Monoclonal gammopathies: Electronic subspecialty consultation.

Importance: Electronic consultation (e-consult) is an important component of care for patients in the Veterans Health Administration who require subspecialty consultation but not urgent face-to-face evaluation. Monoclonal gammopathy of undetermined significance (MGUS) is a common reason for e-consult. While often benign, MGUS requires careful evaluation and persistent surveillance over time.

Preclinical Medical Student Hematology/Oncology Education Environment.

To better prepare medical students to care for patients in today's changing health-care environment as they transition to continuing their education as residents, many US medical schools have been reviewing and modifying their curricula and are considering integration of newer adult learning techniques, including team-based learning, flipped classrooms, and other active learning approaches (Assoc Am Med Coll. 2014). Directors of hematology/oncology (H/O) courses requested an assessment of today's H/O education environment to help them respond to the ongoing changes in the education content and environment that will be necessary to meet this goal.

Acquired von Willebrand syndrome in a patient with monoclonal gammopathy of undetermined significance.

Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder that typically presents as mucocutaneous bleeding in individuals with no personal or family history of bleeding disorder. Here we present a case in which a patient presented with profound epistaxis and was found to have AVWS in the setting of monoclonal gammopathy of undetermined significance (MGUS).

Evaluation of the impact of HIV serostatus, tobacco smoking and CD4 counts on epidermoid anal cancer survival.

Tobacco smoking and HIV infection increase the risk of epidermoid anal cancer (EAC). No published studies have examined smoking and EAC outcomes, and the literature is discrepant regarding outcomes of HIV-positive patients with EAC. The goal of this study was to examine smoking history, HIV status and outcomes in EAC patients.

Teaching hematology to second year medical students: results of a national survey of hematology course directors.

Increasing clinical productivity expectations at academic medical centers and new faculty effort reporting requirements for NIH-supported investigators challenge the tradition of faculty volunteerism for medical student teaching. To better define the structure, content, and financial support of second year medical school hematology courses nationwide, we mailed a survey to the hematology course directors at 85 of the 125 accredited US medical schools. The 58 course directors who returned the survey represent all regions of the US and both public and private medical schools.

AMG531 stimulates megakaryopoiesis in vitro by binding to Mpl.

Thrombopoietin (TPO) plays a pivotal role in megakaryopoiesis. TPO initiates its biological effects by binding to its receptor Mpl. A recombinant protein consisting of a carrier Fc domain linked to multiple Mpl-binding domains was constructed, and is called AMG531.

Internalization of the thrombopoietin receptor is regulated by 2 cytoplasmic motifs.

Receptor-mediated internalization appears to be the primary mean of regulating the plasma level of thrombopoietin (TPO). However, the processes that regulate Mpl internalization have not previously been described. Using the cytokine-dependent cell line BaF3, we have identified 2 distinct motifs within the cytoplasmic domain of Mpl that underlie ligand-dependent internalization.

Identification and characterization of an isoform of murine Mpl.

A new isoform of the full-length murine thrombopoietin (Tpo) receptor was isolated from a murine spleen cDNA library. This isoform, c-mpl-II, differs from full-length c-mpl (c-mpl-I) by virtue of deletion of 180 nucleotides that encode 60 amino acids located in the extracellular domain of Mpl. Normal murine megakaryocytes were found to express both c-mpl-I and c-mpl-II transcripts.

Membrane localization is not required for Mpl function in normal hematopoietic cells.

Cellular trafficking of growth factor receptors, including cross-talk among receptors at the cell surface, may be important for signal transduction in normal hematopoietic cells. To test this idea, the signaling domain of Mpl (the thrombopoietin receptor) was targeted to the plasma membrane, or to the cytoplasm of murine marrow cells, and the ability of the cells to proliferate and differentiate in response to Mpl dimerized at the plasma membrane or free in the cytoplasm was assessed. Constructs encoding the signaling domain of Mpl linked to an FK506 binding protein domain (to permit dimerization by the membrane-permeable ligand AP20187) with or without a myristylation sequence (to target the receptor to the plasma membrane) and a hemagglutinin epitope tag were generated and introduced into murine marrow cells using a murine stem cell virus (MSCV)-based retroviral vector.

The fifth immunoglobulin-like domain of the Kit receptor is required for proteolytic cleavage from the cell surface.

Stem cell factor (SCF) initiates its biological effects by binding to its receptor Kit. Cell surface Kit is proteolytically cleaved to generate soluble Kit. Structure-function analysis of the extracellular region of Kit has implicated the first three immunoglobulin-like domains in SCF binding, and the fourth immunoglobulin-like domain in receptor dimerization.

Soluble Kit receptor blocks stem cell factor bioactivity in vitro.

Stem cell factor (SCF) is a growth factor that promotes the survival, proliferation, and differentiation of hematopoietic cells. SCF and its receptor, Kit, are normally present in both cell surface and soluble forms. Both forms of Kit can bind SCF.

Basis of hematopoietic defects in platelet-derived growth factor (PDGF)-B and PDGF beta-receptor null mice.

Platelet-derived growth factor (PDGF)-B and PDGF beta-receptor (PDGFR beta) deficiency in mice is embryonic lethal and results in cardiovascular, renal, placental, and hematologic disorders. The hematologic disorders are described, and a correlation with hepatic hypocellularity is demonstrated. To explore possible causes, the colony-forming activity of fetal liver cells in vitro was assessed, and hematopoietic chimeras were demonstrated by the transplantation of mutant fetal liver cells into lethally irradiated recipients.

Tyrosine 462 of the membrane-proximal F'-G' loop of murine Mpl is not essential for high-affinity binding of thrombopoietin.

The ligand binding site of Mpl, the thrombopoietin (Tpo) receptor, has not been determined. Tyr(462)of murine Mpl corresponds to Tyr(421)of the common beta chain of the human IL-3, IL-5 and GM-CSF receptors. Tyr(421)has been identified as essential for high-affinity ligand binding.

Signaling via Src family kinases is required for normal internalization of the receptor c-Kit.

Stem cell factor (SCF) exerts its biological effects by binding to a specific receptor, the tyrosine kinase c-Kit, which is expressed on the cell surface. Although normal cellular trafficking of growth factor receptors may play a critical role in the modulation of receptor function, the mechanisms that regulate the distribution of c-Kit on the cell surface and the internalization of c-Kit have not been fully defined. We investigated whether signal transduction via Src family kinases is required for normal c-Kit trafficking.

Deletion of the extracellular membrane-distal cytokine receptor homology module of Mpl results in constitutive cell growth and loss of thrombopoietin binding.

The thrombopoietin receptor, Mpl, is a member of the cytokine receptor superfamily. The extracellular domain of Mpl contains two copies of the cytokine receptor homology module (CRM). Mpl is encoded by c-mpl, the cellular homologue of the oncogene v-mpl.

Interferon-alpha treatment of posttransplant lymphoproliferative disorder in recipients of solid organ transplants.

Posttransplant lymphoproliferative disorder (PTLD) has been treated with decreased immunosuppression, antiviral medications, anti-B lymphocyte agents, radiation therapy, and/or chemotherapy. However, a standardized stepwise approach to treatment has not been previously evaluated. In the present study, 19 consecutive patients presenting to a single institution with newly diagnosed PTLD were treated according to a sequential protocol that consisted of (1) a reduction in immunosuppressive medications plus, if feasible, resection or definitive radiation therapy of localized disease, (2) interferon-alpha, and (3) systemic chemotherapy.

Teaching the clinical interpretation of peripheral blood smears to a second-year medical school class using the PeripheralBlood-Tutor computer program.

The interpretation of peripheral blood smears has an important role in the diagnosis of hematologic diseases and is, therefore, part of the education of physicians and technologists. We describe a computer program, PeripheralBlood-Tutor (Lippincott-Raven, Philadelphia, Pa), that teaches the morphologic features of normal and abnormal peripheral blood smears; we also describe the evaluation of the effectiveness of the program in 133 second-year medical students who were required to use the program in their hematology course. The version of the PeripheralBlood-Tutor used in the study had 2 distinct but equivalent 20-question examinations; one examination, the pretest, was taken before the students viewed the contents of the program, and the other examination, the posttest, was taken after completing the program.

Biology of thrombopoietin.

Thrombopoietin is a hematopoietic growth factor that stimulates megakaryopoiesis. Recent results indicate that thrombopoietin has multilineage hematopoietic effects both in vitro and in vivo. Clinical studies of thrombopoietin have begun, and are reviewed.

Analysis of c-kit receptor dimerization by fluorescence resonance energy transfer.

Stem cell factor (SCF) binding to the c-kit receptor triggers homodimerization and intermolecular tyrosine phosphorylation of the c-kit receptor, thus initiating signal transduction. Receptor dimerization is a critical early step in this process. Prior biochemical studies of c-kit receptor dimerization have mainly used affinity cross-linking techniques, which are beset with problems including low efficiency of cross-linking and the usual requirement for radiolabeled SCF to detect the cross-linked complex.

Human platelets display high-affinity receptors for thrombopoietin.

Thrombopoietin (Tpo) is a major regulator of megakaryopoiesis both in vivo and in vitro. Tpo initiates its biologic effects by binding to the Mpl receptor, which is a member of the hematopoietin receptor family. To define the Tpo binding characteristics of the Mpl receptor, we iodinated purified 70-kD recombinant human Tpo using the Bolton-Hunter reagent.

The recipient origin of posttransplant lymphoproliferative disorders in pulmonary transplant patients. A report of three cases.

Background: An increased incidence of posttransplant lymphoproliferative disorders (PTLD) as a result of immunosuppression has been suggested in combined heart-lung transplantation compared with other solid organ transplants, and represents a significant source of morbidity and mortality among lung transplant patients. Although infection with the Epstein-Barr virus has been implicated in the pathogenesis of PTLD, it is unclear if the PTLD is of donor or recipient origin in lung transplant patients.

Methods: The case histories and histologic, immunophenotypic, and molecular genetic findings for the three patients who developed PTLD in the authors' transplantation program are presented.

FLT3 receptor expression on the surface of normal and malignant human hematopoietic cells.

FLT3 ligand is a hematopoietic growth factor that plays a key role in growth of primitive hematopoietic cells. FLT3 receptor mRNA is found in early hematopoietic progenitors and in human myeloid leukemia blasts. Much less is known about the surface expression of FLT3 receptor on human hematopoietic cells.

Thrombopoietin stimulates colony-forming unit-megakaryocyte proliferation and megakaryocyte maturation independently of cytokines that signal through the gp130 receptor subunit.

Thrombopoietin (Tpo), the ligand for the c-Mpl receptor, is a major regulator of megakaryopoiesis. Treatment of mice with Tpo raises the platelet count fourfold within a few days. Conversely, c-mpl knock-out mice have platelet counts that are 15% that of normal.