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Biomedical subjects

Theodore B Moore

Publications and source records attributed to Theodore B Moore.

17 recordsLinked to original sources
PubMed2007

ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia.

In 15% to 30% of patients with acute myeloid leukemia (AML), aberrant proliferation is a consequence of a juxtamembrane mutation in the FLT3 gene (FMS-like tyrosine kinase 3-internal tandem duplication [FLT3-ITD]), causing constitutive kinase activity. ABT-869 (a multitargeted receptor tyrosine kinase inhibitor) inhibited the phosphorylation of FLT3, STAT5, and ERK, as well as Pim-1 expression in MV-4-11 and MOLM-13 cells (IC(50) approximately 1-10 nM) harboring the FLT3-ITD. ABT-869 inhibited the proliferation of these cells (IC(50) = 4 and 6 nM, respectively) through the induction of apoptosis (increased sub-G(0)/G(1) phase, caspase activation, and PARP cleavage), whereas cells harboring wild-type (wt)-FLT3 were less sensitive. In normal human blood spiked with AML cells, ABT-869 inhibited phosphorylation of FLT3 (IC(50) approximately 100 nM), STAT5, and ERK, and decreased Pim-1 expression. In methylcellulose-based colony-forming assays, ABT-869 had no significant effect up to 1000 nM on normal hematopoietic progenitor cells, whereas in AML patient samples harboring both FLT3-ITD and wt-FLT3, ABT-869 inhibited colony formation (IC(50) = 100 and 1000 nM, respectively). ABT-869 dose-dependently inhibited MV-4-11 and MOLM-13 flank tumor growth, prevented tumor formation, regressed established MV-4-11 xenografts, and increased survival by 20 weeks in an MV-4-11 engraftment model. In tumors, ABT-869 inhibited FLT3 phosphorylation, induced apoptosis (transferase-mediated dUTP nick-end labeling [TUNEL]) and decreased proliferation (Ki67). ABT-869 is under clinical development for AML.

Animals↗
PubMed2006

FMS-like tyrosine kinase 3 in normal hematopoiesis and acute myeloid leukemia.

Ligand-mediated activation of the FMS-like tyrosine kinase 3 (FLT3) receptor is important for normal proliferation of primitive hematopoietic cells. However, activating mutations in FLT3 induce ligand-independent downstream signaling that promotes oncogenesis through pathways involved in proliferation, differentiation, and survival. FLT3 mutations are identified as the most frequent genetic abnormality in acute myeloid leukemia and are also observed in other leukemias. Multiple small-molecule inhibitors are under development to target aberrant FLT3 activity that confers a poor prognosis in patients.

Clinical Trials as Topic↗
PubMed2006

Changing outcomes for children requiring intensive care following hematopoietic stem cell transplantation.

Past literature has shown that respiratory failure following hematopoietic stem cell transplant is associated with a universally poor outcome with mortality rates approaching 100%. More recent studies have suggested that patient survival is improving. We report our experience with the patients from our institution, a large children's hospital, who were admitted to the intensive care unit (ICU). Medical records of 183 patients, who received a bone marrow transplant between 1992 and early 2004, who were <20 yr of age, were retrospectively reviewed. Various factors that might influence mortality were examined. Over the course of the study, the ICU survival increased from 18% during the period 1992-1999 to 59% between 2000 and early 2004. In the latter period, 54% of the patients discharged from the ICU were alive at 100 days post-transplant. Factors that were significant predictors of poor outcome were malignancy as the reason for transplant, dialysis during the ICU stay, or extreme respiratory failure with a ratio of arterial oxygen tension (PaO2)/inspired oxygen concentration (FiO2) <300. Analysis of patients who required a high positive end-expiratory pressure or were ventilated with permissive hypercapnia showed that they also had a higher mortality. The impact on survival of factors such as age at time of transplant, graft-vs.-host disease, pneumonia, bacteremia, sepsis, post-transplant days, Pediatric Risk of Mortality III score, engraftment status, or veno-occlusive disease did not reach statistical significance in this cohort. Survival has improved for children who require intensive care following a bone marrow transplant, even for those who require mechanical ventilation. Patients with extreme respiratory failure and those requiring dialysis continue to have poor outcome. Because of an overall improvement in survival, children whose condition following transplant requires intensive care should be treated aggressively.

Adolescent↗
PubMed2005

Prospective phase 1/2 study of rituximab in childhood and adolescent chronic immune thrombocytopenic purpura.

We assessed safety and efficacy of rituximab in a prospective study of 36 patients, age 2.6 to 18.3 years, with severe chronic immune thrombocytopenic purpura (ITP). The primary outcome of sustained platelets above 50 x 10(9)/L (50,000/mm3) during 4 consecutive weeks, starting in weeks 9 to 12, was achieved by 11 of 36 patients (31%, confidence interval [CI], 16% to 48%). Median response time was 1 week (range, 1 to 7 weeks). Attainment of the primary outcome was not associated with age, prior pharmacologic responses, prior splenectomy, ITP duration, screening platelet count, refractoriness, or IgM reduction. First-dose, infusion-related toxicity was common (47%) despite premedication. Significant drug-related toxicities included third-dose hypotension (n = 1) and serum sickness (n = 2). Peripheral B cells were depleted in all subjects. IgM decreased 3.4% per week, but IgG did not significantly decrease. Rituximab was well tolerated, with manageable infusion-related side effects, but 6% of subjects developed serum sickness. Rituximab is beneficial for some pediatric patients with severe, chronic ITP.

Adolescent↗
PubMed2005

The role of CREB as a proto-oncogene in hematopoiesis and in acute myeloid leukemia.

CREB is a transcription factor that functions in glucose homeostasis, growth factor-dependent cell survival, and memory. In this study, we describe a role of CREB in human cancer. CREB overexpression is associated with increased risk of relapse and decreased event-free survival. CREB levels are elevated in blast cells from patients with acute myeloid leukemia. To understand the role of CREB in leukemogenesis, we studied the biological consequences of CREB overexpression in primary human leukemia cells, leukemia cell lines, and transgenic mice. Our results demonstrate that CREB promotes abnormal proliferation and survival of myeloid cells in vitro and in vivo through upregulation of specific target genes. Thus, we report that CREB is implicated in myeloid cell transformation.

ATP-Binding Cassette Transporters↗
PubMed2005

Invasive fungal infections in pediatric oncology patients: 11-year experience at a single institution.

The purpose of this study was to determine the incidence of fungal infections in pediatric hematology and oncology (PHO) patients and to describe variations regarding site of infection, organisms, and mortality. The records of 1,052 patients presenting to the UCLA PHO service with various malignancies from 1991 to 2001 were retrospectively reviewed. No patient received invasive antifungal prophylaxis. Transplant patients were excluded. The 11-year incidence of fungal infections in this pediatric oncology cohort was 4.9%. There was a linear increase in the incidence of fungal infections from 2.9% to 7.8% between 1996 and 2001 (P = 0.001). Patients with acute leukemia represented 36% of the population but had a disproportionate incidence (67%) of fungal infections. Adolescents had twice the expected incidence of infection (P < 0.0001). Overall, Candida sp. was the major pathogen. Over time, a trend of fewer infections caused by Candida and more due to Aspergillus was noted. Blood-borne infections decreased over time, while those in the urinary and respiratory tracts increased (P = 0.04). Sixty-two percent of infections occurred in neutropenic patients. PHO patients had an overall mortality of 21%, but those with fungal infections experienced a 2.6-fold higher mortality that was not attributable to infections alone. Empiric antifungal therapy had no effect on mortality rates. Concurrent nonfungal infections did not increase mortality rates. The incidence of fungal infections increased over time, possibly as a result of advances in antibacterial and chemotherapeutic regimens. Adolescents and patients with leukemia were especially at risk. Fungal infections are a poor prognostic factor, independent of fungal-related mortality. New diagnostic methods allowing for early detection and treatment as well as more effective therapies are needed.

Adolescent↗
PubMed2004

Comparison of bone marrow aspirates and biopsies in pediatric patients with ALL at days 7 and 14 of induction therapy.

The percentage of blasts in the bone marrow aspirates at day 7 or 14 of induction therapy in pediatric ALL patients is an indicator of rapid early response and an independent prognostic factor for long term outcome. Discrepancies between the percentages of blasts in bone marrow aspirates compared to biopsies have been reported. In a retrospective study on 44 consecutive patients diagnosed with ALL between 1998 and 2001, important differences were observed in the percentage of blasts between bone marrow aspirates and biopsies at days 7 and 14 of induction therapy.

Adolescent↗
PubMed2004

Severe lactic acidosis in a 14-year-old female with metastatic undifferentiated carcinoma of unknown primary.

A 14-year-old girl was found to have a large, non-tender breast mass with anemia and thrombocytopenia. The diagnosis of an undifferentiated carcinoma of unknown primary was made after open breast biopsy of the mass with negative immunohistochemical studies for breast malignancies. Further evaluation showed extensive metastatic disease affecting the bone marrow, ribs, liver, and brain with magnetic resonance imaging evidence of carcinomatous meningitis. Despite 2 months of chemotherapy and intensive supportive care, the patient died of severe lactic acidosis and disseminated intravascular coagulation after exaggerated menstrual bleeding. The association of severe lactic acidosis and undifferentiated carcinoma of unknown primary in an adolescent has not been previously described.

Acidosis, Lactic↗
PubMed2004

Megatherapy and stem cell transplantation for Ewing's family of tumors: a critical review of current literature.

Although a multimodal approach consisting of chemotherapy and local control with surgery and/or radiation has improved survival in children with Ewing's sarcoma family of tumors, the prognosis for patients with high-risk disease remains poor. More aggressive treatments with high-dose myeloablative chemotherapy followed by stem cell rescue have been utilized in an attempt to improve survival in these patients. Although many studies have been published, it is difficult to interpret the data since patient populations were heterogeneous with respect to disease stage, prior therapy, conditioning and stem cell source. Furthermore, there was no uniform definition of high risk, the sample sizes were small and most studies lacked appropriate control groups. Assessment of the utility of megatherapy will require prospective controlled studies.

Antineoplastic Agents↗
PubMed2002

Expression of cyclic adenosine monophosphate response-element binding protein in acute leukemia.

Cyclic adenosine monophosphate response-element binding protein (CREB) is a nuclear protein that regulates expression of genes that control cell proliferation, differentiation, and survival. To analyze CREB expression in leukemia cells, we conducted Western blot analysis of bone marrow cells obtained from patients with acute lymphoblastic leukemia, patients with acute myeloid leukemia, and patients without active leukemia. CREB was expressed at a higher frequency in bone marrow cells from patients with acute lymphoid or myeloid leukemia than in patients with leukemia remission or without leukemia. Our results indicate that CREB expression could be a useful marker for leukemia in patients with acute disease and suggest a role for CREB in leukemogenesis.

Adolescent↗
PubMed2002

Cell surface antigen and molecular targeting in the treatment of hematologic malignancies.

Conventional cytotoxic therapy of hematologic malignancies is often associated with significant morbidity. This morbidity is often due to the lack of specificity for hematopoietic cells. Therefore, the concept of targeted therapy for patients with hematologic malignancies has received attention for many years. The goal of monoclonal antibody therapy is to target specific cell surface antigens on malignant hematopoietic cells, while sparing normal cells and tissues. Currently, monoclonal antibodies are being evaluated for their cytotoxic effects as well as their ability to deliver toxic agents or radiation. Rituximab, a chimeric anti-CD20 antibody, has shown response rates of approximately 50% with minimal toxicity in patients with refractory indolent lymphoma. Campath-1H (anti-CD52) has shown encouraging results in patients previously treated for chronic lymphocytic leukemia, with response rates up to 33%, although with significant toxicity. Anti-CD33 antibodies are being used to deliver cytotoxic agents, such as calicheamicin to patients with acute myeloid leukemia with response rates up to 30%. In addition, anti-CD33 and anti-CD45 antibodies have been used to deliver radiation directly to leukemic cells. (131)I-labeled anti-CD45 antibodies are being studied in combination with conventional preparative regimens in patients receiving bone marrow transplantation. Lastly, the therapeutic agent STI571 (signal transduction inhibitor 571) has demonstrated the capability of targeting specific molecular abnormalities seen in hematologic malignancies. STI571 targets the tyrosine kinase activity of the bcr-abl fusion protein seen in chronic myeloid leukemia. STI571 has induced complete hematologic responses in up to 98% of patients evaluated in clinical trials.

Animals↗
PubMedDate not supplied

RNA interference and human disease.

The completion of the human genome project has left researchers searching for an efficient method to study gene function in mammalian cells. RNA interference (RNAi) is an evolutionarily conserved post-transcriptional gene silencing (PTGS) mechanism mediated by double-stranded RNA (dsRNA). The dsRNA is processed into small duplex RNA molecules of approximately 21-22 nucleotides (nts) termed small interfering RNAs (siRNAs) by a RNase III enzyme called Dicer. Interaction of siRNAs with a multi-protein complex, termed the RNA-induced silencing complex (RISC), results in sequence specific association of the activated RISC complex with the cognate RNA transcript. This interaction leads to sequence-specific cleavage of the target transcript. Originally discovered in Caenorhabditis elegans, the study of RNAi in mammalian cells has blossomed in the last couple of years with the discovery that introduction of siRNA molecules directly into somatic mammalian cells circumvents the non-specific response vertebrate cells have against larger dsRNA molecules. Emerging as a powerful tool for reverse genetic analysis, RNAi is rapidly being applied to study the function of many genes associated with human disease, in particular those associated with oncogenesis and infectious disease. This review summarizes the mechanism of RNAi and provides an overview of its current applications in medicine.

Animals↗