Study of cohabitation and interconnection effects on normal and leukaemic stem cells dynamics in acute myeloid leukaemia

On the basis of recent studies, understanding the intimate relationship between normal and leukaemic stem cells is very important in leukaemia treatment. The authors’ aim in this work is to clarify and assess the effect of coexistence and interconnection phenomenon on the healthy and cancerous stem cell dynamics. To this end, they perform the analysis of two time‐delayed stem cell models in acute myeloid leukaemia. The first model is based on decoupled healthy and cancerous stem cell populations (i.e. there is no interaction between cell dynamics) and the second model includes interconnection between both population''s dynamics. By using the positivity of both systems, they build new linear functions that permit to derive global stability conditions for each model. Moreover, knowing that most common types of haematological diseases are characterised by the existence of oscillations, they give conditions for the existence of a limit cycle (oscillations) in a particularly interesting healthy situation based on Poincare–Bendixson theorem. The obtained results are simulated and interpreted to be significant in understanding the effect of interconnection and would lead to an improvement in leukaemia treatment.Inspec keywords: cellular biophysics, cancer, blood, stability, patient treatmentOther keywords: healthy stem cell dynamics, cancerous stem cell dynamics, time‐delayed stem cell models, acute myeloid leukaemia, cancerous stem cell populations, leukaemia treatment, normal stem cells dynamics, leukaemic stem cells dynamics, intimate relationship, interconnection effects, cohabitation effects, decoupled stem cell populations, global stability conditions, haematological diseases, oscillations, limit cycle, Poincare–Bendixson theorem     

Genetic susceptibility to childhood leukaemia

The aetiology of leukaemias among children is believed to be distinct from that of adults, mainly due to the clearer role for early life exposures, including those in utero. However, few risk factors have been established, because of the challenge of studying a disease with relatively low incidence. Identified risk factors, including ionizing radiation, chemotherapeutic agents and specific genetic abnormalities, explain < 10% of incidence. Although the causes for the remaining 90% are unknown, it is possible that genetic susceptibility factors, either alone or in conjunction with environmental factors, may be involved. In this paper, the authors (a) review the evidence surrounding genetic susceptibility factors, with emphasis on the genes' main effects; (b) review some recent developments in the Northern California Childhood Leukaemia Study (NCCLS) as a case study of design and practical considerations in genetic epidemiology research and (c) highlight both challenges and future directions in this exciting research area.     

Residential exposures to pesticides and childhood leukaemia

Like many chemicals, carcinogenicity of pesticides is poorly characterised in humans, especially in children, so that the present knowledge about childhood leukaemia risk derives primarily from epidemiological studies. Overall, case-control studies published in the last decade have reported positive associations with home use of insecticides, mostly before the child's birth, while findings for herbicides are mixed. Previous studies relied solely on self-reports, therefore lacking information on active ingredients and effects of potential recall bias. Few series to date have examined the influence of children's genetic susceptibility related to transport and metabolism of pesticides. To overcome these limitations, investigators of the Northern California Childhood Leukaemia Study (NCCLS) have undertaken, in collaboration with a multidisciplinary team, a comprehensive assessment of residential pesticide exposure, including: (1) quality control of self-reports; (2) home pesticide inventory and linkage to the Environmental Protection Agency to obtain data on active ingredients; (3) collection and laboratory analyses of approximately 600 home dust samples for over 60 pesticides and (4) geographic information studies using California environmental databases to assess exposure to agricultural pesticides. The NCCLS is also conducting large-scale genotyping to evaluate the role of genes in xenobiotic pathways relevant to the transport and metabolism of pesticides. A better quantification of children's exposures to pesticides at home is critical to the evaluation of childhood leukaemia risk, especially for future gene-environment interaction studies.     

Exposure to infections through day-care attendance and risk of childhood leukaemia

There is growing evidence supporting a role for infections in the aetiology of childhood leukaemia. Hypotheses proposed by both Greaves and Kinlen describe childhood leukaemia to be a rare response to one or more common infections acquired through personal contacts. Previous epidemiological studies have used day-care attendance as an indicator of the increased likelihood of early and frequent exposure to infections. It is well-documented that in developed countries, exposures to common infections occur more frequently in this type of setting. Within the Northern California Childhood Leukaemia Study, the role of social contact has been assessed and a unique 'child-hours' summary measure incorporating information on the number of months attending a day-care, mean hours per week at this day-care and the number of children in the day-care setting was constructed. In this review, the previously reported day-care results have been described, showing that in non-Hispanic White children, children in the highest category of total child-hours of exposure had a reduced risk of acute lymphoblastic leukaemia (ALL), particularly common B-cell precursor ALL (c-ALL), compared with children without such exposures, with evidence of a dose-response effect. In addition, a literature review of relevant studies has been conducted, examining the relationship between day-care attendance and risk of childhood ALL. Overall, the 14 studies identified provided consistent support for this hypothesis, with the majority of studies reporting some evidence of a reduced risk. A meta-analysis is currently underway, which will provide a quantitative evaluation of the overall consistency and strength of the association between day-care attendance or social contact and risk of childhood ALL.     

Artificial stem cell niches

Stem cells are characterized by their dual ability to reproduce themselves (self-renew) and specialize (differentiate), yielding a plethora of daughter cells that maintain and regenerate tissues. In contrast to their embryonic counterparts, adult stem cells retain their unique functions only if they are in intimate contact with an instructive microenvironment, termed stem cell niche. In these niches, stem cells integrate a complex array of molecular signals that, in concert with induced cell-intrinsic regulatory networks, control their function and balance their numbers in response to physiologic demands. This progress report provides a perspective on how advanced materials technologies could be used (i) to engineer and systematically analyze specific aspects of functional stem cells niches in a controlled fashion in vitro and (ii) to target stem cell niches in vivo. Such "artificial niches" constitute potent tools for elucidating stem cell regulatory mechanisms with the capacity to directly impact the development of novel therapeutic strategies for tissue regeneration.     

A mathematical model of subpopulation kinetics for the deconvolution of leukaemia heterogeneity

Acute myeloid leukaemia is characterized by marked inter- and intra-patient heterogeneity, the identification of which is critical for the design of personalized treatments. Heterogeneity of leukaemic cells is determined by mutations which ultimately affect the cell cycle. We have developed and validated a biologically relevant, mathematical model of the cell cycle based on unique cell-cycle signatures, defined by duration of cell-cycle phases and cyclin profiles as determined by flow cytometry, for three leukaemia cell lines. The model was discretized for the different phases in their respective progress variables (cyclins and DNA), resulting in a set of time-dependent ordinary differential equations. Cell-cycle phase distribution and cyclin concentration profiles were validated against population chase experiments. Heterogeneity was simulated in culture by combining the three cell lines in a blinded experimental set-up. Based on individual kinetics, the model was capable of identifying and quantifying cellular heterogeneity. When supplying the initial conditions only, the model predicted future cell population dynamics and estimated the previous heterogeneous composition of cells. Identification of heterogeneous leukaemia clones at diagnosis and post-treatment using such a mathematical platform has the potential to predict multiple future outcomes in response to induction and consolidation chemotherapy as well as relapse kinetics.     

Host, family and community proxies for infections potentially associated with leukaemia

Three hypotheses have proposed the involvement of infections in the aetiology of childhood leukaemia, suggesting either a specific leukaemogenic infection or a series of common infections that lead to a dysregulation of the immune system. Much of the evidence for the link with infections has been based on epidemiological observations, often using proxy measures of infection. Proxy measures include population mixing, parental occupation, age distribution of incidence, spatial and space-time clustering of cases, birth order and day care during infancy. This paper discusses the proxies used and examines to what extent a commonly used proxy measure, birth order, is a fair representation of either specific infections or general infectious load. It is clear that although leukaemia, and other diseases, may be linked with infections, one needs to (1) measure specific and general infections with more accuracy and (2) understand how proxy measures relate to real infections in the population.     

Exposure assessment and other challenges in non-ionizing radiation studies of childhood leukaemia

Studies of electromagnetic fields (EMF) and the development of childhood leukaemia face unique difficulties. EMF are imperceptible, ubiquitous, have multiple sources, and can vary greatly over time and distances. Childhood leukaemia and high average exposures to magnetic fields are both quite rare. Thus, a major challenge in EMF epidemiology is the small number of highly exposed cases and the necessity for retrospective assessment of exposure. Only studies designed to minimize bias while maximizing our ability to detect an association, should one exist, would have a potential to contribute to our understanding. New approaches are needed; the most promising in the extremely low-frequency range involves a study of a highly exposed cohort of children who have lived in apartments next to built-in transformers or electrical equipment rooms. Another promising avenue is an investigation of possible joint effects of environmental exposures and genetic co-factors. An exposure assessment methodology for residential radiofrequency fields is still in its infancy. Rapid changes in technology and exponential increases in its use make exposure assessment more difficult and urgent.     

Hip stem fatigue test prediction

The accuracy of fatigue test prediction methods for the standard fatigue testing of hip stems was evaluated against the experimental results of static and fatigue tests. Axial unnotched strain-controlled material fatigue tests provided the required cyclic material properties. Finite element analysis of the hip stems predicted a maximum tensile stress to within 3–7% of strain gauge measurements. The four methods investigated accurately predicted hip stem fatigue strength at 5 million cycles (?1% to ?9% errors). The strain–life methods successfully predicted fatigue life (factors 1/7.0–9.2 of the test) at high and low stress amplitudes of 352 and 315 MPa, respectively. The classical stress–life method was only accurate (factor 1/1.9) for the low stress level. The current study has demonstrated that fatigue test prediction methods can be applied with confidence to support standard fatigue testing of hip stems. Further studies can expand the understanding of these methods and their clinical relevance by investigating effects due to variable amplitude loading and environment.     

Assessing stem cell research productivity

Honour Index (HoI), a method to evaluate research performance within different research fields, was derived from the impact factor (IF). It can be used to rate and compare different categories of journals. HoI was used in this study to determine the scientific productivity of stem cell research in the Asian Four Dragons (Hong Kong, Singapore, South Korea and Taiwan) from 1981 to 2001. The methodology applied in this study represents a synthesis of universal indicator studies and bibliometric analyses of subfields at the micro-level. We discuss several comparisons, and conclude the developmental trend in stem cell research for two decades. This revised version was published online in August 2006 with corrections to the Cover Date.     

Exposure to electromagnetic fields and the risk of childhood leukaemia: a review

Extremely low-frequency magnetic fields have been classified as possibly carcinogenic to humans, mainly based on epidemiological studies consistently showing an association between long-term average exposures to magnetic fields above 0.3/0.4 microT and the risk of childhood leukaemia. No mechanism to explain this finding has been established and no support for a causal link emerged from experimental studies. Chance or bias cannot be ruled out with reasonable confidence as an explanation for the observed association. If the association is causal, it explains only a small fraction of childhood leukaemia cases. There were some reports of childhood leukaemia clusters in the vicinity of high-power radio and television broadcast transmitters in studies in Australia and Italy. However, recent large-scale systematic studies in Korea and Germany show no association between exposure to radio frequency electromagnetic fields emitted from broadcast towers and childhood leukaemia risk. Studies on mobile phone use and leukaemia risk in adolescents and young adults may be indicated.     

Childhood leukaemia following medical diagnostic exposure to ionizing radiation in utero or after birth

A statistical association between childhood leukaemia and an abdominal X-ray examination of the pregnant mother was first reported in 1956 from a case-control study of childhood cancer mortality conducted in Great Britain. This study, later called the Oxford Survey of Childhood Cancers (OSCC), was continued and eventually showed a highly statistically significant approximately 50% proportional increase in the risk of childhood leukaemia associated with antenatal diagnostic radiography. The association has been confirmed by many case-control studies carried out around the world, the appropriately combined results of which show a highly statistically significant increase in risk that is compatible with the OSCC finding. There is no doubt about the reality of the statistical association, but a causal interpretation has been questioned. On balance, however, the evidence points to low-level irradiation of the fetus increasing the risk of leukaemia in childhood, with an excess relative risk coefficient of around 50 Gy(-1) (equivalent to an excess absolute risk coefficient of about 3% Gy(-1)), although the uncertainty associated with these coefficients is considerable and they are likely to be overestimates. In contrast to exposure in utero, the evidence from case-control studies for an association between childhood leukaemia and postnatal exposure to medical diagnostic irradiation is equivocal and sometimes conflicting. Since standard radiation risk models predict that low-level exposure in the early years of life should produce an increased risk of childhood leukaemia that is roughly similar to that arising from fetal exposure, this absence of persuasive evidence is likely to be due to various problems with the studies. This is unfortunate given the rise in relatively high dose diagnostic procedures (e.g. paediatric CT scans) that would be predicted to materially increase the relative risk of childhood leukaemia.     

Incidence, time trends and regional variation of childhood leukaemia in Germany and Europe

This paper presents data on the German and Europe-wide incidence, time trends and regional variations of childhood leukaemia. Data were provided by the German Childhood Cancer Registry (GCCR), a population-based cancer registry recording all cases of malignant diseases in children under 15 y of age residing in Germany and by the Automated Childhood Cancer Information System (ACCIS) co-ordinated at International Agency for Research on Cancer, Lyon, that combines and evaluates data from several European population-based cancer registries. The incidence of leukaemia (44.0 per million) has increased in Europe as well as in Germany in the last decades (0.6% annually on average). Germany shows no systematic aggregation of regions with low or high cancer incidence in terms of regional clustering. Incidence rates differ between European regions with the highest rates in Northern Europe (48.0 per million) and the lowest rates in Eastern Europe (39.1). Altogether, the results from ACCIS and the GCCR show good agreement.     

The UK Childhood Cancer Study: maternal occupational exposures and childhood leukaemia and lymphoma

Risks of childhood leukaemia and lymphoma were investigated for specific work-related exposures of mothers in the UK Childhood Cancer Study. Interviews with parents of 1881 leukaemia and lymphoma cases (0-14 years) and 3742 controls collected job histories recording exposure to eight specific agents. Exposure was (1) self-reported and (2) reviewed, based mainly on exposure probability and exposure level. Completeness, consistency and sufficiency evaluated data quality. Of all job exposures which were self-reported as exposed, 33% cases and 34% controls remained classified as exposed after review, with the remainder designated as partially exposed or unexposed. No review of underreporting of exposure was made. Data quality was 'good' for 26% of cases and 24% of controls. For self-reported exposure, significant risks of acute lymphoblastic leukaemia (ALL) were observed for solvents and petrol in all time windows. For reviewed exposure, solvents remained significant for ALL during pregnancy and postnatally. Restricting analyses to good-quality information removed all significant results. Refinement of exposure assessment revealed misclassification of self-reported exposures and data quality influenced risk assessment. Maternal exposure to solvents should further be investigated. These findings must invoke caution in the interpretation of risks reliant on self-reported occupational data.     

A spur to stem cell research

正China Society for Cell Biology released six standards on stem cells and China National Accreditation Service for Conformity Assessment (CNAS) awarded the country's first biobanking accreditation certificate to China National Stem Cell Resource Center on March 20.