Biomedical subjects

John D Shaughnessy

Publications and source records attributed to John D Shaughnessy.

25 records · Page 2Linked to original sources

PubMed2003

Global gene expression profiling in the study of multiple myeloma.

Multiple myeloma (MM) is a rare but uniformly fatal malignancy of antibody-secreting plasma cells. Although several key molecular events in disease initiation or progression have been confirmed (eg, FGFR3/MMSET activation) or implicated (eg, chromosome 13 deletion), the mechanisms of MM development remain enigmatic. Although it is generally indistinguishable morphologically, MM importantly exhibits a tremendous degree of variability in its clinical course, with some patients surviving only months and others for many years. However, measures of current laboratory parameters can account for no more than 20% of this outcome variability. Furthermore, the means by which current drugs impart their anti-MM effect are mostly unknown. The development of serious comorbidities, such as osteopenia and/or focal lytic lesions of bone, is also poorly understood. Finally, very little knowledge exists concerning the molecular triggers for the conversion of benign monoclonal gammopathy of undetermined significance (MGUS) to overt MM. Given that abnormal gene expression lies at the heart of most if not all cancers, high-throughput global gene expression profiling has become a powerful tool for investigating the molecular biology and clinical behaviors Here I discuss recent progress made in addressing many of these issues through the molecular dissection of the transcriptome of normal plasma cells, MGUS, and MM.

Antineoplastic Agents↗

PubMed2003

The distinct gene expression profiles of chronic lymphocytic leukemia and multiple myeloma suggest different anti-apoptotic mechanisms but predict only some differences in phenotype.

We compared gene expression in purified tumor cells from untreated patients with chronic lymphocytic (CLL) (n=24) and newly diagnosed multiple myeloma (MM) (n=29) using the Affymetrix HuGeneFL microarray with probes for approximately 6800 genes. Hierarchical clustering analysis showed that CLL and MM have distinct expression profiles (class prediction). Gene and protein expression (measured by flow cytometry) correlated well for CD19, CD20, CD23, and CD138 in CLL and MM, but not for immunoglobulin light chain, CD38 and CD79b in CLL, or CD45 and CD52 in MM. CLL and MM differentially expressed 18% of 130 apoptosis related genes, suggesting differences in mechanisms of cell survival.

Antigens, CD↗

PubMed2003

Interpreting the molecular biology and clinical behavior of multiple myeloma in the context of global gene expression profiling.

Multiple myeloma (MM) is a rare but uniformly fatal malignancy of antibody-secreting plasma cells (PCs). Although several key molecular events in disease initiation or progression have been confirmed (e.g. FGFR3/MMSET activation) or implicated (e.g. chromosome 13 deletion), the mechanisms of MM development remain enigmatic. Importantly, although generally being indistinguishable morphologically, MM exhibits a tremendous degree of variability in clinical course, with some patients surviving only months and others many years. However, current laboratory parameters can account for no more than 20% of this outcome variability. Furthermore, the means by which current drugs impart their anti-MM effect are also mostly unknown. In addition, the mechanisms by which MM cells contribute to serious comorbidities, such as osteopenia and/or focal lytic lesions of bone, are also poorly understood. Finally, very little knowledge exists concerning the molecular events leading to benign hyperplasia and/or overt malignancy of PCs. Given that abnormal gene expression lies at the heart of most, if not all, cancers, high-throughput global gene expression profiling has become a powerful tool for investigating molecular biology and clinical behavior of diseases. Here, we discuss recent progress made in addressing many of the above issues through the molecular dissection of the transcriptome of normal PCs and MM.

Cell Differentiation↗

PubMed2002

Integrating cytogenetics and gene expression profiling in the molecular analysis of multiple myeloma.

Multiple Myeloma (MM), is a currently incurable malignancy of a terminally differentiated antibody secreting plasma cell (PC) that can be controlled with high dose therapy and stem cell support. Conventional cytogenetic analysis has revealed a genomic instability that sets MM apart from the other blood cell cancers. In spite of this "genomic chaos" recurrent structural rearrangements and ploidy changes have aided the identification of important molecular mechanisms of disease etiology and that have also proved to be useful clinical landmarks. Yet, abnormal cytogenetics, present in only 30% of cases, combined with other clinical parameters, only account for 20% of the variability in clinical outcome, which can range from 2 months to > 10 years. Thus, the genomic chaos may mask a unifying chromosome abnormality, e.g. Philadelphia chromosome in CML, or may indicate that MM is a broad descriptor of constellation of many distinct clinical and molecular entities. The advent of microarray profiling of global gene expression patterns is providing evidence that both of these possibilities may be true. We will discuss how the integration of conventional and molecular cytogenetics with gene expression profiling has confirmed past observations and, yet fundamentally changed the way we view the disease.

Chromosome Aberrations↗

PubMed2002

Early results of total therapy II in multiple myeloma: implications of cytogenetics and FISH.

Long-term follow-up on Total Therapy I revealed, with a median follow-up of about 10 years, median durations of event-free survival (EFS) and overall survival (OS) of 37 and 80 mos in the 88% of patients lacking cytogenetic abnormalities (CA) of chromosome 13 compared to only 28 and 34 mos in those with CA 13. Total Therapy II (TT II) was developed to test whether more intensive remission induction and post-tandem transplant consolidation chemotherapy prior to interferon maintenance could further improve clinical outcome. All patients were also randomized to +/- thalidomide at a starting dose of 400 mg. Results obtained in the first 231 patients enrolled in TT II are presented for the two study arms combined (data for effect of thalidomide still blinded). Three-year projection of EFS and OS are 71% and 77%. On an intent-to-treat basis, 66% achieved complete remission (CR) or near-CR. Major independent adverse features associated with shortened survival included CA and chromosome 13 deletion using interphase FISH. CA identified 29 among 102 patients with FISH 13 deletion who had a very grave prognosis (3 yr EFS, 32%; OS 49%) compared to all remaining patients who enjoyed 3 yr EFS of 79% and OS of 83%. Thus, both cytogenetics and FISH are recommended in the initial evaluation of patients with MM.

Aged↗

PubMed2002

CGO: utilizing and integrating gene expression microarray data in clinical research and data management.

Clinical GeneOrganizer (CGO) is a novel windows-based archiving, organization and data mining software for the integration of gene expression profiling in clinical medicine. The program implements various user-friendly tools and extracts data for further statistical analysis. This software was written for Affymetrix GeneChip *.txt files, but can also be used for any other microarray-derived data. The MS-SQL server version acts as a data mart and links microarray data with clinical parameters of any other existing database and therefore represents a valuable tool for combining gene expression analysis and clinical disease characteristics.

Computational Biology↗

PubMed2002

Multiple myeloma.

This update provides new insights into the biology, diagnosis, prognosis, and treatment of multiple myeloma (MM) and its complications. In Section I, Drs. John Shaughnessy, Jr., and Bart Barlogie first correlate global gene microarray expression profiling of patient MM samples with normal plasma cells to provide the basis for a developmental stage-based classification of MM. The powerful clinical utility of these analyses is illustrated in delineating mechanism of drug action, identifying novel therapeutic targets, and providing a molecular analysis not only of the tumor cell, but also of the tumor microenvironment, in MM. In Section II, Dr. Jean-Luc Harousseau reviews the rationale and current results of high dose therapy and autologous stem cell transplantation in MM, including optimal patient selection, prognostic factors, conditioning regimens, sources of stem cells, use of tandem transplantation, and maintenance therapy. He then provides an update on the results of allotransplantation approaches in MM, focusing on proposed methods to reduce toxicity and exploit the graft-versus-MM alloimmune effect by transplantation earlier in the disease course, T cell depletion, and nonmyeloablative transplantation. In Section III, Dr. G. David Roodman provides recent insights into the mechanisms of osteoclast activation, interactions between bone and MM cells, adhesive interactions in MM bone disease, and osteoblast suppression. These recent advances not only provide insights into pathogenesis of MM bone disease, but also form the framework for novel therapeutics. In Section IV, Dr. Kenneth Anderson provides an up-to-date discussion of the role of the bone marrow microenvironment in promoting growth, survival, drug resistance, and migration of MM cells and the signaling cascades mediating these sequelae. These studies provide the framework for evaluation of novel therapeutics targeting the MM cell-host interaction in vivo in animal models and in derived clinical trials.

Animals↗