Genetic alterations of phosphoinositide 3-kinase subunit genes in human glioblastomas

Genetic alterations of PI3K (phosphoinositide 3-kinase) subunits have been documented in a number of tumor types, with increased PI3K activity linked to gene amplification and mutation of catalytic subunits, as well as mutations of regulatory subunits. Among high grade gliomas, activation of the PI3K-AKT signaling pathway through loss of PTEN function is common. We therefore investigated whether genetic alteration of class IA PI3Ks might provide a mechanism for deregulation of this pathway in glioblastomas. We studied a series of glioblastomas with FISH to assess copy number of catalytic subunits (PIK3CA and PIK3CD) and with PCR-SSCP to screen for somatic mutations of conserved regions of both catalytic and regulatory subunits. FISH revealed frequent balanced copy number increases of both PIK3CA and PIK3CD, and one case showed an extra copy limited to PIK3CA. One glioblastoma exhibited a 9-bp deletion that encompassed the exon-intron junction of exon 12 of PIK3R1, documenting for the first time a mutation within a PI3K regulatory subunit in human glioblastoma. This deletion would be predicted to yield a truncated protein that lacks the inhibitory domain, resulting in increased PI3K activity. Furthermore, the case with selected PIK3CA copy number gain and the case with a truncating PIK3R1 mutation both featured AKT activation without PTEN mutation. These results suggest that genetic alterations of class IA PI3K subunit genes can occasionally play a role in human glioblastoma by activating the PI3K-AKT signaling pathway independently of PTEN mutation.     

A locus for posterior polymorphous corneal dystrophy (PPCD3) maps to chromosome 10

Posterior polymorphous corneal dystrophy (PPCD) is an autosomal dominant disorder characterized by corneal endothelial abnormalities, which can lead to blindness due to loss of corneal transparency and sometimes glaucoma. We mapped a new locus responsible for PPCD in a family in which we excluded the previously reported PPCD locus on 20q11, and the region containing COL8A2 on chromosome 1. Results of a 317-marker genome scan provided significant evidence of linkage of PPCD to markers on chromosome 10, with single-point LOD scores of 2.63, 1.63, and 3.19 for markers D10S208 (at (circumflex)theta = 0.03), D10S1780 (at (circumflex)theta = 0.00), and D10S578 (at (circumflex)theta = 0.06). A maximum multi-point LOD score of 4.35 was found at marker D10S1780. Affected family members shared a haplotype in an 8.55 cM critical interval that was bounded by markers D10S213 and D10S578. Our finding of another PPCD locus, PPCD3, on chromosome 10 indicates that PPCD is genetically heterogeneous. Guttae, a common corneal finding sometimes observed along with PPCD, were found among both affected and unaffected members of the proband's sib ship, but were absent in the younger generations of the family. Evaluation of phenotypic differences between family members sharing the same affected haplotype raises questions about whether differences in disease severity, including differences in response to surgical interventions, could be due to genetic background or other factors independent of the PPCD3 locus.     

A small-conductance charybdotoxin-sensitive,apamin-resistant Ca2+-activated K+ channel in aortic smooth muscle cells (A7r5 line and primary culture)

A small conductance K⁺ channel was identified in smooth muscle cells of the rat aortic cell line A7r5 and also in rat aortic smooth muscle cells in primary culture, using conventional single-channel recording techniques. The single-channel conductance shows no rectification, either in the range –70 to +40 mV under asymmetrical conditions (9.1 pS), or in the range –100 to +50 mV in symmetrical 150 mM K⁺ (37 pS). Channel activity is reversibly inhibited by extracellular application of charybdotoxin, with a concentration of 8 nM producing half-maximal inhibition. It is unaffected by apamin or scyllatoxin. Channel activity depends on the presence of free Ca²⁺ on the cytosolic face of the membrane, with an activation zone between 0.1 and 1 M. This small-conductance, charybdotoxin-sensitive, Ca²⁺-regulated K⁺ channel is activated by vasoconstrictors such as vasopressin and endothelin.     

Recombinant congenic strains of mice from B10.D2 and DBA/2: Their contribution to behavior genetic research and application to audiogenic seizures

Recombinant congenic strains (RCS) represent a series of related strains, each of which carries a small fraction of the genome of one strain (donor strain) on the genetic background of another strain (background strain). Recombinant inbred strains (RIS) are commonly used to identify major gene segregation and linkage and associations between behavior and quantitative trait loci, whereas recombinant congenic strains (RCS) open other complementary leads. The variability in the reactivity of RCS to a trait is thus the expression of few minor-effect genes originating from the donor strain, because the probability that major genes are present in any one RCS is low. Unlike RIS in which minor-effect genes are often masked by major genes, RCS enable the effects of minor genes to be studied. With our method, for a given trait, an estimate can be made of the gene strength distribution as well as an estimate of the minimal number of genes involved having a certain strength.This study was supported by the Centre National de la Recherche Scientifique (URA 1924 and CSEAL-UPS 44, CNRS), Université René-Descartes, Paris V UFR Biomédicale, and the Fondation pour la Recherche Médicale.     

Remodeling of the ICF: A commentary

Since its publication in 2001 the International Classification of Functioning, Disability and Health (ICF) has attracted debate about the content and the model presented. After almost 20 years use, regular updating since 2008 and with the prospect of a new edition in 2020 there is increasing interest in the ICF as a tool to meet contemporary information requirements. Information on functioning is important across not only health systems, but all areas where change in functioning is important: education, employment, and social welfare for example. This commentary responds to the issues raised in a commentary by Mitra & Shakespeare in 2019 and supports review of the ICF in the current context by informing users and providers of data on human functioning how they might engage in the maintenance, updating, and modernisation of the ICF.     

Promoting a Culture of Prevention in Albania: the “Si Je?” Program

Prevention Science - Albania is a small country on the Balkan Peninsula that recently implemented an innovative primary healthcare program called “Si Je?” (How are you?) which allowed...     

Can Policy Promote Adoption or Outcomes of Evidence-based Prevention Programming?: a Case Illustration of Positive Behavioral Interventions and Supports

Prevention Science - This study examined the impact of a state policy requiring that any school with a habitual truancy rate of 8% or higher to be trained in Tier 1 school-wide Positive Behavioral...     

Liver-First Approach for Synchronous Colorectal Metastases: Analysis of 7360 Patients from the LiverMetSurvey Registry

Annals of Surgical Oncology - The liver-first approach in patients with synchronous colorectal liver metastases (CRLM) has gained wide consensus but its role is still to be clarified. We aimed to...