Drug screening on Hutchinson Gilford progeria pluripotent stem cells reveals aminopyrimidines as new modulators of farnesylation.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by a dramatic appearance of premature aging. HGPS is due to a single-base substitution in exon 11 of the LMNA gene (c.1824C>T) leading to the production of a toxic form of the prelamin A protein called progerin.

In Vitro and In Vivo Modulation of Alternative Splicing by the Biguanide Metformin.

Major physiological changes are governed by alternative splicing of RNA, and its misregulation may lead to specific diseases. With the use of a genome-wide approach, we show here that this splicing step can be modified by medication and demonstrate the effects of the biguanide metformin, on alternative splicing. The mechanism of action involves AMPK activation and downregulation of the RBM3 RNA-binding protein.

Cytostatic Effect of Repeated Exposure to Simvastatin: A Mechanism for Chronic Myotoxicity Revealed by the Use of Mesodermal Progenitors Derived from Human Pluripotent Stem Cells.

Statin treatment of hypercholesterolemia can lead to chronic myotoxicity which is, in most cases, alleviated by drug withdrawal. Cellular and molecular mechanisms of this adverse effect have been elusive, in particular because of the lack of in vitro models suitable for long-term exposures. We have taken advantage of the properties of human pluripotent stem cell-derived mesodermal precursors, that can be maintained unaltered in vitro for a long period of time, to develop a model of repeated exposures to simvastatin during more than 2 weeks.

Human pluripotent stem cells in drug discovery and predictive toxicology.

Human pluripotent stem cells are a biological resource most commonly considered for their potential in cell therapy or, as it is now called, 'regenerative medicine'. However, in the near future, their most important application for human health may well be totally different, as they are more and more envisioned as opening new routes for pharmacological research. Pluripotent stem cells indeed possess the main attributes that make them theoretically fully equipped for the development of cell-based assays in the fields of drug discovery and predictive toxicology.

[Embryonic stem cells in pharmacology].

Because of their self-renewal and pluripotency properties, human embryonic stem cells (hES) receive a marked attention from scientists and clinicians for regenerative medicine. The most recent application of hES cells may however reside in their use as a tool in drug development. The currently available cellular models for preclinical testing consist in primary and immortalized cells that display limitations in terms of available amount and likeliness to their in vivo counterparts, respectively.

Knockin mice expressing fluorescent delta-opioid receptors uncover G protein-coupled receptor dynamics in vivo.

The combination of fluorescent genetically encoded proteins with mouse engineering provides a fascinating means to study dynamic biological processes in mammals. At present, green fluorescent protein (GFP) mice were mainly developed to study gene expression patterns or cell morphology and migration. Here we used enhanced GFP (EGFP) to achieve functional imaging of a G protein-coupled receptor (GPCR) in vivo.

DNA amplification of HIV genome in hemophiliacs and in newborns from seropositive mothers.

We evaluated the validity of DNA enzymatic amplification (PCR) in a population at risk for HIV-1 infection, consisting of hemophiliacs and children born to seropositive mothers. All but one of the seropositive hemophiliacs and controls were found positive with the three sets of primers. All the seronegative patients and controls were found negative in PCR.

A randomized study of on-line plasma perfusion over protein A-sepharose and 5-fluorouracil chemotherapy in patients with metastatic colorectal carcinoma.

To evaluate the safety of on-line plasma perfusion over protein-A sepharose and the therapeutic advantage of combining plasma perfusion (PP) over protein-A sepharose with 5-fluorouracil (5-FU) chemotherapy in patients with metastatic colorectal carcinoma (MCRC), thirty patients were randomized after surgery of primary CRC to receive a combination of 5-FU and PP over protein-A sepharose (group A), or a combination of 5-FU and PP over sepharose (group B), or 5-FU alone (group C). Bi-weekly on-line PP over 200 ml protein-A sepharose gel (group A) or 200 ml sepharose gel (group B) were performed with a Cobe 2997 blood cell separator for a maximum of 19 treatments per patient. 5-FU was given at 1000 mg/m2/d on days 1-5 of a 4-weekly cycle until progression.

[Wellcozyme: a new kit for the detection of anti-HIV antibodies. Considerations apropos of the initial trials].

We tested the Wellcozyme anti-HTLV III kit on: 600 blood donors fresh sera, simultaneously tested by Elavia (Diagnostics Pasteur) or Vironostika (Organon); 20 plasmas, known to be anti-HIV negative; 22 sera, already labelled, and a panel of 10 specimens from the "Retrovirus" study group of the French National Society of Blood Transfusion, also tested by Elavia, Vironostika, Abbott HTLV III EIA and by two confirmatory tests: Immuno-blot (Diagnostics Pasteur) and Abbott confirmatory test. The Wellcome kit is, at present, the only one to use a competitive Elisa method and not to require any sample predilution. The method is easy to perform, rapid (results in 1 h 30 time) and it tests as well serum as plasma.

[A modification in technology improves the specificity of the Du Pont de Nemours immunoenzyme kit for the detection of anti-HIV antibodies].

Du Pont De Nemours perfected a new enzyme immunoassay for the screening of anti-HIV 1 antibodies, characterized by its rapidity: 2 hours of incubation, when the normal procedure needed 3 hours 30 minutes of incubation. We tested with the normal procedure and the shortened one 4,025 randomly selected blood donors. 55 samples of the SNTS panel and 10 sera representing the Western-Blot reference panel of the "Retrovirus" study group of the SNTS.

[Deformability of thawed erythrocytes: introduction of a new preservative solution].

Recently, KANE et al. (Centre de Transfusion Sanguine, Strasbourg) designed an original preservative medium, called ESOC, allowing a prolonged storage of thawed RBC. We studied on 15 days the evolution of thawed RBC deformability, while RBC where kept preserved, on the one hand in this ESOC solution, on the other hand in physiologic water, without any preservative medium.