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Biomedical subjects

M W Kieran

Publications and source records attributed to M W Kieran.

At least 19 recordsLinked to original sources
PubMed2006

A pilot study of dose-intensified procarbazine, CCNU, vincristine for poor prognosis brain tumors utilizing fibronectin-assisted, retroviral-mediated modification of CD34+ peripheral blood cells with O6-methylguanine DNA methyltransferase.

Administration of chemotherapy is often limited by myelosuppression. Expression of drug-resistance genes in hematopoietic cells has been proposed as a means to decrease the toxicity of cytotoxic agents. In this pilot study, we utilized a retroviral vector expressing methylguanine DNA methyltransferase (MGMT) to transduce hematopoietic progenitors, which were subsequently used in the setting of alkylator therapy (procarbazine, CCNU, vincristine (PCV)) for poor prognosis brain tumors. Granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood progenitor cells were collected by apheresis and enriched for CD34+ expression. Nine subjects were infused with CD34+-enriched cells treated in a transduction procedure involving a 4-day exposure to cytokines with vector exposure on days 3 and 4. No major adverse event was related to the gene therapy procedure. Importantly, the engraftment kinetics of the treated product was similar to unmanipulated peripheral blood stem cells, suggesting that the ex vivo manipulation did not significantly reduce engrafting progenitor cell function. Gene-transduced cells were detected in all subjects. Although the level and duration was limited, patients receiving cells transduced using fibronectin 'preloaded' with virus supernatant appeared to show improved in vivo marking frequency. These findings demonstrate the feasibility and safety of utilizing MGMT-transduced CD34+ peripheral blood progenitor cells in the setting of chemotherapy.

Adolescent↗
PubMed2001

Myelopoiesis in the zebrafish, Danio rerio.

Genome-wide chemical mutagenesis screens in the zebrafish (Danio rerio) have led to the identification of novel genes affecting vertebrate erythropoiesis. In determining if this approach could also be used to clarify the molecular genetics of myelopoiesis, it was found that the developmental hierarchy of myeloid precursors in the zebrafish kidney is similar to that in human bone marrow. Zebrafish neutrophils resembled human neutrophils, possessing segmented nuclei and myeloperoxidase-positive cytoplasmic granules. The zebrafish homologue of the human myeloperoxidase (MPO) gene, which is specific to cells of the neutrophil lineage, was cloned and used to synthesize antisense RNA probes for in situ hybridization analyses of zebrafish embryos. Granulocytic cells expressing zebrafish mpo were first evident at 18 hours after fertilization (hpf) in the posterior intermediate cell mass (ICM) and on the anterior yolk sac by 20 hpf. By 24 hpf, mpo-expressing cells were observed along the ICM and within the developing vascular system. Thus, the mpo gene should provide a useful molecular probe for identifying zebrafish mutants with defects in granulopoiesis. The expression of zebrafish homologues was also examined in 2 other mammalian hematopoietic genes, Pu.1, which appears to initiate a commitment step in normal mammalian myeloid development, and L-Plastin, a gene expressed by human monocytes and macrophages. The results demonstrate a high level of conservation of the spatio-temporal expression patterns of these genes between zebrafish and mammals. The morphologic and molecular genetic evidence presented here supports the zebrafish as an informative model system for the study of normal and aberrant human myelopoiesis. (Blood. 2001;98:643-651)

Amino Acid Sequence↗
PubMed2001

Antiangiogenesis therapy. Current and future agents.

Approaches to cancer therapy for most tumors in adults and children have changed little in 50 years: surgery, radiation, and chemotherapy are standard for many solid tumors. When the concept of angiogenesis in cancer biology was introduced in the 1970s, there was little recognition of the therapeutic potential of attacking a tumor's blood supply. Advances in understanding the molecular processes that regulate tumor blood supply and novel agents that can interfere with them have generated a great deal of scientific interest and excitement. This article reviews the current understanding of angiogenesis and its role in cancer then discusses new therapeutic options in animals and humans, with a focus on pediatric tumors and the potential for treating them.

Angiogenesis Inhibitors↗
PubMed2001

Memory deficits among children with craniopharyngiomas.

OBJECTIVE: To describe neuropsychological functioning (with a specific focus on cognition and memory) after surgical treatment of craniopharyngiomas. METHODS: Sixteen patients who were between 6 and 15 years of age at the time of surgery comprised the sample. Each child had been treated for a craniopharyngioma with surgery only, on Dana-Farber Cancer Institute Protocol 92-077. RESULTS: The overall level of cognitive functioning was well within the average range, with both language and visuospatial functioning being generally intact; however, specific memory problems, in both the language and visuospatial domains, were evident. CONCLUSION: Although general cognitive functioning was intact after the surgical treatment of craniopharyngiomas, difficulties in the retrieval of learned information were observed. Neuropsychological assessments, with a focus on memory recall, should be a component of the medical management plan for each child.

Adolescent↗
PubMed2000

Advances in pediatric neuro-oncology.

A number of exciting advances have been reported over the past few years in the understanding and treatment of children with brain tumors. The present review highlights many of the publications from this period, focusing on their relevance within the major diagnostic and treatment domains of pediatric oncology (surgery, radiation therapy, chemotherapy, neuropathology, and neuroradiology). Although many of the publications cited provide confirmation of previously reported work, when taken together they form a good framework of the state of the field from the past few years.

Child↗
PubMed1999

Concentration-dependent positive and negative regulation of a MAP kinase by a MAP kinase kinase.

There are at least three distinct MAP kinase signaling modules in mammalian cells, distinguished by the family of kinases (Erk, SAPK/JNK, or p38) that is ultimately activated. Many input signals activate multiple MAP kinase cascades, and the mechanisms that control the specificity of signal output are not well understood. We show that SEK1/MKK4, a MAP kinase kinase proposed to activate SAPK/JNK, is a very potent inhibitor of p54 SAPK beta/JNK3 both in vitro and in vivo if present at equimolar or higher ratios. In contrast SEK can activate SAPK when present in substoichiometric amounts, but this activation is slow, consistent with the rate-limiting step in activation being the dissociation of an inactive SEK:SAPK complex. The N-terminal unique region of SEK is both necessary and partially sufficient for inhibition of SAPK, and is also necessary for activation of SAPK by SEK in vitro. We have also used the p38 MAP kinase and its activator MKK6 to examine the regulatory relationships among different kinases involved in stress responses. We show using purified kinases that inhibitory activity is specific for the combination of SEK and SAPK: SEK can activate but not inhibit p38, and MKK6 can activate but not inhibit SAPK beta and p38. These results reveal a potential mechanism for regulating stress-activated kinases, adding to a growing body of evidence suggesting that MAP kinases are controlled by relatively stable interactions with their activators.

Animals↗
PubMed1999

Innovative therapies for pediatric brain tumors.

Success in the treatment of pediatric brain tumors has lagged behind that of other pediatric cancers. This paper highlights many of the advances that have taken place over the past few years in the surgical, radiotherapeutic, and chemotherapeutic approaches to central nervous system lesions that we hope will lead to a dramatic improvement in outcome. Innovations in neurosurgical and radiotherapeutic techniques have resulted in decreasing toxicity although substantial improvement in cure rates has not been observed. Many new techniques such as gene therapy, angiogenesis inhibitors, immunotherapy, and others that have not been part of the classic approach to these lesions are now in clinical trials in the hope that they will impact on the survival of these patients. The scientific basis for these new treatment modalities and preliminary clinical results are discussed.

Brain Neoplasms↗
PubMed1998

The cloche and spadetail genes differentially affect hematopoiesis and vasculogenesis.

In vertebrates, hematopoietic and vascular progenitors develop from ventral mesoderm. The first primitive wave of hematopoiesis yields embryonic red blood cells, whereas progenitor cells of subsequent definitive waves form all hematopoietic cell lineages. In this report we examine the development of hematopoietic and vasculogenic cells in normal zebrafish and characterize defects in cloche and spadetail mutant embryos. The zebrafish homologs of lmo2, c-myb, fli1, flk1, and flt4 have been cloned and characterized in this study. Expression of these genes identifies embryonic regions that contain hematopoietic and vascular progenitor cells. The expression of c-myb also identifies definitive hematopoietic cells in the ventral wall of the dorsal aorta. Analysis of b316 mutant embryos that carry a deletion of the c-myb gene demonstrates that c-myb is not required for primitive erythropoiesis in zebrafish even though it is expressed in these cells. Both cloche and spadetail mutant embryos have defects in primitive hematopoiesis and definitive hematopoiesis. The cloche mutants also have significant decreases in vascular gene expression, whereas spadetail mutants expressed normal levels of these genes. These studies demonstrate that the molecular mechanisms that regulate hematopoiesis and vasculogenesis have been conserved throughout vertebrate evolution and the clo and spt genes are key regulators of these programs.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Thrombopoietin rescues in vitro erythroid colony formation from mouse embryos lacking the erythropoietin receptor.

The interaction of the hormone erythropoietin and its receptor (EpoR) is though to be required for normal hematopoiesis. To define the role of EpoR in this process, the murine EpoR was disrupted by homologous recombination. Mice lacking the EpoR died in utero at embryonic day 11-12.5 with severe anemia. Embryonic erythropoiesis was markedly diminished, while fetal liver hematopoiesis was blocked at the proerythroblast stage. Other cell types known to express EpoR, including megakaryocytes, mast, and neural cells were morphologically normal. Reverse transcription-coupled PCR analysis of RNA from embryonic yolk sac, peripheral blood, and fetal liver demonstrated near normal transcripts levels for EKLF, thrombopoietin (Tpo), c-MPL, GATA-1, GATA-2, and alpha- and embryonic beta H1-globin but non for adult beta maj-globin. While colony-forming unit-erythroid (CFU-E) and burst-forming unit-erythroid (BFU-E) colonies were not present in cultures derived from EpoR-/- liver or yolk sac cells, hemoglobin-containing BFU-E colonies were detected in cultures treated with recombinant Tpo and Kit ligand or with Tpo and interleukin 3 and 11. Rescued BFU-E colonies expressed adult beta-globin and c-MPL and appeared morphologically normal. Thus, erythroid progenitors are formed in vivo in mice lacking the EpoR, and our studies demonstrate that a signal transmitted through the Tpo receptor c-MPL stimulates proliferation and terminal differentiation of these progenitors in vitro.

Animals↗
PubMed1996

Stress- and mitogen-activated signal transduction in hematopoietic cells.

The ability of an organism to respond to its environment is critical to survival. The mechanisms by which cells recognize and interpret different stimuli vary enormously and can be manifested by proliferation, differentiation, apoptosis, or altered metabolic activity. Recently, a series of signaling cascades was identified that links actions on the cell surface with activation or suppression of transcription. These signals are transmitted via phosphorylation and include the stress-activated protein kinases and the mitogen-activated protein kinases. This review describes these cascades in reference to the hematopoietic cell lineages.

Animals↗
PubMed1995

Intraembryonic hematopoietic cell migration during vertebrate development.

Vertebrate hematopoietic stem cells are derived from vental mesoderm, which is postulated to migrate to both extra- and intraembryonic positions during gastrula and neurula stages. Extraembryonic migration has previously been documented, but the origin and migration of intraembryonic hematopoietic cells have not been visualized. The zebrafish and most other teleosts do not form yolk sac blood islands during early embryogenesis, but instead hematopoiesis occurs solely in a dorsal location known as the intermediate cell mass (IM) or Oellacher. In this report, we have isolated cDNAs encoding zebrafish homologs of the hematopoietic transcription factors GATA-1 and GATA-2 and have used these markers to determine that the IM is formed from mesodermal cells in a posterior-lateral position on the yolk syncytial layer of the gastrula yolk sac. Surprisingly, cells of the IM then migrate anteriorly through most of the body length prior to the onset of active circulation and exit onto the yolk sac. These findings support a hypothesis in which the hematopoietic program of vertebrates is established by variations in homologous migration pathways of extra- and intraembryonic progenitors.

Amino Acid Sequence↗
PubMed1992

Portohepatic shunt in a Down syndrome patient with an interchange trisomy 47,XY,-2,+der(2),+der(21)t(2;21)(p13;q22.1)mat.

A rare vascular portohepatic anomaly was identified in a Down syndrome patient with a 47,XY,-2,+der(2),+der(21)t(2;21)(p13;q22.1) mat chromosomal complement. This vascular defect involves a direct communication between the right portal vein and the inferior vena cava (IVC). We discuss the possibility that this vascular defect is a rare manifestation in Down syndrome. Alternatively, the existence of these 2 rare events in the same patient raises the possibility that they are causally related.

Chromosomes, Human, Pair 2↗
PubMed1989

Lymphocyte homing.

The phenomenon of "homing" is discussed with respect to patterns of lymphocyte circulation and the molecules on the surface of both endothelium and lymphocytes that mediate this process. In addition, the data are analysed in the context of a model for lymphocyte homing.

Animals↗
PubMed1984

Correlation of erythrocytic peripheral blood chimaerism and putative bone marrow precursors bearing erythroid differentiation (B-G) antigens using monoclonal antibodies immobilized on fluorescent latex spheres.

The degree of erythroid chimaerism from chickens made chimaeric following stem cell infusion as embryos has been determined using a sensitive and simple procedure with monoclonal antibodies (MAbs) specific for erythroid differentiation (B-G) antigens. Highly labelled fluorescent latex beads coupled to specific MAbs have allowed for the detection of very low frequency chimaeric cell subpopulations. A direct correlation between the chimaerism of the bone marrow cells, from which mature RBCs had been eliminated, and the percentage RBC chimaerism in the blood was found. This comprises additional evidence that the B-G bearing bone marrow cells are precursors for mature RBCs.

Animals↗
PubMed1983

Organ specific metastasis with special reference to avian systems.

Many malignant tumors demonstrate a definite propensity for metastasis to specific organs despite the fact that tumor cells with the potential for metastasis may circulate randomly throughout the body. Current concepts of organ specific metastasis (OSM) center around the generation of tumor cell variants with enhanced capacity for metastasis to specific organs. At present three hypotheses, mechanical, seed and soil, and specific tumor cell adherence (STCA), stand out as possible explanations for OSM. These possible mechanisms of OSM are by no means mutually exclusive. Recent efforts to understand OSM have included the selection of organ-specific metastasizing variants from tumor cell lines and an examination of their surface and metastatic properties. OSM-selected cell lines from many different tumor systems have been used to examine the relative contributions of the three mechanisms. While examples of each mechanism have been reported, the relative contributions of each for different tumor systems may differ substantially. Therefore, generalizations about the behavior of tumors based on studies with just a few tumor lines and systems may not be valid. There is substantial evidence that cell surface molecules are important in the process of OSM and homing of lymphocytes to specific lymph nodes. Monoclonal antibodies have been produced against putative cell surface receptors and initial biochemical characterization has begun. There is much evidence that cell surface glycoconjugates can serve as specific recognition structures on normal cells and in addition, may play important roles in OSM. The role of these carbohydrates is discussed. The chick embryo as a model system is discussed as it offers several advantages for the study of metastasis in general and OSM in particular. A variety of human and murine tumors, including some freshly isolated, have been shown to grow and metastasize in these embryos. Furthermore, cell lines which have been selected for OSM in adults show similar patterns of metastasis in chick embryos indicating that this system may be an especially attractive one for the analysis of OSM.

Animals↗