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Biomedical subjects

Lisa M Rimsza

Publications and source records attributed to Lisa M Rimsza.

At least 19 recordsLinked to original sources
PubMed2006

Differential effects of recombinant thrombopoietin and bone marrow stromal-conditioned media on neonatal versus adult megakaryocytes.

Umbilical cord blood (CB) is a valuable source of stem cells for transplantation, but CB transplantations are frequently complicated by delayed platelet engraftment. The reasons underlying this are unclear. We hypothesized that CB- and peripheral-blood (PB)-derived megakaryocytes (MKs) respond differently to the adult hematopoietic microenvironment and to thrombopoietin (Tpo). To test this, we cultured CB- and PB-CD34(+) cells in adult bone marrow stromal conditioned media (CM) or unconditioned media (UCM) with increasing concentrations of recombinant Tpo and compared the effects of these conditions on CB-versus PB-MKs. PB-MKs reached highest ploidy in response to UCM + 100 ng/mL rTpo, and the addition of CM inhibited their maturation. In contrast, CB-MKs reached highest ploidy in CM without rTpo, and high rTpo concentrations (> 0.1 ng/mL) inhibited their maturation. This is the first evidence that human neonatal and adult MKs have substantially different biologic responses to Tpo and potentially to other cytokines.

Adult↗
PubMed2006

Molecular diagnosis of Burkitt's lymphoma.

BACKGROUND: The distinction between Burkitt's lymphoma and diffuse large-B-cell lymphoma is crucial because these two types of lymphoma require different treatments. We examined whether gene-expression profiling could reliably distinguish Burkitt's lymphoma from diffuse large-B-cell lymphoma. METHODS: Tumor-biopsy specimens from 303 patients with aggressive lymphomas were profiled for gene expression and were also classified according to morphology, immunohistochemistry, and detection of the t(8;14) c-myc translocation. RESULTS: A classifier based on gene expression correctly identified all 25 pathologically verified cases of classic Burkitt's lymphoma. Burkitt's lymphoma was readily distinguished from diffuse large-B-cell lymphoma by the high level of expression of c-myc target genes, the expression of a subgroup of germinal-center B-cell genes, and the low level of expression of major-histocompatibility-complex class I genes and nuclear factor-kappaB target genes. Eight specimens with a pathological diagnosis of diffuse large-B-cell lymphoma had the typical gene-expression profile of Burkitt's lymphoma, suggesting they represent cases of Burkitt's lymphoma that are difficult to diagnose by current methods. Among 28 of the patients with a molecular diagnosis of Burkitt's lymphoma, the overall survival was superior among those who had received intensive chemotherapy regimens instead of lower-dose regimens. CONCLUSIONS: Gene-expression profiling is an accurate, quantitative method for distinguishing Burkitt's lymphoma from diffuse large-B-cell lymphoma.

Adolescent↗
PubMed2006

Loss of major histocompatibility class II gene and protein expression in primary mediastinal large B-cell lymphoma is highly coordinated and related to poor patient survival.

Loss of major histocompatibility class II (MHC II) expression in diffuse large B-cell lymphoma (DLBCL) correlates with worse outcome, possibly from decreased immunosurveillance. Primary mediastinal B-cell lymphoma (PMBCL) is a subtype of DLBCL which reportedly has frequent loss of MHC II proteins; however, PM-BCL has better survival than DLBCL. To investigate this paradox, we used geneexpression profiling (GEP) data and immunohistochemistry to study expression of MHC II and its regulatory genes and to determine their relationship to PMBCL survival. We found that GEP levels correlated between MHC II genes and the transcriptional regulator MHC2TA but not other adjacent genes, implying that transcriptional regulation of MHC II in PMBCL was intact and that MHC II gene deletion was unlikely. MHC II average expression was lower than in certain subtypes of DLBCL; however, only 12% had complete loss of MHC II expression. Poor patient survival in PMBCL correlated with incremental decreases in MHC II expression. Although overall survival was better, survival of the lowest 10% of MHC II expressers was similarly poor in DLBCL and PMBCL. MHC II expression may define a therapeutic target in both these diseases.

DNA↗
PubMed2006

Immunohistochemical classification of de novo, transformed, and relapsed diffuse large B-cell lymphoma into germinal center B-cell and nongerminal center B-cell subtypes correlates with gene expression profile and patient survival.

CONTEXT: Diffuse large B-cell lymphoma (DLBCL) can be assigned to prognostic subgroups, including germinal center B-cell (GCB) and activated B-cell subgroups, by using gene expression profiling and, reportedly, immunohistochemistry for CD10, Bcl-6, and multiple myeloma-1/interferon regulatory factor-4 (MUM1/IRF4). OBJECTIVE: To compare 2 commercial MUM1/IRF4 antibody formulations for accuracy in subtyping DLBCL against gene expression profiling, compare subtyping to patient survival, and evaluate the usefulness of GCB and non-GCB subtyping in relapsed and transformed DLBCL. DESIGN: Evaluation of 2 commercial MUM1/IRF4 antibodies, ICSTAT/M17 and Mum-1p, by using 40 cases of de novo, relapsed, and transformed DLBCL; and comparison of the results obtained with gene expression profiling and survival. RESULTS: Immunohistochemistry predicted the gene expression profiling subtype 71.8% and 69.2% of the time overall with use of the Mum-1p and ICSTAT/M17 antibodies, respectively, and 100% and 91.7% of the time when MUM1/IRF4 expression determined subtype. Gene expression profiling and immunohistochemistry revealed nearly identical 5-year overall survival rates for the GCB vs non-GCB subtypes (68.0% for GCB vs 24.7% for non-GCB with use of gene expression profiling [P = .03] and 70.2% vs 18.4%, respectively, with use of immunohistochemistry [P < .001]). When de novo, transformed, and relapsed cases were analyzed separately, 5-year overall survival rates were also significantly different. CONCLUSIONS: Immunohistochemistry can be used to subclassify DLBCL, including a very small series of transformed and relapsed cases, into GCB and non-GCB subtypes and predict survival rates similar to those predicted by use of gene expression profiling. The 2 MUM1/IRF4 antibodies performed similarly.

B-Lymphocytes↗
PubMed2005

Loss of major histocompatibility class II expression in non-immune-privileged site diffuse large B-cell lymphoma is highly coordinated and not due to chromosomal deletions.

Decreased major histocompatibility class II (MHCII) expression is associated with poor survival in diffuse large B-cell lymphoma (DLBCL). Immune-privileged site DLBCL (IP-DLBCL) patients reportedly have frequent large deletions at the MHCII locus whereas the mechanism of decreased expression in non-IP-DLBCL is unknown. Gene expression profiling data were used for correlation analyses between expression levels of MHCII genes with each other and their transcriptional regulator, CIITA. Comparative genomic hybridization (CGH) assessed chromosomal alterations at MHCII-related loci. Finally, a map was created of expression of genes that are telomeric, within, or centromeric to the MHCII locus. Correlation coefficients among MHCII genes ranged from 0.73 to 0.92, whereas those between adjacent and intervening genes were lower (-0.12 to 0.49). Correlations between MHCII and CIITA expression were higher (0.53 to 0.60) than between CIITA and neighboring genes (-0.05 to 0.22). In 23 MHCII(-) cases, CGH detected 2 losses and 2 gains at MHCII loci. Expression of genes telomeric, within, and centromeric to MHCII loci were near normal in most MHCII(-) cases. Large deletions of the MHCII locus are uncommon in non-IP-DLBCL, implicating altered transcription as the operative mechanism for decreased expression.

Centromere↗
PubMed2005

Effects of hypoxia on megakaryocyte progenitors obtained from the umbilical cord blood of term and preterm neonates.

BACKGROUND: Placental insufficiency is associated with early-onset thrombocytopenia in preterm neonates. Prior studies demonstrated a reduction in circulating megakaryocyte (Mk) progenitors, suggesting decreased platelet production. We hypothesized that decreased Mk production is the result of a direct inhibitory effect of hypoxia on the proliferation of Mk progenitors, or a hypoxia-induced change in the fetal hematopoietic environment. OBJECTIVE: To test the effects of hypoxia on the clonogenic maturation of Mk progenitors obtained from term and preterm cord blood CD34(pos) cells, either cultured alone or in conjunction with CD34(neg) light density mononuclear cells (LDMCs). METHODS: CD34(pos) cells and CD34(neg) LDMCs were isolated from the cord blood of term and preterm deliveries, and mobilized peripheral blood CD34(pos) cells were obtained from healthy adults. CD34(pos) cells were then cultured alone or co-cultured with CD34(neg) LDMCs in a semisolid, serum-free media containing rTpo, IL-3, and IL-6. Cultures were exposed to 20%, 5%, or 1% oxygen for 10-12 days. Mk colonies were then quantified following immunohistochemical staining. RESULTS: Pure CD34(pos) cells from preterm (n = 5) and term (n = 5) neonates and from adults (n = 4) generated similar numbers of Mk colonies in all three oxygen concentrations. However, the number of Mk colonies in preterm co-cultures was progressively lower with decreasing O(2) concentrations. CONCLUSIONS: Hypoxia did not appear to directly inhibit colony formation of Mk progenitors from preterm and term cord blood CD34(pos) cells. However, co-culture studies showed a decrease in Mk colony formation with hypoxia, suggesting an indirect inhibitory effect of hypoxia on Mk clonogenic maturation mediated by non-progenitor cells in the hematopoietic microenvironment.

Antigens, CD34↗
PubMed2005

A redox signature score identifies diffuse large B-cell lymphoma patients with a poor prognosis.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease in which approximately 40% of the patients respond well to current chemotherapy, but the prognosis for the other 60% is poor. The Leukemia/Lymphoma Molecular Profiling Project (LLMPP) used microarray technology to define a molecular profile for each of 240 patients with DLBCL and develop a molecular outcome predictor score that accurately predicted patient survival. Data from our laboratory and others suggest that alterations in antioxidant defense enzyme levels and redox environment can be oncogenic and affect the response to glucocorticoid treatment, one of the components of combination chemotherapy regimens for lymphoma. The goal of the current study was to reanalyze the LLMPP microarray data to determine whether the levels of antioxidant defense enzymes and redox proteins were correlated with prognosis in DLBCL. We found that patients with DLBCL with the worst prognosis, according to the outcome predictor score, had decreased expression of catalase, glutathione peroxidase, manganese superoxide dismutase, and VDUP1, a protein that inhibits thioredoxin activity. The data suggest that the patients with the worst prognosis combine a decrease in antioxidant defense enzyme expression with an increase in thioredoxin system function (the redox signature score).

Animals↗
PubMed2005

CD58 expression decreases as nonmalignant B cells mature in bone marrow and is frequently overexpressed in adult and pediatric precursor B-cell acute lymphoblastic leukemia.

We used flow cytometry to determine the CD58 expression on nonmalignant B cells at different stages of maturation in the bone marrow and compared it with that of blasts in adult and pediatric precursor B-cell acute lymphoblastic leukemia (B-ALL). The mean fluorescence intensity (MFI) of CD58 expression decreased significantly as nonmalignant B cells differentiated in the bone marrow from an early to a mature stage. Few nonneoplastic B cells at a mid or mature stage of development expressed CD58 MFI values comparable to those seen in leukemic cases. Early-stage nonneoplastic B-cell precursors expressed relatively higher CD58 levels, which frequently overlapped with the variable level of CD58 expression observed among leukemic blasts. As a group, however, the malignant precursor B-ALL cells showed significantly higher expression of CD58 than nonmalignant B-cell populations at any maturational stage. These findings support the potential usefulness of CD58 expression in the diagnosis and monitoring of precursor B-ALL, but only when blasts express high levels of CD58.

Adolescent↗
PubMed2004

Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells.

BACKGROUND: Patients with follicular lymphoma may survive for periods of less than 1 year to more than 20 years after diagnosis. We used gene-expression profiles of tumor-biopsy specimens obtained at diagnosis to develop a molecular predictor of the length of survival. METHODS: Gene-expression profiling was performed on 191 biopsy specimens obtained from patients with untreated follicular lymphoma. Supervised methods were used to discover expression patterns associated with the length of survival in a training set of 95 specimens. A molecular predictor of survival was constructed from these genes and validated in an independent test set of 96 specimens. RESULTS: Individual genes that predicted the length of survival were grouped into gene-expression signatures on the basis of their expression in the training set, and two such signatures were used to construct a survival predictor. The two signatures allowed patients with specimens in the test set to be divided into four quartiles with widely disparate median lengths of survival (13.6, 11.1, 10.8, and 3.9 years), independently of clinical prognostic variables. Flow cytometry showed that these signatures reflected gene expression by nonmalignant tumor-infiltrating immune cells. CONCLUSIONS: The length of survival among patients with follicular lymphoma correlates with the molecular features of nonmalignant immune cells present in the tumor at diagnosis.

Adult↗
PubMed2004

Benign B-cell precursors (hematogones) are the predominant lymphoid population in the bone marrow of preterm infants.

Bone marrow (BM) findings in 3rd-trimester stillborns and full-term living neonates have been previously described. However, there is no information regarding BM composition in living preterm infants. Specifically, it is unknown whether the BM lymphocytosis seen in full-term infants at 1-4 weeks of age also occurs in preterm infants. Furthermore, the lineage of these cells has never been investigated. We used a panel of immunohistochemical stains to characterize the BM composition in 11 neonates (8 living and 3 deceased). Unlike in the other age groups, immature B cells (hematogones) were the most common lymphoid population, accounting for 10-60% (mean 34%) of all cells. In two additional cases (both living patients), flow cytometry revealed a level of 3.8% of immature B cells in a <1-week-old neonate and 25.7% in a 19-week-old infant. Immature B cells were not identified in 6 peripheral blood samples from preterm neonates. These findings are pertinent for the interpretation of BM and peripheral blood samples in this age group as survival improves and diagnostic samples become more common.

Antigens, CD↗
PubMed2004

Loss of MHC class II gene and protein expression in diffuse large B-cell lymphoma is related to decreased tumor immunosurveillance and poor patient survival regardless of other prognostic factors: a follow-up study from the Leukemia and Lymphoma Molecular Profiling Project.

The Leukemia and Lymphoma Molecular Profiling Project recently published results from DNA microarray analyses of 240 diffuse large B-cell lymphomas (DLBCLs). Four gene expression "signatures" were identified as correlated with patient outcome, including the major histocompatibility complex (MHC) class II genes (eg, HLA-DRA) which correlated with better survival. We further analyzed the effects of HLA-DRA on survival and correlated gene expression with protein status and tumor-infiltrating lymphocytes. The 5-year overall survival was 24% in the lowest 10% of HLA-DRA expression, 37% in the 10% to 25% group, 50% in the 25% to 50% group, and 55% for patients in the highest 50%. Further analysis demonstrated that the hazard ratio of death was a nonlinear function of HLA-DRA expression. Adjustment for the International Prognostic Index did not alter the impact of HLA-DRA on survival. Other MHC class II genes were found to predict survival similarly. Microarray HLA-DRA expression correlated with the presence or absence of human leukocyte antigen-DR (HLA-DR) protein in 20 of 22 cases assessed. Fewer tumor-infiltrating CD8(+) T cells were detected in MHC class II-negative cases compared with positive cases (2.8% versus 11.0%; P =.001), supporting the hypothesis that loss of tumor immunosurveillance has a devastating effect on patient outcome in DLBCL.

Follow-Up Studies↗
PubMed2004

A neonate with severe thrombocytopenia and radio-ulnar synostosis.

Bone marrow failure syndromes can be associated with abnormalities of the forearms. We observed a neonate with congenital thrombocytopenia who had bilateral radio-ulnar synostosis and fifth finger clinodactly. We performed an evaluation of the mechanism causing the thrombocytopenia using a combination of direct and indirect measures of thrombopoiesis. These tests indicated decreased platelet production. This entity of congenital hyporegenerative thrombocytopenia with bilateral radio-ulnar synostosis and fifth-finger clinodactly is an uncommon but easily recognizable form of congenital amegakaryocytic thrombocytopenia (CAMT). This entity can be distinguished from the TAR syndrome (thrombocytopenia and absent radii) by the distinctive orthopedic issues, different underlying genetic mutations, and a more worrisome prognosis for CAMT than for TAR.

Diagnosis, Differential↗
PubMed2004

Pseudothrombocytopenia in a preterm neonate.

Severe and prolonged thrombocytopenia is not uncommon among ill preterm infants. Pseudothrombocytopenia, which has the appearance of severe and prolonged thrombocytopenia, has not been described in this population. We observed a preterm neonate who had EDTA-independent pseudothrombocytopenia and conclude that this condition should be considered when severe and prolonged thrombocytopenia occurs in a neonate in the absence of clinical signs of platelet-type hemorrhage.

Diagnostic Errors↗
PubMed2004

Reticulated platelet percentages in term and preterm neonates.

OBJECTIVES: The authors aimed to determine whether their reticulated platelet percentage (RP%) analysis technique was suitable for use in term and preterm neonates and to characterize RP% values among nonthrombocytopenic neonates. METHODS: The authors modified a whole blood method that uses dual-color CD41 staining for platelet gating and thiazole orange for RNA content, combined with RNase treatment of half the sample to subtract non-RNA fluorescence. The RP% was measured in samples from 10 healthy adults and then a longitudinal study was performed in 15 nonthrombocytopenic preterm neonates on days of life 0 to 1, 2 to 5, 6 to 10, and then weekly until day 28. The authors also performed a cross-sectional study of RP% in 22 nonthrombocytopenic neonates of different gestational age (GA) and postconceptional age (PCA). RESULTS: Overall, neonates had a higher RP% (2.7 +/- 1.6%) than adults (1.1 +/- 0.5%; P < 0.01). In preterm neonates, an increase in the RP% occurred between days 0 and 1 (3.3 +/- 1.3%) and days 2 and 5 (5.1 +/- 1.8%; P = 0.003). By days 6 to 10, the RP% decreased to 3.2 +/- 1.1% and remained unchanged throughout the rest of the study period. In neonates less than 7 days old, an inverse relationship was observed between RP% and GA (n = 20, r = -0.70; P = 0.0005). A correlation between RP% and PCA was not seen in neonates 7 days of age or older. CONCLUSIONS: This method for determining RP% is suitable for use in term and preterm neonates. In preterm infants, the RP% significantly increases over the first 2 to 5 days of life and then decreases to a stable level over the first 28 days. RP% is generally higher in neonates than in adults. Among preterm infants in the first week of life, the RP% is inversely related to GA.

Adult↗
PubMed2003

Effects of anoxia on megakaryocyte progenitors derived from cord blood CD34pos cells.

BACKGROUND: Severe hypoxic insults to the fetus and neonate are associated with the development of thrombocytopenia. The thrombocytopenia in some cases is the result of disseminated intravascular coagulation, but that mechanism fails to account for all, perhaps the majority, of cases. OBJECTIVE: We hypothesized that human fetal megakaryocyte (Mk) progenitors are directly adversely affected by transient anoxia. DESIGN AND METHODS: To test this, we isolated CD34pos cells from the umbilical cord blood of 10 healthy term neonates, and exposed these to 0% or 20% O2 for 24 h, with or without recombinant thrombopoietin (rTpo, 50 ng/mL). After 24 h, a portion of the CD34pos cells were harvested for flow cytometric evaluation of apoptosis. The remaining cells were cultured for an additional 10-12 days, under normoxic conditions, in a collagen-based serum-free system containing rTpo, IL-3, and IL-6. In this way, we sought to determine the effect of transient anoxia on clonogenic capacity of Mk progenitors. RESULTS: Contrary to our hypothesis, anoxia did not increase either apoptosis or cell death of the CD34pos cells. The addition of rTpo was protective, with a significant decrease in apoptosis and cell death (P < 0.0001), and an increase in the number of Mk colonies cultured (P = 0.04). There was no difference between the normoxic and anoxic groups in proliferative potential of the Mk progenitor cells. CONCLUSIONS: The thrombocytopenia observed in neonates following an acute hypoxic event is not likely due to a direct deleterious effect of hypoxia on Mk progenitors.

Antigens, CD34↗
PubMed2002

Developmental changes in the expression of transcription factors GATA-1, -2 and -3 during the onset of human medullary haematopoiesis.

Regulation of gene expression during the ontogeny of haematopoiesis in the human fetal bone marrow is poorly understood. Studies in mice demonstrated that GATA-1, -2 and -3 play pivotal roles in haematopoiesis. In this study, we identified GATA-1-, GATA-2- and GATA-3-expressing cells in bone marrow sections and analysed the expression of GATA-transcription factors during the development of human fetal bone marrow haematopoiesis using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). We showed that GATA-1, -2 and -3 were expressed only in haematopoietic cells in the bone marrow. RT-PCR analysis demonstrated that (1) GATA-1 expression significantly increased during gestation; (2) GATA-2 expression peaked at the onset of medullary haematopoiesis, declined thereafter, and remained at a constant level after 30 weeks post conception; and (3) GATA-3 expression revealed no changes during development. The results indicated that the onset of medullary haematopoiesis in humans is accompanied by high expression of GATA-2, reflecting high proliferation rates of early haematopoietic progenitor cells, whereas expression of GATA-1 mirrors haematopoietic activity.

Bone Marrow↗