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Cutaneous wounds, both acute and chronic, begin with loss of the integrity, and thus barrier function, of the skin. Surgery and trauma produce acute wounds. There are 22 million surgical procedures per year in the United States alone, based on data from the American College of Surgeons, resulting in a prevalence of 6.67%. Acute traumatic wounds requiring repair total 8 million per year, 2.42% or 24.2 per 1000. The cost of wound care is increasing; it approached USD 100 billion for just Medicare in 2018. This burden for wound care will continue to rise with population aging, the increase in metabolic syndrome, and more elective surgeries. To heal a wound, an orchestrated, evolutionarily conserved, and complex series of events involving cellular and molecular agents at the local and systemic levels are necessary. The principal factors of this important function include elements from the neurological, cardiovascular, immune, nutritional, and endocrine systems. The objectives of this review are to provide clinicians engaged in wound care and basic science researchers interested in wound healing with an updated synopsis from recent publications. We also present data from our primary investigations, testing the hypothesis that cannabidiol can alter cutaneous wound healing and documenting their effects in wild type (C57/BL6) and db/db mice (Type 2 Diabetes Mellitus, T2DM). The focus is on the potential roles of the endocannabinoid system, cannabidiol, and the important immune-regulatory wound cytokine IL-33, a member of the IL-1 family, and connective tissue growth factor, CTGF, due to their roles in both normal and abnormal wound healing. We found an initial delay in the rate of wound closure in B6 mice with CBD, but this difference disappeared with time. CBD decreased IL-33 + cells in B6 by 70% while nearly increasing CTGF + cells in db/db mice by two folds from 18.6% to 38.8% (p < 0.05) using a dorsal wound model. We review the current literature on normal and abnormal wound healing, and document effects of CBD in B6 and db/db dorsal cutaneous wounds. CBD may have some beneficial effects in diabetic wounds. We applied 6-mm circular punch to create standard size full-thickness dorsal wounds in B6 and db/db mice. The experimental group received CBD while the control group got only vehicle. The outcome measures were rate of wound closure, wound cells expressing IL-33 and CTGF, and ILC profiles. In B6, the initial rate of wound closure was slower but there was no delay in the time to final closure, and cells expressing IL-33 was significantly reduced. CTGF + cells were higher in db/bd wounds treated with CBD. These data support the potential use of CBD to improve diabetic cutaneous wound healing.
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Cannabidiol , Piel , Cicatrización de Heridas , Cicatrización de Heridas/efectos de los fármacos , Animales , Cannabidiol/farmacología , Cannabidiol/uso terapéutico , Humanos , Piel/metabolismo , Piel/efectos de los fármacos , Ratones , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológicoRESUMEN
Glioblastoma (GBM) is the most common form of malignant primary brain tumor with a high mortality rate. The aim of the present study was to investigate the clinical significance of Family with Sequence Similarity 3, Member C, FAM3C, in GBM using bioinformatic-integrated analysis. First, we performed the transcriptomic integration analysis to assess the expression profile of FAM3C in GBM using several data sets (RNA-sequencing and scRNA-sequencing), which were obtained from TCGA and GEO databases. By using the STRING platform, we investigated FAM3C-coregulated genes to construct the protein-protein interaction network. Next, Metascape, Enrichr, and CIBERSORT databases were used. We found FAM3C high expression in GBM with poor survival rates. Further, we observed, via FAM3C coexpression network analysis, that FAM3C plays key roles in several hallmarks of cancer. Surprisingly, we also highlighted five FAM3Ccoregulated genes overexpressed in GBM. Specifically, we demonstrated the association between the high expression of FAM3C and the abundance of the different immune cells, which may markedly worsen GBM prognosis. For the first time, our findings suggest that FAM3C not only can be a new emerging biomarker with promising therapeutic values to GBM patients but also gave a new insight into a potential resource for future GBM studies.
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Biomarcadores de Tumor , Neoplasias Encefálicas , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Glioblastoma , Humanos , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/mortalidad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Mapas de Interacción de Proteínas , Pronóstico , Transcriptoma , Redes Reguladoras de Genes , Biología Computacional/métodos , Tasa de Supervivencia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/biosíntesis , CitocinasRESUMEN
Hair is a biofilament with unique multi-dimensional values. In human, in addition to physiologic impacts, hair loss and hair related disorders can affect characteristic features, emotions, and social behaviors. Despite significant advancement, there is a dire need to explore alternative novel therapies with higher efficacy, less side effects and lower cost to promote hair growth to treat hair deficiency. Glucocorticoid-induced leucine zipper (GILZ) is a protein rapidly induced by glucocorticoids. Studies from our group and many others have suggested that a synthetic form of GILZ, TAT-GILZ, a fusion peptide of trans-activator of transcription and GILZ, can function as a potent regulator of inflammatory responses, re-establishing and maintaining the homeostasis. In this study, we investigate whether TAT-GILZ could promote and contribute to hair growth. For our pre-clinical model, we used 9-12 week-old male BALB/c and nude (athymic, nu/J) mice. We applied TAT-GILZ and/or TAT (vehicle) intradermally to depilated/hairless mice. Direct observation, histological examination, and Immunofluorescence imaging were used to assess the effects and compare different treatments. In addition, we tested two current treatment for hair loss/growth, finasteride and minoxidil, for optimal evaluation of TAT-GILZ in a comparative fashion. Our results showed, for the first time, that synthetic TAT-GILZ peptide accelerated hair growth on depilated dorsal skin of BALB/c and induced hair on the skin of athymic mice where hair growth was not expected. In addition, TAT-GILZ was able to enhance hair follicle stem cells and re-established the homeostasis by increasing counter inflammatory signals including higher regulatory T cells and glucocorticoid receptors. In conclusion, our novel findings suggest that reprofiling synthetic TAT-GILZ peptide could promote hair growth by increasing hair follicle stem cells and re-establishing homeostasis.
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Alopecia , Folículo Piloso , Cabello , Factores de Transcripción , Animales , Masculino , Ratones , Cabello/crecimiento & desarrollo , Cabello/efectos de los fármacos , Folículo Piloso/efectos de los fármacos , Folículo Piloso/crecimiento & desarrollo , Humanos , Alopecia/tratamiento farmacológico , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Ratones Endogámicos BALB C , Proteínas Recombinantes de Fusión/farmacología , Proteínas Recombinantes de Fusión/administración & dosificación , Ratones Desnudos , Ratones Pelados , Modelos Animales de Enfermedad , Glucocorticoides/farmacologíaRESUMEN
Glioblastoma (GBM) is an extremely aggressive primary brain tumor with poor prognosis, short survival time post-diagnosis and high recurrence. Currently, no cure for GBM exists. The identification of an effective therapeutic modality for GBM remains a high priority amongst medical professionals and researches. In recent studies, inhalant cannabidiol (CBD) has demonstrated promise in effectively inhibiting GBM tumor growth. However, exactly how CBD treatment affects the physiology of these tumor cells remains unclear. Stress granules (SG) (a sub-class of biomolecular condensates (BMC)) are dynamic, membrane-less intracellular microstructures which contain proteins and nucleic acids. The formation and signaling of SGs and BMCs plays a significant role in regulating malignancies. This study investigates whether inhaled CBD may play an intervening role towards SGs in GBM tumor cells. Integrated bioinformatics approaches were preformed to gain further insights. This includes use of Immunohistochemistry and flow cytometry to measure SGs, as well as expression and phosphorylation of eukaryotic initiation factor-2α (eIF2α). The findings of this study reveal that CBD receptors (and co-regulated genes) have the potential to play an important biological role in the formation of BMCs within GBM. In this experiment, CBD treatment significantly increased the volume of TIAR-1. This increase directly correlated with elevation in both eIF2α expression and p-eIF2α in CBD treated tissues in comparison to the placebo group (p < 0.05). These results suggest that inhalant CBD significantly up-regulated SGs in GBM, and thus support a theory of targeting BMCs as a potential therapeutic substrate for treating GBM.
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Neoplasias Encefálicas , Cannabidiol , Glioblastoma , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patología , Cannabidiol/farmacología , Humanos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Gránulos de Estrés/metabolismo , Gránulos de Estrés/efectos de los fármacos , Línea Celular Tumoral , Factor 2 Eucariótico de Iniciación/metabolismoRESUMEN
The SET gene has four transcripts reported in NCBI, coding two isoforms of SET proteins. The most known function of SET protein is inhibiting protein phosphatase 2A, a tumor suppressor, which has been associated with different biological processes. In this review, our focus was on exploring the other SET functions related to epigenetic mechanisms, which impact cellular migration, cell cycle and apoptosis.
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Apoptosis , Epigénesis Genética , Humanos , Procesamiento Proteico-Postraduccional , Isoformas de ProteínasRESUMEN
Groups (Grp) 3 and 4 are aggressive molecular subgroups of medulloblastoma (MB), with high rates of leptomeningeal dissemination. To date, there is still a paucity of biomarkers for these subtypes of MBs. In this study, we investigated the clinical significance and biological functions of Musashi-1 (MSI1) in Grp3 and Grp4-MBs. First, we assessed the expression profile of MSI1 in 59 primary MB samples (15-WNT, 18-SHH, 9-Grp3, and 17-Grp4 subgroups) by qRT-PCR. MSI1 mRNA expression levels were also validated in an additional public dataset of MBs (GSE85217). The ROC curve was used to validate the diagnostic standards of MSI1 expression. Next, the potential correlated cell-cycle genes were measured by RNA-Seq. Cell cycle, cell viability, and apoptosis were evaluated in a Grp3/Grp4 MB cell line after knockdown of MSI1 and cisplatin treatment. We identified an overexpression of MSI1 with a high accuracy to discriminate Grp3/Grp4-MBs from non-Grp3/Grp4-MBs. We identified that MSI1 knockdown not only triggered transcriptional changes in the cell-cycle pathway, but also affected G2/M phase in vitro, supporting the role of knockdown of MSI1 in cell-cycle arrest. Finally, MSI1 knockdown decreased cell viability and sensitized D283-Med cells to cisplatin treatment by enhancing cell apoptosis. Based on these findings, we suggest that MSI1 modulates cell-cycle progression and may play a role as biomarker for Grp3/Grp4-MBs. In addition, MSI1 knockdown combined with cisplatin may offer a potential strategy to be further explored in Grp3/Grp4-MBs.
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Members of the HDAC family are predictive biomarkers and regulate the tumorigenesis in several cancers. However, the role of these genes in the biology of intracranial ependymomas (EPNs) remains unexplored. Here, an analysis of eighteen HDACs genes in an EPN transcriptomic dataset, revealed significantly higher levels of HDAC4 in supratentorial ZFTA fusion (ST-ZFTA) compared with ST-YAP1 fusion and posterior fossa EPNs, while HDAC7 and SIRT2 were downregulated in ST-ZFTA. HDAC4 was also overexpressed in ST-ZFTA as measured by single-cell RNA-Seq, quantitative real time-polymerase chain reaction, and immunohistochemistry. Survival analyses showed a significantly worse outcome for EPNs with higher HDAC4 and SIRT1 mRNA levels. Ontology enrichment analysis showed an HDAC4-high signature consistent with viral processes while collagen-containing extracellular matrix and cell-cell junction were enriched in those with an HDAC4-low signature. Immune gene analysis demonstrated a correlation between HDAC4 expression and low levels of NK resting cells. Several small molecules compounds targeting HDAC4 and ABCG2, were predicted by in silico analysis to be effective against HDAC4-high ZFTA. Our results provide novel insights into the biology of the HDAC family in intracranial ependymomas and reveal HDAC4 as a prognostic marker and potential therapeutic target in ST-ZFTA.
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Neoplasias Encefálicas , Ependimoma , Humanos , Pronóstico , Factores de Transcripción/genética , Ependimoma/genética , Ependimoma/metabolismo , Neoplasias Encefálicas/genética , Perfilación de la Expresión Génica , Histona Desacetilasas/genética , Proteínas Represoras/genéticaRESUMEN
Medulloblastoma is the most common type of pediatric malignant primary brain tumor, and about one-third of patients die due to disease recurrence and most survivors suffer from long-term side effects. MB is clinically, genetically, and epigenetically heterogeneous and subdivided into at least four molecular subgroups: WNT, SHH, Group 3, and Group 4. We evaluated common differentially expressed genes between a Brazilian RNA-seq GSE181293 dataset and microarray GSE85217 dataset cohort of pediatric MB samples using bioinformatics methodology in order to identify hub genes of the molecular subgroups based on PPI network construction, survival and functional analysis. The main finding was the identification of five hub genes from the WNT subgroup that are tumor suppressors, and whose lower expression is related to a worse prognosis for MB patients. Furthermore, the common genes correlated with the five tumor suppressors participate in important pathways and processes for tumor initiation and progression, as well as development and differentiation, and some of them control cell stemness and pluripotency. These genes have not yet been studied within the context of MB, representing new important elements for investigation in the search for therapeutic targets, prognostic markers or for understanding of MB biology.
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Neoplasias Encefálicas , Neoplasias Cerebelosas , Meduloblastoma , Humanos , Niño , Meduloblastoma/genética , Meduloblastoma/metabolismo , Meduloblastoma/patología , Pronóstico , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/metabolismo , Neoplasias Cerebelosas/patología , Perfilación de la Expresión Génica , Biomarcadores de Tumor/genéticaRESUMEN
The Group 3 Medulloblastoma (Grp3-MB) is an aggressive molecular subtype with a high incidence of metastasis and deaths. In this study, were used an RNA sequencing data (RNA-Seq) from a Brazilian cohort of MBs to identify hub genes associated with the metastatic risk. Data validation were performed by using multiple large datasets from MBs (GSE85217, GSE37418, and EGAS00001001953). DESeq2 package in R software was used to identify the differentially expressed genes (DEGs) in our RNA-Seq data. The DEGs data were accessed to construct the modules/graphs of co-expression and to identify hub genes through Cytoscape platform. The coregulated genes were enriched by the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and the protein-protein interaction (PPI) network was visualized by Cytoscape. The Kaplan-Meier plotter and ROC curves were used to validate the diagnostic and prognostic values of specific biomarkers identified through this model. We identified that inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) as a downregulated hub gene, with a high diagnostic accuracy to Grp3-MBs and associated with tumor metastasis. In addition, we identified genes significantly correlated with ITPR1 that were associated with metastasis in Grp3-MB (ATP1A2, MTTL7A, and RGL1) and worst overall survival in MBs (ANTXR1 and RGL1). Our findings suggest that the ITPR1 hub gene is potentially involved in the metastatic process for Grp3-MB. Our data also provide evidence of targets that may serve as prognostic predictors and/or regulators for the metastatic process that maybe explored for further research of individualized therapy to Grp3-MBs.
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Neoplasias Cerebelosas , Meduloblastoma , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Cerebelosas/genética , Biología Computacional , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Inositol , Receptores de Inositol 1,4,5-Trifosfato/genética , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Meduloblastoma/genética , Proteínas de Microfilamentos/metabolismo , Pronóstico , Receptores de Superficie Celular/genéticaRESUMEN
Advances in genomics have led to the identification of twelve relevant molecular subtypes within medulloblastoma (MB). The alpha subtype of Sonic hedgehog-driven MB is resistant to therapy (including smoothened inhibitors) due to activation of genes from the non-canonical SHH pathway, such as MYCN, YAP1, or TP53. Using retrospective cohort microarray data, we found that YAP1 is overexpressed in SHH alpha MB and patients profiled as resistant to SMO inhibitors compared to good responders. Here, we performed YAP1 depletion via CRISPR/Cas9 in two in vitro models of SHH-like MB cells and found that this protein is involved in responsiveness to the SMO inhibitor regarding proliferation, apoptosis, and colony formation. Further, considering the synergic combination of YAP1 depletion with SMO inhibition, we assessed single-cell RNA-seq data from five patients and found that SMO and YAP1 are enriched within cells of SHH MB. Importantly, our data suggest that YAP1 is not only a reliable biomarker for cellular response to SMOi but may indicate prospective testing of combination therapy using YAP1 and SMO inhibitors in preclinical models of SHH MB.
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Adrenocortical carcinoma (ACC) is a rare, but highly aggressive cancer of the adrenal cortex with a generally poor prognosis. Despite being rare, completely resected ACCs present a high risk of recurrence. Musashi-2 (MSI2) has recently been recognized as a potential prognostic biomarker and therapeutic target in many cancers. However, no studies have evaluated the clinical significance of MSI2 expression in ACC. Here, we addressed MSI2 expression and its association with ACC prognosis and clinicopathological parameters. MSI2 expression was analyzed in TCGA, GSE12368, GSE33371, and GSE49278 ACC datasets; and its correlation with other genes and immune cell infiltration were investigated by using the R2: Genomics Analysis and Visualization Platform and TIMER databases, respectively. Enrichment analysis was performed with the DAVID Functional Annotation Tool. Kaplan-Meier curves, log-rank tests, and Cox regression analyses were used to explore the prognostic role of MSI2 in ACC. Our findings demonstrated the potential value of MSI2 overexpression as an independent predictor of poor prognosis in patients with completely resected ACC (hazard ratio 6.715, 95% confidence interval 1.266 - 35.620, p =.025). In addition, MSI2 overexpression was associated with characteristics of unfavorable prognosis, such as cortisol excess (p = .002), recurrence (p =.003), and death (p =.015); positively correlated with genes related to steroid biosynthesis (p < .05); and negatively correlated with immune-related pathways (p < .05). Our findings demonstrate that MSI2 has value as a prognostic marker for completely resected ACC and reinforce the investigation of its role as a possible therapeutic target for patients with ACC.
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Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , Biomarcadores de Tumor/inmunología , Regulación Neoplásica de la Expresión Génica/inmunología , Proteínas de Neoplasias/inmunología , Proteínas de Unión al ARN/inmunología , Neoplasias de la Corteza Suprarrenal/inmunología , Neoplasias de la Corteza Suprarrenal/mortalidad , Carcinoma Corticosuprarrenal/inmunología , Carcinoma Corticosuprarrenal/mortalidad , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esteroides/inmunologíaRESUMEN
ABSTRACT Aberrant expression of long non-coding RNAs (lncRNAs) has been detected in several types of cancer, including acute lymphoblastic leukemia (ALL), but lncRNA mapped on transcribed ultraconserved regions (T-UCRs) are little explored. The T-UCRs uc.112, uc.122, uc.160 and uc.262 were evaluated by quantitative real-time PCR in bone marrow samples from children with T-ALL (n = 32) and common-ALL/pre-B ALL (n = 30). In pediatric ALL, higher expression levels of uc.112 were found in patients with T-ALL, compared to patients with B-ALL. T-cells did not differ significantly from B-cells regarding uc.112 expression in non-tumor precursors from public data. Additionally, among B-ALL patients, uc.112 was also found to be increased in patients with hyperdiploidy, compared to other karyotype results. The uc.122, uc.160, and uc.262 were not associated with biological or clinical features. These findings suggest a potential role of uc.112 in pediatric ALL and emphasize the need for further investigation of T-UCR in pediatric ALL.
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Humanos , Femenino , Diploidia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Médula Ósea , Reacción en Cadena de la PolimerasaRESUMEN
Aberrant expression of long non-coding RNAs (lncRNAs) has been detected in several types of cancer, including acute lymphoblastic leukemia (ALL), but lncRNA mapped on transcribed ultraconserved regions (T-UCRs) are little explored. The T-UCRs uc.112, uc.122, uc.160 and uc.262 were evaluated by quantitative real-time PCR in bone marrow samples from children with T-ALL (n=32) and common-ALL/pre-B ALL (n=30). In pediatric ALL, higher expression levels of uc.112 were found in patients with T-ALL, compared to patients with B-ALL. T-cells did not differ significantly from B-cells regarding uc.112 expression in non-tumor precursors from public data. Additionally, among B-ALL patients, uc.112 was also found to be increased in patients with hyperdiploidy, compared to other karyotype results. The uc.122, uc.160, and uc.262 were not associated with biological or clinical features. These findings suggest a potential role of uc.112 in pediatric ALL and emphasize the need for further investigation of T-UCR in pediatric ALL.
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Cancer targeted therapy, either alone or in combination with conventional chemotherapy, could allow the survival of patients with neoplasms currently considered incurable. In recent years, the dysregulation of the Rho-associated coiled-coil kinases (ROCK1 and ROCK2) has been associated with increased metastasis and poorer patient survival in several tumor types, and due to their essential roles in regulating the cytoskeleton, have gained popularity and progressively been researched as targets for the development of novel anti-cancer drugs. Nevertheless, in a pediatric scenario, the influence of both isoforms on prognosis remains a controversial issue. In this review, we summarize the functions of ROCKs, compile their roles in human cancer and their value as prognostic factors in both, adult and pediatric cancer. Moreover, we provide the up-to-date advances on their pharmacological inhibition in pre-clinical models and clinical trials. Alternatively, we highlight and discuss detrimental effects of ROCK inhibition provoked not only by the action on off-targets, but most importantly, by pro-survival effects on cancer stem cells, dormant cells, and circulating tumor cells, along with cell-context or microenvironment-dependent contradictory responses. Together these drawbacks represent a risk for cancer cell dissemination and metastasis after anti-ROCK intervention, a caveat that should concern scientists and clinicians.
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Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinasas Asociadas a rho/antagonistas & inhibidores , Animales , Antineoplásicos/efectos adversos , Humanos , Terapia Molecular Dirigida , Metástasis de la Neoplasia , Neoplasias/enzimología , Neoplasias/mortalidad , Neoplasias/patología , Inhibidores de Proteínas Quinasas/efectos adversos , Transducción de Señal , Resultado del Tratamiento , Quinasas Asociadas a rho/metabolismoRESUMEN
TP53 p.R337H germline mutation is highly prevalent in the Southern region of Brazil. We sought to investigate TP53 p.R337H mutation in pediatric tumor samples from a population settled in a geographic area of high prevalence for this variant. Mutation assessment and genetic counseling for carriers/relatives were provided. 6/57 tumor samples were heterozygous for TP53 p.R337H. As expected, a high frequency was observed within adrenocortical tumors (3/3) and choroid plexus carcinomas (2/2). Interestingly, the TP53 R337H mutation was found in one case of pediatric rhabdomyosarcoma with Li-Fraumeni pedigree. Our finding expands the spectrum of childhood cancer associated with this germline mutation.
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Mutación de Línea Germinal , Neoplasias/genética , Proteína p53 Supresora de Tumor/genética , Neoplasias de la Corteza Suprarrenal/epidemiología , Neoplasias de la Corteza Suprarrenal/genética , Brasil/epidemiología , Carcinoma/epidemiología , Carcinoma/genética , Preescolar , Neoplasias del Plexo Coroideo/epidemiología , Neoplasias del Plexo Coroideo/genética , Estudios de Cohortes , Femenino , Humanos , Masculino , Tasa de Mutación , Neoplasias/epidemiología , Mutación Puntual , Rabdomiosarcoma/epidemiología , Rabdomiosarcoma/genéticaRESUMEN
We evaluated the potential effects of ATO in different pediatric SHH-MB cell lines (ONS-76: TP53-wild type; DAOY and UW402: TP53-mutated). MB cell lines molecular subgroup was confirmed and TP53 mutations were validated. Cell viability, clonogenicity and apoptosis were evaluated after ATO treatment at different concentrations (1-16 µM) alone or combined with irradiation doses (0.5, 1, 2 and 4 Gy). Rad51 and Ku86 proteins were evaluated by WB. ATO treatment reduced cell viability for all SHH-MB cell lines. Significant decrease of clonogenic capacity and higher apoptosis rates were also observed after ATO exposure, being cell death more pronounced (>70%) for the SHH-MB TP53-mutated. Combined treatment of ATO with irradiation also reduced colonies formation in UW402 tumor cells, which was independent of DNA damage repair proteins Rad51 and Ku86. In silico analyses suggested that a set of genes from cell cycle and p53 pathways are differentially expressed in SHH tumor subtypes, suggesting that cell lines may respond to therapies according to the gene expression profiles. Herein, we showed ATO cytotoxicity in pediatric SHH cell lines, with marked radiosensitizing effect for the MB-SHH TP53-mutated cells. These results highlight the potential of ATO, alone or in combination with radiotherapy, supporting further clinical investigations.
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Apoptosis/efectos de los fármacos , Trióxido de Arsénico/farmacología , Meduloblastoma/tratamiento farmacológico , Fármacos Sensibilizantes a Radiaciones/farmacología , Línea Celular Tumoral , Niño , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Meduloblastoma/metabolismo , Meduloblastoma/patología , Proteínas de Neoplasias/metabolismoRESUMEN
Musashi comprises an evolutionarily conserved family of RNA-binding proteins (RBP) that regulate cell fate decisions during embryonic development and play key roles in the maintenance of self-renewal and differentiation of stem cells and adult tissues. More recently, several studies have shown that any dysregulation of MSI1 and MSI2 can lead to cellular dysfunctions promoting tissue instability and tumorigenesis. Moreover, several reports have characterized many molecular interactions between members of the Musashi family with ligands and receptors of the signaling pathways responsible for controlling normal embryonic development: Notch, Transforming Growth Factor Beta (TGF-ß), Wingless (Wnt) and Hedgehog Signaling (Hh); all of which, when altered, are strongly associated with cancer onset and progression, especially in pediatric tumors. In this context, the present review aims to compile possible cross-talks between Musashi proteins and members of the above cited molecular pathways for which dysregulation plays important roles during carcinogenesis and may be modulated by these RBP.
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Regulación de la Expresión Génica , Proteínas del Tejido Nervioso/fisiología , Proteínas de Unión al ARN/fisiología , Transducción de Señal , Animales , Carcinogénesis , Diferenciación Celular , Desarrollo Embrionario , HumanosRESUMEN
Abdominal tumors (AT) in children account for approximately 17% of all pediatric solid tumor cases, and frequently exhibit embryonal histological features that differentiate them from adult cancers. Current molecular approaches have greatly improved the understanding of the distinctive pathology of each tumor type and enabled the characterization of novel tumor biomarkers. As seen in abdominal adult tumors, microRNAs (miRNAs) have been increasingly implicated in either the initiation or progression of childhood cancer. Moreover, besides predicting patient prognosis, they represent valuable diagnostic tools that may also assist the surveillance of tumor behavior and treatment response, as well as the identification of the primary metastatic sites. Thus, the present study was undertaken to compile up-to-date information regarding the role of dysregulated miRNAs in the most common histological variants of AT, including neuroblastoma, nephroblastoma, hepatoblastoma, hepatocarcinoma, and adrenal tumors. Additionally, the clinical implications of dysregulated miRNAs as potential diagnostic tools or indicators of prognosis were evaluated.
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Neoplasias Abdominales/genética , MicroARNs/genética , Neoplasias Abdominales/metabolismo , Animales , Niño , Humanos , MicroARNs/biosíntesisRESUMEN
Oral squamous cell carcinoma (OSCC) is the most frequent oral malignant neoplasia. As consequence of OSCC treatment, oral mucositis (OM) is one of the most common adverse effects of OSCC treatment. Currently, there is no consensus for OM treatment. The purpose of the current study was to test the combination of red and infrared low-level laser therapy (LLLT) for OM treatment. Primary culture of human fibroblast was performed to identify LLLT dose. After laboratory tests, a two-arm parallel, single-blind, controlled study was conducted. The two arms were group 1, both 660- and 808-nm wavelengths (300 J/cm2, 9 J of total energy, 100 mW, spot size 3 mm2), and group 2, only 660-nm wavelength (300 J/cm2, 9 J of total energy, 100 mW, spot size 3 mm2). Both treatments were performed twice a week. Group 1 presented a reduction of mucositis grade in comparison to group 2. Group 1 also presented reduction of analgesics prescription. But no significant differences between groups 1 and 2 were observed according to the pain scale. In conclusion, the current study demonstrated that a combination of red and infrared at a higher dose (300 J/cm2) reduced both oral mucositis grade and analgesics prescription. The effects of the combination of RT and LLLT are unclear and need more studies.
Asunto(s)
Analgésicos/uso terapéutico , Terapia por Luz de Baja Intensidad , Dolor/radioterapia , Estomatitis/tratamiento farmacológico , Estomatitis/radioterapia , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Fibroblastos/patología , Fibroblastos/efectos de la radiación , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Método Simple CiegoRESUMEN
BACKGROUND: Sleeve gastrectomy (SG) has been used as a multipurpose surgical procedure for the treatment of obesity. OBJECTIVES: The present study aimed to assess the effects of SG on the metabolic and inflammatory profile and renin-angiotensin system (RAS) expression in the white adipose tissue of male rats with obesity induced by a high-fat diet. METHODS: Male Wistar rats were treated with a standard diet or high-fat diet and submitted to SG or sham surgery. The glycemic and lipid profiles and gene expression of inflammatory markers and RAS components in adipose tissue were evaluated. RESULTS: SG led to weight loss, decreased adiposity (p < 0.01) and a reduction in plasma glucose (p < 0.05), C-peptide (p < 0.05), insulin (p < 0.001) and total cholesterol (p < 0.05) levels. In addition, SG led to a decrease in the expression of tumor necrosis factor-alpha (TNF-α) (p < 0.01), interleukin- 6 (IL-6) (p < 0.001), angiotensinogen (AGT) (p < 0.001) and angiotensin converting enzyme (ACE) (p < 0.05) and increased the expression of angiotensin converting enzyme 2 (ACE2) (p < 0.05) in white adipose tissue. No statistically significant differences were observed for AT1 (p = 0.10) and Mas (p = 0.22) receptors. CONCLUSION: This study showed that SG leads to weight loss and improves metabolic parameters. Changes in the expression of RAS components and of inflammatory molecules in adipose tissue seem to play a role the before beneficial effects of the SG.