Circulating tumour DNA sequence analysis as an alternative to multiple myeloma bone marrow aspirates.
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ABSTRACT:
PROVIDER: S-EPMC5437268 | BioStudies |
REPOSITORIES: biostudies
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Project description:Samples in this series are pre-treatment bone marrow aspirates from multiple myeloma patients Experiment Overall Design: Samples in this series are: CD-138-selected plasma cells from bone marrow of newly diagnosed multiple myeloma patients susequently treated with Total Therapy
| E-GEOD-4581 | BioStudies
Project description:Multiple myeloma is an incurable, bone marrow-dwelling malignancy that disrupts bone homeostasis causing skeletal damage and pain. Mechanisms underlying myeloma-induced bone destruction are poorly understood and current therapies do not restore lost bone mass. Using transcriptomic profiling of isolated bone lining cell subtypes from a murine myeloma model, we find that bone morphogenetic protein (BMP) signalling is upregulated in stromal progenitor cells. BMP signalling has not previously been reported to be dysregulated in myeloma bone disease. Inhibition of BMP signalling in vivo using either a small molecule BMP receptor antagonist or a solubilized BMPR1a-FC receptor ligand trap prevents trabecular and cortical bone volume loss caused by myeloma, without increasing tumour burden. BMP inhibition directly reduces osteoclastogenesis, increases osteoblasts and bone formation, and suppresses bone marrow sclerostin levels. In summary we describe a novel role for the BMP pathway in myeloma-induced bone disease that can be therapeutically targeted.
| S-EPMC6778199 | BioStudies
Project description:<h4>Background</h4>The aim of this study was to gain insight into breast cancer dormancy by examining different measures of minimal residual disease (MRD) over time in relation to known prognostic factors.<h4>Methods</h4>Sixty-four primary breast cancer patients on follow-up (a median of 8.3 years post surgery) who were disease free had sequential bone marrow aspirates and blood samples taken for the measurement of disseminated tumour cells (DTCs), circulating tumour cells (CTCs) by CellSearch and qPCR measurement of overlapping (96-bp and 291-bp) amplicons in circulating free DNA (cfDNA).<h4>Results</h4>The presence of CTCs was correlated with the presence of DTCs measured by immunocytochemistry (P=0.01) but both were infrequently detected. Increasing cfDNA concentration correlated with ER, HER2 and triple-negative tumours and high tumour grade, and the 291-bp amplicon was inversely correlated with DTCs measured by CK19 qRT-PCR (P=0.047).<h4>Conclusion</h4>Our results show that breast cancer patients have evidence of MRD for many years after diagnosis despite there being no overt evidence of disease. The inverse relationship between bone marrow CK19 mRNA and the 291-bp amplicon in cfDNA suggests that an inverse relationship between a measure of cell viability in the bone marrow (DTCs) and cell death in the plasma occurs during the dormancy phase of breast cancer.
| S-EPMC3261674 | BioStudies
Project description:To aid preclinical development of novel therapeutics for myeloma, an in vivo model which recapitulates the human condition is required. An important feature of such a model is the interaction of myeloma cells with the bone marrow microenvironment, as this interaction modulates tumour activity and protects against drug-induced apoptosis. Therefore NOD/SCID?c(null) mice were injected intra-tibially with luciferase-tagged myeloma cells. Disease progression was monitored by weekly bioluminescent imaging (BLI) and measurement of paraprotein levels. Results were compared with magnetic resonance imaging (MRI) and histology. Assessment of model suitability for preclinical drug testing was investigated using bortezomib, melphalan and two novel agents. Cells engrafted at week 3, with a significant increase in BLI radiance occurring between weeks 5 and 7. This was accompanied by an increase in paraprotein secretion, MRI-derived tumour volume and CD138 positive cells within the bone marrow. Treatment with known anti-myeloma agents or novel agents significantly attenuated the increase in all disease markers. In addition, intra-tibial implantation of primary patient plasma cells resulted in development of myeloma within bone marrow. In conclusion, using both myeloma cell lines and primary patient cells, we have developed a model which recapitulates human myeloma by ensuring the key interaction of tumour cells with the microenvironment.
| S-EPMC3578800 | BioStudies
Project description:Samples in this series are pre-treatment bone marrow aspirates from multiple myeloma patients Experiment Overall Design: Samples in this series are: CD-138-selected plasma cells from bone marrow of newly diagnosed multiple myeloma patients susequently treated with Total Therapy
2008-06-13 | E-GEOD-4581 | ArrayExpress
Project description:<h4>Background</h4>Analysis of cell-free DNA (cfDNA) is promising for broad applications in clinical settings, but with significant bias towards late-stage cancers. Although recent studies have discussed the diverse and degraded nature of cfDNA molecules, little is known about its impact on the practice of cfDNA analysis.<h4>Methods</h4>We developed single-strand library preparation and hybrid-capture-based cfDNA sequencing (SLHC-seq) to analysis degraded cfDNA fragments. Next we used SLHC-seq to perform cfDNA profiling in 112 pancreatic cancer patients, and the results were compared with 13 previous reports. Extensive analysis was performed in terms of cfDNA fragments to explore the reasons for higher detection rate of KRAS mutations in the circulation of pancreatic cancers.<h4>Findings</h4>By applying the new approach, we achieved higher efficiency in analysis of mutations than previously reported using other detection assays. 791 cancer-specific mutations were detected in plasma of 88% patients with KRAS hotspots detected in 70% of all patients. Only 8 mutations were detected in 28 healthy controls without any known oncogenic or truncating alleles. cfDNA profiling by SLHC-seq was largely consistent with results of tissue-based sequencing. SLHC-seq rescued short or damaged cfDNA fragments along to increase the sensitivity and accuracy of circulating-tumour DNA detection.<h4>Interpretation</h4>We found that the small mutant fragments are prevalent in early-stage patients, which provides strong evidence for fragment size-based detection of pancreatic cancer. The new pipeline enhanced our understanding of cfDNA biology and provide new insights for liquid biopsy.
| S-EPMC6442234 | BioStudies
Project description:BACKGROUND:Hepatocyte growth factor (HGF) is a pleiotropic cytokine which can lead to cancer cell proliferation, migration and metastasis. In multiple myeloma (MM) patients it is an abundant component of the bone marrow. HGF levels are elevated in 50% of patients and associated with poor prognosis. Here we aim to investigate its source in myeloma. METHODS:HGF mRNA levels in bone marrow core biopsies from healthy individuals and myeloma patients were quantified by real-time PCR. HGF gene expression profiling in CD138+ cells isolated from bone marrow aspirates of healthy individuals and MM patients was performed by microarray analysis. HGF protein concentrations present in peripheral blood of MM patients were measured by enzyme-linked immunosorbent assay (ELISA). Cytogenetic status of CD138+ cells was determined by fluorescence in situ hybridization (FISH) and DNA sequencing of the HGF gene promoter. HGF secretion in co-cultures of human myeloma cell lines and bone marrow stromal cells was measured by ELISA. RESULTS:HGF gene expression profiling in both bone marrow core biopsies and CD138+ cells showed elevated HGF mRNA levels in myeloma patients. HGF mRNA levels in biopsies and in myeloma cells correlated. Quantification of HGF protein levels in serum also correlated with HGF mRNA levels in CD138+ cells from corresponding patients. Cytogenetic analysis showed myeloma cell clones with HGF copy numbers between 1 and 3 copies. There was no correlation between HGF copy number and HGF mRNA levels. Co-cultivation of the human myeloma cell lines ANBL-6 and JJN3 with bone marrow stromal cells or the HS-5 cell line resulted in a significant increase in secreted HGF. CONCLUSIONS:We here show that in myeloma patients HGF is primarily produced by malignant plasma cells, and that HGF production by these cells might be supported by the bone marrow microenvironment. Considering the fact that elevated HGF serum and plasma levels predict poor prognosis, these findings are of particular importance for patients harbouring a myeloma clone which produces large amounts of HGF.
| S-EPMC4022385 | BioStudies
Project description:This a model from the article:
A mathematical model of bone remodeling dynamics for normal bone cell populations and myeloma bone disease
Bruce P Ayati, Claire M Edwards, Glenn F Webb and John P Wikswo.
Biology Direct2010 Apr 20;5(28).
20406449,
Abstract:
BACKGROUND:
Multiple myeloma is a hematologic malignancy associated with the development of a destructive osteolytic bone disease.
RESULTS:
Mathematical models are developed for normal bone remodeling and for the dysregulated bone remodeling that occurs in myeloma bone disease. The models examine the critical signaling between osteoclasts (bone resorption) and osteoblasts (bone formation). The interactions of osteoclasts and osteoblasts are modeled as a system of differential equations for these cell populations, which exhibit stable oscillations in the normal case and unstable oscillations in the myeloma case. In the case of untreated myeloma, osteoclasts increase and osteoblasts decrease, with net bone loss as the tumor grows. The therapeutic effects of targeting both myeloma cells and cells of the bone marrow microenvironment on these dynamics are examined.
CONCLUSIONS:
The current model accurately reflects myeloma bone disease and illustrates how treatment approaches may be investigated using such computational approaches.
Note:
The paper describes three models 1) Zero-dimensional Bone Model without Tumour, 2) Zero-dimensional Bone Model with Tumour and 3) Zero-dimensional Bone Model with Tumour and Drug Treatment. This model corresponds to the Zero-dimensional Bone Model without Tumour.
Typos in the publication:
Equation (4): The first term should be (β1/α1)^(g12/Γ) and not (β2/α2)^(g12/Γ)
Equation (14): The first term should be (β1/α1)^(((g12/(1+r12))/Γ) and not (β2/α2)^(((g12/(1+r12))/Γ)
Equation (13): The first term should be (β1/α1)^((1-g22+r22)/Γ) and not (β1/α1)^((1-g22-r22)/Γ)
All these corrections has been implemented in the model, with the authors agreement.
Beyond these, there are several mismatches between the equation numbers that are mentioned in for each equation and the reference that has been made to these equations in the figure legend.
2011-12-06 | BIOMD0000000401 | BioModels
Project description:This a model from the article:
A mathematical model of bone remodeling dynamics for normal bone cell populations and myeloma bone disease
Bruce P Ayati, Claire M Edwards, Glenn F Webb and John P Wikswo.
Biology Direct2010 Apr 20;5(28).
20406449,
Abstract:
BACKGROUND:
Multiple myeloma is a hematologic malignancy associated with the development of a destructive osteolytic bone disease.
RESULTS:
Mathematical models are developed for normal bone remodeling and for the dysregulated bone remodeling that occurs in myeloma bone disease. The models examine the critical signaling between osteoclasts (bone resorption) and osteoblasts (bone formation). The interactions of osteoclasts and osteoblasts are modeled as a system of differential equations for these cell populations, which exhibit stable oscillations in the normal case and unstable oscillations in the myeloma case. In the case of untreated myeloma, osteoclasts increase and osteoblasts decrease, with net bone loss as the tumor grows. The therapeutic effects of targeting both myeloma cells and cells of the bone marrow microenvironment on these dynamics are examined.
CONCLUSIONS:
The current model accurately reflects myeloma bone disease and illustrates how treatment approaches may be investigated using such computational approaches.
Note:
The paper describes three models 1) Zero-dimensional Bone Model without Tumour, 2) Zero-dimensional Bone Model with Tumour and 3) Zero-dimensional Bone Model with Tumour and Drug Treatment. This model corresponds to the Zero-dimensional Bone Model with Tumour.
Typos in the publication:
Equation (4): The first term should be (β1/α1)^(g12/Γ) and not (β2/α2)^(g12/Γ)
Equation (14): The first term should be (β1/α1)^(((g12/(1+r12))/Γ) and not (β2/α2)^(((g12/(1+r12))/Γ)
Equation (13): The first term should be (β1/α1)^((1-g22+r22)/Γ) and not (β1/α1)^((1-g22-r22)/Γ)
All these corrections has been implemented in the model, with the authors agreement.
Beyond these, there are several mismatches between the equation numbers that are mentioned in for each equation and the reference that has been made to these equations in the figure legend.
2011-11-25 | BIOMD0000000402 | BioModels
Project description:By generating a paired single cell RNA-sequencing database of the tumor niche from 10 newly diagnosed MM patients, we created a unique dataset allowing the in-depth analyses of stromal-immune interactions within the tumor microenvironment. Using this database, we identified the presence of inflammatory stromal fibroblasts in the bone marrow of Myeloma patients.The stromal inflammation was associated with NF-κB signaling, and sources of IL-1β or TNFα were specific immune subsets previously shown to be altered in MM, suggesting the presence of an immune cell-mediated feed-forward loop of bone marrow inflammation in MM. By tracking inflammatory signatures over time in individual patients undergoing first-line treatment using bulk RNA sequencing, we show that bone marrow inflammation is not reverted by successful anti-tumor therapy (see related accession number), suggesting a role for stromal fibroblasts and bone marrow inflammation in disease persistence or relapse.
| E-MTAB-9139 | BioStudies