French Institute of Health and Medical Research

About: French Institute of Health and Medical Research is a government organization based out in Paris, France. It is known for research contribution in the topics: Population & Receptor. The organization has 109367 authors who have published 174236 publications receiving 8365503 citations.

Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia.

Abstract: Imatinib mesylate is considered standard of care for first-line treatment of chronic phase chronic myeloid leukemia (CML-CP). In the phase III, randomized, open-label International Randomized Study of Interferon vs STI571 (IRIS) trial, previously untreated CML-CP patients were randomized to imatinib (n=553) or interferon-alpha (IFN) plus cytarabine (n=553). This 6-year update focuses on patients randomized to receive imatinib as first-line therapy for newly diagnosed CML-CP. During the sixth year of study treatment, there were no reports of disease progression to accelerated phase (AP) or blast crisis (BC). The toxicity profile was unchanged. The cumulative best complete cytogenetic response (CCyR) rate was 82%; 63% of all patients randomized to receive imatinib and still on study treatment showed CCyR at last assessment. The estimated event-free survival at 6 years was 83%, and the estimated rate of freedom from progression to AP and BC was 93%. The estimated overall survival was 88% -- or 95% when only CML-related deaths were considered. This 6-year update of IRIS underscores the efficacy and safety of imatinib as first-line therapy for patients with CML.

In vivo recordings of brain activity using organic transistors

Abstract: In vivo electrophysiological recordings of neuronal circuits are necessary for diagnostic purposes and for brain-machine interfaces. Organic electronic devices constitute a promising candidate because of their mechanical flexibility and biocompatibility. Here we demonstrate the engineering of an organic electrochemical transistor embedded in an ultrathin organic film designed to record electrophysiological signals on the surface of the brain. The device, tested in vivo on epileptiform discharges, displayed superior signal-to-noise ratio due to local amplification compared with surface electrodes. The organic transistor was able to record on the surface low-amplitude brain activities, which were poorly resolved with surface electrodes. This study introduces a new class of biocompatible, highly flexible devices for recording brain activity with superior signal-to-noise ratio that hold great promise for medical applications.

S6K1(-/-)/S6K2(-/-) mice exhibit perinatal lethality and rapamycin-sensitive 5'-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway.

Abstract: Recent studies showed that the 40S ribosomal protein S6 kinase (S6K) p70S6K/p85S6K, termed S6K1 (51), is a major effector of cell growth. This conclusion stems from gene deletion studies with Drosophila (39) and with mice (51) as well as recent studies with cell cultures (11). The loss of the Drosophila S6K (dS6K) gene is semilethal, with the few surviving adults having a severely reduced body size. The larvae of such flies exhibit a long developmental delay, consistent with a twofold increase in cell cycle doubling times. The few surviving adults are quite lethargic, living no longer than 2 weeks, and females are sterile. Surprisingly, the reduction in mass is strictly due to a decrease in cell size rather than to a decrease in cell number (39). In mice, removal of this kinase is not lethal, but the mice are approximately 20% smaller at birth (51). Such mice exhibit normal fasting glucose levels but are mildly glucose intolerant due to markedly reduced levels of circulating insulin (42). Reduced insulin levels are caused by a reduction in pancreatic endocrine mass and an impairment of insulin secretion, which can be traced to a selective reduction in β-cell size. Unexpectedly, the effects on body mass and hypoinsulinemia do not appear to be attributable to a reduction in S6 phosphorylation, as this response proved to be largely intact in S6K1-deficient animals (51). However, S6 phosphorylation in such animals was still sensitive to the bacterial macrolide rapamycin (51), which inhibits the mammalian target of rapamycin (mTOR) (1, 7, 16, 48), the upstream S6K1 kinase (4, 8, 18), suggesting the existence of a second S6K. Subsequent searches of expressed sequence tag databases and biochemical studies led to the identification of S6K2, which exhibited overall homology of over 80% with S6K1 in the highly conserved kinase and linker domains (17, 47, 51). In all tissues examined from S6K1-deficient mice, S6K2 transcripts were upregulated (51). From this observation, it was reasoned that S6K1 and S6K2 functions were redundant and that a deletion of the S6K1 gene led to a compensatory increase in the expression of S6K2. In parallel studies, it was demonstrated that rapamycin suppressed the serum-induced translational upregulation of a family of mRNAs which contain a polypyrimidine tract at their 5′ end (5′-terminal oligopyrimidine [5′TOP] mRNAs) (20, 55). These mRNAs largely code for components of the translational apparatus, most notably, ribosomal proteins (37). Earlier studies had shown that the translation of such transcripts is under selective translational control (22) and requires an intact 5′TOP tract (19, 49). In addition, a dominant interfering allele of S6K1 inhibited the mitogen-induced translational upregulation of 5′TOP mRNAs to the same extent as rapamycin, whereas an activated allele of S6K1, which exhibits a substantial degree of rapamycin resistance, largely protected these transcripts from the inhibitory effects of rapamycin (19, 49). Seemingly consistent with these arguments, in embryonic stem (ES) cells from which S6K1 had been homologously deleted by selection with high doses of G418, serum no longer had an effect on the upregulation of 5′TOP mRNAs, nor was there a redistribution of 5′TOP mRNAs from polysomes to nonpolysomes in the presence of rapamycin (24). However, S6 phosphorylation was initially reported to be abolished in these cells (24), despite the fact that it was largely intact in cells and tissues derived from S6K1−/− mice (51). This difference seemed to be resolved in subsequent studies, where S6 phosphorylation was detected in these same S6K1−/− ES cells and S6K2 was present and active (31, 60). Despite these observations, it was again recently reported that S6 phosphorylation was absent from these same cells (53). Furthermore, it was also claimed in the latter study that S6K activation, S6 phosphorylation, and rapamycin had little impact on 5′TOP mRNA translation in PC12 cells (53), although others working with these same cells had reported earlier that rapamycin treatment abolished the selective recruitment of these transcripts from small to large polysomes (44). Obviously, cells lacking both S6K1 and S6K2 would facilitate such studies. Therefore, we set out to delete the S6K2 gene from mice and to determine whether we could generate S6K1−/−/S6K2−/− mice. Here we report on the deletion of the S6K2 gene and the effects of deleting both S6K1 and S6K2 on animal growth and viability as well as on S6 phosphorylation, cell proliferation, and 5′TOP mRNA translation.

Menarche, menopause, and breast cancer risk: Individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies

Abstract: BACKGROUND:Menarche and menopause mark the onset and cessation, respectively, of ovarian activity associated with reproduction, and affect breast cancer risk. Our aim was to assess the strengths of their effects and determine whether they depend on characteristics of the tumours or the affected women.METHODS:Individual data from 117 epidemiological studies, including 118 964 women with invasive breast cancer and 306 091 without the disease, none of whom had used menopausal hormone therapy, were included in the analyses. We calculated adjusted relative risks (RRs) associated with menarche and menopause for breast cancer overall, and by tumour histology and by oestrogen receptor expression.FINDINGS:Breast cancer risk increased by a factor of 1·050 (95% CI 1·044-1·057; p<0·0001) for every year younger at menarche, and independently by a smaller amount (1·029, 1·025-1·032; p<0·0001), for every year older at menopause. Premenopausal women had a greater risk of breast cancer than postmenopausal women of an identical age (RR at age 45-54 years 1·43, 1·33-1·52, p<0·001). All three of these associations were attenuated by increasing adiposity among postmenopausal women, but did not vary materially by women's year of birth, ethnic origin, childbearing history, smoking, alcohol consumption, or hormonal contraceptive use. All three associations were stronger for lobular than for ductal tumours (p<0·006 for each comparison). The effect of menopause in women of an identical age and trends by age at menopause were stronger for oestrogen receptor-positive disease than for oestrogen receptor-negative disease (p<0·01 for both comparisons).INTERPRETATION:The effects of menarche and menopause on breast cancer risk might not be acting merely by lengthening women's total number of reproductive years. Endogenous ovarian hormones are more relevant for oestrogen receptor-positive disease than for oestrogen receptor-negative disease and for lobular than for ductal tumours.