The benzophenanthridine alkaloid fagaronine induces erythroleukemic cell differentiation by gene activation.

Fagaronine, a benzophenanthridine alkaloid from Fagara zanthoxyloides Lam. (Rutaceae), has been tested on the erythroleukemic cell line K562 in order to explain some previous results on cell differentiation. In this study we showed that fagaronine induces a significant hemoglobinization of the human erythroleukemic cell line K562.

Coronary stenosis detection by 16-slice computed tomography in heart transplant patients: comparison with conventional angiography and impact on clinical management.

Objectives: We sought to find a non-invasive alternative to conventional coronary angiography (CCA) for serial detection and follow-up of coronary stenosis due to cardiac allograft vasculopathy in heart transplant patients.

Background: Cardiac allograft vasculopathy is the main factor limiting long-term success of heart transplantation. It is usually detected by CCA.

Evaluation of the Bio-Rad VARIANT II HbA2/HbA1C Dual Program for measurement of hemoglobin concentrations and detection of variants.

In this work data obtained on the VARIANT II hemoglobin analyzer using the Dual Kit elution system were compared to those obtained with the beta-Thalassemia Short Program. Since many laboratories still use an earlier model of the hemoglobin analyzer, the Variant 1, these data were also compared to those obtained with the latter instrument. Our study is divided into two parts.

Overexpression of Bcl-2 is associated with apoptotic resistance to the G-quadruplex ligand 12459 but is not sufficient to confer resistance to long-term senescence.

The triazine derivative 12459 is a potent G-quadruplex interacting agent that inhibits telomerase activity. This agent induces time- and dose-dependent telomere shortening, senescence-like growth arrest and apoptosis in the human A549 tumour cell line. We show here that 12459 induces a delayed apoptosis that activates the mitochondrial pathway.

[Regulation of telomeres length: making the telomeres accessible?].

Under a normal state, the extremities of chromosomes, telomeres, are protected against undesired fusion events. Alterations of the telomere structure are associated with genetic instability, while erosion of the telomeric repeats, occurring at each cell division, provides a mechanism controlling the long-term proliferation of somatic cells. Although the structure and composition of the human telomerase enzyme are now well characterized, the protein partners regulating the stability and conformation of its DNA substrate, the telomeric end, are much less known.

Apoptosis related to telomere instability and cell cycle alterations in human glioma cells treated by new highly selective G-quadruplex ligands.

Telomerase represents a relevant target for cancer therapy. Molecules able to stabilize the G-quadruplex (G4), a structure adopted by the 3'-overhang of telomeres, are thought to inhibit telomerase by blocking its access to telomeres. We investigated the cellular effects of four new 2,6-pyridine-dicarboxamide derivatives displaying strong selectivity for G4 structures and strong inhibition of telomerase in in vitro assays.

Hb Montfermeil [beta 130(H8) Tyr-->Cys]: suggests a key role for the interaction between helix A and H in oxygen affinity of the hemoglobin molecule.

Hb Montfermeil [beta130(H8) Tyr-->Cys] is a high oxygen affinity variant causing erythrocytosis. The cysteine replacement is buried in the inside of the beta chain where it alters the interactions between helix A and H, with a further effect on helix E. This position has already been proposed to contribute to the difference in oxygen affinity between human and bovine hemoglobins.

Stabilization of the c-myc gene promoter quadruplex by specific ligands' inhibitors of telomerase.

A parallel G-quadruplex structure was recently identified in the NHE III(1) element of the c-myc gene promoter that functioned as a transcriptional repressor. Different series of telomeric G-quadruplex interacting ligands reported to block telomerase activity were evaluated in a new PCR stop assay on the c-myc quadruplex (Pu22myc). Results indicated that the cationic porphyrin TMPyP4 previously described to stabilize c-myc quadruplex and to cause transcription inhibition efficiently inhibited the assay but with a narrow selectivity when parallel experiments were performed with an oligonucleotide (Pu22mu) containing mutations in the guanine repeat which is unable to form a quadruplex.

G-quadruplex interacting agents targeting the telomeric G-overhang are more than simple telomerase inhibitors.

The extremities of chromosomes end at telomeres in a G-rich single stranded overhang that may adopt peculiar structures such as T-loop and G-quadruplex. G-quadruplex is a poor substrate for telomerase activity and different classes of small molecule ligands that selectively stabilize this structure and inhibit telomerase activity have been selected by screening or synthesized by oriented chemistry. These ligands differ from catalytic inhibitors of telomerase by several points that were discussed in the present review, with a special emphasis on their biological activity as potential antitumor agents.

Interaction of telomestatin with the telomeric single-strand overhang.

The extremities of chromosomes end in a G-rich single-stranded overhang that has been implicated in the onset of the replicative senescence. The repeated sequence forming a G-overhang is able to adopt a peculiar four-stranded DNA structure in vitro called a G-quadruplex, which is a poor substrate for telomerase. Small molecule ligands that selectively stabilize the telomeric G-quadruplex induce telomere shortening and a delayed growth arrest.

[Transradial approach for diagnostic angiography].

Seventy five arteriographies were performed via the transradial route using 5F 130cm - long catheter. Prior to puncture the radial artery was evaluated with Allen test. Satisfying quality examinations were obtained for the thoracic aorta, selective carotid arteries examinations, infra renal aorta, pelvic and legs arteries.

Telomerase downregulation induced by the G-quadruplex ligand 12459 in A549 cells is mediated by hTERT RNA alternative splicing.

Ligand 12459, a potent G-quadruplex-interacting agent that belongs to the triazine series, was previously shown to downregulate telomerase activity in the human A549 lung carcinoma cell line. We show here that the downregulation of telomerase activity is caused by an alteration of the hTERT splicing pattern induced by 12459, i.e.

[Aneurysm of the persistent sciatic artery].

The authors report a case of persistent sciatic artery presenting with limb ischemia and pulsatile mass in the buttock treated only by femoro tibio peroneal by pass graft since follow up helical CTA at six months showed spontaneous aneurysmal exclusion by thrombosis of the persistent sciatic artery above the aneurysm. Review of the literature confirms the rarity of this anomaly, which is frequently associated with aneurysmal transformation and its specific inherent complications. It is treated by femoro popliteal shunt with endovascular embolization.

Lamellipodium extension and cadherin adhesion: two cell responses to cadherin activation relying on distinct signalling pathways.

Cell adhesion molecules of the cadherin family contribute to the regulation of cell shape and fate by mediating strong intercellular adhesion through Ca2+-dependent interaction of their ectodomain and association of their cytoplasmic tail to actin. However, the mechanisms co-ordinating cadherinmediated adhesion with the reorganization of the actin cytoskeleton remain elusive. Here, the formation of de novo contacts was dissected by spreading cells on a highly active N-cadherin homophilic ligand.

Outbreaks of serogroup X meningococcal meningitis in Niger 1995-2000.

In the African meningitis belt, the recurrent meningococcal meningitis epidemics are generally caused by serogroup A. In the past 20 years, other serogroups have been detected, such as X or W135, which have caused sporadic cases or clusters. We report here 134 meningitis cases caused by Neisseria meningitidis serogroup X that occurred in Niamey between 1995 and 2000.

Selective interactions of ethidiums with G-quadruplex DNA revealed by surface-enhanced Raman scattering.

Complexes formed between G-quadruplex (G4)-conformed oligonucleotides and four ethidium derivatives were studied by surface-enhanced Raman spectroscopy (SERS) to detail the topology of complexes that support a G4 stabilization. Ethidium bromide (EB), which presents a weak ability to stabilize oligonucleotides in G4 conformation, displayed no SERS intensity modification when bound to G4, as compared with the free EB. Three ethidium derivatives have been selected due to their higher ability to stabilize G4 than EB.

Resistance to senescence induction and telomere shortening by a G-quadruplex ligand inhibitor of telomerase.

The molecular mechanisms induced by G-quadruplex ligands to trigger senescence in mammalian cells are still unknown, although the critical role of telomerase is highly suspected. JFA2 cells selected for resistance to senescence induced by the G-quadruplex ligand 12459 presented an overexpression of hTERT transcript that correlated to a functional increase in telomerase activity and telomere length. Consistently, treatment with 12459 failed to trigger senescence and telomere shortening in JFA2 cells.

Resistance to the short term antiproliferative activity of the G-quadruplex ligand 12459 is associated with telomerase overexpression and telomere capping alteration.

Ligands that stabilize the telomeric G-rich single-stranded DNA overhang into G-quadruplex can be considered as potential antitumor agents that block telomere replication. Ligand 12459, a potent G-quadruplex ligand that belongs to the triazine series, has been previously shown to induce both telomere shortening and apoptosis in the human A549 cell line as a function of its concentration and time exposure. We show here that A549 clones obtained after mutagenesis and selected for resistance to the short term effect of ligand 12459 frequently displayed hTERT transcript overexpression (2-6-fold).

Short insertion in a hemoglobin chain: Hb Esch, an unstable alpha1 variant with duplication of the sequence Ala65-Leu-Thr-Asn68.

Hemoglobin (Hb) Esch, is an alpha1 variant, expressed at less than 5%, resulting from the duplication of the 12 nucleotides corresponding to CD65 through 68. The effect of this insertion is the repetition of the sequence Ala-Leu-Thr-Asn, which corresponds to the last turn of helix E. In this variant the presence of a one-turn elongated helix E causes instability and increased ligand affinity.

Selective interaction of ethidium derivatives with quadruplexes: an equilibrium dialysis and electrospray ionization mass spectrometry analysis.

The telomeric G-rich single-stranded DNA can adopt in vitro an intramolecular quadruplex structure, which has been shown to directly inhibit telomerase activity. The reactivation of this enzyme in immortalized and most cancer cells suggests that telomerase is a relevant target in oncology, and telomerase inhibitors have been proposed as new potential anticancer agents. In this paper, we have analyzed the selectivity of four ethidium derivatives and ethidium itself toward different G-quadruplex species, with electrospray mass spectrometry and competitive equilibrium dialysis and evaluated their inhibitory properties against telomerase.

[G-quadruplex DNA: myth or reality?].

The peculiar sequence of telomeric DNA, composed of repetitions of the GGTTAG motif allows the formation of an unusual DNA conformation based on guanine-quadruplex (G-quadruplex). Small molecules that bind and stabilize telomeric DNA under its G-quadruplex conformation are able to impair telomerase activity. Several recent reports have shown that G-quadruplex ligands could block telomerase activity in cancer cells and represent a new experimental approach to limit cancer growth.

Reduced activation of phosphatidylinositol-3 kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes.

To understand better the defects in the proximal steps of insulin signaling during type 2 diabetes, we used differentiated human skeletal muscle cells in primary culture. When compared with cells from control subjects, myotubes established from patients with type 2 diabetes presented the same defects as those previously evidenced in vivo in muscle biopsies, including defective stimulation of phosphatidylinositol (PI) 3-kinase activity, decreased association of PI 3-kinase with insulin receptor substrate (IRS)-1 and reduced IRS-1 tyrosine phosphorylation during insulin stimulation. In contrast to IRS-1, the signaling through IRS-2 was not altered.

Interactions of cryptolepine and neocryptolepine with unusual DNA structures.

Cryptolepine, the main alkaloid present in the roots of Cryptolepis sanguinolenta, presents a large spectrum of biological properties. It has been reported to behave like a DNA intercalator with a preference for GC-rich sequences. In this study, dialysis competition assay and mass spectrometry experiments were used to determine the affinity of cryptolepine and neocryptolepine for DNA structures among duplexes, triplexes, quadruplexes and single strands.