ABSTRACT
Data about biosimilar Peg-filgrastim (bioPEG) in autologous stem cell transplant (ASCT) are still scarce. The aim of this study has been to assess efficacy and safety of bioPEG among lymphoma and myeloma patients undergoing ASCT, comparing these data with historical controls receiving other G-CSFs. Furthermore, an economic evaluation has been included to estimate the savings by using bioPEG. This is a prospective cohort study comparing lymphoma and myeloma patients undergoing ASCT and receiving bioPEG (n = 73) with three historical consecutive cohorts collected retrospectively who received other G-CSFs (Lenograstim - Leno - n = 101, biosimilar Filgrastim - bioFIL n = 392, and originator Peg-filgrastim - oriPEG n = 60). We observed a significantly shorter time to neutrophils and platelet engraftment (p < 0.001) in patients treated with bioPEG and oriPEG. Moreover, patients who received bioPEG showed a shorter hospitalization time (p < 0.001) and a lower transfusion need (p < 0.001). We did not observe any significant difference in terms of transplant-related mortality, mucositis, and diarrhea among the four groups. No serious adverse events were associated with bioPEG. Similar data were obtained after running a stratified analysis for lymphomas and myeloma separately conducted by using a propensity score matching. The average total cost per patient of bioPEG was 18218.9 compared to 23707.8, 20677.3 and 19754.9 of Leno, oriPEG, and bioFIL, respectively. In conclusion, bioPEG seems to be as effective as the originator and more effective than short-acting G-CSFs in terms of post-transplant engraftment in myeloma and lymphoma patients undergoing ASCT. Moreover, bioPEG was cost-effective when compared with the other G-CSFs.
Subject(s)
Biosimilar Pharmaceuticals , Lymphoma , Multiple Myeloma , Humans , Filgrastim/adverse effects , Lenograstim , Multiple Myeloma/drug therapy , Biosimilar Pharmaceuticals/adverse effects , Retrospective Studies , Prospective Studies , Lymphoma/drug therapy , Granulocyte Colony-Stimulating Factor , Stem Cell Transplantation , Recombinant Proteins , Hematopoietic Stem Cell MobilizationABSTRACT
The 5th Workshop IRE on Translational Oncology was held in Rome (Italy) on 27-28 March at the IRCCS Regina Elena National Cancer Institute. This meeting entitled "The New World of RNA diagnostics and therapeutics" highlightes the significant progress in the RNA field made over the last years. Research moved from pure discovery towards the development of diagnostic biomarkers or RNA-base targeted therapies seeking validation in several clinical trials. Non-coding RNAs in particular have been the focus of this workshop due to their unique properties that make them attractive tools for the diagnosis and therapy of cancer.This report collected the presentations of many scientists from different institutions that discussed recent oncology research providing an excellent overview and representative examples for each possible application of RNA as biomarker, for therapy or to increase the number of patients that can benefit from precision oncology treatment.In particular, the meeting specifically emphasized two key features of RNA applications: RNA diagnostic (Blandino, Palcau, Sestito, Díaz Méndez, Cappelletto, Pulito, Monteonofrio, Calin, Sozzi, Cheong) and RNA therapeutics (Dinami, Marcia, Anastasiadou, Ryan, Fattore, Regazzo, Loria, Aharonov).
Subject(s)
Neoplasms , Humans , Neoplasms/diagnosis , Neoplasms/genetics , Neoplasms/therapy , Precision Medicine , Biomarkers , Medical Oncology , ItalyABSTRACT
BACKGROUND: Altered microRNA profiles have been observed not only in tumour tissues but also in biofluids, where they circulate in a stable form thus representing interesting biomarker candidates. This study aimed to identify a microRNA signature as a non-invasive biomarker and to investigate its impact on glioma biology. METHODS: MicroRNAs were selected using a global expression profile in preoperative serum samples from 37 glioma patients. Comparison between serum samples from age and gender-matched controls was performed by using the droplet digital PCR. The ROC curve and Kaplan-Meier survival analyses were used to evaluate the diagnostic/prognostic values. The functional role of the identified signature was assessed by gain/loss of function strategies in glioma cells. RESULTS: A three-microRNA signature (miR-1-3p/-26a-1-3p/-487b-3p) was differentially expressed in the serum of patients according to the isocitrate dehydrogenase (IDH) genes mutation status and correlated with both patient Overall and Progression Free Survival. The identified signature was also downregulated in the serum of patients compared to controls. Consistent with these results, the signature expression and release in the conditioned medium of glioma cells was lower in IDH-wild type cells compared to the mutated counterpart. Furthermore, in silico analysis of glioma datasets showed a consistent deregulation of the signature according to the IDH mutation status in glioma tumour tissues. Ectopic expression of the signature negatively affects several glioma functions. Notably, it impacts the glioma invasive phenotype by directly targeting the invadopodia-related proteins TKS4, TKS5 and EFHD2. CONCLUSIONS: We identified a three microRNA signature as a promising complementary or even an independent non-invasive diagnostic/prognostic biomarker. The signature displays oncosuppressive functions in glioma cells and impacts on proteins crucial for migration and invasion, providing potential targets for therapeutic intervention.
Subject(s)
Brain Neoplasms , Circulating MicroRNA , Glioma , MicroRNAs , Humans , Brain Neoplasms/pathology , Biomarkers, Tumor/genetics , Glioma/pathology , MicroRNAs/genetics , Prognosis , Isocitrate Dehydrogenase/genetics , Adaptor Proteins, Vesicular Transport/metabolism , Calcium-Binding ProteinsABSTRACT
Diffuse large B-cell lymphoma (DLBCL) is an aggressive, heterogeneous neoplasm where prognostication and therapeutic decision are challenging. The available prognostic tools are not able to identify all patients refractory to treatment. MicroRNAs, small RNAs frequently deregulated in cancer, stably circulate in biofluids, representing interesting candidates for non-invasive biomarkers. Here we validated serum miR-22, an evolutionarily conserved microRNA, as a prognostic/predictive biomarker in DLBCL. Moreover, we found that its expression and release from DLBCL cells are related to therapy response and adversely affect cell proliferation. These results suggest that miR-22 is a promising complementary or even independent non-invasive biomarker for DLBCL management.
Subject(s)
Lymphoma, Large B-Cell, Diffuse/blood , MicroRNAs/blood , RNA, Neoplasm/blood , Adult , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/blood , Cell Division/genetics , Cyclophosphamide/administration & dosage , Doxorubicin/administration & dosage , Exosomes/chemistry , Genes, bcl-2 , Genes, myc , Humans , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/mortality , Molecular Sequence Annotation , Prednisone/administration & dosage , Prognosis , Prospective Studies , Proto-Oncogene Proteins c-bcl-6/genetics , Rituximab/administration & dosage , Vincristine/administration & dosageABSTRACT
Gliomas are diffusely growing tumours arising from progenitors within the central nervous system. They encompass a range of different molecular types and subtypes, many of which have a well-defined profile of driver mutations, copy number changes and DNA methylation patterns. A majority of gliomas will require surgical intervention to relieve raised intracranial pressure and reduce tumour burden. A proportion of tumours, however, are located in neurologically sensitive areas and a biopsy poses a significant risk of a deficit. A majority of gliomas recur after surgery, and monitoring tumour burden of the recurrence is currently achieved by imaging. However, most imaging modalities have limitations in assessing tumour burden and infiltration into adjacent brain, and sometimes imaging is unable to discriminate between tumour recurrence and pseudo-progression. Liquid biopsies, obtained from body fluids such as cerebrospinal fluid or blood, contain circulating nucleic acids or extracellular vesicles containing tumour-derived components. The studies for this systematic review were selected according to PRISMA criteria, and suggest that the detection of circulating tumour-derived nucleic acids holds great promises as biomarker to aid diagnosis and prognostication by monitoring tumour progression, and thus can be considered a pathway towards personalized medicine.
Subject(s)
Biomarkers, Tumor/blood , Biomarkers, Tumor/cerebrospinal fluid , Cell-Free Nucleic Acids/blood , Cell-Free Nucleic Acids/cerebrospinal fluid , Glioma/blood , Glioma/cerebrospinal fluid , Glioma/diagnosis , Humans , Liquid BiopsyABSTRACT
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous neoplasm with diverse genetic abnormalities and outcomes. To date, DLBCL is invasively diagnosed by tissue biopsy and few biomarkers are available to predict patient outcome, treatment response and progression. The identification of patient-specific biomarkers would allow a "personalized medicine" approach for DLBCL patients. In this regard, "liquid biopsies" hold great promise, capturing the entire genetic landscape of the tumour and allowing a rapid and dynamic management of cancer. Liquid biopsy studies particularly focus on cell-free nucleic acids, such as cell-free DNA (cfDNA) and microRNAs, which are easy to collect and analyse. In accordance with the PRISMA criteria, we performed a systematic review on circulating nucleic acids as potential biomarkers for DLBCL management. The results suggest that combining information from the genetic (cfDNA) and epigenetic (microRNAs) landscape of the disease could lead to developing an integrated network of non-invasive biomarkers for the better management of DLBCL.
Subject(s)
Biomarkers, Tumor , Circulating MicroRNA , Circulating Tumor DNA , Lymphoma, Large B-Cell, Diffuse , RNA, Neoplasm , Biomarkers, Tumor/blood , Biomarkers, Tumor/genetics , Circulating MicroRNA/blood , Circulating MicroRNA/genetics , Circulating Tumor DNA/blood , Circulating Tumor DNA/genetics , Humans , Liquid Biopsy , Lymphoma, Large B-Cell, Diffuse/blood , Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/therapy , RNA, Neoplasm/blood , RNA, Neoplasm/geneticsSubject(s)
Hematopoietic Stem Cell Transplantation , Lymphoma , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carmustine , Cytarabine , Etoposide , Humans , Lymphoma/therapy , Melphalan , Progression-Free Survival , Stem Cell Transplantation , Transplantation Conditioning , Transplantation, AutologousABSTRACT
BACKGROUND: High grade non-muscle-invasive bladder cancer (HG-NMIBC) is a heterogeneous disease with variable risk of progression. Urinary microRNAs are promising biomarkers for BC detection and surveillance. Let-7c-5p miRNA, clustered with miR-99a-5p and -125b-5p, is deregulated in cancer, including BC. The aim of this study is to evaluate urinary let-7c cluster expression in Ta/T1 HG-NMIBC patients and its impact on progression-free survival (PFS). METHODS: Quantitative Real-Time-Polymerase-Chain-Reaction (qRT-PCR) was used to analyze the let-7c cluster expression in 57 urine and 49 neoplastic paired tissue samples prospectively collected from transurethral resection (TUR) HG-NMIBC patients. Twenty urine and 10 bladder tissue samples were collected and analyzed as normal controls. QRT-PCR was also used to detect intra-/extra-cellular let-7c cluster in BC cells. Receiver Operating Characteristic (ROC) curves were used to identify urinary miRNAs cut-off values predicting T-stage and PFS. Uni/multivariable Cox regression was performed to identify predictors of PFS. A nomogram predicting progression risk and a decision curve analysis (DCA) were performed. RESULTS: Urinary let-7c was significantly up-regulated in patients compared with controls, while the whole cluster was down-regulated in tumor tissues. Supporting these findings, in vitro comparison of extra-/intra-cellular ratios of cluster levels between BC cells, showed a higher ratio for let-7c in HG-NMIBC versus low-grade cells. Urinary let-7c cluster expression was increased in higher T-stage and was an independent predictor of progression. Lower EORTC-score and downregulation of urinary cluster were predictors of higher PFS on univariable Cox regression, while on multivariable analysis only cluster expression was an independent progression predictor. On DCA, a benefit was evident for patients with a PFS probability > 20%. CONCLUSIONS: Urinary let-7c cluster evaluation may improve prognosis, identifying patients at risk of progression and addressing early radical treatment.
Subject(s)
MicroRNAs/urine , Urinary Bladder Neoplasms/urine , Aged , Biomarkers, Tumor/genetics , Biomarkers, Tumor/urine , Disease Progression , Female , Humans , Male , Neoplasm Grading , Pilot Projects , Progression-Free Survival , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathologyABSTRACT
Hsa-mir-143 and hsa-let-7c have been reported to be deregulated in multiple neoplasms. The main purpose of this study was to investigate the expression of these miRNAs in bladder cancer (BCa) and to analyze the association between their expression profiles and clinical and epidemiological parameters. Ninety BCa specimens were included. Expression patterns of miR-143 and let-7c were assessed by qRT-PCR using Taqman specific probes. Validated and predicted targets of these miRNA's were identified using CSmiRTar and DAVID tools, respectively. miR-143 was downregulated in tumors compared to controls (mean fold-change (FC) = 0.076). Its expression was significantly higher in MIBC compared to NMIBC (p = 0,001). Its value as a potential biomarker discriminating non invasive tumors from the invasive ones was confirmed by ROC curve (AUC = 0.768; p = 0.0001). Also, this down-regulation positively correlates with frequency of tobacco use (p = 0,04) and chronic alcohol consumption (p = 0,04). Let-7c was overexpressed in BCa samples (mean (FC = 9.92) compared to non tumoral ones but was not associated to clinical and epidemiological parameters. A comprehensive overview of miR-143 targets and pathways implicated in BCa initiation, diagnosis or prognosis using bioinformatical analysis, was conducted. While both deregulated miRNAs may contribute to urothelial tumorigenesis, the deregulation of miR-143 was significantly correlated to epidemiological and clinical parameters.
Subject(s)
Gene Expression Profiling , Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , Urinary Bladder Neoplasms/epidemiology , Urinary Bladder Neoplasms/genetics , Aged , Case-Control Studies , Female , Humans , Male , MicroRNAs/metabolism , ROC Curve , Risk FactorsABSTRACT
Unlike allogeneic transplant, autologous stem cell transplantation (ASCT) represents a procedure with a low-risk of cytomegalovirus (CMV) symptomatic reactivation-infection/end-organ disease (CMV complications) and invasive fungal disease (IFD). However, novel drugs for the treatment of lymphoproliferative malignancies could cause an increase of such opportunistic infections, even after ASCT. To the best of our knowledge, there are no published data demonstrating an association between CMV and IFD in the autologous setting, while this association has been widely reported in allogeneic transplantation. We have reviewed our series of 347 ASCT in myeloma and lymphoma patients performed over a period of 14 years with the aim of investigating the descriptive and analytical epidemiology of bacterial, CMV and IFD complications, focusing on the association between CMV and IFD. Patients with myeloma have significantly fewer bacterial infections and IFD than patients with lymphoma, but a similar rate of CMV complications. Descriptive epidemiological data are consistent with the literature, indicating an overall incidence of 36%, 3.5% and 15.5% for bacterial infections, IFD and CMV complications, with a case mortality rate of 4%, 16.7% and 3.7%, respectively. A strong correlation between CMV and IFD exists, with 8 cases of IFD out of a total of 12 presenting a CMV complication. At multivariate analysis, a diagnosis of lymphoma, ≥3 previous treatment lines and age ≥60 years were found to be independent risk factors for IFD. Duration of neutropenia (ANC < 500/mm³) ≥7 days represents an independent risk factor for CMV complications, where neutropenia most likely represents a crude surrogate biomarker indicating a deeper and longer state of overall immunosuppression. From our data we conclude that (1) myeloma patients are at lower risk of bacterial infections and IFD as compared with lymphoma patients but are at equal risk of CMV complications, most likely as a consequence of a selective impact of bortezomib on Herpes Viruses infection control; (2) a significant association exists between CMV and IFD, although a possible cause-effect relationship remains to be determined; (3) IFD is a rare complication after ASCT but burdened by a mortality rate of about 17%, with peak rates in older lymphoma patients who underwent more intensive therapeutic regimens.
Subject(s)
Cytomegalovirus Infections/complications , Hematopoietic Stem Cell Transplantation/adverse effects , Invasive Fungal Infections/complications , Lymphoproliferative Disorders/microbiology , Lymphoproliferative Disorders/virology , Opportunistic Infections/complications , Adolescent , Adult , Aged , Cohort Studies , Female , Humans , Male , Middle Aged , Multivariate Analysis , Risk Factors , Transplantation, Autologous/adverse effects , Young AdultABSTRACT
MicroRNAs, non-coding regulators of gene expression, are likely to function as important downstream effectors of many transcription factors including MYB. Optimal levels of MYB are required for transformation/maintenance of BCR-ABL-expressing cells. We investigated whether MYB silencing modulates microRNA expression in Philadelphia-positive (Ph+) leukemia cells and if MYB-regulated microRNAs are important for the "MYB addiction" of these cells. Thirty-five microRNAs were modulated by MYB silencing in lymphoid and erythromyeloid chronic myeloid leukemia-blast crisis BV173 and K562 cells; 15 of these were concordantly modulated in both lines. We focused on the miR-17-92 cluster because of its oncogenic role in tumors and found that: i) it is a direct MYB target; ii) it partially rescued the impaired proliferation and enhanced apoptosis of MYB-silenced BV173 cells. Moreover, we identified FRZB, a Wnt/ß-catenin pathway inhibitor, as a novel target of the miR-17-92 cluster. High expression of MYB in blast cells from 2 Ph+leukemia patients correlated positively with the miR-17-92 cluster and inversely with FRZB. This expression pattern was also observed in a microarray dataset of 122 Ph+acute lymphoblastic leukemias. In vivo experiments in NOD scid gamma mice injected with BV173 cells confirmed that FRZB functions as a Wnt/ß-catenin inhibitor even as they failed to demonstrate that this pathway is important for BV173-dependent leukemogenesis. These studies illustrate the global effects of MYB expression on the microRNAs profile of Ph+cells and supports the concept that the "MYB addiction" of these cells is, in part, caused by modulation of microRNA-regulated pathways affecting cell proliferation and survival.
Subject(s)
Blast Crisis/metabolism , Gene Expression Regulation, Leukemic , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , MicroRNAs/biosynthesis , Multigene Family , Proto-Oncogene Proteins c-myb/biosynthesis , RNA, Neoplasm/biosynthesis , Transcriptional Activation , Animals , Blast Crisis/drug therapy , Blast Crisis/genetics , Blast Crisis/pathology , Humans , K562 Cells , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Mice , Mice, Inbred NOD , Mice, SCID , MicroRNAs/genetics , Proto-Oncogene Proteins c-myb/genetics , RNA, Neoplasm/genetics , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of tumors, with aggressive clinical course that renders prognostication and choice of treatment strategy difficult. Chemo-immunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) is the current first-line treatment. MicroRNAs (miRNAs) are under investigation as novel diagnostic and prognostic biomarkers in several malignancies, including malignant lymphomas. While tissue miRNAs in DLBCL patients have been extensively studied as biomarkers, only few reports to date have evaluated the role of circulating/serum miRNAs as potential prognostic factors. Here circulating/serum miRNAs, including miR-22, were investigated as potential non-invasive biomarkers, with the aim of a better prognostic stratification of DLBCL patients. METHODS: MiRNAs were selected by global expression profile of serum miRNAs of DLBCL patients, The Cancer Genome Atlas (TCGA) analysis and literature research. Serum and tissues miRNA expression profile in de novo DLBCL patients, consecutively enrolled for this study, were detected by quantitative real-time polymerase chain reaction. Relative expression was calculated using the comparative Ct method. Statistical significance was determined using the Mann-Whitney rank sum and Fisher's exact test. Survival analysis was conducted through the use of Kaplan-Meier method. Spearman's Rho was applied to study the correlation between miRNA distributions and days to first relapse. Experimentally validated miRNA-target interactions were assessed by miRTarBase database. Negative miRNA-mRNA correlation was evaluated in TCGA DLBCL dataset. Pathway analysis was performed by the functional annotation clustering DAVID tool. RESULTS: We showed a significant modulation of serum miR-22 after R-CHOP treatment compared with basal values but no difference between baseline serum miRNAs values of DLBCL patients and healthy controls. High expression level of serum miR-22 in DLBCL at diagnosis (n = 36) is associated with a worse PFS and is independent of the currently used clinical prognostic index. Integrative and pathways analysis of miR-22 identified target genes involved in different important pathways such as p53 signaling. CONCLUSIONS: Our data suggest that miR-22 is of potential interest as non-invasive biomarker to predict clinical outcome in DLBCL patients. Characterization of miR-22 pathways can pave the way to the development of targeted therapy approaches for specific subgroups of DLBCL patients.
Subject(s)
Lymphoma, Large B-Cell, Diffuse/genetics , MicroRNAs/metabolism , Adult , Aged , Aged, 80 and over , Cohort Studies , Female , Humans , Lymphoma, Large B-Cell, Diffuse/metabolism , Lymphoma, Large B-Cell, Diffuse/pathology , Male , Middle Aged , Pilot Projects , Prognosis , Prospective Studies , Young AdultABSTRACT
Lamin A is a component of the nuclear matrix that also controls proliferation by largely unknown mechanisms. NF-Y is a ubiquitous protein involved in cell proliferation composed of three subunits (-YA -YB -YC) all required for the DNA binding and transactivation activity. To get clues on new NF-Y partner(s) we performed a mass spectrometry screening of proteins that co-precipitate with the regulatory subunit of the complex, NF-YA. By this screening we identified lamin A as a novel putative NF-Y interactor. Co-immunoprecipitation experiments and confocal analysis confirmed the interaction between the two endogenous proteins. Interestingly, this association occurs on euchromatin regions, too. ChIP experiments demonstrate lamin A enrichment in several promoter regions of cell cycle related genes in a NF-Y dependent manner. Gain and loss of function experiments reveal that lamin A counteracts NF-Y transcriptional activity. Taking advantage of a recently generated transgenic reporter mouse, called MITO-Luc, in which an NF-Y-dependent promoter controls luciferase expression, we demonstrate that lamin A counteracts NF-Y transcriptional activity not only in culture cells but also in living animals. Altogether, our data demonstrate the occurrence of lamin A/NF-Y interaction and suggest a possible role of this protein complex in regulation of NF-Y function in cell proliferation.
Subject(s)
CCAAT-Binding Factor/metabolism , Lamin Type A/metabolism , Multiprotein Complexes/metabolism , Transcription, Genetic , Animals , CCAAT-Binding Factor/genetics , Cell Line, Tumor , Cell Proliferation , Chromatin Immunoprecipitation , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Gene Expression Regulation , High-Throughput Nucleotide Sequencing , Humans , Lamin Type A/genetics , Mice , Mice, Transgenic , Promoter Regions, Genetic , Protein Binding , Protein Transport , Response ElementsABSTRACT
BACKGROUND: Malignant gliomas are the most common primary brain tumors in adults and challenging cancers for diagnosis and treatment. They remain a disease for which non-invasive, diagnostic and/or prognostic novel biomarkers are highly desirable. Altered microRNA (miRNA) profiles have been observed in tumor tissues and biological fluids. To date only a small set of circulating/serum miRNA is found to be differentially expressed in brain tumors compared to normal controls. Here a restricted signature of circulating/serum miRNA including miR-15b*,-23a, -99a, -125b, -133a, -150*, -197, -340, -497, -548b-5p and let-7c were investigated as potential non-invasive biomarkers in the diagnosis of glioma patients. METHODS: Serum and tissues miRNAs expression in patients with brain cancers (n = 30) and healthy controls (n = 15) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Relative expression was calculated using the comparative Ct method. Statistical significance (p ≤ 0,05) was determined using the Mann-Whitney rank sum and Fisher's exact test. Diagnostic accuracy of miRNAs in distinguishing glioblastoma multiforme (GBM) from lower grade cancer was assessed by the Receiver Operating Characteristic (ROC) curve analysis. To validate the role of the identified miRNAs in cancer a comprehensive literature search was conducted using PubMed, Web of Science (Core Collection) and Scopus databases. RESULTS: We observed a decrease of miR-497 and miR-125b serum levels depending on tumor stages with reduced level in GBM than lower grade tumors. The ROC curve analysis distinguishing GBM from lower grade cases yielded an area under the curve (AUC) of 0.87 (95 % confidence interval (CI) = 0.712-1) and of 0.75 (95 % CI = 0.533-0.967) for miR-497 and -125b, respectively. GBM patients are more likely to show a miR-497 and -125b down-regulation than the lower grade group (p = 0.002 and p = 0.024, respectively). These results were subsequently compared with evidence from 19 studies included in the final systematic review. CONCLUSIONS: Although multiple biomarkers are currently leveraged in the clinic to detect specific cancer types, no such standard blood biomolecules are used as yet in gliomas. Our data suggest that serum miR-497 and -125b could be a novel diagnostic markers with good perspectives for future clinical applications in patients with glioma.
Subject(s)
Brain Neoplasms/diagnosis , Gene Expression Profiling/methods , Glioblastoma/diagnosis , Glioma/diagnosis , MicroRNAs/blood , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Brain Neoplasms/genetics , Diagnosis, Differential , Down-Regulation , Female , Gene Expression Regulation, Neoplastic , Glioblastoma/genetics , Glioma/genetics , Humans , Male , Neoplasm Grading , ROC CurveABSTRACT
Resveratrol (3,4',5-trihydroxystilbene; RSV) acts on cancer cells in several ways, inducing cell cycle delay and apoptotic death, and enhancing ionizing radiation (IR)-mediated responses. However, fewer studies have examined RSV effects on normal cells. We have treated human lymphocytes in vitro with RSV, either alone or combined with IR, to evaluate its potential use as a radioprotector. We measured the effects of RSV on induction of DNA damage, repair kinetics, and modulation of histone deacetylase activity.
Subject(s)
Radiation, Ionizing , Stilbenes/pharmacology , Apoptosis/drug effects , Apoptosis/radiation effects , Cell Cycle/drug effects , Cell Cycle/radiation effects , DNA Damage/drug effects , DNA Damage/radiation effects , Flow Cytometry , Humans , Lymphocytes/drug effects , Lymphocytes/radiation effects , ResveratrolABSTRACT
Melanoma, the most lethal form of skin cancer, is frequently associated with alterations in several genes, among which the Bcl-2 oncogene plays an important role in progression, chemosensitivity and angiogenesis. Also microRNA (miRNA) are emerging as modulators of melanoma development and progression, and among them, miR-211, located within the melastatin-1/TRPM1 (transient receptor potential cation channel, subfamily M, member 1 protein) gene, is prevalently expressed in the melanocyte lineage and acts as oncosuppressor. Using several human melanoma cell lines and their Bcl-2 stably overexpressing derivatives, we evaluated whether there was a correlation between expression of Bcl-2 and miR-211. Western blot analysis and quantitative real-time polymerase chain reaction demonstrated reduced expression of pri-miR-211, miR-211, TRPM1, and MLANA levels, after Bcl-2 overexpression, associated with increased expression of well-known miR-211 target genes. Overexpression of mature miR-211 in Bcl-2 overexpressing cells rescued Bcl-2 ability to increase cell migration. A decreased nuclear localization of microphthalmia-associated transcription factor (MITF), a co-regulator of both miR-211 and TRPM1, and a reduced MITF recruitment at the TRPM1 and MLANA promoters were also evidenced in Bcl-2 overexpressing cells by immunofluorescence and chromatin immunoprecipitation experiments, respectively. Reduction of Bcl-2 expression by small interference RNA confirmed the ability of Bcl-2 to modulate miR-211 and TRPM1 expression. © 2015 Wiley Periodicals, Inc.