RESUMO
MYC deregulation is common in human cancer and has a role in sustaining the aggressive cancer stem cell populations. MYC mediates a broad transcriptional response controlling normal biological programmes, but its activity is not clearly understood. We address MYC function in cancer stem cells through the inducible expression of Omomyc-a MYC-derived polypeptide interfering with MYC activity-taking as model the most lethal brain tumour, glioblastoma. Omomyc bridles the key cancer stemlike cell features and affects the tumour microenvironment, inhibiting angiogenesis. This occurs because Omomyc interferes with proper MYC localization and itself associates with the genome, with a preference for sites occupied by MYC This is accompanied by selective repression of master transcription factors for glioblastoma stemlike cell identity such as OLIG2, POU3F2, SOX2, upregulation of effectors of tumour suppression and differentiation such as ID4, MIAT, PTEN, and modulation of the expression of microRNAs that target molecules implicated in glioblastoma growth and invasion such as EGFR and ZEB1. Data support a novel view of MYC as a network stabilizer that strengthens the regulatory nodes of gene expression networks controlling cell phenotype and highlight Omomyc as model molecule for targeting cancer stem cells.
Assuntos
Regulação Neoplásica da Expressão Gênica , Genes myc , Glioblastoma/genética , Células-Tronco Neoplásicas/fisiologia , Fragmentos de Peptídeos/genética , Proteínas Proto-Oncogênicas c-myc/genética , Fatores de Transcrição/genética , Inibidores da Angiogênese , Apoptose , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diferenciação Celular , Proliferação de Células , Receptores ErbB/genética , Glioblastoma/fisiopatologia , Humanos , Proteínas Inibidoras de Diferenciação/genética , MicroRNAs/genética , Proteínas do Tecido Nervoso/genética , Fator de Transcrição 2 de Oligodendrócitos , Ligação Proteica , Ativação Transcricional , Microambiente Tumoral/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genéticaRESUMO
The dysfunction of the primary cilium, a complex, evolutionarily conserved, organelle playing an important role in sensing and transducing cell signals, is the unifying pathogenetic mechanism of a growing number of diseases collectively termed "ciliopathies", typically characterized by multiorgan involvement. Developmental defects of the central nervous system (CNS) characterize a subset of ciliopathies showing clinical and genetic overlap, such as Joubert syndrome (JS) and Meckel syndrome (MS). Although several knock-out mice lacking a variety of ciliary proteins have shown the importance of primary cilia in the development of the brain and CNS-derived structures, developmental in vitro studies, extremely useful to unravel the role of primary cilia along the course of neural differentiation, are still missing. Mouse embryonic stem cells (mESCs) have been recently proven to mimic brain development, giving the unique opportunity to dissect the CNS differentiation process along its sequential steps. In the present study we show that mESCs express the ciliary proteins Meckelin and Jouberin in a developmentally-regulated manner, and that these proteins co-localize with acetylated tubulin labeled cilia located at the outer embryonic layer. Further, mESCs differentiating along the neuronal lineage activate the cilia-dependent sonic hedgehog signaling machinery, which is impaired in Meckelin knock-out cells but results unaffected in Jouberin-deficient mESCs. However, both lose the ability to acquire a neuronal phenotype. Altogether, these results demonstrate a pivotal role of Meckelin and Jouberin during embryonic neural specification and indicate mESCs as a suitable tool to investigate the developmental impact of ciliary proteins dysfunction.
Assuntos
Células-Tronco Embrionárias/citologia , Proteínas de Membrana/metabolismo , Células-Tronco Neurais/citologia , Neurogênese , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Adaptadoras de Transporte Vesicular , Animais , Linhagem da Célula , Células Cultivadas , Cílios/metabolismo , Células-Tronco Embrionárias/efeitos dos fármacos , Células-Tronco Embrionárias/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Proteínas de Membrana/genética , Camundongos , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Fenótipo , Proteínas Proto-Oncogênicas/genética , Tretinoína/farmacologia , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismoRESUMO
OBJECTIVES: Despite the wide diffusion of minimally invasive approaches, such as laparoscopic (LRP) and robot-assisted radical prostatectomy (RALP), few studies compare the results of these techniques with the retropubic radical prostatectomy (RRP) approach. The aim of this study is to compare the surgical, functional, and oncological outcomes and cost-effectiveness of RRP, LRP, and RALP. METHODS: A systematic review of the literature was performed in the PubMed and Embase databases in December 2013. A 'free-text' protocol using the term 'radical prostatectomy' was applied. A total of 16,085 records were found. The authors reviewed the records to identify comparative studies to include in the review. RESULTS: 44 comparative studies were identified. With regard to the perioperative outcome, LRP and RALP were more time-consuming than RRP, but blood loss, transfusion rates, catheterisation time, hospitalisation duration, and complication rates were the most optimal in the laparoscopic approaches. With regard to the functional and oncological results, RALP was found to have the best outcomes. CONCLUSION: Our study confirmed the well-known perioperative advantage of minimally invasive techniques; however, available data were not sufficient to prove the superiority of any surgical approach in terms of functional and oncologic outcomes. On the contrary, cost comparison clearly supports RRP.
Assuntos
Laparoscopia/métodos , Prostatectomia/métodos , Neoplasias da Próstata/cirurgia , Procedimentos Cirúrgicos Robóticos/métodos , Análise Custo-Benefício , Custos de Cuidados de Saúde , Humanos , Laparoscopia/efeitos adversos , Laparoscopia/economia , Laparoscopia/mortalidade , Masculino , Complicações Pós-Operatórias , Prostatectomia/efeitos adversos , Prostatectomia/economia , Prostatectomia/mortalidade , Neoplasias da Próstata/economia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Fatores de Risco , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Procedimentos Cirúrgicos Robóticos/economia , Procedimentos Cirúrgicos Robóticos/mortalidade , Resultado do TratamentoRESUMO
Acquired Hemophilia A (AHA) is a rare bleeding diathesis characterized by the development of autoantibodies against factor VIII (FVIII). About half of the cases are idiopathic and the other half are associated with autoimmune diseases, postpartum problems, infections, inflammatory bowel disease, drugs, lymphoproliferative disorders or solid tumors . AHA is associated with malignancies in 7-15% of cases. We report a case of AHA in a 65 year old patient with prostatic carcinoma, who underwent retropubic radical prostatectomy (RP).
RESUMO
Background: The T1 substaging of bladder cancer (BCa) potentially impacts disease progression. The objective of the study was to compare the prognostic accuracy of two substaging systems on the recurrence and progression of primary pathologic T1 (pT1) BCa and to test a nomogram based on pT1 substaging for predicting recurrence-free survival (RFS) and progression-free survival (PFS). Methods: The medical records of 204 patients affected by pT1 BCa were retrospectively reviewed. Substaging was defined according to the depth of lamina propria invasion in T1a-c and the extension of the lamina propria invasion to T1-microinvasive (T1m) or T1-extensive (T1e). Uni- and multivariable Cox regression models evaluated the independent variables correlated with recurrence and progression. The predictive accuracies of the two substaging systems were compared by Harrell's C index. Multivariate Cox regression models for the RFS and PFS were also depicted by a nomogram. Results: The 5-year RFS was 47.5% with a significant difference between T1c and T1a (p = 0.02) and between T1e and T1m (p < 0.001). The 5-year PFS was 75.9% with a significant difference between T1c and T1a (p = 0.011) and between T1e and T1m (p < 0.001). Model T1m-e showed a higher predictive power than T1a-c for predicting RFS and PFS. In the univariate and multivariate model subcategory T1e, the diameter, location, and number of tumors were confirmed as factors influencing recurrence and progression after adjusting for the other variables. The nomogram incorporating the T1m-e model showed a satisfactory agreement between model predictions at 5 years and actual observations. Conclusions: Substaging is significantly associated with RFS and PFS for patients affected by T1 BCa and should be included in innovative prognostic nomograms.
RESUMO
The COVID-19 outbreak, in a few weeks, overloaded Italian hospitals, and the majority of medical procedures were postponed. During the pandemic, with hospital reorganization, clinical and learning activities performed by residents suffered a forced remodulation. The objective of this study is to investigate how urology training in Italy has been affected during the COVID-19 era. In this multi-academic study, we compared residents' training during the highest outbreak level with their previous activity. Overall 387 (67.1%) of the 577 Italian Urology residents participated in a 72-h anonymous online survey with 36 items sent via email. The main outcomes were clinical/surgical activities, social distancing, distance learning, and telemedicine. Clinical and learning activity was significantly reduced for the overall group, and after categorizing residents as those working only in COVID hospitals, both "junior" and "senior" residents, and those working in any of three geographical areas created (Italian regions were clustered in three major zones according to the prevalence of COVID-19). A significant decrease in outpatient activity, invasive diagnostic procedures, and endoscopic and major surgeries was reported. Through multivariate analysis, the specific year of residency has been found to be an independent predictor for all response modification. Being in zone 3 and zone 2 and having "senior" resident status were independent predictors associated with a lower reduction of the clinical and learning activity. Working in a COVID hospital and having "senior" resident status were independent predictors associated with higher reduction of the outpatient activity. Working in zone 3 and having "senior" resident status were independent predictors of lower and higher outpatient surgical activity, respectively. Working in a COVID hospital was an independent predictor associated with robotic surgical activity. The majority of residents reported that distance teaching and multidisciplinary virtual meetings are still not used, and 44.8% reported that their relationships with colleagues decreased. The COVID-19 pandemic presents an unprecedented challenge, including changes in the training and education of urology residents. The COVID era can offer an opportunity to balance and implement innovative solutions that can bridge the educational gap and can be part of future urology training.
RESUMO
Electromotive drug administration (EMDA) increases the local drug efficacy by controlling and enhancing transmembranous transport into tissue. EMDA of intravesical mitomycin-C (MMC) has been used for treatment of non-muscle invasive bladder cancer (NMIBC) for about a decade on the basis of laboratory studies that demonstrated an enhanced administration rate of MMC into all bladder wall layers after EMDA compared to standard instillation/passive diffusion (PD). Higher MMC concentrations might have a clinical impact since EMDA was associated with lower recurrence rates than PD in randomized studies. Further data suggest that EMDA/MMC is at least equivalent to BCG in treatment of high-risk bladder tumours. In addition, BCG combined with EMDA/MMC as well as preoperative EMDA/MMC are new therapeutic strategies with promising preliminary results in terms of higher remission rates and longer remission times. In summary, these findings suggest that EMDA for MMC delivery in the bladder could be a major therapeutic breakthrough in the treatment of NMIBC.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Eletroquimioterapia , Mitomicina/administração & dosagem , Neoplasias da Bexiga Urinária/tratamento farmacológico , Administração Intravesical , Humanos , Invasividade Neoplásica , Neoplasias da Bexiga Urinária/patologiaRESUMO
CONTEXT: - Patients with non-small cell lung cancer harboring ALK receptor tyrosine kinase ( ALK), ROS proto-oncogene 1 ( ROS1), and ret proto-oncogene ( RET) gene rearrangements can benefit from specific kinase inhibitors. Detection of fusion genes is critical for determining the best treatment. Assessing rearrangements in non-small cell lung cancer remains challenging, particularly for lung cytology. OBJECTIVE: - To examine the possible application of the multiplex, transcript-based NanoString system (NanoString Technologies, Seattle, Washington) in the evaluation of fusion genes in lung adenocarcinoma samples. DATA SOURCES: - This study is a narrative literature review. Studies about NanoString, gene fusions, and lung adenocarcinoma were collected from PubMed (National Center for Biotechnology Information, Bethesda, Maryland). We found 7 articles about the application of the NanoString system to detect fusion genes on formalin-fixed, paraffin-embedded tumor tissues and one article evaluating the adequacy of lung cytologic specimens for NanoString gene expression analysis. CONCLUSIONS: - To maximize the yield of molecular tests on small lung biopsies, the NanoString nCounter system has been suggested to detect fusion genes. NanoString fusion gene assays have been successfully applied on formalin-fixed, paraffin-embedded tissues. Although there are only a few studies available, the application of NanoString assays may also be feasible in lung cytology. According to available data, the NanoString system could strengthen the routine molecular characterization of lung adenocarcinoma.
Assuntos
Adenocarcinoma de Pulmão/genética , Biomarcadores Tumorais/análise , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Nanotecnologia/métodos , Fusão Oncogênica , Proteínas de Fusão Oncogênica/análise , Biomarcadores Tumorais/genética , Humanos , Proto-Oncogene MasRESUMO
The c-MYC oncoprotein is a DNA binding transcription factor that enhances the expression of many active genes. c-MYC transcriptional signatures vary according to the transcriptional program defined in each cell type during differentiation. Little is known on the involvement of c-MYC in regulation of gene expression programs that are induced by extracellular cues such as a changing microenvironment. Here we demonstrate that inhibition of c-MYC in glioblastoma multiforme cells blunts hypoxia-dependent glycolytic reprogramming and mitochondria fragmentation in hypoxia. This happens because c-MYC inhibition alters the cell transcriptional response to hypoxia and finely tunes the expression of a subset of Hypoxia Inducible Factor 1-regulated genes. We also show that genes whose expression in hypoxia is affected by c-MYC inhibition are able to distinguish the Proneural subtype of glioblastoma multiforme, thus potentially providing a molecular signature for this class of tumors that are the least tractable among glioblastomas.
Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Metabolismo Energético/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Fragmentos de Peptídeos/farmacologia , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/farmacologia , Hipóxia Tumoral , Microambiente Tumoral , Sítios de Ligação , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Glicólise/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Transcrição Gênica/efeitos dos fármacosRESUMO
BACKGROUND: Fine-needle aspiration cytology (FNAC) has been widely accepted as the most crucial step in the preoperative assessment of thyroid nodules. Testing for the expression of specific genes should improve the accuracy of FNAC diagnosis, especially when it is performed in samples with indeterminate cytology. METHODS: In total, 69 consecutive FNACs that had both cytologic and histologic diagnoses were collected, and expression levels of 34 genes were determined in RNA extracted from FNAC cells by using a custom digital mRNA counting assay. A supervised k-nearest neighbor (K-nn) learning approach was used to build a 2-class prediction model based on a subset of 27 benign and 26 malignant FNAC samples. Then, the K-nn models were used to classify the 16 indeterminate FNAC samples. RESULTS: Malignant and benign thyroid nodules had different gene expression profiles. The K-nn approach was able to correctly classify 10 FNAC samples as benign, whereas only 1 sample was grouped in the malignant class. Two malignant FNAC samples were incorrectly classified as benign, and 3 of 16 samples were unclassified. CONCLUSIONS: Although the current data will require further confirmation in a larger number of cases, the preliminary results indicate that testing for specific gene expression appears to be useful for distinguishing between benign and malignant lesions. The results from this study indicate that, in indeterminate FNAC samples, testing for cancer-specific gene expression signatures, together with mutational analyses, could improve diagnostic accuracy for patients with thyroid nodules.
Assuntos
Perfilação da Expressão Gênica , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/genética , Nódulo da Glândula Tireoide/patologia , Adulto , Biópsia por Agulha , Estudos de Coortes , Citodiagnóstico/métodos , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/análise , Neoplasias da Glândula Tireoide/cirurgia , Nódulo da Glândula Tireoide/cirurgia , Tireoidectomia/métodosRESUMO
The c-Myc protein is dysregulated in many human cancers and its function has not been fully elucitated yet. The c-Myc inhibitor Omomyc displays potent anticancer properties in animal models. It perturbs the c-Myc protein network, impairs c-Myc binding to the E-boxes, retaining transrepressive properties and inducing histone deacetylation. Here we have employed Omomyc to further analyse c-Myc activity at the epigenetic level. We show that both Myc and Omomyc stimulate histone H4 symmetric dimethylation of arginine (R) 3 (H4R3me2s), in human glioblastoma and HEK293T cells. Consistently, both associated with protein Arginine Methyltransferase 5 (PRMT5)--the catalyst of the reaction--and its co-factor Methylosome Protein 50 (MEP50). Confocal experiments showed that Omomyc co-localized with c-Myc, PRMT5 and H4R3me2s-enriched chromatin domains. Finally, interfering with PRMT5 activity impaired target gene activation by Myc whereas it restrained Omomyc-dependent repression. The identification of a histone-modifying complex associated with Omomyc represents the first demonstration of an active role of this miniprotein in modifying chromatin structure and adds new information regarding its action on c-Myc targets. More importantly, the observation that c-Myc may recruit PRMT5-MEP50, inducing H4R3 symmetric di-methylation, suggests previously unpredictable roles for c-Myc in gene expression regulation and new potential targets for therapy.
Assuntos
Histonas/metabolismo , Fragmentos de Peptídeos/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Arginina/metabolismo , Western Blotting , Linhagem Celular Tumoral , Cromatina/genética , Cromatina/metabolismo , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Células HEK293 , Humanos , Metilação , Microscopia Confocal , Fragmentos de Peptídeos/genética , Ligação Proteica , Proteína-Arginina N-Metiltransferases/genética , Proteínas Proto-Oncogênicas c-myc/genética , Interferência de RNARESUMO
Prostatic calculi occur very often in men, but exceptionally they cause an almost total destruction of the prostatic parenchyma. Preferred treatment in order to obtain complete resolution is either transurethral resection or suprapubic simple prostatectomy. We report for the first time a radical prostatectomy as a unique chance for huge prostatic stones in a 56-years old man with severe urinary symptoms. We perform a retropubic radical prostatectomy using a nerve sparing technique. There were no intraoperative or postoperative complications. Though radical prostatectomy is an invasive approach to treat a young man affected by prostatic stones and without prostate cancer, we chose to perform it because of the impossibility to obtain complete recovery with transurethral or suprapubic simple prostatectomy.
Assuntos
Cálculos/cirurgia , Prostatectomia , Doenças Prostáticas/cirurgia , Cálculos/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prostatectomia/métodos , Doenças Prostáticas/patologiaRESUMO
The neurotrophins Ngf, Bdnf, NT-3, NT4-5 have key roles in development, survival, and plasticity of neuronal cells. Their action involves broad gene expression changes at the level of transcription and translation. MicroRNAs (miRs)-small RNA molecules that control gene expression post-transcriptionally-are increasingly implicated in regulating development and plasticity of neural cells. Using PC12 cells as a model system, we show that Ngf modulates changes in expression of a variety of microRNAs, including miRs known to be modulated by neurotrophins-such as the miR-212/132 cluster-and several others, such as miR-21, miR-29c, miR-30c, miR-93, miR-103, miR-207, miR-691, and miR-709. Pathway analysis indicates that Ngf-modulated miRs may regulate many protein components of signaling pathways involved in neuronal development and disease. In particular, we show that miR-21 enhances neurotrophin signaling and controls neuronal differentiation induced by Ngf. Notably, in a situation mimicking neurodegeneration-differentiated neurons deprived of Ngf-this microRNA is able to preserve the neurite network and to support viability of the neurons. These findings uncover a broad role of microRNAs in regulating neurotrophin signaling and suggest that aberrant expression of one or more Ngf-modulated miRs may be involved in neurodegenerative diseases.
Assuntos
MicroRNAs/fisiologia , Fator de Crescimento Neural/fisiologia , Neurônios/patologia , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , MicroRNAs/biossíntese , MicroRNAs/genética , Neuritos/ultraestrutura , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Neurogênese/fisiologia , Neurônios/metabolismo , Células PC12 , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/genética , Transdução de Sinais/fisiologiaRESUMO
The transcription factor ID2 is an important repressor of neural differentiation strongly implicated in nervous system cancers. MicroRNAs (miRNAs) are increasingly involved in differentiation control and cancer development. Here we show that two miRNAs upregulated on differentiation of neuroblastoma cells--miR-9 and miR-103--restrain ID2 expression by directly targeting the coding sequence and 3' untranslated region of the ID2 encoding messenger RNA, respectively. Notably, the two miRNAs show an inverse correlation with ID2 during neuroblastoma cell differentiation induced by retinoic acid. Overexpression of miR-9 and miR-103 in neuroblastoma cells reduces proliferation and promotes differentiation, as it was shown to occur upon ID2 inhibition. Conversely, an ID2 mutant that cannot be targeted by either miRNA prevents retinoic acid-induced differentiation more efficient than wild-type ID2. These findings reveal a new regulatory module involving two microRNAs upregulated during neural differentiation that directly target expression of the key differentiation inhibitor ID2, suggesting that its alteration may be involved in neural cancer development.
Assuntos
Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteína 2 Inibidora de Diferenciação/biossíntese , MicroRNAs/biossíntese , Proteínas de Neoplasias/biossíntese , Neuroblastoma/metabolismo , RNA Neoplásico/biossíntese , Tretinoína/farmacologia , Animais , Bovinos , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Proteína 2 Inibidora de Diferenciação/genética , Macaca mulatta , Camundongos , MicroRNAs/genética , Proteínas de Neoplasias/genética , Neuroblastoma/genética , Neuroblastoma/patologia , RNA Neoplásico/genética , Ratos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
Although the c-Myc oncogene is frequently deregulated in human cancer, its involvement in the pathogenesis of glioblastoma is not clear. We conducted immunohistochemical analysis of the expression of c-Myc, polycomb ring finger oncogene (BMI1), and acetylation of the lysine 9 (H3K9Ac) of histone 3 in 48 patients with glioblastoma who underwent surgery followed by radiotherapy and temozolomide treatment. The expression of c-Myc, BMI1, and H3K9ac was correlated with clinical characteristics and outcome. We found that overexpression of c-Myc was significantly associated with that of BMI1 (P = .009), and that patients who harbored glioblastomas overexpressing c-Myc and BMI1 showed significantly longer overall survival (P < .0001 and P = .0009, respectively). Our results provide the first evidence of the prognostic value of c-Myc and associated genes in patients with glioblastoma. The favorable effect of c-Myc and BMI1 expression on survival is likely mediated by the sensitization of cancer cells to radiotherapy and temozolomide through the activation of apoptotic pathways.
Assuntos
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/radioterapia , Terapia Combinada , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/mortalidade , Glioblastoma/radioterapia , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Complexo Repressor Polycomb 1 , Prognóstico , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Repressoras/genética , Taxa de Sobrevida , Temozolomida , Resultado do TratamentoRESUMO
Recent evidence points to Myc--a multifaceted bHLHZip transcription factor deregulated in the majority of human cancers--as a priority target for therapy. How to target Myc is less clear, given its involvement in a variety of key functions in healthy cells. Here we report on the action mechanism of the Myc interfering molecule termed Omomyc, which demonstrated astounding therapeutic efficacy in transgenic mouse cancer models in vivo. Omomyc action is different from the one that can be obtained by gene knockout or RNA interference, approaches designed to block all functions of a gene product. This molecule--instead--appears to cause an edge-specific perturbation that destroys some protein interactions of the Myc node and keeps others intact, with the result of reshaping the Myc transcriptome. Omomyc selectively targets Myc protein interactions: it binds c- and N-Myc, Max and Miz-1, but does not bind Mad or select HLH proteins. Specifically, it prevents Myc binding to promoter E-boxes and transactivation of target genes while retaining Miz-1 dependent binding to promoters and transrepression. This is accompanied by broad epigenetic changes such as decreased acetylation and increased methylation at H3 lysine 9. In the presence of Omomyc, the Myc interactome is channeled to repression and its activity appears to switch from a pro-oncogenic to a tumor suppressive one. Given the extraordinary therapeutic impact of Omomyc in animal models, these data suggest that successfully targeting Myc for cancer therapy might require a similar twofold action, in order to prevent Myc/Max binding to E-boxes and, at the same time, keep repressing genes that would be repressed by Myc.
Assuntos
Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Fragmentos de Peptídeos/farmacologia , Fragmentos de Peptídeos/uso terapêutico , Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Animais , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Regulação para Baixo/genética , Epigênese Genética , Fibroblastos/metabolismo , Humanos , Espaço Intracelular/metabolismo , Camundongos , Neoplasias/patologia , Regiões Promotoras Genéticas/genética , Ligação Proteica , Transporte Proteico , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/farmacologia , Proteínas Proto-Oncogênicas c-myc/uso terapêutico , Ratos , Proteínas Repressoras/metabolismo , Soro , Transcrição Gênica , Ativação Transcricional/genética , Regulação para Cima/genéticaRESUMO
Hemangiomas are slowly growing benign vascular tumours which rarely involve the kidney. They usually occur in the mucosa or subepithelial tissue of the pelvis, in the pyramid of the kidney and in the cortex. We report a case of cavernous hemangioma presenting as a solid, paradoxically avascular mass of the right renal hilum.