Molecular signature of retinoic acid treatment in acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia characterized by a block of differentiation at the promyelocytic stage. APL patients respond to pharmacological concentrations of all-trans retinoic acid ( RA) and disease remission correlates with terminal differentiation of leukemic blasts. The PML/RAR oncogenic transcription factor is responsible for both the pathogenesis of APL and for its sensitivity to RA. In order to identify physiological targets of RA therapy, we analysed gene expression profiles of RA-treated APL blasts and found 1056 common target genes. Comparing these results to those obtained in RA-treated U937 cell lines revealed that transcriptional response to RA is largely dependent on the expression of PML/RAR. Several genes involved in the control of differentiation and stem cell renewal are early targets of RA regulation, and may be important effectors of RA response. Modulation of chromatin modifying genes was also observed, suggesting that specific structural changes in local chromatin domains may be required to promote RA-mediated differentiation. Computational analysis of upstream genomic regions in RA target genes revealed nonrandom distribution of transcription factor binding sites, indicating that specific transcriptional regulatory complexes may be involved in determining RA response

Acetaldehyde binding energies: a coupled experimental and theoretical study

Acetaldehyde is one of the most common and abundant gaseous interstellar complex organic molecules, found in cold and hot regions of the molecular interstellar medium. Its presence in the gas-phase depends on the chemical formation and destruction routes, and its binding energy (BE) governs whether acetaldehyde remains frozen onto the interstellar dust grains or not. In this work, we report a combined study of the acetaldehyde BE obtained via laboratory TPD (Temperature Programmed Desorption) experiments and theoretical quantum chemical computations. BEs have been measured and computed as a pure acetaldehyde ice and as mixed with both polycrystalline and amorphous water ice. Both calculations and experiments found a BE distribution on amorphous solid water that covers the 4000--6000 K range, when a pre-exponential factor of $1.1\times 10^{18}s^{-1}$ is used for the interpretation of the experiments. We discuss in detail the importance of using a consistent couple of BE and pre-exponential factor values when comparing experiments and computations, as well as when introducing them in astrochemical models. Based on the comparison of the acetaldehyde BEs measured and computed in the present work with those of other species, we predict that acetaldehyde is less volatile than formaldehyde, but much more than water, methanol, ethanol, and formamide. We discuss the astrochemical implications of our findings and how recent astronomical high spatial resolution observations show a chemical differentiation involving acetaldehyde, which can easily explained as due to the different BEs of the observed molecules.Comment: 12 pages, 6 figure

Selective Synthesis of a Salt and a Cocrystal of the Ethionamide-Salicylic Acid System

Herein is presented a rare example of salt/cocrystal polymorphism involving the adduct between ethionamide (ETH) and salicylic acid (SAL). Both the salt and cocrystal forms have the same stoichiometry and composition and are both stable at room temperature. The synthetic procedure was successfully optimized in order to selectively obtain both polymorphs. The two adducts' structures were thoroughly investigated by means of single-crystal X-ray diffraction, solid-state NMR spectroscopy, and density functional theory (DFT) calculations. From the solid-state NMR point of view, the combination of mono- and multinuclear experiments (1H MAS, 13C and 15N CPMAS, 1H-{14N} D-HMQC, 1H-14N PM-S-RESPDOR) provided undoubted spectroscopic evidence about the different positions of the hydrogen atom along the main N\ub7\ub7\ub7H\ub7\ub7\ub7O interaction. In particular, the 1H-14N PM-S-RESPDOR allowed N-H distance measurements through the 1H detected signal at a very high spinning speed (70 kHz), which remarkably agree with those derived by DFT optimized X-ray diffraction, even on a natural abundance real system. The thermodynamic relationship between the salt and the cocrystal was inquired from the experimental and computational points of view, enabling the characterization of the two polymorphs as enantiotropically related. The performances of the two forms in terms of dissolution rate are comparable to each other but significantly higher with respect to the pure ETH

Timber gridshells: beyond the drawing board

In March 2011, a week-long workshop that invited participation from all architecture and architectural technology students at Sheffield Hallam University, UK was organised with the objective of enhancing students’ thinking and experience by construction thinking. It was aimed at creating a sense of realness to realise a design project collectively. Timber was set as the material of exploration. The students had to make use of bending to design and create a timber gridshell structure. This made use of a quality traditionally felt to be a structural weakness of the material. To do this, students form-found non-mathematically and non-digitally using paper gridmats. This paper describes the aims, activity and outcome of the timber gridshell workshop as a way of preparing architects and technologists of the future and introducing the challenges of architectural design in terms of economics and construction process, aesthetics, effective communication and structural intuition by working with a given material – all important aspects in achieving effective architecture

Sequential valproic acid/all-trans retinoic acid treatment reprograms differentiation in refractory and high risk acute myeloid leukemia.

Epigenetic alterations of chromatin due to aberrant histone deacetylase (HDAC) activity and transcriptional silencing of all-trans retinoic acid (ATRA) pathway are events linked to the pathogenesis of acute myeloid leukemia (AML) that can be targeted by specific treatments. A pilot study was carried out in eight refractory or high-risk AML patients not eligible for intensive therapy to assess the biological and therapeutic activities of the HDAC inhibitor valproic acid (VPA) used to remodel chromatin, followed by the addition of ATRA, to activate gene transcription and differentiation in leukemic cells. Hyperacetylation of histones H3 and H4 was detectable at therapeutic VPA serum levels (>or=50 microg/mL) in blood mononuclear cells from seven of eight patients. This correlated with myelomonocytic differentiation of leukemic cells as revealed by morphologic, cytochemical, immunophenotypic, and gene expression analyses. Differentiation of the leukemic clone was proven by fluorescence in situ hybridization analysis showing the cytogenetic lesion +8 or 7q- in differentiating cells. Hematologic improvement, according to established criteria for myelodysplastic syndromes, was observed in two cases. Stable disease and disease progression were observed in five and one cases, respectively. In conclusion, VPA-ATRA treatment is well tolerated and induces phenotypic changes of AML blasts through chromatin remodeling. Further studies are needed to evaluate whether VPA-ATRA treatment by reprogramming differentiation of the leukemic clone might improve the response to chemotherapy in leukemia patients

The novel CXCR4 antagonist POL5551 mobilizes hematopoietic stem and progenitor cells with greater efficiency than Plerixafor

Mobilized blood has supplanted bone marrow (BM) as the primary source of hematopoietic stem cells for autologous and allogeneic stem cell transplantation. Pharmacologically enforced egress of hematopoietic stem cells from BM, or mobilization, has been achieved by directly or indirectly targeting the CXCL12/CXCR4 axis. Shortcomings of the standard mobilizing agent, granulocyte colony-stimulating factor (G-CSF), administered alone or in combination with the only approved CXCR4 antagonist, Plerixafor, continue to fuel the quest for new mobilizing agents. Using Protein Epitope Mimetics technology, a novel peptidic CXCR4 antagonist, POL5551, was developed. In vitro data presented herein indicate high affinity to and specificity for CXCR4. POL5551 exhibited rapid mobilization kinetics and unprecedented efficiency in C57BL/6 mice, exceeding that of Plerixafor and at higher doses also of G-CSF. POL5551-mobilized stem cells demonstrated adequate transplantation properties. In contrast to G-CSF, POL5551 did not induce major morphological changes in the BM of mice. Moreover, we provide evidence of direct POL5551 binding to hematopoietic stem and progenitor cells (HSPCs) in vivo, strengthening the hypothesis that CXCR4 antagonists mediate mobilization by direct targeting of HSPCs. In summary, POL5551 is a potent mobilizing agent for HSPCs in mice with promising therapeutic potential if these data can be orroborated in humans

Genetic lesions disrupting calreticulin 3′-untranslated region in JAK2 mutation-negative polycythemia vera

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An overview of historical and contemporary concrete shells, their construction and factors in their general disappearance

Only through understanding why concrete shells’ loss in popularity over the course of modern history can designers be equipped with the skills to create and apply this type of construction. Through modifications to design processes, construction stages, material understanding and relevant formwork improvements will architects and designers be able to meet the demands of the 21st century and beyond. To understand why concrete shells are no longer commonly built is to understand its construction process. An amorphous material, the fundamental relationship between formwork and the resultant concrete shell needs to be raised, appreciated, understood and analyzed for a holistic understanding of concrete shells. Through understanding this, issues and factors affecting concrete shells can be tackled and designed out in reviving this type of structures because they can be efficient in structural performance, economical in cost and provide high aesthetic value. This paper discusses concrete shells as an architectural solution by asking the question to what constituted their popularity and factors that led to their demise in the modern age of technological advancement, construction process and environmental concerns. This paper presents a cultural perspective and an overview of seminal, historical and contemporary concrete shells so as to bring about a renaissance of such structures in our built environment once again because of all the benefits it can offer.</p