Expression data from CD138+ cells obtained from MM patients at diagnosis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE16791 | GEO | 2013/06/01
SECONDARY ACCESSION(S): PRJNA117549
REPOSITORIES: GEO
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Project description:Thalidomide-dexamethasone (TD) combination is an effective induction therapy for newly diagnosed multiple myeloma patients, candidates for subsequent autologous stem cell transplantation (ASCT). Since maximization of tumor response before ASCT may favorably affect the clinical outcomes, we designed a study to identify a gene expression profile (GEP) signature predictive of attainment of complete response to TD induction therapy. CD138+ bone marrow samples obtained at diagnosis from 112/311 patients were analyzed. Two subsequent time phases were planned. Firstly, a GEP supervised analysis, performed on a training set of 32 patients, allowed to identify 157 probe sets differentially expressed in complete responder + near complete responder (CR+nCR) versus ?partial responder patients. Than, we generated an 8-gene GEP signature predicting at diagnosis the probability to achieve CR+nCR to TD induction therapy. The performance of this assay was subsequently validated in an 80 patients training set. The 8-gene signature provide a negative predictive value of 93% and a positive predictive value of 44%. The 8 genes were down-regulated in patients who achieved at least a nCR. These results could be an important first step to adopting a diagnostic assay, used to determine, at diagnosis, patients who will respond more favourably to a particular treatment strategy. This series of microarray experiments contains the gene expression profiles of purified plasma cells (PCs) obtained from 32 newly diagnosed multiple myeloma (MM). PCs were purified from bone marrow specimens, using CD138 immunomagnetic microbeads. The purity of the positively selected PCs was assessed by flow cytometry and was > 90% in all cases. 5 micrograms of total RNA was processed and hybridized to the Affymetrix HG U133 Plus 2.0 GeneChip following the manufacturer's instructions.
2013-06-01 | E-GEOD-16791 | biostudies-arrayexpress
Project description:A subanalysis of the GIMEMA-MMY-3006 trial was performed to characterize treatment-emergent peripheral neuropathy (PN) in patients randomized to thalidomide-dexamethasone (TD) or bortezomib-TD (VTD) before and after double autologous transplantation (ASCT) for multiple myeloma (MM). 236 patients randomized to VTD and 238 to TD were stratified according to the emergence of grade ≥2 PN. Gene expression profiles (GEP) of CD138+ plasma cells were analyzed from 122 VTD-treated patients. The incidence of grade ≥2 PN was 35% in the VTD arm and 10% in the TD arm (p<0.001). PN resolved in 88% and 95% of patients in VTD and TD groups, respectively. Rates of complete/near complete response, progression-free and overall survival were not adversely affected by emergence of grade ≥2 PN. Baseline characteristics were not risk factors for PN, while GEP analysis revealed the deregulated expression of genes implicated in cytoskeleton rearrangement, neurogenesis and axonal guidance. In conclusion, in comparison with TD, incorporation of VTD into ASCT was associated with a higher incidence of PN which, however, was reversible in most of the patients and did not adversely affect their outcomes nor their ability to subsequently receive ASCT. GEP analysis suggests an interaction between myeloma genetic profiles and development of VTD-induced PN.
2014-12-23 | GSE58133 | GEO
Project description:A subanalysis of the GIMEMA-MMY-3006 trial was performed to characterize treatment-emergent peripheral neuropathy (PN) in patients randomized to thalidomide-dexamethasone (TD) or bortezomib-TD (VTD) before and after double autologous transplantation (ASCT) for multiple myeloma (MM). 236 patients randomized to VTD and 238 to TD were stratified according to the emergence of grade M-bM-^IM-%2 PN. Gene expression profiles (GEP) of CD138+ plasma cells were analyzed from 122 VTD-treated patients. The incidence of grade M-bM-^IM-%2 PN was 35% in the VTD arm and 10% in the TD arm (p<0.001). PN resolved in 88% and 95% of patients in VTD and TD groups, respectively. Rates of complete/near complete response, progression-free and overall survival were not adversely affected by emergence of grade M-bM-^IM-%2 PN. Baseline characteristics were not risk factors for PN, while GEP analysis revealed the deregulated expression of genes implicated in cytoskeleton rearrangement, neurogenesis and axonal guidance. In conclusion, in comparison with TD, incorporation of VTD into ASCT was associated with a higher incidence of PN which, however, was reversible in most of the patients and did not adversely affect their outcomes nor their ability to subsequently receive ASCT. GEP analysis suggests an interaction between myeloma genetic profiles and development of VTD-induced PN. 120 samples have been analyzed; the homogeneity of samples has been ensured by the immunomagnetic enrichment procedure: only >90% pure CD138+ cells have been employed.
2014-12-23 | E-GEOD-58133 | biostudies-arrayexpress
Project description:The prime focus of the current therapeutic strategy for Multiple Myeloma (MM) is an early and deep tumour burden reduction; this characterizes and defines the complete response (CR). To date, no description of the characteristics of the plasma cells (PC) prone to achieve CR has been reported. This study aimed at the molecular characterization of PC derived from MM patients who achieved CR after bortezomib-thalidomide-dexamethasone (VTD) first line therapy. One hundred and eighteen MM primary tumours obtained from homogeneously treated patients were globally profiled both for gene expression and for single nucleotide polymorphism genotype. Genomic results were used to obtain a predictor of sensitivity to VTD induction therapy, as well as to describe both the transcription and the genomic profile of PC derived from patients with MM who will respond optimally to primary induction therapy. By analysing the gene profiles of CR patients, we identified a 5-gene signature predicting CR with an overall median accuracy of 75% (range: 72%-85%). In addition, we highlighted the differential expression of a series of genes, whose deregulation, accordingly to their reported functions, might explain the CR patientsâ sensitivity to VTD therapy. We also showed that a small copy number loss, covering 606Kb on chromosome 1p22.1 was the most significantly associated with CR patients. The study provides insights into the genomic landscape of PC obtained from newly diagnosed MM patients achieving CR after VTD and shows that patients might be accurately stratified according to their sensitivity to VTD. 118 samples have been analyzed; the homogeneity of samples has been ensured by the immunomagnetic enrichment procedure: only >90% pure CD138+ cells have been employed. Response to vtd therapy (provided in each sample record); CR: complete response nCR: near complete response VGPR: Very good partial response PR: partial response SD: Stable disease
2015-12-31 | E-GEOD-68871 | biostudies-arrayexpress
Project description:During many years, chemo-immunotherapy fludarabine-cyclophosphamide-rituximab (FCR) was considered as the gold standard for the first line treatment of medically fit patients with symptomatic B-chronic lymphocytic leukemia (CLL). Over the last decade, targeted biotherapies have revolutionized the management of B-CLL patients' treatment and almost entirely supplanted FCR. However, no biomarker still exists to predict the complete remission (CR) with undetectable minimal residual disease (uMRD), which remains so far the best predictive factor for survival. Circulating miRNAs represent a class of molecular biomarkers which expression is altered in hematological disorders including B-CLL. Our present study aimed at identifying before treatment circulating miRNAs that predict the treatment outcome in previously untreated B-CLL patients (NCT 01370772, https://clinicaltrials.gov/ct2/show/NCT01370772). Using hierarchical clustering of miRNA expression profiles discriminating 8 patients who achieved CR with bone marrow (BM) uMRD, from 8 patients who do not achieved CR and displayed detectable BM MRD, we identified 25 miRNAs differentially expressed before treatment. The expression of 11 representative miRNAs was further validated on a larger cohort (n=123). Based on the dosage of 5 miRNAs at diagnosis, a decision tree was constructed to predict treatment outcome. Our results identified 6 groups of patients with a distinct probability of being CR with BM uMRD to FCR treatment, ranging from 72% (miR-125b, miR-15b and miR-181c high) to 4% (miR-125b and miR-193b low). Progression-free survival (PFS) was significantly different between the established groups (p=0.019). None of the patients displaying high expression levels of miR-125b, miR-15b and miR-181c (HHH group) relapsed during the follow-up of the study. In contrast, patients with miR-15b low and miR-412 high (HLH group), and patients with low expression levels of miR-125b and miR-193b (LL group) demonstrated a significant low PFS. By RNA sequencing blood at diagnosis, we compared mRNA expression profiles of these three groups, achieving or not CR with uMRD. We identified that patients relapsing after treatment are characterized by significant enrichment of gene signatures related to cell cycle, MYC target genes, metabolism and translation regulation at diagnosis. Conversely, patients achieving CR with uMRD displayed significant enrichment in genes related to communication between CLL cells and the microenvironment, immune system activation and upregulation of polycomb PRC2 complex target genes at diagnosis. Our results suggest that blood miRNAs are potent predictive biomarkers for treatment efficacy of FCR and might be implicated in the FCR efficacy in B-CLL patients. Further investigations could establish whether these miRNAs might also be used to stratify patients for new-generation treatments. Overall, our work provides insight into unmet need for the treatment of B-CLL patients and identified pathways potentially predictive of patients’ remission.
2022-10-11 | GSE214763 | GEO
Project description:MicroRNAs(miRNAs) are a class of small non-coding RNAs that have been shown to play a crucial role in normal hematopoiesis and leukemogenesis. In this study, we aimed to identify key miRNAs relevant to differentiation arrest in acute myeloid leukemia (AML). Next-generation small RNA sequencing (RNA-seq) was performed on paired bone marrow samples from 5 AML patients at initial diagnosis and first complete remission (CR). Differentially expressed miRNAs (DEMs) at initial diagnosis as compared to CR were analyzed for each case.
2023-12-27 | GSE244813 | GEO
Project description:Diffuse large B-cell lymphoma (DLBCL) has striking clinical and molecular variability. Although a more precise identification of the multiple determinants of this variability is still under investigation, there is a consensus that high-clinical-risk DLBCL cases require a risk-adapted therapy, since intensification of chemotherapy with autologous stem-cell transplantation (ASCT) has been shown to improve the prognosis for high-risk patients in randomised clinical trials. In spite of this, the protocols used for these patients have a high morbidity, associated with ASCT and the use of multiple drugs. This makes it important to identify patients that may take benefit from risk-adapted therapies, through the recognition of biological markers that provide information about both the tumoral cells and the microenvironment. Unfortunately, many of the studies so far performed have relied on heterogeneous series of patients, staged or treated with different protocols. For instance, some of the variability in DLBCL arises from the fact that this diagnosis is applied to de novo and secondary tumours, nodal and extranodal, irrespective of clinical stage, patient age and associated infections. Additionally, DLBCL includes some specific variants, such as mediastinal DLBCL and T/HRBCL, with specific prognostic parameters. This could prevent the identification of potential predictive biomarkers, because the results of many studies show that the search for predictive biomarkers should be promoted in the context of samples of clinically homogeneous patients enrolled in clinical trials. A further source of variability is the dependence of some predictive markers on specific therapeutic approaches, as is the case for the Bcl6 expression in DLBCL, since Bcl-6+ cases have been shown not to benefit from the addition of R to CHOP. Here we have analysed a series of high-clinical-risk DLBCLs by a two-stage approach, first identifying functional signatures by expression analysis, then analysing surrogate biomarkers using tissue microarrays (TMAs). This eclectic approach could reveal new aspects of the relationship between the neoplastic cells and the microenvironment, leading to the identification of previously unknown prognostic markers. At the same time, the use of functional signatures to analyse expression-profiling data avoids the poor reproducibility of the data obtained from gene-by-gene analysis, and benefits from the existence of a growing body of data concerning the major pathways deregulated in DLBCL. To avoid the bias of semiquantitative scoring, in this study we have quantified the markers included in the multivariate analysis. Experiment Overall Design: Patients Experiment Overall Design: The study was performed in a series of 74 high-clinical-risk DLBCL patients included in a prospective trial from the GEL/TAMO Spanish Group (Grupo Español de Linfomas / Trasplante de Médula �sea) between June 2001 and June 2005. High risk was defined as having either an age-adjusted IPI score >=2 or IPI <2 with a high β2 microglobulin level. Experiment Overall Design: All patients received therapy with MegaCHOP, after which, patients were again evaluated for response by CT and Ga 67S. Patients with CT response and negative Ga 67S received another MegaCHOP cycle followed by BEAM and ASCT. Those patients with positive Ga 67S or without CT response underwent salvage treatment with Ifosfamide and Etoposide (IFE) for two courses, followed by BEAM and ASCT whenever a response had been achieved. From June 2003 Rituximab was added to the schema, before administering ASCT. Those patients with less than a Partial Response (PR) or progressive disease after IFE were removed from the study. Experiment Overall Design: Diagnoses were revised by a panel of pathologists, following the World Health Organization (WHO)9 criteria. Only primary DLBCLs were included in this analysis. T-cell/histiocyte-rich large B-cell lymphomas (T/HRLBCLs) and mediastinal DLBCLs were excluded. Experiment Overall Design: Patients included in this biological analysis were consecutive, selected only on the basis of the availability of formalin-fixed paraffin-embedded or frozen tissue representative of the tumour at diagnosis. The final number of cases analysed was 50. Frozen diagnostic tissue was available from a subset of ten of these patients. Experiment Overall Design: Informed consent was obtained from the patients included in the trial under the supervision of the Local Ethical Committees. Experiment Overall Design: Identifying biological function surrogate markers for clinical prediction Experiment Overall Design: The expression profile was initially analysed in the ten samples from which frozen tissue was available. These included four patients who had died after treatment failure and six who were alive, with complete remission, and free of disease. Experiment Overall Design: All frozen tissue corresponded to a representative area of the tumour with more than 60% of viable tumoral cells present. Experiment Overall Design: We used a multistep gene-set-enrichment approach to identify functional pathways deregulated in DLBCLs resistant to the treatment strategy. Experiment Overall Design: The design of the analysis was as follows (details on the procedure are included as Supplementary information on material and Methods) : Experiment Overall Design: 1. Microarray analysis, using both cDNA and oligonucleotide microarrays in a set of 10 frozen diagnostic samples. Experiment Overall Design: 2. Identification of biological function representative of differentially expressed genes, using the Gene Ontology database (http://bioinformatics.weizmann.ac.il/cards) Experiment Overall Design: 3. Selection of surrogate immunohistochemical markers (representative of the biological function identified) Experiment Overall Design: 4. Immunohistochemical study on Tissue Microarrays containing diagnostic initial biopsy tissue in a set of 50 patients Experiment Overall Design: a. Semiquantitative scoring Experiment Overall Design: b. Quantification of the most relevant markers Experiment Overall Design: Identification of biological markers predicting treatment response Experiment Overall Design: The relations between the semiquantitative measurement of the 60 proteins evaluated and the clinical outcome were analysed. The clinical end-points were: a) CR after 3 MegaCHOP, b) CR after IFE and, c) absence of progression after consolidation with HDT/ ASCT. Experiment Overall Design: The chi-square statistic was used to assess associations between the protein-expression levels and the intermediate step of treatment. Significant relationships (p<0.05) and non-significant trends (p<0.1) were identified. Experiment Overall Design: Failure was defined as progression or death attributable to the tumour. Failure-free survival (FFS) curves were plotted using the Kaplan-Meier method. Statistical significance of associations between individual variables and FFS was determined using the log-rank test. Significant relationships (p<0.05) and non-significant trends (p<0.1) were identified. Experiment Overall Design: Genes were clustered on the basis of their biological similarities. Experiment Overall Design: The accumulations or alternations of marker alterations were analysed by the chi-square and Spearman correlation tests. Only significant relationships (p<0.05) were considered further. Experiment Overall Design: One surrogate marker for each altered main cellular function was selected. These markers were considered in order to develop a multivariate logistic regression model predicting failure of treatment. Proteins found to be potentially informative in this analysis were automatically scored. Experiment Overall Design: Various multivariate models were fitted using step-up (forward) and step-down (backwards) variable selection and other heuristic procedures. By comparing the fits of these models, a final predictive logistic regression model was obtained. The final model estimates the odds ratio (OR), 95% confidence interval (CI) and significance (P) of each variable. General applicability of the model was tested by leave-one-out cross-validation. Different predictor models were found when using leave-one-out cross validation but these showed only small variations in the weight of each marker. Accuracy was also tested by the Receiver Operating Characteristic (ROC) curve, which estimates the discriminating ability of the model. The fit of the final model was assessed by the Hosmer-Lemeshow test. Experiment Overall Design: To demonstrate the predictive capacity of the model, patients were ranked according to this score and then divided into quartiles. Experiment Overall Design: Statistical analyses were performed using SPSS and R tools.
2008-04-06 | E-GEOD-9429 | biostudies-arrayexpress
Project description:Current staging classifications do not accurately predict the benefit of high-dose chemotherapy (HDC) with autologous stem-cell transplantation (ASCT) for patients with diffuse large B-cell lymphoma (DLBCL) at high risk (age-adjusted International Index [aaIPI] score 2 or 3), who have achieved first complete remission after R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone) treatment. We aim to construct a genetic prognostic model for improving individualized risk stratification and response prediction for HDC/ASCT therapy. We identified differentially expressed mRNAs associated with relapse of DLBCL.
2023-08-16 | GSE156309 | GEO
Project description:We report here mRNA-seq data of wild-type and Nat4-deletion mutant yeast cells. We also report mRNA-seq data of wild-type yeast cells grown under non-calorie restriction (NCR) and calorie restriction (CR) conditions.
2016-11-22 | GSE86242 | GEO
Project description:Despite extensive research on SARS-CoV-2 vaccination responses in healthy individuals, there is comparatively little known beyond antibody titers and T-cell responses in the vulnerable cohort of patients after allogeneic hematopoietic stem cell transplantation (ASCT). In this study, we assessed the serological response and performed longitudinal multimodal analyses including T cell functionality and single-cell RNA sequencing combined with TCR/BCR profiling in the context of BNT162b2 vaccination in ASCT patients. In addition, these data were compared to publicly available data sets of healthy vaccinees. Protective antibody titers were achieved in 40% of patients. We identified a distorted B and T cell distribution, a reduced TCR diversity, and increased levels of exhaustion marker expression as possible causes for the poorer vaccine response rates in ASCT patients. IGHV gene rearrangement after vaccination proved to be highly variable in ASCT patients. Changes in TCRα and TCRβ gene rearrangement after vaccination differed from patterns observed in healthy vaccinees as well as unvaccinated ASCT patients and associated transplant donors. Crucially, ASCT patients elicited comparable proportions of SARS-CoV-2 vaccine-induced (VI) CD8+ T cells, characterized by a distinct gene expression pattern that is associated with SARS-CoV-2 specificity in healthy individuals. Our study underlines the impaired immune system and thus the lower vaccine response rates in ASCT patients. However, since protective vaccine responses and VI-CD8+ T cells can be induced in part of ASCT patients, our data advocate early post-transplant vaccination due to the high risk of infection in this vulnerable group.
2024-03-07 | GSE253948 | GEO