PI3K Signaling in Normal B Cells and Chronic Lymphocytic Leukemia (CLL).

B cells provide immunity to extracellular pathogens by secreting a diverse repertoire of antibodies with high affinity and specificity for exposed antigens. The B cell receptor (BCR) is a transmembrane antibody, which facilitates the clonal selection of B cells producing secreted antibodies of the same specificity. The diverse antibody repertoire is generated by V(D)J recombination of heavy and light chain genes, whereas affinity maturation is mediated by activation-induced cytidine deaminase (AID)-mediated mutagenesis. These processes, which are essential for the generation of adaptive humoral immunity, also render B cells susceptible to chromosomal rearrangements and point mutations that in some cases lead to cancer. In this chapter, we will review the central role of PI3K s in mediating signals from the B cell receptor that not only facilitate the development of functional B cell repertoire, but also support the growth and survival of neoplastic B cells, focusing on chronic lymphocytic leukemia (CLL) B cells. Perhaps because of the central role played by PI3K in BCR signaling, B cell leukemia and lymphomas are the first diseases for which a PI3K inhibitor has been approved for clinical use

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Reduced Serum and Hypoxic Culture Conditions Enhance the Osteogenic Potential of Human Mesenchymal Stem Cells

Current protocols for inducing osteogenic differentiation in mesenchymal stem/stromal cells (MSCs) in culture for tissue engineering applications depend on the use of biochemical supplements. However, standard in vitro culture conditions expose cells to ambient oxygen concentrations and high levels of serum (21% O(2), 10% FBS) that do not accurately recapitulate the physiological milieu. While we and others have examined MSC behavior under hypoxia, the synergistic effect of low serum levels, such as those present in ischemic injury sites, on osteogenic differentiation has not been clearly examined. We hypothesized that a concomitant reduction of serum and O(2) would enhance in vitro osteogenic differentiation of MSCs by more accurately mimicking the fracture microenvironment. We show that serum deprivation, in conjunction with hypoxia, potentiates osteogenic differentiation in MSCs. These data demonstrate the role of serum levels in regulating osteogenesis and its importance in optimizing MSC differentiation strategies

Role of Allostatic Load in Sociodemographic Patterns of Pain Prevalence in the U.S. Population

Persistent stressors associated with sociodemographic disadvantage exert a physiologic toll, labeled “allostatis load”, that contributes to disparities in some health conditions. We investigated the contribution of allostatic load to pain prevalence in US adults. Interviews with 14,184 adults in the 1999–2004 National Health and Nutrition Examination Survey asked about severe headache, pain that lasted >24 hours, and widespread pain. Ten biomarkers of allostatic load were quantified from blood (glycated hemoglobin), serum (C-reactive protein, homocysteine, cholesterol, triglycerides), urine (creatinine, albumin) and physical measurements (body mass index, systolic and diastolic blood pressure). Log-binomial regression models estimated prevalence ratios (PR) and 95% confidence intervals (95%CIs). Prevalence ranged from 3.4% for widespread pain to 26.9% for pain >24 hours. After adjustment for demographic characteristics, low income was associated with greater prevalence of pain >24 hours (PR=1.65, 95%CI=1.49, 1.83), severe headache (PR=2.05, 95%CI=1.68, 2.50) and widespread pain (PR=3.67, 95%CI=2.56, 5.27). Racial/ethnic minorities had lower prevalence of all three pain conditions than non-Hispanic Whites. While greater allostatic load was associated with elevated prevalence of pain, allostatic load did not meaningfully attenuate prevalence ratios associated with income or race/ethnicity. We conclude that greater pain prevalence among low income groups is not explained by greater allostatic load