Prognostic value of structural chromosomal rearrangements and small cell clones with high hyperdiploidy in children with acute lymphoblastic leukemia

In this study, 107 children with acute lymphoblastic leukemia (ALL) were analysed for the presence of hyperdiploidy by cytogenetics and interphase fluorescence in situ hybridisation (I-FISH). Structural aberrations in hyperdiploid cells were investigated by multiple colour FISH (mFISH). Clones with high hyperdiploidy (>50 chromosomes) (HeH) were found in 46 patients (43%). In nine of these (20%), the abnormal clone was present in <20% of the total cell population. There was no significant difference in EFS between those patients with HeH in 2.5-20% or >20% of cells. Structural rearrangements in the HeH clone were found in 10 patients (22%). In this study, HeH karyotypes containing structural aberrations were an indication of a poor prognosis in childhood ALL.     

Potentials for RNAi in sarcoma research and therapy: Ewing's sarcoma as a model

Existing data identify EWS-FLI1 as indispensable for sustained Ewing's sarcoma growth and as the ideal therapeutic target in this disease. The siRNA may hold great promises as a fusion gene specific agent. RNAi mediated suppression of EWS-FLI1 is likely to result in an altered tumor cell phenotype including changes in chemosensitivity, and a restored differentiation potential. Thus, RNAi may serve as an adjuvant to chemotherapy. As a therapeutic means however, RNAi is hampered by limitations in the delivery of the agent and emergence of resistant clones. In vitro suppression of EWS-FLI1 expression will allow to define the phenotypic characteristics of dormant tumor cells that may give rise to late relapses, enabling improved diagnosis and treatment even of minimal residual disease.     

A Seminar/Case-Based Approach to Teaching Removable Partial Dentures to Predoctoral Students

This article describes a seminar/case-based, instructional model designed to simulate removable partial denture (RPD) problem-solving and decision-making processes encountered in third-year clinic in dental school and in dental general practice. Groups of approximately 20 second-year students (in the 3-year program) meet in a series of six 1-hour seminars during the first days of the course. Following the seminars, students complete an exercise on mouth preparation and multiple clasp and major connector designs on prototype casts. This is followed by survey-design exercises on casts of dentitions representing six variations of RPD requirements. Instructors assist students during the practice phase of each class. Each 2-hour practice session is followed by a 1-hour practical examination. The last day of the course is devoted to a comprehensive final practical examination on both maxillary and mandibular casts, incorporating any of the design features previously studied.     

Recognition of DNA modified by antitumor cisplatin by "latent" and "active" protein p53

Tumor suppressor protein p53 possesses two DNA-binding sites. One that is located within its core domain is responsible for sequence-specific DNA binding of the protein, non-specific binding to internal segments of single- or double-stranded DNA, and to certain kinds of non-B DNA structures. The other that is contained in the C-terminus of the protein binds to damaged DNA. Binding of active, latent, and in vitro-activated p53 protein to DNA fragments modified by antitumor cisplatin was studied using electrophoretic mobility shift assay in agarose gels and immunoblotting analysis. We found that both latent and active p53 forms bound to random sequences of DNA globally modified by cisplatin with a higher affinity than to unmodified DNA. Interestingly, the latent form exhibited a more pronounced selectivity for platinated DNA than the active p53. Consistently with this observation, the preference of the latent form for platinated DNA decreased as a consequence of the activation of latent p53 by phosphorylation at the protein kinase C site within its C-terminus or by binding of the monoclonal antibody Bp53-10.1. Competition experiments involving a 20-bp consensus sequence of p53 suggested that the p53 core domain was a primary binding site of the active p53 when it bound to DNA fragments lacking consensus sequence, but modified by cisplatin. In addition, the latent protein was found to selectively interact with DNA modified by cisplatin probably via its C-terminus.     

Identification of five new families strengthens the link between childhood choroid plexus carcinoma and germline TP53 mutations

We present five families of paediatric patients suffering from choroid plexus carcinoma in which we found germline TP53 mutations. Only one of the families conformed to the criteria of Li-Fraumeni syndrome and only three (including the Li-Fraumeni syndrome family) met the Chompret criteria for germline TP53 mutation testing. In the remaining two families no family history of cancer was identified and/or the parents of the patient were shown not to carry the mutation. Our results give further support to the notion that the occurrence of this rare paediatric tumour, especially in combination with a positive family history of cancer, but possibly also without any family history, may be an indicator of a germline TP53 mutation. The identification of this genetic defect has important consequences for cancer prevention and treatment in affected families.     

Caregiver-reported health outcomes of preschool children born at 28 to 32 weeks' gestation

OBJECTIVE: We conducted a population-based survey of caregivers of all preschoolers at 42 months of age who had been admitted at birth in 1996-1997 to a tertiary neonatal intensive care unit in British Columbia (BC), Canada. METHODS: In this paper, we examine health status (measured by Health Status Classification System [HSCS-PS]), health-related quality of life (HRQL) (measured by Infant and Toddler Quality of Life Questionnaire), and behavioral outcomes (measured by Child Behavior Checklist) of the preschoolers in the sample who were born at 28-32 weeks gestational age (GA) in comparison to those born at <28 weeks GA. In addition, we compare these outcomes to health status, HRQL, and behavioral outcomes of a cohort of healthy full-term infants identified from the primary care practices at two of the hospital sites in BC in 1996-1997. RESULTS: From the total identified sample of 555 children, the survey was completed for 50 children born at <28 weeks GA, 201 children born at 28-32 weeks GA, and 393 healthy full-term subjects. The developmental outcomes of the preschoolers born at 28-32 weeks GA was very similar to those born at <28 weeks GA. We also found increased parental report of problems related to health status and HRQL among the 28-32 weeks GA group. When compared with the term cohort, the 28-32 weeks GA group had poorer outcomes in all HRQL domains. CONCLUSION: This study discusses the importance of continued neurodevelopmental follow-up care of infants born at 28-32 weeks GA in addition to those infants born <28 weeks GA.     

Phthalate metabolites in urine samples from Danish children and correlations with phthalates in dust samples from their homes and daycare centers

Around the world humans use products that contain phthalates, and human exposure to certain of these phthalates has been associated with various adverse health effects. The aim of the present study has been to determine the concentrations of the metabolites of diethyl phthalate (DEP), di(n-butyl) phthalate (DnBP), di(iso-butyl) phthalate (DiBP), butyl benzyl phthalate (BBzP) and di(2-ethylhexyl) phthalate (DEHP) in urine samples from 441 Danish children (3–6 years old). These children were subjects in the Danish Indoor Environment and Children's Health study. As part of each child's medical examination, a sample from his or her first morning urination was collected. These samples were subsequently analyzed for metabolites of the targeted phthalates. The measured concentrations of each metabolite were approximately log-normally distributed, and the metabolite concentrations significantly correlated with one another. Additionally, the mass fractions of DEP, DnBP, DiBP and BBzP in dust collected from the children's bedrooms and daycare centers significantly correlated with the concentrations of these phthalates’ metabolites (monoethyl phthalate (MEP), mono-n-butyl phthalate (MnBP), mono-isobutyl phthalate (MiBP) and monobenzyl phthalate (MBzP), respectively) in the children's urine. Such correlations indicate that indoor exposures meaningfully contributed to the Danish children's intake of DEP, DnBP, DiBP and BBzP. This was not the case for DEHP. The urine concentrations of the phthalate metabolites measured in the present study were remarkably similar to those measured in urine samples from children living in countries distributed over four continents. These similarities reflect the globalization of children's exposure to phthalate containing products.     

Compound heterozygosity for a β∘-thalassemia (frameshift codons 38/39; -C) and a nondeletional swiss type of HPFH (A→C at NT -110, Gγ) in a Czechoslovakian family

Summary We have analyzed the levels and composition of the fetal hemoglobin (Hb F) in several members of a Czechoslovakian family with a heterozygosity for a newly discovered -thalassemia (codons 38/39; -C), or for a newly detected nondeletional hereditary persistence of fetal hemoglobin (a form of Swiss-HPFH with an AC mutation at nucleotide –100 5 to the Cap site of G), or with a compound heterozygosity for these two conditions. The Hb F level in the -thalassemia heterozygotes averaged 0.3% with low G values ( 28%) and relatively high AT values ( 50%), that in the two Swiss-HPFH heterozygotes averaged 0.8% with 95% G, while that of the compound heterozygote was 3.1% with 95% G. The low Hb F levels were determined with a recently published cation exchange high-performance liquid chromatography (HPLC) procedure that is accurate at the 0.1%–0.2% Hb F level [3]. This method, together with a reversed-phase HPLC procedure, made it possible to detect this unusual type of nondeletional G-HPFH and provided the data indicating that the increased Hb F in the compound heterozygote was derived mainly from the chromosome with the HPFH determinant.This study was supported in part by USPHS Research Grant HLB-41544     

Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies

Mounting evidence indicates that grouping of chronic lymphocytic leukemia (CLL) into distinct subsets with stereotyped BCRs is functionally and prognostically relevant. However, several issues need revisiting, including the criteria for identification of BCR stereotypy and its actual frequency as well as the identification of "CLL-biased" features in BCR Ig stereotypes. To this end, we examined 7596 Ig VH (IGHV-IGHD-IGHJ) sequences from 7424 CLL patients, 3 times the size of the largest published series, with an updated version of our purpose-built clustering algorithm. We document that CLL may be subdivided into 2 distinct categories: one with stereotyped and the other with nonstereotyped BCRs, at an approximate ratio of 1:2, and provide evidence suggesting a different ontogeny for these 2 categories. We also show that subset-defining sequence patterns in CLL differ from those underlying BCR stereotypy in other B-cell malignancies. Notably, 19 major subsets contained from 20 to 213 sequences each, collectively accounting for 943 sequences or one-eighth of the cohort. Hence, this compartmentalized examination of VH sequences may pave the way toward a molecular classification of CLL with implications for targeted therapeutic interventions, applicable to a significant number of patients assigned to the same subset.