Single-cell analysis of Crohn’s disease lesions identifies a pathogenic cellular module associated with resistance to anti-TNF therapy
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE134881 | GEO | 2019/08/21
REPOSITORIES: GEO
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Project description:Clinical benefits of cytokine blockade in ileal Crohn’s disease (iCD) are limited to a subset of patients. Here we applied single cell technologies to iCD lesions to address whether cellular heterogeneity contributes to treatment resistance. We found that a subset of patients expressed a unique cellular module in inflamed tissues that consisted of IgG plasma cells, inflammatory mononuclear phagocytes, activated T cells and stromal cells, which we named the GIMATS module. Analysis of ligand-receptor interaction pairs identified a distinct connectivity network that likely drives the GIMATS module. Strikingly, the GIMATS module was also present in a subset of patients in 4 independent iCD cohorts (n=441), and its presence at diagnosis correlated with failure to achieve corticosteroid-free durable remission upon anti-TNF therapy. These results emphasize the limitations of current diagnostic assays and the potential for single cell mapping tools to identify novel biomarkers of treatment response and tailored therapeutic opportunities
2019-08-29 | GSE134809 | GEO
Project description:Although corticosteroids remain a mainstay of therapy for UC, a meta-regression of cohort studies in acute severe ulcerative colitis (UC) showed that 29% of patients fail corticosteroid therapy and require escalation of medical management or colectomy. We aimed to determine whether genes expressed in whole blood early following initiation of intravenous corticosteroid treatment can be associated with response. 20 corticosteroid responsive (PUCAI < 35 by day 5) and 20 corticosteroid resistant patients (PUCAI ≥ 35 by day 5 and need for 2nd line medical therapy or colectomy by hospital discharge) were selected from a prospectively accrued cohort of patients hospitalized for intravenous corticosteroid treatment of severe UC. Total RNA was extracted from blood samples collected on day 3 of intravenous corticosteroid therapy. The eluted transcriptomes were quantified on Affymetrix Human Gene 1.0 ST arrays. The data was analysed by the local-pooled error method for discovery of differential gene expression and false discovery rate correction was applied to adjust for multiple comparisons. P-values less than 0.05 after correction were considered significant.
2010-08-31 | E-GEOD-21231 | biostudies-arrayexpress
Project description:In chronic phase chronic myeloid leukemia (CP-CML) patients treated with frontline imatinib, failure to achieve early molecular response (EMR failure: BCR-ABL1 >10% (IS) at 3 months) is predictive of inferior outcomes. Identifying patients at high-risk of EMR failure at diagnosis provides an opportunity to intensify frontline therapy and potentially avoid EMR failure. We studied blood samples from 96 CP-CML patients at diagnosis and identified 365 genes that were aberrantly expressed in 13 patients who subsequently failed to achieve EMR, with a gene signature significantly enriched for stem cell phenotype (e.g. Myc, b-catenin, Hoxa9/Meis1), cell cycle, and reduced immune response pathways. We selected a 17-gene panel to predict EMR failure and validated this signature on an independent patient cohort. Patients classified as high-risk with our gene expression signature (HR-GES) exhibited significantly higher rates of EMR failure compared to low-risk (LR-GES) patients (78% vs 5%; p<0.0001) with an overall accuracy of 93%. Furthermore, HR-GES patients who received frontline nilotinib had a relatively low rate of EMR failure (10%). However HR-GES patients still had inferior deep molecular response achievement rate by 24 months compared to LR-GES patients. This novel multi-gene signature may be useful for selecting patients at high risk of EMR failure on standard therapy, who may benefit from trials of more potent kinase inhibitors or other experimental approaches.
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Project description:Although in 80% of CLL cases that require therapy is possible to achieve a complete remission using a combination of fludarabine, anti-CD20 in conjunction with cyclophosphamide and/or mitoxantrone, 20% of patients do not achieve disease control with this conventional approach. The main reason of complete remission failure is chemorefractoriness to fludarabine that occurs in up to 10% of patients requiring treatment. In order to identify new molecular predictors of refractoriness as well as druggable therapeutic targets, we combined next-generation sequencing and copy number analyses. Affymetrix SNP array analysis was performed according to the manufacturer's directions on DNA extracted from cryopreserved diagnostic samples.
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Project description:Although corticosteroids remain a mainstay of therapy for UC, a meta-regression of cohort studies in acute severe ulcerative colitis (UC) showed that 29% of patients fail corticosteroid therapy and require escalation of medical management or colectomy. We aimed to determine whether genes expressed in whole blood early following initiation of intravenous corticosteroid treatment can be associated with response.
2010-08-31 | GSE21231 | GEO
Project description:Although in 80% of CLL cases that require therapy is possible to achieve a complete remission using a combination of fludarabine, anti-CD20 in conjunction with cyclophosphamide and/or mitoxantrone, 20% of patients do not achieve disease control with this conventional approach. The main reason of complete remission failure is chemorefractoriness to fludarabine that occurs in up to 10% of patients requiring treatment. In order to identify new molecular predictors of refractoriness as well as druggable therapeutic targets, we combined next-generation sequencing and copy number analyses. Affymetrix SNP array analysis was performed according to the manufacturer's directions on DNA extracted from cryopreserved diagnostic samples. Copy number analysis of Affymetrix SNP 6.0 arrays was performed for 10 FR-CLL samples and their paired normal (non-tumoral) DNA samples, processed in the same experiment and deposited (discovery set). The analysis was then extended to 29 additional FR-CLL tumoral samples and 3 Normal DNAs processed in the same experiment, including the Reference Normal DNA provided by Affymetrix (screening set).
2014-04-30 | E-GEOD-51711 | biostudies-arrayexpress
Project description:This study aimed to identify whether c-Myc could facilitate prediction of "7+3" induction failure in de novo acute myeloid leukaemia (AML) with high-risk cytogenetics. Seventy-five untreated de novo AML patients who completed the "7+3" induction therapy were enrolled (24 patients from a prospective cohort; 51 patients from a retrospective cohort) and stratified into complete remission (CR) and non-CR groups. Myc-associated molecular signature between the CR and non-CR groups in the prospective cohort was compared after gene set enrichment analysis. c-Myc protein expression was assessed via immunohistochemical staining. A high c-Myc-immunopositivity was defined when ≥ 40% of bone marrow myeloblasts were c-Myc (+). Our results revealed that AML patients who did not achieve CR by the "7+3" induction therapy had a higher Myc gene expression than those that achieved CR (p=0.047). Myc gene expression was positively correlated with c-Myc protein expression (p=0.014). Although the non-CR group did not have more c-Myc protein expression compared to that in the CR group (p=0.151), combination of high c-Myc-immunopositivity and high-risk cytogenetics increased the probability of "7+3" induction failure compared to that in high-risk cytogenetics alone. Induction strategies other than “7+3” might be a solution for de novo patients with high c-Myc-immunopositivity and high-risk cytogenetics.
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Project description:Canine lymphoma is the most common hematological cancer in dogs and shares many molecular and clinical characteristics with human Non-Hodgkin lymphoma (NHL). The standard treatment for canine lymphoma is the “CHOP” sequential multiagent chemotherapy protocol consisting of Cyclophosphamide, Doxorubicin (Hydroxydaunorubicin), Vincristine (Oncovin™), and Prednisone. Approximately 70 - 85% of patients treated with CHOP achieve clinical remission. However, duration of remission varies and the majority of dogs eventually relapse. To identify possible biomarkers for patients failing to achieve remission in response to CHOP, we performed RNA-Seq analysis on 25 cases of canine lymphoma taken at the start of their CHOP therapy regime, and determined patient progression free survival (PFS).
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Project description:Background Identification of patients at risk of tuberculosis relapse following treatment would revolutionize clinical trials of new drugs and regimens and facilitate clinical management. The study aim was to determine whether tuberculosis patients who subsequently suffer relapse have different immune responses to mycobacteria in vitro compared to patients who remain cured for two years post-treatment. Methods First episode pulmonary tuberculosis patients were recruited into a surrogate marker study in Cape Town, South Africa. Peripheral blood samples were collected at diagnosis and after two and four weeks of tuberculosis treatment. Diluted blood was cultured with live Mycobacterium tuberculosis for six days and cellular RNA was frozen. Gene expression in samples from ten patients who subsequently relapsed, confirmed by stain genotyping, was compared to those who remained cured using Affymetrix microarrays. Results At diagnosis, the expression of 668 genes was significantly different in samples from patients who subsequently relapsed compared to successfully cured patients, and these differences persisted for at least four weeks. Gene Ontology and biological pathways analyses revealed the most significant difference was up-regulation of genes involved in cytotoxic cell-mediated killing, such as perforin, granulysin and fas ligand. Results were confirmed by qRT-PCR in a wider patient cohort. Conclusions These data show that patients who will subsequently relapse exhibit altered immune responses at diagnosis, including excessively robust cytolytic responses to M. tuberculosis in vitro, compared to patients who will achieve durable cure. Together with microbiological and clinical indices, these differences could be exploited for patient stratification in drugs trials, or for host-directed therapy development. Venous blood samples were diluted in culture medium and stimulated with live M. tuberculosis for 6 days. Samples from 10 TB patients who subsequently relapsed and 10 patients whore remained disease-free for 2 years. Samples collected at TB diagnosis and after 2 weeks or 4 weeks of treatment of first TB episode.
2015-09-10 | E-GEOD-67589 | biostudies-arrayexpress
Project description:In high income countries 90% of the patients achieve complete remission after induction chemotherapy. However, 30-40% of these patients suffer from relapse. These patients face a dismal prognosis, as the majority (>60%) of relapsed patients die within 5 years. As a result, outcome for pediatric acute myeloid leukemia (AML) patients remains poor and has stabilized over the past 15 years. To prevent or better treat relapse of AML is the best option to improve outcome. Despite patient specific differences, most patients do respond to initial therapy. This suggests that at relapse, mechanisms are active that cause the altered response to chemotherapy. Detailed understanding of mechanisms that cause relapse remain largely elusive. To gain insight in the molecular pathways that characterize relapsed AML, we performed genome wide gene expression profiling on paired initial diagnosis and relapsed AML samples of 23 pediatric AML patients. We used pathway analysis to find which molecular pathways are involved in altered gene expression between diagnosis and relapse samples of individual AML patients. 23 paired diagnosis and relapse bone marrow or peripheral blood samples were collected and cryo-preserved. They were later thawed and processed for hybridization to Affymetrix U133 Plus 2.0 arrays.
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