RESUMO
DNA glycosylases initiate the base excision repair (BER) pathway by catalyzing the removal of damaged or mismatched bases from DNA. The Arabidopsis DNA glycosylase methyl-CpG-binding domain protein 4 like (MBD4L) is a nuclear enzyme triggering BER in response to the genotoxic agents 5-fluorouracil and 5-bromouracil. To date, the involvement of MBD4L in plant physiological processes has not been analyzed. To address this, we studied the enzyme functions in seeds. We found that imbibition induced the MBD4L gene expression by generating two alternative transcripts, MBD4L.3 and MBD4L.4. Gene activation was stronger in aged than in non-aged seeds. Seeds from mbd4l-1 mutants displayed germination failures when maintained under control or ageing conditions, while 35S:MBD4L.3/mbd4l-1 and 35S:MBD4L.4/mbd4l-1 seeds reversed these phenotypes. Seed nuclear DNA repair, assessed by comet assays, was exacerbated in an MBD4L-dependent manner at 24 h post-imbibition. Under this condition, the BER genes ARP, APE1L, and LIG1 showed higher expression in 35S:MBD4L.3/mbd4l-1 and 35S:MBD4L.4/mbd4l-1 than in mbd4l-1 seeds, suggesting that these components could coordinate with MBD4L to repair damaged DNA bases in seeds. Interestingly, the ATM, ATR, BRCA1, RAD51, and WEE1 genes associated with the DNA damage response (DDR) pathway were activated in mbd4l-1, but not in 35S:MBD4L.3/mbd4l-1 or 35S:MBD4L.4/mbd4l-1 seeds. These results indicate that MBD4L is a key enzyme of a BER cascade that operates during seed imbibition, whose deficiency would cause genomic damage detected by DDR, generating a delay or reduction in germination.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , DNA Glicosilases , Reparo do DNA , Germinação , Sementes , Sementes/genética , Sementes/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , DNA Glicosilases/metabolismo , DNA Glicosilases/genética , Regulação da Expressão Gênica de Plantas , Dano ao DNARESUMO
La hemorragia digestiva determinada por una fístula entre manga gástrica y seudoaneurisma de arteria esplénica o polo superior de bazo es infrecuente. Se presenta un caso clínico de una paciente de 52 años con antecedentes de cirugía de manga gástrica y fuga anastomótica. Ingresó por hemorragia digestiva alta grave. Se operó de emergencia y realizó punto hemostático sobre cara posterior de manga gástrica. Se reintervino por resangrado realizándose la gastrectomía y esplenopancreatectomía distal por solución de continuidad de arteria esplénica. Dada la inestabilidad hemodinámica se efectuó un esofagostoma y yeyunostomía, reconstruyéndose a los 8 meses con buena evolución.
Gastrointestinal bleeding caused by a fistula between the gastric sleeve and a pseudoaneurysm of the splenic artery or upper pole of the spleen is uncommon. A clinical case of a 52-year-old patient with a history of gastric sleeve surgery and anastomotic leak is presented. She was admitted for severe upper gastrointestinal bleeding. She underwent emergency surgery and performed a hemostatic stitch on the posterior face of the gastric sleeve. She underwent reoperation due to rebleeding, performing gastrectomy and distal splenopancreatectomy due to discontinuation of the splenic artery. Given the hemodynamic instability, an esophagostomy and jejunostomy were performed, reconstructing at 8 months with good evolution.
O sangramento gastrointestinal causado por uma fístula entre a manga gástrica e um pseudoaneurisma da artéria esplênica ou pólo superior do baço é incomum. Apresenta-se o caso clínico de um paciente de 52 anos com história de cirurgia de manga gástrica e fístula anastomótica. Ele foi internado por hemorragia digestiva alta grave. Uma operação de emergência foi realizada e um ponto hemostático foi realizado na face posterior da manga gástrica. Foi reoperado por ressangramento, realizando gastrectomia e esplenopancreatectomia distal por descontinuação da artéria esplênica. Dada a instabilidade hemodinâmica, foi realizada esofagostomia e jejunostomia, reconstruindo aos 8 meses com boa evolução.
Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Artéria Esplênica/patologia , Fístula Gástrica/complicações , Cirurgia Bariátrica/efeitos adversos , Gastrectomia , Hemorragia Gastrointestinal/cirurgia , Complicações Pós-Operatórias , Doença Catastrófica , Emergências , Hemorragia Gastrointestinal/etiologiaRESUMO
The association between some bacterial infections and colon cancer is well documented. The most described is Streptococcus bovis infection. Another bacteria related to intestinal neoplasms is Clostridium septicum. We present the case of a 62-year-old man who consulted for abdominal pain associated with diarrhea and fever. A computed tomography scan of the abdomen and pelvis was performed, which revealed thickening of the cecum walls with an apparent break in continuity at its free edge. An exploratory laparotomy was performed which confirmed the presence of peritonitis and cecal perforation. A right hemicolectomy and terminal ileostomy were performed. The histopathological study revealed the presence of signet ring cell type adenocarcinoma associated with ischemia. The blood cultures results demonstrated the presence of C. septicum. The patient died due to fulminant sepsis.
Assuntos
Infecções por Clostridium , Clostridium septicum , Neoplasias do Colo , Perfuração Intestinal , Sepse , Infecções por Clostridium/complicações , Neoplasias do Colo/complicações , Neoplasias do Colo/cirurgia , Humanos , Perfuração Intestinal/diagnóstico por imagem , Masculino , Pessoa de Meia-IdadeRESUMO
Meningioma (MN) is an important cause of disability, and predictive tools for estimating the risk of recurrence are still scarce. The need for objective and cost-effective techniques addressed to this purpose is well known. In this study, we present methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) as a friendly method for deepening the understanding of the mechanisms underlying meningioma progression. A large follow-up allowed us to obtain 50 samples, which included the primary tumor of 20 patients in which half of them are suffering one recurrence and the other half are suffering more than one. We histologically characterized the samples and performed MS-MLPA assays validated by FISH to assess their copy number alterations (CNA) and epigenetic status. Interestingly, we determined the increase in tumor instability with higher values of CNA during the progression accompanied by an increase in epigenetic damage. We also found a loss of HIC1 and the hypermethylation of CDKN2B and PTEN as independent prognostic markers. Comparison between grade 1 and higher primary MN's self-evolution pointed to a central role of GSTP1 in the first stages of the disease. Finally, a high rate of alterations in genes that are related to apoptosis and autophagy, such as DAPK1, PARK2, BCL2, FHIT, or VHL, underlines an important influence on cell-death programs through different pathways.
RESUMO
Desmoplastic infantile astrocytoma (DIA) is rare, cystic and solid tumor of infants usually found in superficial cerebral hemispheres. Although DIA is usually benign, uncommon cases bearing malignant histological and aggressive clinical features have been described in the literature. We report a newborn patient who was diagnosed with a DIA and died postresection. Pathologic examination revealed that the main part of the tumor had benign features, but the internal region showed areas with a more aggressive appearance, with higher-proliferative cells, anaplastic GFAP positive cells with cellular polymorphism, necrosis foci, vascular hyperplasia with endothelial proliferation and microtrombosis. Genetic study, performed in both regions of the tumor, showed a BRAF V600E mutation and a homozygous deletion in PTEN, without changes in other relevant genes like EGFR, CDKN2A, TP53, NFKBIA, CDK4, MDM2 and PDGFRA. Although PTEN homozygous deletions are described in gliomas, the present case constitutes the first report of a PTEN mutation in a DIA, and this genetic feature may be related to the malignant behavior of a usually benign tumor. These genetic findings may point at the need of further and deeper genetic characterization of DIAs, in order to better understand the biology of this tumor and to obtain new prognostic approaches, a better clinical management and targeted therapies, especially in malignant cases of DIA.
Assuntos
Astrocitoma , Neoplasias Encefálicas , Ganglioglioma , Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Ganglioglioma/genética , Homozigoto , Humanos , Mutação/genética , PTEN Fosfo-Hidrolase/genética , Fenótipo , Proteínas Proto-Oncogênicas B-raf/genética , Deleção de SequênciaRESUMO
Resumen La asociación entre algunas infecciones bacterianas y cáncer de colon está bien documentada. La más descrita es la infección por Streptococcus bovis. Otra bacteria relacionada a neoplasias intestinales es Clostridium septicum. Presentamos el caso clínico de un varón de 62 años que consultó por dolor abdominal, diarrea y fiebre. Se realizó una tomografía computada de abdomen y pelvis que evidenció un engrosamiento de las paredes del ciego con una aparente solución de continuidad en su borde libre. En una laparotomía exploradora se confirmó la presencia de peritonitis y perforación cecal, siendo sometido a una hemicolectomía derecha e ileostomía terminal. El estudio histopatológico reveló la presencia de un adenocarcinoma de tipo células en anillo de sello asociado a isquemia. Los hemocultivos fueron positivos a C. septicum. El paciente falleció por una sepsis fulminante.
Abstract The association between some bacterial infections and colon cancer is well documented. The most described is Streptococcus bovis infection. Another bacteria related to intestinal neoplasms is Clostridium septicum. We present the case of a 62-year-old man who consulted for abdominal pain associated with diarrhea and fever. A computed tomography scan of the abdomen and pelvis was performed, which revealed thickening of the cecum walls with an apparent break in continuity at its free edge. An exploratory laparotomy was performed which confirmed the presence of peritonitis and cecal perforation. A right hemicolectomy and terminal ileostomy were performed. The histopathological study revealed the presence of signet ring cell type adenocarcinoma associated with ischemia. The blood cultures results demonstrated the presence of C. septicum. The patient died due to fulminant sepsis.
Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Infecções por Clostridium/complicações , Neoplasias do Colo/cirurgia , Neoplasias do Colo/complicações , Sepse , Clostridium septicum , Perfuração Intestinal/diagnóstico por imagemRESUMO
BACKGROUND: Liver resection represents the curative treatment of choice for patients with colorectal liver metastases (CRLM). Laparoscopic hepatectomy in CRLM is considered a safe approach. However, the information on their oncological results in the different series is deficient. This study aimed to compare the surgical margin, overall survival (OS), and disease-free survival (DFS) in patients with oncological resections of CRLM according to the type of surgical approach performed. METHODS: Between April 2007 and June 2017, 263 patients with CRLM underwent hepatic resection. Inclusion criteria were initial resectability, tumor size ≤ 50 mm, 3 or less metastases, no bilobar involvement, and absence of extrahepatic disease. A propensity score was performed to adjust the indication bias. RESULTS: Eighty-two patients were included (56 open and 26 laparoscopic). Twenty-eight (50%) patients had synchronous presentation in the open approach and 6 (23%) in the laparoscopic approach (p = 0.021), with more frequent simultaneous open resections (p = 0.037). The resection margin was positive (R1) in 5 patients with an open approach and 2 with a laparoscopic approach (8.9% and 7.6% respectively; p = 0.852). Nine patients (16%) with conventional approach and 2 (7.7%) with laparoscopic approach had local complications (p = 0.3). There was one death in the open group and none in the laparoscopic. There were no significant differences in OS and DFS rate between both groups (1-3 years, OS: 92-77% and 96-75% respectively; 1-3 years, DFS: 63-20% and 73-36% respectively). CONCLUSIONS: There were no significant differences in terms of surgical margin, OS rate, and DFS rate between the laparoscopic and open approach in patients with CRLM.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Laparoscopia , Neoplasias Hepáticas , Neoplasias Retais , Neoplasias do Colo/cirurgia , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Hepatectomia/métodos , Humanos , Laparoscopia/métodos , Margens de Excisão , Neoplasias Retais/cirurgia , Estudos Retrospectivos , Resultado do TratamentoAssuntos
Proteínas de Arabidopsis , Arabidopsis , DNA Glicosilases , Processamento Alternativo/genética , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , DNA Glicosilases/genética , DNA Glicosilases/metabolismo , Reparo do DNA , Resposta ao Choque Térmico/genéticaRESUMO
Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. This cancer shows rapid, highly infiltrative growth, that invades individually or in small groups the surrounding tissue. The aggressive tumor biology of GBM has devastating consequences with a median survival of 15 months. GBM often has Epidermal Growth Factor Receptor (EGFR) abnormalities. Despite recent advances in the study of GBM tumor biology, it is unclear whether mutations in GBM are related to EGFR amplification and relevant phenotypes like tumor infiltration. This study aimed to perform whole-exome sequencing analysis in 30 human GBM samples for identifying mutational portraits associated with EGFR amplification and infiltrative patterns. Our results show that EGFR-amplified tumors have overall higher mutation rates than EGFR-no-amplified. Six genes out of 2029 candidate genes show mutations associated with EGFR amplification status. Mutations in these genes for GBM are novel, not previously reported in GBM, and with little presence in the TCGA database. GPR179, USP48, and BLK show mutation only in EGFR-amplified cases, and all the affected cases exhibit diffuse infiltrative patterns. On the other hand, mutations in ADGB, EHHADH, and PTPN13, were present only in the EGFR-no-amplified group with a more diverse infiltrative phenotype. Overall, our work identified different mutational portraits of GBM related to well-established features like EGFR amplification and tumor infiltration.
RESUMO
Glioblastoma multiforme (GB) is one of the most aggressive tumors. Despite continuous efforts to improve its clinical management, there is still no strategy to avoid a rapid and fatal outcome. EGFR amplification is the most characteristic alteration of these tumors. Although effective therapy against it has not yet been found in GB, it may be central to classifying patients. We investigated somatic-copy number alterations (SCNA) by multiplex ligation-dependent probe amplification in a series of 137 GB, together with the detection of EGFRvIII and FISH analysis for EGFR amplification. Publicly available data from 604 patients were used as a validation cohort. We found statistical associations between EGFR amplification and/or EGFRvIII, and SCNA in CDKN2A, MSH6, MTAP and ADD3. Interestingly, we found that both EGFRvIII and losses on ADD3 were independent markers of bad prognosis (p = 0.028 and 0.014, respectively). Finally, we got an unsupervised hierarchical classification that differentiated three clusters of patients based on their genetic alterations. It offered a landscape of EGFR co-alterations that may improve the comprehension of the mechanisms underlying GB aggressiveness. Our findings can help in defining different genetic profiles, which is necessary to develop new and different approaches in the management of our patients.
Assuntos
Neoplasias Encefálicas/genética , Proteínas de Ligação a Calmodulina/metabolismo , Glioblastoma/genética , Família Multigênica , Neoplasias Encefálicas/patologia , Variações do Número de Cópias de DNA/genética , Receptores ErbB/metabolismo , Feminino , Amplificação de Genes , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Transdução de Sinais/genética , Análise de SobrevidaRESUMO
Primary meningeal melanocytomas are rare tumors of the central nervous system. Although they are considered benign neoplasms, some reports describe recurrent rates up to 45%. Little is known about their genetic and epigenetic landscape because of their infrequency. Even less has been described about markers with prognostic value. Here we describe a patient who developed a primary meningeal melanocytoma, suffered 3 recurrences in a period of 6 years and died of the tumor. The genetic and epigenetic changes explored confirmed GNAQ mutation as an initiating event. We found an epigenetic alteration of GSTP1, a feature that has recently been described in meningiomas, from the beginning of the disease. In addition, there was loss of heterozygosity in BRCA1 beginning in the second recurrence that was linked to an increase in the proliferation index; this suggested a progression pathway similar to the one described in uveal melanomas. These findings underscore the necessity of further research focused on these tumors.
Assuntos
Proteína BRCA1/genética , Melanoma/genética , Melanoma/patologia , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patologia , Recidiva Local de Neoplasia/genética , Proliferação de Células/genética , Evolução Fatal , Feminino , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Glutationa S-Transferase pi/genética , Humanos , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/patologiaRESUMO
Migration of glioblastoma cells into surrounding tissue is one of the main features that makes this tumor incurable. We evaluated whole-genome miRNA expression profiling associated with different EGFR amplification patterns in 30 cases of primary glioblastoma. From the 64 miRNAs that showed differential expression between tumors with a high level of EGFR amplification and tumors without EGFR amplification, 40% were related with cell migration, being miR-200c the most differentially expressed between these two groups. We investigated the effect of miR-200c on ZEB1 expression and cell migration in an in vitro transfection model with a miR-200c mimic, a miR-200c inhibitor and siRNA targeting EGFR in three short-term cultures with different levels of EGFR amplification obtained from resected glioblastomas. The cell culture with the highest EGFR amplification level presented the lowest miR-200c expression and the status of EGFR modulated the effect of miR-200c on ZEB1 expression. Silencing EGFR led to miR-200c upregulation and ZEB1 downregulation in transfected cultures, except in the presence of high levels of EGFR. Likewise, miR-200c upregulation decreased ZEB1 expression and inhibited cell migration, especially when EGFR was not amplified. Our results suggest that modulating miR-200c may serve as a novel therapeutic approach for glioblastoma depending on EGFR status.
Assuntos
Biomarcadores Tumorais/metabolismo , Amplificação de Genes , Regulação Neoplásica da Expressão Gênica , Glioblastoma/patologia , MicroRNAs/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Apoptose , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Receptores ErbB/genética , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Mutação , Prognóstico , Células Tumorais Cultivadas , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genéticaRESUMO
Glioblastoma (GBM) is the most common malignant primary tumor of the central nervous system. With no effective therapy, the prognosis for patients is terrible poor. It is highly heterogeneous and EGFR amplification is its most frequent molecular alteration. In this light, we aimed to examine the genetic heterogeneity of GBM and to correlate it with the clinical characteristics of the patients. For that purpose, we analyzed the status of EGFR and the somatic copy number alterations (CNAs) of a set of tumor suppressor genes and oncogenes. Thus, we found GBMs with high level of EGFR amplification, low level and with no EGFR amplification. Highly amplified tumors showed histological features of aggressiveness. Interestingly, accumulation of CNAs, as a measure of tumor mutational burden, was frequent and significantly associated to shortened survival. EGFR-amplified GBMs displayed both a higher number of concrete CNAs and a higher global tumor mutational burden than their no EGFR-amplified counterparts. In addition to genetic changes previously described in GBM, we found PARK2 and LARGE1 CNAs associated to EGFR amplification. The set of genes analyzed allowed us to explore relevant signaling pathways on GBM. Both PARK2 and LARGE1 are related to receptor tyrosine kinase/PI3K/PTEN/AKT/mTOR-signaling pathway. Finally, we found an association between the molecular pathways altered, EGFR amplification and a poor outcome. Our results underline the potential interest of categorizing GBM according to their EGFR amplification level and the usefulness of assessing the tumor mutational burden. These approaches would open new knowledge possibilities related to GBM biology and therapy.
Assuntos
Variações do Número de Cópias de DNA , Amplificação de Genes , Glioblastoma/genética , Glioblastoma/mortalidade , Adulto , Idoso , Biomarcadores Tumorais , Biópsia , Progressão da Doença , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Glioblastoma/patologia , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Análise de Sobrevida , Adulto JovemRESUMO
Glioblastoma multiforme (GBM) is the most aggressive human brain tumor, and GBM stem cells (GSC) may be responsible for its recurrence and therapeutic resistance. Toll-like receptors (TLRs), which recognize multiple ligands (endogenous and pathogen-associated) and trigger the immune response of mature immune cells, are also expressed by hematopoietic stem and progenitor cells, where their activation results in the differentiation of these cells into myeloid cells. Since TLR expression has been recently described in neural cells, including neural stem cells, we studied TLR expression by GSCs and the effect of stimulation by TLR ligands on promoting GSC differentiation into mature GBM cells. First, our results showed heterogeneous TLR expression by GBM cells from human tumors and, for the first time, by human GSCs defined by their CD133+ and CD44+ phenotypes. Next, the effect of TLR ligands was studied in in vitro cell cultures of neurospheres and CD44+ cells obtained from two GBM cell lines (U-87 and U-118). The expression of GSC markers diminished in the presence of Pam3CSK4 or LPS (TLR2 and TLR4 ligands, respectively), thus indicating TLR-dependent differentiation. Interestingly, simultaneous treatment with Pam3CSK4 plus temozolomide (TMZ), the reference drug in GBM treatment, significantly increased cell death compared to the effect of the ligand alone, which showed no toxicity, or TMZ alone. These results suggest a synergistic effect between Pam3CSK4 and TMZ based on the induction of TLR-dependent GSC differentiation towards mature GBM cells, which exhibited increased sensitivity to chemotherapy, and provide new perspectives in GBM therapy.
Assuntos
Antineoplásicos Alquilantes/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Lipopeptídeos/farmacologia , Temozolomida/farmacologia , Neoplasias Encefálicas/genética , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Glioblastoma/genética , Humanos , Receptores Toll-Like/genéticaRESUMO
A novel cell line derived from a human glioblastoma (GB), named GB-val4, has been established and characterized. GB-val4 cells were hyperdiploid, with many numerical and structural chromosomal rearrangements. The cell line did not show mutations in IDH1/IDH2 genes or EGFR amplification, but it presented two missense mutations in TP53, which imply a very low p53 protein activity within the cell line. Cells also had gain of TP73 copies, hypermethylation of APC, CASP8 and RASSF1, increased expression of ARF1, CDH1 and NF-κB and decreased expression of CDKN2A. Tumorigenity was demonstrated by transplant of GB-val4 cells into athymic nude mice, where solid tumors were grown. Interestingly, a high percentage of GB-val4 cells presented expression of GSC markers CD133 or CD44. These GSC markers were increased in neurosphere cultures, which better mimic solid tumor conditions and maintain the genetic features of the tumor cells. In this study, we aimed to define the characteristics of this novel cell line and its applications in human cancer research. With its genetic features and a poor p53 activity, GB-val4 cells resemble GB tumors. Moreover, the important presence of GSCs in adherent cultures and especially in neurosphere cultures makes GB-val4 an attractive tool to study cancer stem cells, deepen in the knowledge the molecular pathways of GB and develop new therapeutic strategies for patients with these tumors.
Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glioblastoma/genética , Glioblastoma/patologia , Mutação de Sentido Incorreto , Proteína Supressora de Tumor p53/genética , Antígeno AC133/genética , Antígeno AC133/metabolismo , Animais , Carcinogênese , Linhagem Celular Tumoral , Diploide , Expressão Gênica , Rearranjo Gênico , Glioblastoma/terapia , Humanos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Terapia de Alvo MolecularRESUMO
BACKGROUND AND OBJECTIVE: Several trials have evaluated the effect of disease management programs in heart failure (HF) with diverse results. The aim of this study was to develop a simple nurse-led clinic intervention program for patients with HF and assess whether this intervention positively affects the prognosis of patients, their care costs and perceived quality of life (QoL). METHODS: Between 2011 and 2013, 127 patients with reduced ejection fraction were prospectively randomly allocated (1:2) to standard care or intervention program. Primary composite endpoint was all-cause mortality and hospital readmissions. Secondary endpoints were all-cause mortality, all-cause hospital readmissions, readmissions for HF, time to first readmission and QoL improvements assessed by "Minnesota Living with Heart Failure Questionnaire" (MLHFQ). An intention-to-treat analysis was performed. RESULTS: After a median follow-up of 2-years, no differences were found in the primary composite endpoint. Likewise, there were no differences between groups in the predefined secondary endpoints of mortality and readmissions from any cause. However, in the intervention group, readmissions for HF were significantly reduced (35% vs. 18%; p=0.04) and QoL significantly improved (MLHFQ±SD: 2.29±14 vs. 10.9±14.75; p=0.04). CONCLUSIONS: In patients with HF, the use of a nurse-led intervention program significantly improves perceived QoL and reduce HF hospital readmissions.
Assuntos
Gerenciamento Clínico , Insuficiência Cardíaca/terapia , Pesquisa em Avaliação de Enfermagem/métodos , Readmissão do Paciente , Qualidade de Vida , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Custos de Cuidados de Saúde , Insuficiência Cardíaca/economia , Insuficiência Cardíaca/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Inquéritos e QuestionáriosRESUMO
Meningiomas are the most frequent primary brain tumor. Usually, they are curable by surgery, but even after seemingly complete resection, some low-grade lesions recur. Despite recent improvements, signatures having prognostic value in grade I tumors remain poorly characterized. The frequency and delicate location of these tumors suggest that the risk of recurrence might be more accurately predicted. Herein, we show an easy way to evaluate the methylation status of meningiomas and its correlation with the prognosis of the disease. A series of 120 meningiomas, including primary tumors and recurrences, were analyzed histopathologically, and 24 tumor suppressor genes (TSGs) were studied by methylation-specific multiple ligation probe amplification. Long-term follow-up was conducted to classify patients with grade I primary tumors according to their outcomes. We found that hypermethylation in at least one TSG is frequent. The number of hypermethylated TSG per case was significantly higher in recurrences than in primary tumors and in primary benign meningiomas that recurred than in tumors from patients who showed no evidence of disease during follow-up. Finally, hypermethylation in RASSF1A, MLH1, and CDKN2B was an independent prognostic factor associated with the time to recurrence of these benign tumors that were biologically aggressive. To our knowledge, this is one of the widest studies of primary grade I tumors of patients who developed a tumor recurrence. The frequency of epigenetic changes suggests that hypermethylation is an early event in meningiomas, whereas the accumulation of epigenetic changes is related to greater biological aggressiveness and may be a signature of potential clinical relevance.
Assuntos
Epigênese Genética , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patologia , Meningioma/genética , Meningioma/patologia , Recidiva Local de Neoplasia/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Metilação de DNA/genética , Feminino , Genes Supressores de Tumor , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Pleomorphic undifferentiated sarcoma (PUS), also called malignant fibrous histiocytoma, is a soft tissue sarcoma which occurs predominantly in the extremities. Its origin is a poorly defined mesenchymal cell, which derives to histiocytic and fibroblastic cells. The patient, a 58 year-old man, presented a lesion located in the forearm composed by spindle cells and multinucleated giant cells, which expressed vimentin and adopted a histological pattern formed by irregular-swirling fascicles. Cells were cultured in vitro and a new cell line was established. We characterized this new cell line by histological analyses, cytogenetics (using G-bands and spectral karyotype technique) and cytometric analyses. Cells were grown in culture for more than 100 passages. They had elongated or polygonal morphology. The cells presented a saturation rate of 70,980 cells/cm2, a plating efficiency of 21.5% and a mitotic index of 21 mitoses per field. The cell line was tumorigenic in nude mice. The ploidy study using flow cytometry revealed an aneuploid peak with a DNA index of 1.43. A side population was detected, demonstrating the presence of stem and progenitor cells. Cytogenetics showed a hypotriploid range with many clonal unbalanced rearrangements. Loss of p53 gene was evidenced by MLPA. We describe, for the first time, the characterization of a new human PUS TP53-null cell line called mfh-val2. Mfh-val2 presents a wide number of applications as a TP53-null cell line and a great interest in order to characterize genetic alterations influencing the oncogenesis or progression of PUS and to advance in the biological investigation of this tumor.