exact tests were used to analyze the association variables. The barriers and alternative ways to overcome barriers were analyzed in the FG.
Results
Comprehensive management was mostly defined as access to multiple treatments (54%), and this concept was expanded in the FG toward understanding CLP at all levels. Monoparental families spend their income on treatments (29%) than nuclear families (0%) (P = .001). All parents with high education levels were familiar with healthcare centers specialized in CLP as opposed to 66.7% of parents with basic primary education (P < .05). Regarding the timeliness of appointments, 12.2% of parents earning between 1 and 2 minimum wages reported some kind of difficulty, whereas those earning less than one minimum wage reported difficulties in 66.7% of cases (P = .046).
Conclusions
All participants reported barriers, which increased or decreased depending on their socioeconomic status. The FG allowed the discussion of alternatives to overcome barriers, such as structural, solidarity, and self-management actions.
Introduction:
Craniofacial growth is a dynamic and unpredictable process influenced by genetic and environmental factors, presenting phenotypic and gender differences.
Objective:
Evaluate the ...differences in craniofacial growth and development in a group of Colombian individuals with complete unilateral and bilateral cleft lip and palate (CLP) and without CLP, classified by gender and age.
Setting and Sample Population:
Five hundred forty-one profile radiographs of 126 patients with unilateral CLP, 126 with bilateral CLP, and 289 without CLP. All patients of affected groups had a history of CLP correction surgery without nasoalveolar molding with orthopedic and orthodontic treatments.
Materials and Methods:
This cross-sectional study was performed comparing 8 cephalometric measurements on radiographs, 5 linear/3 angular. Analysis was performed by median and interquartile range for all cephalometric measurements. Comparison between the groups was performed using Kruskal-Wallis and Mann-Whitney U, with a 95% confidence.
Results:
Significant differences between the groups of patients with and without CLP, between types of clefts and genders. The skeletal structures of patients with CLP were smaller than those of control but improved with growth. Patients with unilateral CLP presented flat profiles and predominant class III malocclusions, while patients with bilateral CLP, at early ages, were class II and in the prepubertal stage, the values were progressively negative until the end of the growth period, suggesting class III. Patients with CLP presented posteroinferior rotation of the mandible, vertical measurements increased, and deflection of the cranial base.
Conclusion:
Given their growth alterations, patients with CLP benefit from orthopedic and orthodontic treatment.
Antecedentes: Diferentes estudios describen el tratamiento ortopedico en pacientes con labio y paladar fisurado o hendido (LPH) con diagnostico de maloclusion clase III; sin embargo, no existe una ...estandarizacion en la tecnica de tratamiento ortopedico en estos pacientes. Objetivo: Determinar la efectividad del tratamiento con mascara facial y un aparato fijo intraoral en pacientes con LPH y maloclusion clase III, que fundamente su implementacion dentro de una guia de manejo integral. Metodos: Se realizo una busqueda en multiples bases de datos electronicas y busqueda manual. Se encontraron 199 articulos a los que se aplicaron como criterios de inclusion: ensayos clinicos aleatorizados o abiertos, en ingles y espanol, pacientes con LPH, edades entre 5 y 12 anos, maloclusion clase III y/o mascara facial y/o protraccion maxilar, evaluados mediante radiografias de perfil, analisis cefalometricosy observacion clinica. Resultados: Se seleccionaron ocho articulos a los que se les hizo analisis de calidad. Los resultados indican que el tratamiento con mascara facial y aparato intraoral fue efectivo en los pacientes con labio y paladar hendido para lograr protraccion maxilar, entre los que la mascara facial con el aparato Hyrax mostro mejores resultados esqueleticos. Conclusion: La mascara facial, junto con el aparato intraoral Hyrax, entre los 8 y los 10 anos, con fuerzas de 450-500 g y una direccion de 10grados-30grados, bajo el plano oclusal utilizado por 12 horas/dia durante minimo 9,2 meses de tratamiento, mostro los mayores cambios esqueleticos en la zona maxilar y mandibular en pacientes con labiopaladar hendido y maloclusion clase III. PALABRAS CLAVE maloclusion clase III; labio y paladar hendido; anomalias craneofaciales; expansion maxilar; mascara facial; protraccion maxilar; Hyrax AREAS TEMATICAS diagnostico; tratamiento; anomalias craneofaciales; ortodoncia. Background: Several studies describe the orthopedic treatment of patients with cleft lip and palate, diagnosed with class III malocclusion; however, there is no standardization in the orthopedic treatment planning in these patients. Objective: To determine the effectiveness of treatment with facemask and a fixed intra-oral appliance for patients with cleft lip and palate and Class III malocclusion. Methods: A literature search conducted in several databases and print journals produced 199 articles. Inclusion criteria were: randomized clinical or open trials, English and Spanish language, patients with cleft lip and palate, 5-12 years of age, Class III malocclusion and/or facemask and/or maxillary protraction, assessment with lateral radiographs, cephalometric analysis, and clinical observation. Results: The sample consisted of eight articles that underwent quality analysis. Results indicate that treatment with facemask and intraoral appliance was effective in patients with cleft lip and palate to achieve maxillary protraction, of which a combination of facemask and Hyrax showed better skeletal results. Conclusion: Treatment with facemask with the intraoral appliance Hyrax, at 8-10 years of age, with 450-500 g forces and a 10degrees-30degrees inclination below the occlusal plane, used at least 12 hours/day for 9.2 months in patients with cleft lip and palate cleft and class III malocclusion, showed major skeletal changes in the maxilla and mandible. KEYWORDS malocclusion angle class III; cleft lip and palate; craniofacial anomalies; maxillary expansion; facemask; maxillary protraction; hyrax THEMATIC FIELDS diagnosis; treatment; craniofacial abnormalities; orthodontics
The orthopalladation of (Z)‐4‐arylidene‐5(4H)‐oxazolones (1a–1o), with electron‐withdrawing substituents (Cl, F, CF3) in the 4‐arylidene ring has been carried out by C–H bond activation. The process ...is regioselective and only the ortho C–H bond of the 4‐arylidene ring is activated. The orthopalladated complexes (2a–2o) have different structures (mono‐, di‐ and trinuclear), although the dinuclear open‐book scaffold, in which the C=C bonds of the arylidene group are in a face‐to‐face transoid arrangement, is prevalent. Irradiation of 2a–2n with blue light promotes the C–C coupling by 2+2‐photocycloaddition of the arylidene C=C bonds and the formation of the dinuclear cyclobutanes (3a–3n). The oxidation of cyclobutane 3d with PhICl2 or Br2 occurs with halogenation of the Pd–C bond and release of the ortho‐halogenated dispirocyclobutane, which can be converted into the ortho‐halo‐1,3‐diaminotruxillic derivatives (5d, 6d, 7d) by oxazolone ring opening in a basic medium.
The regio‐ and stereoselective synthesis of 1,3‐diaminotruxillic cyclobutanes has been achieved from 4‐arylidene‐5(4H)‐oxazolones in three steps: (i) Pd‐assisted C–H bond activation; (ii) Pd‐templated photochemical 2+2‐cycloaddition; (iii) oxidative addition of PhICl2 or Br2 followed by reductive‐elimination by C–X coupling.
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