Physical biomarkers for human hematopoietic stem and progenitor cells.

Adhesion of hematopoietic stem and progenitor cells (HSPCs) to the bone marrow niche plays critical roles in the maintenance of the most primitive HSPCs. The interactions of HSPC-niche interactions are clinically relevant in acute myeloid leukemia (AML), because (i) leukemia-initiating cells adhered to the marrow niche are protected from the cytotoxic effect by chemotherapy and (ii) mobilization of HSPCs from healthy donors' bone marrow is crucial for the effective stem cell transplantation. However, although many clinical agents have been developed for the HSPC mobilization, the effects caused by the extrinsic molecular cues were traditionally evaluated based on phenomenological observations. This review highlights the recent interdisciplinary challenges of hematologists, biophysicists and cell biologists towards the design of defined in vitro niche models and the development of physical biomarkers for quantitative indexing of differential effects of clinical agents on human HSPCs.

Simple Physical Model Unravels Influences of Chemokine on Shape Deformation and Migration of Human Hematopoietic Stem Cells.

We studied the dynamic behavior of human hematopoietic stem cells (HSC) on the in vitro model of bone marrow surfaces in the absence and presence of chemokine (SDF1α). The deformation and migration of cells were investigated by varying the chemokine concentration and surface density of ligand molecules. Since HSC used in this study were primary cells extracted from the human umbilical cord blood, it is not possible to introduce molecular reporter systems before or during the live cell imaging. To account for the experimental observations, we propose a simple and general theoretical model for cell crawling. In contrast to other theoretical models reported previously, our model focuses on the nonlinear coupling between shape deformation and translational motion and is free from any molecular-level process. Therefore, it is ideally suited for the comparison with our experimental results. We have demonstrated that the results in the absence of SDF1α were well recapitulated by the linear model, while the nonlinear model is necessary to reproduce the elongated migration observed in the presence of SDF1α. The combination of the simple theoretical model and the label-free, live cell observations of human primary cells opens a large potential to numerically identify the differential effects of extrinsic factors such as chemokines, growth factors, and clinical drugs on dynamic phenotypes of primary cells.

Guidance for Pediatric Familial Hypercholesterolemia 2017.

This paper describes consensus statement by Joint Working Group by Japan Pediatric Society and Japan Atherosclerosis Society for Making Guidance of Pediatric Familial Hypercholesterolemia (FH) in order to improve prognosis of FH.FH is a common genetic disease caused by mutations in genes related to low density lipoprotein (LDL) receptor pathway. Because patients with FH have high LDL cholesterol (LDL-C) levels from the birth, atherosclerosis begins and develops during childhood which determines the prognosis. Therefore, in order to reduce their lifetime risk for cardiovascular disease, patients with FH need to be diagnosed as early as possible and appropriate treatment should be started.Diagnosis of pediatric heterozygous FH patients is made by LDL-C ≥140 mg/dL, and family history of FH or premature CAD. When the diagnosis is made, they need to improve their lifestyle including diet and exercise which sometimes are not enough to reduce LDL-C levels. For pediatric FH aged ≥10 years, pharmacotherapy needs to be considered if the LDL-C level is persistently above 180 mg/dL. Statins are the first line drugs starting from the lowest dose and are increased if necessary. The target LDL-C level should ideally be ＜140 mg/dL. Assessment of atherosclerosis is mainly performed by noninvasive methods such as ultrasound.For homozygous FH patients, the diagnosis is made by existence of skin xanthomas or tendon xanthomas from infancy, and untreated LDL-C levels are approximately twice those of heterozygous FH parents. The responsiveness to pharmacotherapy should be ascertained promptly and if the effect of treatment is not enough, LDL apheresis needs to be immediately initiated.

Efficacy and Safety of Pitavastatin in Children and Adolescents with Familial Hypercholesterolemia in Japan and Europe.

AIM: Children with Familial Hypercholesterolemia (FH) are widely prescribed statins, and it has been suggested that the effects of statins differ among ethnicities. We compared the efficacy and safety of pitavastatin in children and adolescents with FH in clinical trials conducted in Japan and Europe. METHODS: Low-density lipoprotein cholesterol (LDL-C) reductions, adjusted for confounding factors, and safety were compared between the studies in Japan and Europe. In the Japanese study, 14 males with heterozygous FH, aged 11.8±1.6 years, were randomized to 52-week double-blind treatment with 1 or 2 mg/day pitavastatin. In the European study, 106 children and adolescents with high risk hyperlipidemia (103 heterozygous FH), aged 10.6±2.9 years, were randomized to 12-week double-blind treatment with 1, 2 or 4 mg/day pitavastatin or placebo; 84 of these patients and 29 new patients participated in a 52-week open-label extension study. RESULTS: Age, body weight and baseline LDL-C were identified as factors influencing LDL-C reduction. There were no significant differences in the adjusted mean percentage reduction in LDL-C in Japanese and European children by pitavastatin (24.5% and 23.6%, respectively at 1 mg/day and 33.5% and 30.8%, respectively at 2 mg/day). Pitavastatin was well tolerated without any difference in the frequency or nature of adverse events between the treatment groups, or between the studies. CONCLUSION: There were no significant differences between the efficacy or safety of pitavastatin in Japanese and European children and adolescents with FH, suggesting no relevant ethnic differences in the safety or efficacy of pitavastatin.

Effect of Statin Therapy in 4-Year-Old Dichorionic Diamniotic Twins with Familial Hypercholesterolemia Showing Multiple Xanthomas.

Familial hypercholesterolemia (FH) is characterized by a high level of low-density lipoprotein cholesterol (LDL-C) and is inherited as an autosomal dominant trait. We report 4-year-old dichorionic diamniotic twins (boy and girl) with FH who presented with multiple xanthomas on the face, both knees, both feet, and buttocks. Family history revealed vertical transmission of hypercholesterolemia from father to patients, thereby suggesting dominant inheritance. Lipid data of their mother did not match the criteria of FH. However, lipid data of maternal grandmother and maternal sister matched the criteria of FH. LDL receptor gene analysis of the family revealed that their father was heterozygous for a missense mutation, L547V, their mother was heterozygous for a nonsense mutation, C675X, and patients were compound heterozygous for L547V and C675X. After 10 months of treatment with pitavastatin (2 mg/day) and ezetimibe (10 mg/day), LDL-C decreased from 595 mg/dL to 267 mg/dL in the boy and from 530 mg/dL to 182 mg/dL in the girl. These findings suggest that lipid-lowering therapy with statin may be considered in pediatric patients with compound heterozygous FH (hetero FH) before inducing LDL apheresis, and gene analysis for true diagnosis in pediatric patients with multiple xanthomas should be considered, though they appear to be hetero FH from the family history and lipid data of parents.

Extrauterine growth and adipocytokines in appropriate-for-gestational-age preterm infants.

BACKGROUND: Extra-uterine growth retardation in preterm infants is associated with an increased risk for cardiometabolic diseases later in life. Adipocytokines are also associated with the development of cardiometabolic diseases. We examined the relationship between extra-uterine growth and serum concentrations of adipocytokines and metabolic hormones in preterm infants. METHODS: Serum concentrations of leptin, adiponectin, insulin, IL-6, TNF-α, C-peptide, GIP, GLP-1 and glucagon were measured in 38 appropriate-for-gestational-age preterm infants at birth, and at 33 and 38 weeks of postmenstrual age using a Bio-Plex 200TM suspension array system. RESULTS: Serum concentrations of leptin were not correlated with body weight at any time point. However, serum concentrations of adiponectin were correlated with body weight at all time points. Serum concentrations of IL-6 were decreased from birth to 33 and 38 weeks. Serum concentrations of TNF-α were not changed. Serum concentrations of C-peptide, GIP and glucagon increased from birth to 33 weeks, and decreased from 33 to 38 weeks. Serum concentrations of insulin and GLP-1 were not changed. CONCLUSION: Changes in serum concentrations of leptin and adiponectin showed unique profiles, thereby suggesting maldevelopment of white adipose tissue. This may affect the future development of adipose tissue and lead to increased risk for cardio-metabolic disorders. This article is protected by copyright. All rights reserved.

Computer simulations of three-dimensional Turing patterns in the Lengyel-Epstein model.

We investigate numerically Turing patterns in the Lengyel-Epstein model in three dimensions. In a bulk homogeneous system under periodic boundary conditions, we obtain not only lamellar, cylindrical, and spherical structures but also several interconnected periodic structures including the Schwartz P-surface structure. In order to examine Turing patterns in the conditions accessible experimentally, we consider inhomogeneous systems where a parameter in the reaction-diffusion equations depends on the space coordinate with either Dirichlet or Neumann boundary conditions. In this situation, we find that a perforated-lamellar structure and an Fddd structure, both of which have a uniaxial symmetry, appear depending on the boundary conditions.

Collision dynamics of traveling bands in systems of deformable self-propelled particles.

We study the soliton-like character of traveling bands in systems of interacting deformable self-propelled particles in two dimensions. The collision dynamics of the model in which migration velocity increases with increasing local density is investigated numerically by changing the relaxation rate of deformations. The bands are unstable upon head-on collisions for larger relaxation rates. This clearly indicates that deformability plays a crucial role of the soliton-like behavior.

Active crystals and their stability.

A recently introduced active phase field crystal model describes the formation of ordered resting and traveling crystals in systems of self-propelled particles. Increasing the active drive, a resting crystal can be forced to perform collectively ordered migration as a single traveling object. We demonstrate here that these ordered migrating structures are linearly stable. In other words, during migration, the single-crystalline texture together with the globally ordered collective motion is preserved even on large length scales. Furthermore, we consider self-propelled particles on a substrate that are surrounded by a thin fluid film. We find that in this case the resulting hydrodynamic interactions can destabilize the order.

Dynamics and electrorheology of sheared immiscible fluid mixtures.

We analyze the electrorheological effect in immiscible fluid mixtures with dielectric mismatch. By taking the electric field effect into account, which couples to the dynamics of domain morphology under flow, we propose a set of electrorheological constitutive equations valid under the condition where the relative magnitude of the flow field is stronger than that of the electric field. Through comparison with recent experiments, we point out a unique dynamical stress response inherent in situations where the cross-coupling between different fields is essential.

Formation and collision of traveling bands in interacting deformable self-propelled particles.

We study the collective dynamics of interacting deformable self-propelled particles whose migration velocity increases with increasing local density. In two-dimensional numerical simulations of this system, the local density dependence on migration velocity leads to traveling bands similar to those previously reported for Vicsek-type models. We show that a pair of straight bands moving in opposite directions survives a head-on collision. Although traveling bands also appear in systems of constant migration velocity subjected to random noise, they are found to be unstable in a head-on collision.