Phase II study of the dual EGFR/HER3 inhibitor duligotuzumab (MEHD7945A) vs. cetuximab in combination with FOLFIRI in RAS wild-type metastatic colorectal cancer

PURPOSE: Duligotuzumab is a dual-action antibody directed against EGFR and HER3. EXPERIMENTAL DESIGN: mCRC patients with KRAS ex2 wild-type received duligotuzumab or cetuximab and FOLFIRI until progression or intolerable toxicity. Mandatory tumor samples underwent mutation and biomarker analysis. Efficacy analysis was conducted in patients with RAS exon 2/3 wild-type tumors. RESULTS: Of 134 randomized patients, 98 were RAS ex2/3 wild-type. Duligotuzumab provided no PFS or OR benefit compared to cetuximab; though there was a trend for lower ORR in the duligotuzumab arm. No relationship was seen between PFS or ORR and ERBB3, NRG1, or AREG expression. There were fewer skin rash events for duligotuzumab but more diarrhea. Although the incidence of grade ≥ 3 AEs was similar, the frequency of serious AEs was higher for duligotuzumab. CONCLUSIONS: Duligotuzumab plus FOLFIRI did not appear to improve the outcomes in patients with RAS exon 2/3 wild-type mCRC compared to cetuximab + FOLFIRI

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

Loss of 4E-BP1 expression has been linked to cancer progression and resistance to mTOR inhibitors, but the mechanism underlying 4E-BP1 downregulation in tumors remains unclear. Here we identify Snail as a strong transcriptional repressor of 4E-BP1. We find that 4E-BP1 expression inversely correlates with Snail level in cancer cell lines and clinical specimens. Snail binds to three E-boxes present in the human 4E-BP1 promoter to repress transcription of 4E-BP1. Ectopic expression of Snail in cancer cell lines lacking Snail profoundly represses 4E-BP1 expression, promotes cap-dependent translation in polysomes, and reduces the anti-proliferative effect of mTOR kinase inhibitors. Conversely, genetic and pharmacological inhibition of Snail function restores 4E-BP1 expression and sensitizes cancer cells to mTOR kinase inhibitors by enhancing 4E-BP1-mediated translation-repressive effect on cell proliferation and tumor growth. Our study reveals a critical Snail-4E-BP1 signaling axis in tumorigenesis, and provides a rationale for targeting Snail to improve mTOR-targeted therapies

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

Biomécanique de l’épithélium cornéen: résistance au stress et implications dans la cicatrisation et le remodelage

International audienceThe corneal epithelium is one of the first tissue barriers of the eye against the environment. In recent years, many studies provided better knowledge of its healing, its behavior and its essential role in the optical system of the eye. At the crossroads of basic science and clinical medicine, the study of the mechanical stresses applied to the cornea makes it possible to learn the behavior of epithelial cells and better understand ocular surface disease. We describe herein the current knowledge about the adhesion systems of the corneal epithelium and their resistance to mechanical stress. We will also describe the involvement of these mechanisms in corneal healing and their role in epithelial dynamics. Adhesion molecules of the epithelial cells, especially hemidesmosomes, allow the tissue cohesion required to maintain the integrity of the corneal epithelium against the shearing forces of the eyelids as well as external forces. Their regeneration after a corneal injury is mandatory for the restoration of a healthy epithelium. Mechanotransduction plays a significant role in regulating epithelial cell behavior, and the study of the epithelium's response to mechanical forces helps to better understand the evolution of epithelial profiles after refractive surgery. A better understanding of corneal epithelial biomechanics could also help improve future therapies, particularly in the field of tissue engineering.L’épithélium cornéen constitue une des premières barrières tissulaires de l’œil face à l’environnement. Au cours des dernières années, de nombreuses recherches ont pu étudier sa cicatrisation, son comportement ainsi que son rôle primordial dans le système optique oculaire. Au croisement de la science fondamentale et de la médecine clinique, l’étude des contraintes mécaniques appliquées à la cornée permet d’appréhender le comportement des cellules épithéliales et de mieux comprendre certaines pathologies de la surface oculaire. Nous décrivons ici l’état actuel des connaissances sur les systèmes d’adhésion de l’épithélium cornéen ainsi que sur leur résistance à un stress mécanique. Nous décrirons aussi l’implication de ces mécanismes dans de la cicatrisation cornéenne et leur rôle dans la dynamique épithéliale. Les molécules d’adhésion des cellules épithéliales, en particulier les hémidesmosomes, permettent une cohésion tissulaire nécessaire au maintien de l’intégrité de l’épithélium cornéen face aux forces de cisaillement des paupières et aux agressions extérieures. Leur régénération après une lésion cornéenne est nécessaire à la restauration d’un épithélium sain. La mécanotransduction joue un rôle non négligeable dans la régulation du comportement des cellules épithéliales, et l’étude de la réaction de l’épithélium aux forces mécaniques aide à mieux comprendre l’évolution des profils épithéliaux à distance d’une chirurgie réfractive. Une meilleure compréhension de la biomécanique de l’épithélium cornéen pourrait aussi permettre d’améliorer les thérapeutiques futures en particulier dans le domaine de l’ingénierie tissulaire

ALK, ROS1, and NTRK Rearrangements in Metastatic Colorectal Cancer

Background: ALK, ROS1, and NTRK fusions occur in 0.2% to 2.4% of colorectal cancers. Pioneer cases of metastatic colorectal cancer (mCRC) patients bearing rearrangements who benefited from anti-ALK, ROS, and TrkA-B-C therapies have been reported previously. Here we aimed at characterizing the clinical and molecular landscape of ALK, ROS1, and NTRK rearranged mCRC. Methods: Clinical features and molecular characteristics of 27 mCRC patients bearing ALK, ROS1, and NTRK rearranged tumors were compared with those of a cohort of 319 patients not bearing rearrangements by means of Fisher's exact, \u3c72 test, or Mann-Whitney test as appropriate. Overall survival curves were estimated with the Kaplan-Meier method and compared using the log-rank test. A Cox proportional hazard model was adopted in the multivariable analysis. Deep molecular and immunophenotypic characterizations of rearranged cases, including those described in The Cancer Genome Atlas database, were performed. All statistical tests were two-sided. Results: Closely recalling the "BRAF history," ALK, ROS1, and NTRK rearrangements more frequently occurred in elderly patients (P = .02) with right-sided tumors (P < .001) and node-spreading (P = .03), RAS wild-type (P < .001), and MSI-high (P < .001) cancers. All patients bearing ALK, ROS1, and NTRK fusions had shorter overall survival (15.6\u2009months, 95% confidence interval [CI] = 0.0 to 20.4\u2009months) than negative patients (33.7\u2009months, 95% CI\u2009=\u200928.3 to 42.1\u2009months), both in the univariate (hazard ratio [HR] = 2.17, 95% CI\u2009=\u20091.03 to 4.57, P < .001) and multivariable models (HR\u2009=\u20092.33, 95% CI\u2009=\u20091.10 to 4.95, P = .02). All four evaluable patients with rearrangements showed primary resistance to anti-epidermal growth factor receptor agents. Frequent association with potentially targetable RNF43 mutations was observed in MSI-high rearranged tumors. Conclusions: ALK, ROS1, and NTRK rearrangements define a new rare subtype of mCRC with extremely poor prognosis. Primary tumor site, MSI-high, and RAS and BRAF wild-type status may help to identify patients bearing these alterations. While sensitivity to available treatments is limited, targeted strategies inhibiting ALK, ROS, and TrkA-B-C provided encouraging results