Association between a high number of isolated lymph nodes in T1 to T4 N0M0 colorectal cancer and the microsatellite instability phenotype

Hypothèse : Les carcinomes colorectaux de stade I ou II microsatellites instables (MSI) sont caractérisés par plus de ganglions lymphatiques isolés sur la pièce de résection par rapport à leurs homologues microsatellites stables (MSS). Conception : Étude prospective. Patients : Le statut MSI a été déterminé de façon prospective chez 135 patients opérables, par l’utilisation d’une PCR pentaplex. Puis, les défauts de réparation des mésappariements de l’ADN ont été étudiés par immunohistochimie. Résultats : Parmi les 82 cancers colorectaux de stade I ou II, 11 étaient MSI et 71 MSS, avec une moyenne (écart-type) de 23,6 (3,1) et 13,7 (1,0) ganglions négatifs, respectivement (p = .001). Le nombre moyen de ganglions pour tous les cancers colorectaux de stade I ou II analysés dans notre hôpital était de 15. La prévalence des MSI dans les tumeurs avec plus de 15 ganglions prélevés était de 25 % (9 sur 36) et 82 % (9 sur 11) des tumeurs MSI appartenaient à ce groupe. Conclusions : Un nombre élevé de ganglions isolés en cas de cancer colorectal de stade I ou II est associé au phénotype MSI. Le bon pronostic qui est habituellement associé à des tumeurs ayant un nombre élevé de ganglions N0 pourrait refléter la prévalence élevée des MSI chez ces tumeurs. Le nombre de ganglions examinés comme un critère de qualité doit être utilisé avec prudence. Limiter le phénotypage MSI aux tumeurs colorectales de stade I ou II ayant plus que le nombre moyen de ganglions identifie presque toutes les tumeurs MSI.Hypothèse : Les carcinomes colorectaux de stade I ou II microsatellites instables (MSI) sont caractérisés par plus de ganglions lymphatiques isolés sur la pièce de résection par rapport à leurs homologues microsatellites stables (MSS). Conception : Étude prospective. Patients : Le statut MSI a été déterminé de façon prospective chez 135 patients opérables, par l’utilisation d’une PCR pentaplex. Puis, les défauts de réparation des mésappariements de l’ADN ont été étudiés par immunohistochimie. Résultats : Parmi les 82 cancers colorectaux de stade I ou II, 11 étaient MSI et 71 MSS, avec une moyenne (écart-type) de 23,6 (3,1) et 13,7 (1,0) ganglions négatifs, respectivement (p = .001). Le nombre moyen de ganglions pour tous les cancers colorectaux de stade I ou II analysés dans notre hôpital était de 15. La prévalence des MSI dans les tumeurs avec plus de 15 ganglions prélevés était de 25 % (9 sur 36) et 82 % (9 sur 11) des tumeurs MSI appartenaient à ce groupe. Conclusions : Un nombre élevé de ganglions isolés en cas de cancer colorectal de stade I ou II est associé au phénotype MSI. Le bon pronostic qui est habituellement associé à des tumeurs ayant un nombre élevé de ganglions N0 pourrait refléter la prévalence élevée des MSI chez ces tumeurs. Le nombre de ganglions examinés comme un critère de qualité doit être utilisé avec prudence. Limiter le phénotypage MSI aux tumeurs colorectales de stade I ou II ayant plus que le nombre moyen de ganglions identifie presque toutes les tumeurs MSI

Dactinomycin induces complete remission associated with nucleolar stress response in relapsed/refractory NPM1-mutated AML

Acute myeloid leukemia (AML) with mutated NPM1 accounts for one-third of newly diagnosed AML. Despite recent advances, treatment of relapsed/refractory NPM1-mutated AML remains challenging, with the majority of patients eventually dying due to disease progression. Moreover, the prognosis is particularly poor in elderly and unfit patients, mainly because they cannot receive intensive treatment. Therefore, alternative treatment strategies are needed. Dactinomycin is a low-cost chemotherapeutic agent, which has been anecdotally reported to induce remission in NPM1-mutated patients, although its mechanism of action remains unclear. Here, we describe the results of a single-center phase 2 pilot study investigating the safety and efficacy of single-agent dactinomycin in relapsed/refractory NPM1-mutated adult AML patients, demonstrating that this drug can induce complete responses and is relatively well tolerated. We also provide evidence that the activity of dactinomycin associates with nucleolar stress both in vitro and in vivo in patients. Finally, we show that low-dose dactinomycin generates more efficient stress response in cells expressing NPM1 mutant compared to wild-type cells, suggesting that NPM1-mutated AML may be more sensitive to nucleolar stress. In conclusion, we establish that dactinomycin is a potential therapeutic alternative in relapsed/refractory NPM1-mutated AML that deserves further investigation in larger clinical studies

Severe pneumococcal pneumonia: impact of new quinolones on prognosis

<p>Abstract</p> <p>Background</p> <p>Most guidelines have been proposing, for more than 15 years, a β-lactam combined with either a quinolone or a macrolide as empirical, first-line therapy of severe community acquired pneumonia (CAP) requiring ICU admission. Our goal was to evaluate the outcome of patients with severe CAP, focusing on the impact of new rather than old fluoroquinolones combined with β-lactam in the empirical antimicrobial treatments.</p> <p>Methods</p> <p>Retrospective study of consecutive patients admitted in a 16-bed general intensive care unit (ICU), between January 1996 and January 2009, for severe (Pneumonia Severity Index > or = 4) community-acquired pneumonia due to non penicillin-resistant <it>Streptococcus pneumoniae </it>and treated with a β-lactam combined with a fluoroquinolone.</p> <p>Results</p> <p>We included 70 patients of whom 38 received a β-lactam combined with ofloxacin or ciprofloxacin and 32 combined with levofloxacin. Twenty six patients (37.1%) died in the ICU. Three independent factors associated with decreased survival in ICU were identified: septic shock on ICU admission (AOR = 10.6; 95% CI 2.87-39.3; p = 0.0004), age > 70 yrs. (AOR = 4.88; 95% CI 1.41-16.9; p = 0.01) and initial treatment with a β-lactam combined with ofloxacin or ciprofloxacin (AOR = 4.1; 95% CI 1.13-15.13; p = 0.03).</p> <p>Conclusion</p> <p>Our results suggest that, when combined to a β-lactam, levofloxacin is associated with lower mortality than ofloxacin or ciprofloxacin in severe pneumococcal community-acquired pneumonia.</p

Multi-omics insights into the biological mechanisms underlying statistical gene-by-lifestyle interactions with smoking and alcohol consumption

Though both genetic and lifestyle factors are known to influence cardiometabolic outcomes, less attention has been given to whether lifestyle exposures can alter the association between a genetic variant and these outcomes. The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium’s Gene-Lifestyle Interactions Working Group has recently published investigations of genome-wide gene-environment interactions in large multi-ancestry meta-analyses with a focus on cigarette smoking and alcohol consumption as lifestyle factors and blood pressure and serum lipids as outcomes. Further description of the biological mechanisms underlying these statistical interactions would represent a significant advance in our understanding of gene-environment interactions, yet accessing and harmonizing individual-level genetic and ‘omics data is challenging. Here, we demonstrate the coordinated use of summary-level data for gene-lifestyle interaction associations on up to 600,000 individuals, differential methylation data, and gene expression data for the characterization and prioritization of loci for future follow-up analyses. Using this approach, we identify 48 genes for which there are multiple sources of functional support for the identified gene-lifestyle interaction. We also identified five genes for which differential expression was observed by the same lifestyle factor for which a gene-lifestyle interaction was found. For instance, in gene-lifestyle interaction analysis, the T allele of rs6490056 (ALDH2) was associated with higher systolic blood pressure, and a larger effect was observed in smokers compared to non-smokers. In gene expression studies, this allele is associated with decreased expression of ALDH2, which is part of a major oxidative pathway. Other results show increased expression of ALDH2 among smokers. Oxidative stress is known to contribute to worsening blood pressure. Together these data support the hypothesis that rs6490056 reduces expression of ALDH2, which raises oxidative stress, leading to an increase in blood pressure, with a stronger effect among smokers, in whom the burden of oxidative stress is greater. Other genes for which the aggregation of data types suggest a potential mechanism include: GCNT4×current smoking (HDL), PTPRZ1×ever-smoking (HDL), SYN2×current smoking (pulse pressure), and TMEM116×ever-smoking (mean arterial pressure). This work demonstrates the utility of careful curation of summary-level data from a variety of sources to prioritize gene-lifestyle interaction loci for follow-up analyses

Search for dark matter annual modulation with DarkSide-50

Dark matter induced event rate in an Earth-based detector is predicted to show an annual modulation as a result of the Earth's orbital motion around the Sun. We searched for this modulation signature using the ionization signal of the DarkSide-50 liquid argon time projection chamber. No significant signature compatible with dark matter is observed in the electron recoil equivalent energy range above $40~{\rm eV_{ee}}$, the lowest threshold ever achieved in such a search.Comment: 8 pages, 4 figure

Directionality of nuclear recoils in a liquid argon time projection chamber

The direct search for dark matter in the form of weakly interacting massive particles (WIMP) is performed by detecting nuclear recoils (NR) produced in a target material from the WIMP elastic scattering. A promising experimental strategy for direct dark matter search employs argon dual-phase time projection chambers (TPC). One of the advantages of the TPC is the capability to detect both the scintillation and charge signals produced by NRs. Furthermore, the existence of a drift electric field in the TPC breaks the rotational symmetry: the angle between the drift field and the momentum of the recoiling nucleus can potentially affect the charge recombination probability in liquid argon and then the relative balance between the two signal channels. This fact could make the detector sensitive to the directionality of the WIMP-induced signal, enabling unmistakable annual and daily modulation signatures for future searches aiming for discovery. The Recoil Directionality (ReD) experiment was designed to probe for such directional sensitivity. The TPC of ReD was irradiated with neutrons at the INFN Laboratori Nazionali del Sud, and data were taken with 72 keV NRs of known recoil directions. The direction-dependent liquid argon charge recombination model by Cataudella et al. was adopted and a likelihood statistical analysis was performed, which gave no indications of significant dependence of the detector response to the recoil direction. The aspect ratio R of the initial ionization cloud is estimated to be 1.037 +/- 0.027 and the upper limit is R < 1.072 with 90% confidence levelComment: 20 pages, 10 figures, submitted to Eur. Phys. J.

Recepteurs de l'acide retinoique: clonage, analyse de la regulation de l'expression et implication dans l'oncogenese

SIGLEAvailable from INIST (FR), Document Supply Service, under shelf-number : T 78031 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

ANALYSE MOLECULAIRE DE L'ACIDE RETINOIQUE ET DE L'ARSENIC DANS LA LEUCEMIE AIGUE PROMYELOCYTAIRE

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF