324 research outputs found
From intrinsic to adaptive clusters in breast cancer
No full textThe heterogeneity of breast cancers and the availability of several therapeutic options requires prognostic and predictive tools for tailoring adjuvant treatments. In this issue of Cancer Cell, Denkert et al. analyze longitudinal gene-expression data from the Penelope-B trial and identify five adaptive clusters with independent prognostic value to established signatures
Copy number variations in endometrial cancer: from biological significance to clinical utility
No full textThe molecular basis of endometrial cancer, which is the most common malignancy of the female reproductive organs, relies not only on onset of mutations but also on copy number variations, the latter consisting of gene gains or losses. In this review, we introduce copy number variations and discuss their involvement in endometrial cancer to determine the perspectives of clinical applicability. We performed a literature analysis on PubMed of publications over the past 30 years and annotated clinical information, including histological and molecular subtypes, adopted molecular techniques for identification of copy number variations, their locations, and the genes involved. We highlight correlations between the presence of some specific copy number variations and myometrial invasion, lymph node metastasis, advanced International Federation of Gynecology and Obstetrics (FIGO) stage, high grade, drug response, and cancer progression. In particular, type I endometrial cancer cells have few copy number variations and are mainly located in 8q and 1q, while type II, high grade, and advanced FIGO stage endometrial cancer cells are aneuploid and have a greater number of copy number variations. As expected, the higher the number of copy number variations the worse the prognosis, especially if they amplify CCNE1, ERBB2, KRAS, MYC, and PIK3CA oncogenes. Great variability in copy number and location among patients with the same endometrial cancer histological or molecular subtype emerged, making them interesting candidates to be explored for the improvement of patient stratification. Copy number variations have a role in endometrial cancer progression, and therefore their detection may be useful for more accurate prediction of prognosis. Unfortunately, only a few studies have been carried out on the role of copy number variations according to the molecular classification of endometrial cancer, and even fewer have explored the correlation with drugs. For these reasons, further studies, also using single cell RNA sequencing, are needed before reaching a clinical application
SCENE: Signature Collection for Endometrial Cancer Prognosis
No full textEndometrial cancer (EC) is the most common malignancy of the female reproductive tract; its prognosis is difficult to predict. Despite the technique of single-cell transcriptomic analysis (scRNA-seq) returning single-cell level expression data and promising to improve the accuracy of prognosis prediction, a tool that correlates transcriptomic signatures with survival is missing. To this aim, we have created SCENE, a database that collects information to correlate EC transcriptomic signatures with patient prognosis. We performed a review of the literature present in PubMed to collect transcriptomic signatures annotated with their characteristics, differential expression between healthy and sick patients, between patients with more and less favourable prognosis, and cellular pathways in which the genes are involved, as well as references to the original studies. The analysis of about 200 studies has allowed us to obtain 700 mRNA signatures, 60 microRNA (miRNA), and 150 long non-coding RNA (lncRNA), involved in 60 molecular pathways. Each signature is annotated with its specific prognostic outcome that it influences, such as overall survival (OS), progression-free survival (PFS), relapse-free survival (RFS), and disease-specific survival (DSS). The SCENE resource collects and annotates information that is widespread in the literature to facilitate the interpretation of transcriptomic data obtained with any technique in EC. In the case of scRNA-seq data, SCENE may reveal cells predisposed to develop therapy resistance and metastasis
A study on the combined interplay between stochastic fluctuations and the number of flagella in bacterial chemotaxis
No full textThe chemotactic pathway allows bacteria to respond and adapt to environmental changes, by tuning the tumbling and running motions that are due to clockwise and counterclockwise rotations of their flagella. The pathway is tightly regulated by feedback mechanisms governed by the phosphorylation and methylation of several proteins. In this paper, we present a detailed mechanistic model for chemotaxis, that considers all of its transmembrane and cytoplasmic components, and their mutual interactions. Stochastic simulations of the dynamics of a pivotal protein, CheYp, are performed by means of tau leaping algorithm. This approach is then used to investigate the interplay between the stochastic fluctuations of CheYp amount and the number of cellular flagella. Our results suggest that the combination of these factors might represent a relevant component for chemotaxis. Moreover, we study the pathway under various conditions, such as different methylation levels and ligand amounts, in order to test its adaptation response. Some issues for future work are finally discussed
Intracellular osteopontin protects from autoimmunity-driven lymphoma development inhibiting TLR9-MYD88-STAT3 signaling
No full textAbstract Background Autoimmune disorders, including Systemic Lupus Erythematosus (SLE), are associated with increased incidence of hematological malignancies. The matricellular protein osteopontin (OPN) has been linked to SLE pathogenesis, as SLE patients show increased serum levels of OPN and often polymorphisms in its gene. Although widely studied for its pro-tumorigenic role in different solid tumours, the role of OPN in autoimmunity-driven lymphomagenesis has not been investigated yet. Methods To test the role of OPN in the SLE-associated lymphomagenesis, the SLE-like prone Faslpr/lpr mutation was transferred onto an OPN-deficient background. Spleen from Faslpr/lpr and OPN-/-Faslpr/lpr mice, as well as purified B cells, were analysed by histopathology, flow cytometry, Western Blot, immunohistochemistry, immunofluorescence and gene expression profile to define lymphoma characteristics and investigate the molecular mechanisms behind the observed phenotype. OPN cellular localization in primary splenic B cells and mouse and human DLBCL cell lines was assessed by confocal microscopy. Finally, gain of function experiments, by stable over-expression of the secreted (sOPN) and intracellular OPN (iOPN) in OPN-/-Faslpr/lpr -derived DLBCL cell lines, were performed for further validation experiments. Results Despite reduced autoimmunity signs, OPN-/-Faslpr/lpr mice developed splenic lymphomas with higher incidence than Faslpr/lpr counterparts. In situ and ex vivo analysis featured such tumours as activated type of diffuse large B cell lymphoma (ABC-DLBCL), expressing BCL2 and c-MYC, but not BCL6, with activated STAT3 signaling. OPN-/-Faslpr/lpr B lymphocytes showed an enhanced TLR9-MYD88 signaling pathway, either at baseline or after stimulation with CpG oligonucleotides, which mimic dsDNA circulating in autoimmune conditions. B cells from Faslpr/lpr mice were found to express the intracellular form of OPN. Accordingly, gene transfer-mediated re-expression of iOPN, but not of its secreted isoform, into ABC-DLBCL cell lines established from OPN-/-Faslpr/lpr mice, prevented CpG-mediated activation of STAT3, suggesting that the intracellular form of OPN may represent a brake to TLR9 signaling pathway activation. Conclusion These data indicate that, in the setting of SLE-like syndrome in which double strand-DNA chronically circulates and activates TLRs, B cell intracellular OPN exerts a protective role in autoimmunity-driven DLBCL development, mainly acting as a brake in the TLR9-MYD88-STAT3 signaling pathway
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Dissecting Melanoma Heterogeneity by Integrative Genomic Analysis for Tailored Anti-Cancer Therapy
No full textCutaneous melanoma is a highly aggressive disease resistant to conventional treatment and characterized by poor prognosis. Targeted therapies against MAPK pathway and immune checkpoint inhibitors have dramatically improved survival of metastatic melanoma patients but the extent and duration of response are variable. Classification based on gene expression profiling have so far allowed identification of melanoma subtypes with distinctive biological features and with potential clinical impact. However, clinical translation of molecular subtypes is hampered by inconsistencies among the different classifications.
Here, through a harmonized bioinformatic analysis of public transcriptomic datasets, we compared and combined nine published classification systems to derive the consensus transcriptional subtypes of melanoma. Beyond confirming previously reported subtypes, our approach enabled the identification of a novel highly mitotic, chromosomally unstable group of melanomas that recapitulated a transitory state from a proliferative, melanocytic, differentiated phenotype to a more mesenchimal invasive program. We provided evidence that this classification has a prognostic role in metastatic melanoma patients, independently from the levels of tumour immune infiltration. We translated consensus subtypes to in vitro melanoma cell lines and combining them with pharmacological data we highlighted subtype-specific sensitivity to MAPK inhibitors and other drugs. Analysis of baseline gene expression data of metastatic melanoma patients treated with MAPK or immune checkpoint inhibitors showed that the predictive role of consensus subtypes in clinical setting remains to be elucidated. Finally, through the analysis of multi-omics data from the same set of patients, we comprehensively characterized the consensus subtypes at the genomic, transcriptional, and epigenomic levels.
Our results showed that melanoma gene expression classifications converged on five biological entities determined by transcriptional and epigenetic events, and with potential implications for prognostication
Association of plasma ceramides with myocardial perfusion in patients with coronary artery disease undergoing stress myocardial perfusion scintigraphy
No full textObjective- It is known that specific plasma ceramides are associated with stress-induced reversible myocardial perfusion defects in patients with established or suspected coronary artery disease undergoing myocardial perfusion scintigraphy (MPS). However, it is currently uncertain whether plasma ceramides are also associated with reduced poststress myocardial perfusion in these patients. Approach and Results- We measured 6 previously identified high-risk plasma ceramide species (ceramide [d18:1/16:0], ceramide [d18:1/18:0], ceramide [d18:1/20:0], ceramide [d18:1/22:0], ceramide [d18:1/24:0], and ceramide [d18:1/24:1]) in 167 consecutive patients with established or suspected coronary artery disease undergoing stress MPS for clinical indications. Plasma ceramides were measured by a targeted liquid chromatography-tandem mass spectrometry assay both at baseline and after MPS. Multivariable linear regression analysis was undertaken to examine the associations (standardized B coefficients) between plasma ceramides and the percentage of poststress myocardial perfusion after adjustment for multiple cardiovascular risk factors. Seventy-eight patients had stress-induced myocardial ischemia on MPS (mainly located in the anteroapical wall). Of the 6 measured plasma ceramides, higher levels of basal ceramide (d18:1/18:0; B=-0.182; P=0.019), ceramide (d18:1/20:0; B=-0.224; P=0.004), ceramide (d18:1/22:0; B=-0.163; P=0.035), and ceramide (d18:1/24:1; B=-0.20; P=0.010) were associated with lower poststress anteroapical wall perfusion. Notably, these significant associations persisted even after adjustment for conventional cardiovascular risk factors, previous coronary artery disease, electrocardiographic left bundle branch block, left ventricular ejection fraction and type of stress testing. Similar results were observed for poststress plasma ceramides. Conclusions- Higher circulating levels of specific ceramides, both at baseline and after stress, were independently associated with lower poststress anteroapical wall perfusion in patients with suspected or established coronary artery disease referred for clinically indicated MPS
Transcriptional Profiles and Stromal Changes Reveal Bone Marrow Adaptation to Early Breast Cancer in Association with Deregulated Circulating microRNAs
No full textThe presence of a growing tumor establishes a chronic state of inflammation that acts locally and systemically. Bone marrow responds to stress signals by expanding myeloid cells endowed with immunosuppressive functions, further fostering tumor growth and dissemination. How early in transformation the cross-talk with the bone marrow begins and becomes detectable in blood is unknown. Here, gene expression profiling of the bone marrow along disease progression in a spontaneous model of mammary carcinogenesis demonstrates that transcriptional modifications in the hematopoietic compartment occurred as early as preinvasive disease stages. The transcriptional profile showed downregulation of adaptive immunity and induction of programs related to innate immunity and response to danger signals triggered by activating transcription factor 3. Transcriptional reprogramming was paralleled by the expansion of myeloid populations at the expense of erythroid and B lymphoid fractions. Hematopoietic changes were associated with modifications of the bone marrow stromal architecture through relocalization and increased density in the interstitial area of Nestin(+) mesenchymal cells expressing CXCL12 and myeloid cells expressing CXCL12 receptor CXCR4. These early events were concomitant with deregulation of circulating miRNAs, which were predicted regulators of transcripts downregulated in the bone marrow and involved in lymphoid differentiation and activation. These data provide a link between sensing of peripheral cancer initiation by the bone marrow and hematopoietic adaptation to distant noxia through transcriptional rewiring toward innate/ inflammatory response programs.Significance: The bone marrow senses distant tissue transformation at premalignant/preinvasive stages, suggesting that circulating messengers, intercepted in the blood, could serve as early diagnostic markers
Association between plasma ceramides and inducible myocardial ischemia in patients with established or suspected coronary artery disease undergoing myocardial perfusion scintigraphy
No full textBackgroundRecent studies have suggested that specific plasma ceramides are independently associated with major adverse cardiovascular events in patients with coronary artery disease (CAD), but it is currently unknown whether plasma ceramide levels are associated with stress-induced reversible myocardial ischemia.MethodsWe measured six previously identified high-risk plasma ceramide molecules [Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0), and Cer(d18:1/24:1)] in 167 consecutive patients with established or suspected CAD who underwent either exercise or dypiridamole myocardial perfusion scintigraphy (MPS) for various clinical indications. Plasma ceramide levels were measured by a targeted liquid chromatography-tandem mass spectrometry assay both at baseline and after MPS.ResultsSeventy-eight patients had inducible myocardial ischemia on stress MPS. Women had significantly higher circulating levels of basal and post-stress Cer(d18:1/16:0) and Cer(d18:1/18:0) compared to men, whereas all other plasma ceramides did not differ between the sexes. Of the six measured plasma ceramides, basal Cer(d18:1/24:1) showed the strongest association with the presence of stress-induced myocardial perfusion defects in univariate analysis (unadjusted-odds ratio 1.48 per 1-SD increment, 95% confidence interval 1.08-2.04). Notably, after adjustment for age, sex, smoking, dyslipidemia, hypertension, diabetes, prior history of CAD, left ventricular ejection fraction, and type of stress testing (exercise vs. dypiridamole), all measured ceramides, except for plasma Cer(d18:1/24:0), were independently associated with the presence of inducible myocardial ischemia.ConclusionsDistinct plasma ceramides are positive and independent predictors of stress-induced myocardial perfusion defects in patients with established or suspected CAD referred for clinically indicated MPS. Further research is needed to examine whether distinct plasma ceramides could be a useful therapeutic target for treatment and management of CAD.<br/
Gene expression signature of non-involved lung tissue associated with survival in lung adenocarcinoma patients
No full textLung adenocarcinoma patients of similar clinical stage and undergoing the same treatments often have marked interindividual variations in prognosis. These clinical discrepancies may be due to the genetic background modulating an individual's predisposition to fighting cancer. Herein, we hypothesized that the lung microenvironment, as reflected by its expression profile, may affect lung adenocarcinoma patients' survival. The transcriptome of noninvolved lung tissue, excised from a discovery series of 204 lung adenocarcinoma patients, was evaluated using whole-genome expression microarrays (with probes corresponding to 28 688 wellannotated coding sequences). Genes associated with survival status at 60 months were identified by Cox regression analysis (adjusted for gender, age and clinical stage) and retested in a validation series of 78 additional cases. RNA-Seq analysis from non-involved lung tissue of 12 patients was performed to characterize the different isoforms of candidate genes. Ten genes for which the loge- transformed hazard ratios expressed the same direction of effect in the discovery (P < 1.0 × 10-3) and validation series comprised the gene expression signature associated with survival: CNTNAP1, PKNOX1, FAM156A, FRMD8, GALNTL1, TXNDC12, SNTB1, PPP3R1, SNX10 and SERPINH1. RNA sequencing highlighted the complex expression pattern of these genes in non-involved lung tissue from different patients and permitted the detection of a read-through gene fusion between PPP3R1 and the flanking gene (CNRIP1) as well as a novel isoform of CNTNAP1. Our findings support the hypothesis that individual genetic characteristics, evidenced by the expression pattern of non-involved tissue, influence the outcome of lung adenocarcinoma patients. © The Author 2013. Published by Oxford University Press
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