Clinical features and major histocompatibility complex genes as potential susceptibility factors in pediatric immune thrombocytopenia

Background/PurposeImmune thrombocytopenia (ITP) is a heterogeneous autoimmune disorder with diverse response rates to treatments that include corticosteroids, intravenous immunoglobulins (IVIG), and splenectomy. The predisposing causes of this autoimmune disorder, one of which is immunogenetic susceptibility, have not been fully determined. We investigated whether clinical features and human leukocyte antigen (HLA) genotypes influence the occurrence, treatment response, and disease duration of childhood ITP in Taiwan.MethodsWe performed HLA genotyping of 70 Taiwanese children with ITP and of 70 healthy controls and compared the data. Demographic data were also collected and evaluated.ResultsThe frequencies of heterozygous HLA-A11 and the HLA-Cw1 allele were both significantly decreased in the ITP group (p = 0.0160 and p = 0.0089, respectively), whereas the frequency of heterozygous HLA-DQ5 was significantly increased in the ITP group (p = 0.0057). Patients with HLA-DRB1*11 or -DRB1*15 were more likely to respond poorly to corticosteroids than IVIG (p = 0.0446 and p = 0.0008, respectively). In addition, we observed a positive association between HLA-A11 homozygosity and the development of persistent or chronic ITP [odds ratio (OR) = 6.3165, p = 0.0479]. The presence of HLA-DRB1*08 was, however, negatively correlated with the development of persistent or chronic ITP (OR = 0.1729, p = 0.0657). Children with antecedent of preceding illness (API) and with a younger age of onset were more likely to experience a better treatment response and shorter course of ITP.ConclusionWe suggest that API, age of onset, and particular HLA class I and class II alleles, may be involved in and influence the occurrence and disease duration of childhood ITP, as well as responses to different therapeutic approaches

Tet oncogene family member 2 gene alterations in childhood acute myeloid leukemia

Background/PurposeMutations in the tet oncogene family member 2 gene (TET2) are frequently found in adult patients with acute myeloid leukemia (AML). Reports of TET2 mutations in children are limited. We assessed the prevalence of TET2 mutations in Taiwanese children with AML and analyzed their prognosis.MethodsBetween 1997 and 2010, a total of 69 consecutive children with AML were enrolled at the National Taiwan University Hospital. The analysis for TET2 mutations was performed using direct sequencing. Clinical characteristics and overall survival (OS) were compared between patients with and without TET2 alterations.ResultsIntronic and missense mutations were identified. No nonsense or frameshift mutations were observed. Two putative disease-causing missense mutations (S609C and A1865G) were identified in one patient. We estimated the prevalence of TET2 mutations in the current patient population to be 1.4%. The most common polymorphism was I1762V (45%), followed by V218M (12%), P29R (6%), and F868L (6%). Patients with polymorphism I1762V had an increased 10-year survival rate compared with patients without I1762V (48.4% vs. 25.7%, p = 0.049) by Chi-square test; OS was not different when examined using the Kaplan–Meier method (p = 0.104).ConclusionThe prevalence of TET2 mutations in children with AML compared with adults with AML was lower and less complex. Patient prognosis associated with TET2 mutations in children requires further investigation

Identification of Variations in the Human Phosphoinositide 3-Kinase P110 Delta Gene in Children with Primary B-Cell Immunodeficiency of Unknown Aetiology

Our recent study demonstrated that defects in p110 delta result in B-cell immunodeficiency that is very similar to that observed in BTK-deficient mice. We revealed that the p 110 delta fit the B-cell signal transduction complex and played a non-redundant role in the development and function of B cells. In humans, most children with primary B-cell immunodeficiency have mutations in the BTK, whereas a few have defects in the components of the B-cell signal transduction complex. But little is known about the genetic variation of p110 delta in children with defects in B-cell immunodeficiency of unknown aetiology. Sixteen patients from 15 unrelated families and 112 normal controls underwent sequence analysis to identify genetic variations of the p110 delta. Allele frequency in each group was also analysed and compared. We identified five single base-pair polymorphic nucleotide exchanges in both patient and control groups with similar allele frequencies, which did not contribute to the immunodeficiency. Three of them are novel (m.953A > G, m. 1200C > T and m. 1561A > G), and the m.953A > G and m.1561A > G nucleotide exchanges are non-synonymous (N253S and T456A, respectively). The novel m.1561A > G was in complete linkage disequilibrium with the known m.873A > G in our study of Taiwanese group. In addition, one novel single base -pair missense mutation, m.3256G > A (E1021K), was identified in one boy with typical clinical features of primary B-cell immunodeficiency and could not be found in either his family or the normal control population. By atomic structural analysis of the amino acid as well as the alignment comparison between species, it resulted in the replacement of the negative-charged amino acid E with the positive-charged amino acid K at codon 1021, located in the highly conservative and important catalytic functional domain. Our findings could shed light on further understanding the polymorphisms of p 110 delta in B-cell immunodeficiency and different populations. Moreover, the 3256G > A missense mutation raised the attention and warranted further extensive analysis to elucidate the role of p110 delta in human immunodeficiency

Essential, Nonredundant Role for the Phosphoinositide 3-Kinase P110 Delta in Signaling by the B-Cell Receptor Complex

Many receptor and nonreceptor tyrosine kinases activate phosphoinositide 3-kinases (P13Ks). To assess the role of the delta isoform of the p110 catalytic subunit of P13Ks, we derived enzyme-deficient mice. The mice are viable but have decreased numbers of mature B cells, a block in pro-B- cell differentiation, and a B1 B-cell deficiency. Both immunoglobulin M receptor-induced Ca2+ flux and proliferation in response to B-cell mitogens are attenuated. Immunoglobulin levels are decreased substantially . The ability to respond to T-cell-independent antigens is markedly reduced, and the ability to respond to T-cell- dependent antigens is completely eliminated. Germinal center formation in the spleen in response to antigen stimulation is disrupted. These results define a nonredundant signaling pathway(s) utilizing the delta isoform of p110 P13K for the development and function of B cells

Identification, Cdna Cloning, and Targeted Deletion of P70, a Novel, Ubiquitously Expressed Sh3 Domain-Containing Protein

In a screen for proteins that interact with Jak2, we identified a previously uncharacterized 70-kDa protein and cloned the corresponding cDNA. The predicated sequence indicates that p70 contains an SH3 domain and a C-terminal domain with similarities to the catalytic motif of phosphoglycerate mutase. p70 transcripts were found in all tissues examined. Similarly, when an antibody raised against a C-terminal peptide to analyze p70 protein expression was used, all murine tissues examined were found to express p70. To investigate the in vivo role of p70, we generated a p70- deficient mouse strain. Mice lacking p70 are viable, develop normally, and do not display any obvious abnormalities. No differences were detected in various hematological parameters, including bone marrow colony- forming ability, in response to cytokines that utilize Jak2. In addition, no impairment in B- and T-cell development and proliferative ability was detected

Phospholipase C Gamma 2 Is Essential for Specific Functions of Fc Epsilon R and Fc Gamma R

Phospholipase Cgamma2 (PLCgamma2) plays a critical role in the functions of the B cell receptor in B cells and of the FcRgamma chain-containing collagen receptor in platelets. Here we report that PLCgamma2 is also expressed in mast cells and monocytes/macrophages and is activated by cross- linking of FcepsilonR and FcgammaR. Although PLCgamma2- deficient mice have normal development and numbers of mast cells and monocytes/ macrophages, we demonstrate that PLCgamma2 is essential for specific functions of FcepsilonR and FcgammaR. While PLCgamma2-deficient mast cells have normal mitogen-activated protein kinase activation and cytokine production at mRNA levels, the mutant cells have impaired FcepsilonR- mediated Ca2+ flux and inositol 1,4,5- trisphosphate production, degranulation, and cytokine secretion. As a physiological consequence of the effect of PLCgamma2 deficiency, the mutant mice are resistant to IgE- mediated cutaneous inflammatory skin reaction. Macrophages from PLCgamma2- deficient mice have no detectable FcgammaR- mediated Ca2+ flux; however, the mutant cells have normal FcgammaR-mediated phagocytosis. Moreover, PLCgamma2 plays a nonredundant role in FcgammaR-mediated inflammatory skin reaction

The Mediating Role of Exercise on Relationships Between Fatigue, Sleep Quality, and Quality of Life for Adolescents With Cancer

[[abstract]]Background: Fatigue and poor sleep are two of the most common and most distressing symptoms for adolescents with cancer. These 2 symptoms concurrently heighten distress, further decreasing quality of life (QoL). Objectives: The aims of this study were to describe the degree of exercise involvement, fatigue, sleep quality,and QoL among adolescents with cancer and to determine whether exercise mediates the relationships between (a) fatigue and QoL and (b) sleep quality and QoL. Methods: A cross-sectional study of 100 participants was conducted. Multiple regression was performed to examine the mediation relationship. Results: Participants in the off-treatment group had a significantly higher degree of exercise involvement, as well as less fatigue, greater sleep quality, and less QoL distress. Exercise partially mediated the adverse effect of fatigue on QoL for adolescents undergoing cancer treatment, accounting for 49.80% of the total variation; exercise partially mediated the adverse effect of poor sleep on QoL for adolescents both in treatment and in survivorship, accounting for 42.06% and 28.71% of the total variations, respectively. Conclusion: Exercise partially mediated the relationship between fatigue and QoL for adolescents in cancer treatment and partially mediated the relationship between sleep quality and QoL both for those in cancer treatment and for those in survivorship. Implications for Practice: Developing tailored exercise programs based on both treatment status and the degree of fatigue and sleep quality is important. In-service education that enhances nurses’ awareness of the importance of exercise in improving adolescents’ QoL is recommended

Physical activity self-efficacy mediates the effect of symptom distress on exercise involvement among adolescents undergoing cancer treatment.

[[abstract]]The objective of this study was to examine whether physical activity self-efficacy mediated the adverse effect of symptom distress on exercise involvement among adolescents undergoing cancer treatment. A secondary data analysis approach was used to analyse a pooled sample of 97 adolescents who were undergoing cancer treatment in paediatric oncology/haematology wards and ambulatory settings in northern Taiwan. Mediation analysis was performed to examine the mediation relationship among physical activity self-efficacy, symptom distress and exercise involvement. The total effect (path c) (p < 0.001), the indirect effect (paths a and b) (p < 0.05 and p < 0.01) and the direct effect (path c') (p < 0.001) were significant. The bootstrapping test was significant (95% CI: -0.356 to -0.016), indicating that physical activity self-efficacy partially mediated the adverse effect of symptom distress on exercise involvement after adjusting for age, gender and cancer diagnosis. Physical activity self-efficacy partially mediates the relationship between symptom distress and exercise involvement for adolescents undergoing cancer treatment. There is an imperative need for healthcare professionals to design interventions to enhance these adolescents' physical activity self-efficacy, increase their exercise involvement and thus improve their quality of life