Cytogenetic and Molecular Predictors of Outcome in Acute Lymphocytic Leukemia: Recent Developments

During the last decade a tremendous technologic progress based on genome-wide profiling of genetic aberrations, structural DNA alterations, and sequence variations has allowed a better understanding of the molecular basis of pediatric and adult B/T- acute lymphoblastic leukemia (ALL), contributing to a better recognition of the biological heterogeneity of ALL and to a more precise definition of risk factors. Importantly, these advances identified novel potential targets for therapeutic intervention. This review will be focused on the cytogenetic/molecular advances in pediatric and adult ALL based on recently published articles

Effect of thermal cycles on rock cliff deformation. Monitoring and interpretation

International audienceClimatic actions are one of the factors controlling the evolution of slopes, this paper is devoted to a specific effect, relatively little studied, related to the effect of climate-driven temperature changes on rock massif deformation. The particularity of the study is to focus on permeable rocks and Temperatures varying in a range which discards freeze/thaw effects. Research has been carried out in relation with the analysis of the real case of a limestone cliff located in the Périgord region, the massif was highly instrumented, results show a slow cyclic accumulation of deformations with time, essentially synchronic with thermal cycles. An advanced constitutive model, specifically developed to capture rock degradation due to the differential expansion of the main minerals composing the rock, has been developed. It has been calibrated on experimental results obtained in the laboratory on block samples tested in a climatic chamber for a long series (several months) of daily thermal cycles. Deformation and shear wave velocity were monitored during the test. Model shows a good agreement with laboratory measurements

Revision of the Eurocodes – aspects of geotechnical and rock engineering design

The Structural Eurocodes (EN 199x) are a suite of European standards for the design of buildings and civil engineering works, published in 2006 by the European Committee for Standardization (CEN) and with implementation starting in 2010. EN 1990 sets the basis of structural design, with the other Eurocodes dealing with different materials and specific aspects of the design; Eurocode 7 (EN 1997) deals with geotechnical aspects. In 2010, CEN began a process of evolving the Eurocodes in order to incorporate improvements that reflect the state-of-the-art in engineering design and the needs of the civil engineering market; to improve the ease-of-use of the standards; and to harmonize practice between countries. The existing EN 1990 is founded on limit state concepts, and reliability of design is provided mainly by a semi-probabilistic method based on partial factors. Applying the same method to geotechnical design has proved to be difficult, and the revised EN 1990 will present improvements concerning geotechnical design. Reflecting these changes, the title of EN 1990 was changed to “Basis of structural and geotechnical design”. Although initially developed for structures involving soils, Eurocode 7 is also applicable to rock engineering design. A major target of the current revision is that the code should treat soil and rock on an equal basis. The evolution of the Eurocode 7 has been accompanied by a group of rock engineering experts working under CEN, who started their activity in 2011. The paper is authored by the current members of this group and presents the situation of the revision of Eurocode 7 in October 2019, namely: the main objectives of the revision; the new structure adopted for the code, with three parts, and the implementation schedule of the revised Eurocodes; the main changes implemented so far in geotechnical design and rock engineering; the main rock engineering aspects still needing to be addressed

Combined Targeting of JAK2 and Bcl-2/Bcl-xL to Cure Mutant JAK2-Driven Malignancies and Overcome Acquired Resistance to JAK2 Inhibitors

To design rational therapies for JAK2-driven hematological malignancies, we functionally dissected the key survival pathways downstream of hyperactive JAK2. In tumors driven by mutant JAK2, Stat1, Stat3, Stat5, and the Pi3k and Mek/Erk pathwayswere constitutively active, and gene expressionprofiling of TEL-JAK2 T-ALL cells revealed theupregulation of prosurvival Bcl-2 family genes. Combining the Bcl-2/Bcl-xL inhibitor ABT-737 with JAK2 inhibitors mediated prolonged disease regressions and cures in mice bearing primary human andmouse JAK2 mutant tumors. Moreover, combined targeting of JAK2 and Bcl-2/Bcl-xL was ableto circumvent and overcome acquired resistance to single-agent JAK2 inhibitor treatment. Thus, inhibiting the oncogenic JAK2 signaling network at two nodal points, at the initiating stage (JAK2) and the effector stage (Bcl-2/Bcl-xL), is highly effectiveand provides a clearly superior therapeutic benefitthan targeting just one node. Therefore, we have defined a potentially curative treatment for hematological malignancies expressing constitutively active JAK2