Hemic and Lymphatic Diseases Commons^™

Mir-155 Expression And Correlation With Clinical Outcome In Pediatric Aml: A Report From Children's Oncology Group., Ranjani Ramamurthy, Maya Hughes, Valerie Morris, Hamid Bolouri, Robert B. Gerbing, Yi-Cheng Wang, Michael R. Loken, Susana C. Raimondi, Betsy A. Hirsch, A S. Gamis, Vivian G. Oehler, Todd A. Alonzo, Soheil Meshinchi

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Aberrant expression of microRNA-155 (miR-155) has been implicated in acute myeloid leukemia (AML) and associated with clinical outcome.

PROCEDURE: We evaluated miR-155 expression in 198 children with normal karyotype AML (NK-AML) enrolled in Children's Oncology Group (COG) AML trial AAML0531 and correlated miR-155 expression levels with disease characteristics and clinical outcome. Patients were divided into quartiles (Q1-Q4) based on miR-155 expression level, and disease characteristics were then evaluated and correlated with miR-155 expression.

RESULTS: MiR-155 expression varied over 4-log10-fold range relative to its expression in normal marrow with a median expression level of 0.825 (range 0.043-25.630) for the entire …

Erratum To: High Expression Of Myocyte Enhancer Factor 2c (Mef2c) Is Associated With Adverse-Risk Features And Poor Outcome In Pediatric Acute Myeloid Leukemia: A Report From The Children's Oncology Group., George S. Laszlo, Todd A. Alonzo, Chelsea J. Gudgeon, Kimberly H. Harrington, Alex Kentsis, Robert B. Gerbing, Yi-Cheng Wang, Rhonda E. Ries, Susana C. Raimondi, Betsy A. Hirsch, A S. Gamis, Soheil Meshinchi, Roland B. Walter

Manuscripts, Articles, Book Chapters and Other Papers

No abstract provided.

A Trial Of Unrelated Donor Marrow Transplantation For Children With Severe Sickle Cell Disease., Shalini Shenoy, Mary Eapen, Julie A. Panepinto, Brent R. Logan, Juan Wu, Allistair Abraham, Joel Brochstein, Sonali Chaudhury, Kamar Godder, Ann E. Haight, Kimberly A. Kasow, Kathryn Leung, Martin Andreansky, Monica Bhatia, Jignesh Dalal, Hilary Haines, Jennifer Jaroscak, Hillard M. Lazarus, John E. Levine, Lakshmanan Krishnamurti, David Margolis, Gail C. Megason, Lolie C. Yu, Michael A. Pulsipher, Iris Gersten, Nancy Difronzo, Mary M. Horowitz, Mark C. Walters, Naynesh Kamani

Manuscripts, Articles, Book Chapters and Other Papers

Children with sickle cell disease experience organ damage, impaired quality of life, and premature mortality. Allogeneic bone marrow transplant from an HLA-matched sibling can halt disease progression but is limited by donor availability. A Blood and Marrow Transplant Clinical Trials Network (BMT CTN) phase 2 trial conducted from 2008 to 2014 enrolled 30 children aged 4 to 19 years; 29 were eligible for evaluation. The primary objective was 1-year event-free survival (EFS) after HLA allele-matched (at HLA-A, -B, -C, and -DRB1 loci) unrelated donor transplant. The conditioning regimen included alemtuzumab, fludarabine, and melphalan. Graft-versus-host disease (GVHD) prophylaxis included calcineurin inhibitor, …

Association Between Prolonged Neutropenia And Reduced Relapse Risk In Pediatric Aml: A Report From The Children's Oncology Group., Lillian Sung, Richard Aplenc, Todd A. Alonzo, Robert B. Gerbing, Yi-Cheng Wang, Soheil Meshinchi, A S. Gamis

Manuscripts, Articles, Book Chapters and Other Papers

Objective was to describe the relationship between the number of sterile site infections and duration of neutropenia during the first four cycles of chemotherapy and the risk of recurrence and overall survival in children with newly diagnosed acute myeloid leukemia (AML). AAML0531 was a Children's Oncology Group randomized phase 3 clinical trial that included 1022 children with de novo AML. For this analysis, we focused on non-Down syndrome favorable and standard risk patients who completed at least 4 cycles of chemotherapy without recurrence or withdrawal during protocol therapy. Those receiving hematopoietic stem cell transplantation in first remission were excluded. Five …

Shorter Remission Telomere Length Predicts Delayed Neutrophil Recovery After Acute Myeloid Leukemia Therapy: A Report From The Children's Oncology Group., Robert B. Gerbing, Todd A. Alonzo, Lillian Sung, Alan S. Gamis, Soheil Meshinchi, Sharon E. Plon, Alison A. Bertuch, Maria M. Gramatges

Manuscripts, Articles, Book Chapters and Other Papers

Purpose Suboptimal outcomes for children with acute myeloid leukemia (AML) necessitate maximally intensive therapy. Consequently, serious adverse events, such as prolonged periods of profound myelosuppression, contribute to AML treatment-related mortality. Telomeres, the repetitive DNA-protein structures at chromosome ends, influence cellular replicative capacity in that critically short telomeres can induce cell senescence or apoptosis. Our objective was to evaluate the impact of telomere length on duration of post-therapy neutropenia in a pediatric AML cohort. Patients and Methods Patients were diagnosed with de novo AML, enrolled in Children's Oncology Group study AAML0531, and included those with (n = 53) and without (n …

Insights Into The Molecular Roles Of Heparan Sulfate Proteoglycans (Hspgs-Syndecans) In Autocrine And Paracrine Growth Factor Signaling In The Pathogenesis Of Hodgkin's Lymphoma, Rajendra Ghardbaran

Publications and Research

Syndecans (SDC, SYND) comprise a group of four structurally related type 1 transmembrane heparan sulfate proteoglycans (HSPGs) that play important roles in tumorigenic processes. SDCs exert signaling via their protein cores and their conserved transmembrane and cytoplasmic domains or by forming complexes with growth factors (GFs). In classical Hodgkin's lymphoma (cHL), a lymphoid neoplasm of predominantly B cell origin, SDC1 and SDC4 are the active SDCs, and a number of GF (vascular endothelial growth factor, fibroblast growth factor, etc.) signaling pathways have been studied. However, despite extensive pre-clinical and clinical research on SDC-mediated GF signaling in many cancer types, there …

The Pathogenesis Of Natural Killer/T Cell Lymphoma, Bei Jiang

Theses & Dissertations

Extranodal natural killer/T-cell lymphomas (NKTCL) are uncommon lymphomas with poor prognosis. In order to gain a better understanding of the molecular pathogenesis of NKTCL, we obtained and compared the global gene expression profile, global somatic mutation profile, and global methylation profile of normal NK cells, malignant NK cell lines, and NKTCL patient samples. We showed that the JAK-STAT pathway was constitutively activated in NKTCL through the cooperation between activation of signal transducer and activator of transcription proteins (STATs) via activating mutations and inactivation of STAT suppressor protein suppressor of cytokine signaling 6 (SOCS6) through promoter hypermethylation. Activating STAT3 and STAT5B …

P27kip1 And P130 Cooperate To Regulate Hematopoietic Cell Proliferation In Vivo, Inês Soeiro, Azim Mohamedali, Hanna M. Romanska, Nicholas C. Lea, Emma S. Child, Janet Glassford, Stephen J. Orr, Claudia Roberts, Kikkeri N. Naresh, El-Nasir Lalani, David J. Mann, Roger J. Watson, N. Shaun B. Thomas, Eric W. -F. Lam

El Nasir Lalani

To investigate the potential functional cooperation between p27^Kip1 and p130 in vivo, we generated mice deficient for both p27^Kip1 and p130. In p27^Kip1−/−;p130^−/− mice, the cellularity of the spleens but not the thymi is significantly increased compared with that of their p27^Kip1−/− counterparts, affecting the lymphoid, erythroid, and myeloid compartments. In vivo cell proliferation is significantly augmented in the B and T cells, monocytes, macrophages, and erythroid progenitors in the spleens of p27^Kip1−/−; p130^−/− animals. Immunoprecipitation and immunodepletion studies indicate that p130 can compensate for the absence …

Efficient Immortalization Of Luminal Epithelial Cells From Human Mammary Gland By Introduction Of Simian Virus 40 Large Tumor Antigen With A Recombinant Retrovirus, Bartek J, Bartkova J, Kyprianou N, El-Nasir Lalani, Staskova Z, Shearer M, Chang S, Taylor Papadimitriou J

El Nasir Lalani

When defined in terms of markers for normal cell lineages, most invasive breast cancer cells correspond to the phenotype of the common luminal epithelial cell found in the terminal ductal lobular units. Luminal epithelial cells cultured from milk, which have limited proliferative potential, have now been immortalized by introducing the gene encoding simian virus 40 large tumor (T) antigen. Infection with a recombinant retrovirus proved to be 50-100 times more efficient than calcium phosphate transfection, and of the 17 cell lines isolated, only 5 passed through a crisis period as characterized by cessation of growth. When characterized by immunohistochemical staining …

Use Of Phage Display To Isolate Specifi C Human Monoclonal Antibody Fragments Against A Potential Target For Multiple Myeloma, Pei Xiong Liew, Feng Ge, Charles A. Gullo, Gerrard Kh Teoh, William Yk Hwang

Charles Gullo

Introduction: Multiple myeloma (MM), a malignancy of plasma cells, accounts for 10% of all haematological malignancies and is currently incurable. Although it can be treated, the disease tends to relapse after several years and becomes increasingly resistant to conventional therapy. Investigations into using humoral therapy for MM are now underway with a view that novel therapeutic agents may provide a more targeted therapy for MM. Materials and Methods: Here, phage display, a faster and more efficient method compared to classical hybridoma fusion technology, was used as a proof-of-concept to isolate several single-chain Fragment variables (scFv) against Ku86. Results: Anti-Ku86 polyclonal …

Conditional Screening For Ultra-High Dimensional Covariates With Survival Outcomes, Hyokyoung Grace Hong, Jian Kang, Yi Li

The University of Michigan Department of Biostatistics Working Paper Series

Identifying important biomarkers that are predictive for cancer patients' prognosis is key in gaining better insights into the biological influences on the disease and has become a critical component of precision medicine. The emergence of large-scale biomedical survival studies, which typically involve excessive number of biomarkers, has brought high demand in designing efficient screening tools for selecting predictive biomarkers. The vast amount of biomarkers defies any existing variable selection methods via regularization. The recently developed variable screening methods, though powerful in many practical setting, fail to incorporate prior information on the importance of each biomarker and are less powerful in …

Pharmacokinetics And Bioequivalence Of A Liquid Formulation Of Hydroxyurea In Children With Sickle Cell Anemia., Jeremie H. Estepp, Chiara Melloni, Courtney D. Thornburg, Paweł Wiczling, Zora Rogers, Jennifer A. Rothman, Nancy S. Green, Robert Liem, Amanda M. Brandow, Shelley E. Crary, Thomas H. Howard, Maurine H. Morris, Andrew Lewandowski, Uttam Garg, William J. Jusko, Kathleen A. Neville, Best Pharmaceuticals For Children Act-Pediatric Trials Network Administrative Core Committee

Manuscripts, Articles, Book Chapters and Other Papers

Hydroxyurea (HU) is a crucial therapy for children with sickle cell anemia, but its off-label use is a barrier to widespread acceptance. We found HU exposure is not significantly altered by liquid vs capsule formulation, and weight-based dosing schemes provide consistent exposure. HU is recommended for all children starting as young as 9 months of age with sickle cell anemia (SCA; HbSS and HbSβspan(0) thalassemia); however; a paucity of pediatric data exists regarding the pharmacokinetics (PK) or the exposure-response relationship of HU. This trial aimed to characterize the PK of HU in children and to evaluate and compare the bioavailability …

Hydroxycarbamide Versus Chronic Transfusion For Maintenance Of Transcranial Doppler Flow Velocities In Children With Sickle Cell Anaemia-Tcd With Transfusions Changing To Hydroxyurea (Twitch): A Multicentre, Open-Label, Phase 3, Non-Inferiority Trial., Russell E Ware, Barry R Davis, William H Schultz, R Clark Brown, Banu Aygun, Sharada Sarnaik, Lori Luchtman-Jones, +Several Additional Authors

Pediatrics Faculty Publications

BACKGROUND: For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions.

METHODS: TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible …

Surgeon's Guide To Anticoagulant And Antiplatelet Medications Part Two: Antiplatelet Agents And Perioperative Management Of Long-Term Anticoagulation., Louise Y Y Yeung, Babak Sarani, Jordan A Weinberg, Paul B Mcbeth, Addison K May

Surgery Faculty Publications

An increasing number of potent antiplatelet and anticoagulant medications are being used for the long-term management of cardiac, cerebrovascular, and peripheral vascular conditions. Management of these medications in the perioperative and peri-injury settings can be challenging for surgeons, mandating an understanding of these agents and the risks and benefits of various management strategies. In this two part review, agents commonly encountered by surgeons in the perioperative and peri-injury settings are discussed and management strategies for patients on long-term antiplatelet and anticoagulant therapy reviewed. In part one, we review warfarin and the new direct oral anticoagulants. In part two, we review …

Examination Of Reticulocytosis Among Chronically Transfused Children With Sickle Cell Anemia., Megha Kaushal, Colleen Byrnes, Zarir Khademian, Natalie Duncan, Naomi L. Luban, Jeffery L Miller, Ross Fasano, Emily R. Meier

Pediatrics Faculty Publications

Sickle cell anemia (SCA) is an inherited hemolytic anemia with compensatory reticulocytosis. Recent studies have shown that increased levels of reticulocytosis during infancy are associated with increased hospitalizations for SCA sequelae as well as cerebrovascular pathologies. In this study, absolute reticulocyte counts (ARC) measured prior to transfusion were analysed among a cohort of 29 pediatric SCA patients receiving chronic transfusion therapy (CTT) for primary and secondary stroke prevention. A cross-sectional flow cytometric analysis of the reticulocyte phenotype was also performed. Mean duration of CTT was 3.1 ± 2.6 years. Fifteen subjects with magnetic resonance angiography (MRA) -vasculopathy had significantly higher …