Puzzling pieces of chromosome 7 loss or deletion

In this issue of Blood, Inaba et al review the challenges and questions to be answered in the molecular and functional dissection of loss of chromosome 7 (monosomy 7 [-7]) and deletion of a segment of the long arm (del(7q)) found in patients with various syndromes involving the myeloid blood cell lineage

Receptor Activator of NF-κB (RANK) Confers Resistance to Chemotherapy in AML and Associates with Dismal Disease Course.

Although treatment options of acute myeloid leukemia (AML) have improved over the recent years, prognosis remains poor. Better understanding of the molecular mechanisms influencing and predicting treatment efficacy may improve disease control and outcome. Here we studied the expression, prognostic relevance and functional role of the tumor necrosis factor receptor (TNFR) family member Receptor Activator of Nuclear Factor (NF)-κB (RANK) in AML. We conducted an experimental ex vivo study using leukemic cells of 54 AML patients. Substantial surface expression of RANK was detected on primary AML cells in 35% of the analyzed patients. We further found that RANK signaling induced the release of cytokines acting as growth and survival factors for the leukemic cells and mediated resistance of AML cells to treatment with doxorubicin and cytarabine, the most commonly used cytostatic compounds in AML treatment. In line, RANK expression correlated with a dismal disease course as revealed by reduced overall survival. Together, our results show that RANK plays a yet unrecognized role in AML pathophysiology and resistance to treatment, and identify RANK as "functional" prognostic marker in AML. Therapeutic modulation of RANK holds promise to improve treatment response in AML patients

Neutralization of B-Cell Activating Factor (BAFF) by Belimumab Reinforces Small Molecule Inhibitor Treatment in Chronic Lymphocytic Leukemia.

The introduction of idelalisib, ibrutinib and venetoclax for treatment of chronic lymphocytic leukemia (CLL) has greatly improved long term survival of patients. However, many patients do not achieve complete remission and suffer from development of resistance upon treatment with these small molecule inhibitors. Here we report that the TNF family member B-cell activating factor (BAFF) mediates resistance of CLL cells to idelalisib, ibrutinib and venetoclax by sustaining survival and preventing apoptosis of the malignant B cells as revealed by analysis of cellular ATP levels and mitochondrial membrane integrity as well as caspase activation, respectively. As BAFF also plays a prominent role in autoimmune diseases, the BAFF-neutralizing antibody belimumab was developed and approved for treatment of systemic lupus erythematosus (SLE). When we employed belimumab in the context of CLL treatment with idelalisib, ibrutinib and venetoclax, BAFF neutralization was found to significantly increase the sensitivity of the leukemic cells to all three small molecule inhibitors. Notably, BAFF neutralization proved to be beneficial independently of clinical stage according to Binet and Rai or IgVH mutational status. Our results identify drug repurposing of belimumab for neutralization of BAFF to complement small molecule inhibitor treatment as a promising therapeutic approach in CLL that is presently undergoing clinical evaluation

Inhibition of NK Reactivity Against Solid Tumors by Platelet-Derived RANKL.

NK cells play an important role in tumor immunosurveillance. Their reactivity is governed by various activating and inhibitory surface receptors, which include several members of the TNF/TNF receptor family. For more than 50 years, it has been recognized that tumor immunosurveillance and in particular NK cell antitumor reactivity is largely influenced by platelets, but the underlying mechanisms remain to be fully elucidated. Here we report that upon activation, which reportedly occurs following interaction with cancer cells, platelets upregulate the TNF family member RANKL. Comparative analysis of the expression of RANK among different NK cell subsets and RANKL on platelets in cancer patients and healthy volunteers revealed a distinct malignant phenotype, and platelet-derived RANKL was found to inhibit the activity of normal NK cells against cancer cells. Notably, NK cell antitumor reactivity could be partially restored by application of denosumab, a RANKL-neutralizing antibody approved for treatment of benign and malignant osteolysis. Together, our data not only unravel a novel mechanism of tumor immune evasion mediated by platelets, but they also provide a functional explanation for the clinical observation that denosumab, beyond protecting from bone loss, may prolong disease-free survival in patients with solid tumors

Neutron Halo Isomers in Stable Nuclei and their Possible Application for the Production of Low Energy, Pulsed, Polarized Neutron Beams of High Intensity and High Brilliance

We propose to search for neutron halo isomers populated via $\gamma$-capture in stable nuclei with mass numbers of about A=140-180 or A=40-60, where the $4s_{1/2}$ or $3s_{1/2}$ neutron shell model state reaches zero binding energy. These halo nuclei can be produced for the first time with new $\gamma$-beams of high intensity and small band width ($\le$ 0.1%) achievable via Compton back-scattering off brilliant electron beams thus offering a promising perspective to selectively populate these isomers with small separation energies of 1 eV to a few keV. Similar to single-neutron halo states for very light, extremely neutron-rich, radioactive nuclei \cite{hansen95,tanihata96,aumann00}, the low neutron separation energy and short-range nuclear force allows the neutron to tunnel far out into free space much beyond the nuclear core radius. This results in prolonged half lives of the isomers for the $\gamma$-decay back to the ground state in the 100 ps-$\mu$s range. Similar to the treatment of photodisintegration of the deuteron, the neutron release from the neutron halo isomer via a second, low-energy, intense photon beam has a known much larger cross section with a typical energy threshold behavior. In the second step, the neutrons can be released as a low-energy, pulsed, polarized neutron beam of high intensity and high brilliance, possibly being much superior to presently existing beams from reactors or spallation neutron sources.Comment: accepted for publication in Applied Physics

Population redistribution in optically trapped polar molecules

We investigate the rovibrational population redistribution of polar molecules in the electronic ground state induced by spontaneous emission and blackbody radiation. As a model system we use optically trapped LiCs molecules formed by photoassociation in an ultracold two-species gas. The population dynamics of vibrational and rotational states is modeled using an ab-initio electric dipole moment function and experimental potential energy curves. Comparison with the evolution of the v"=3 electronic ground state yields good qualitative agreement. The analysis provides important input to assess applications of ultracold LiCs molecules in quantum simulation and ultracold chemistry.Comment: 6 pages, 5 figures, EPJD Topical issue on Cold Quantum Matter - Achievements and Prospect

cGMP stimulation of cystic fibrosis transmembrane conductance regulator Cl- channels co-expressed with cGMP-dependent protein kinase type II but not type Ibeta

In order to investigate the involvement of cGMP-dependent protein kinase (cGK) type II in cGMP-provoked intestinal Cl- secretion, cGMP-dependent activation and phosphorylation of cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channels was analyzed after expression of cGK II or cGK Ibeta in intact cells. An intestinal cell line which stably expresses CFTR (IEC-CF7) but contains no detectable endogenous cGK II was infected with a recombinant adenoviral vector containing the cGK II coding region (Ad-cGK II) resulting in co-expression of active cGK II. In these cells, CFTR was activated by membrane-permeant analogs of cGMP or by the cGMP-elevating hormone atrial natriuretic peptide as measured by 125I- efflux assays and whole-cell patch clamp analysis. In contrast, infection with recombinant adenoviruses expressing cGK Ibeta or luciferase did not convey cGMP sensitivity to CFTR in IEC-CF7 cells. Concordant with the activation of CFTR by only cGK II, infection with Ad-cGK II but not Ad-cGK Ibeta enabled cGMP analogs to increase CFTR phosphorylation in intact cells. These and other data provide evidence that endogenous cGK II is a key mediator of cGMP-provoked activation of CFTR in cells where both proteins are co-localized, e. g. intestinal epithelial cells. Furthermore, they demonstrate that neither the soluble cGK Ibeta nor cAMP-dependent protein kinase are able to substitute for cGK II in this cGMP-regulated function

Forward K+ production in subthreshold pA collisions at 1.0 GeV

K+ meson production in pA (A = C, Cu, Au) collisions has been studied using the ANKE spectrometer at an internal target position of the COSY-Juelich accelerator. The complete momentum spectrum of kaons emitted at forward angles, theta < 12 degrees, has been measured for a beam energy of T(p)=1.0 GeV, far below the free NN threshold of 1.58 GeV. The spectrum does not follow a thermal distribution at low kaon momenta and the larger momenta reflect a high degree of collectivity in the target nucleus.Comment: 4 pages, 3 figure

"Plantar pro gasto": a importância do autoconsumo entre famílias de agricultores do Rio Grande do Sul.

O artigo discute a valoração e importância da produção para o autoconsumo na reprodução social das unidades familiares e caracteriza os alimentos autoconsumidos. Vale-se da pesquisa "Agricultura Familiar, Desenvolvimento Local e Pluriatividade" (UFRGS/UFPel/ CNPq-2003) que propiciou a formação de um banco de dados com informações sobre a dinâmica da agricultura familiar em quatro regiões distintas da geografia gaúcha, suas fontes e tipos de renda, entre estas o autoconsumo. Trazer este debate significa retomar um tema pouco discutido até então, e que, embora marginalizado ou considerado sem importância, desenvolve importante papel como renda não monetária, fortalece a segurança alimentar e adentra esferas da sociabilidade e identidade social. Além da introdução, apresenta-se o papel do autoconsumo na agricultura familiar, o cálculo da produção para o autoconsumo, discussão dos objetivos e resultados, e considerações finais. Os resultados demonstram que a produção para o autoconsumo é uma estratégia recorrente pelas unidades familiares e se diferencia de acordo com a dinâmica da agricultura familiar. Diferença esta expressa em valores relativos (%) e no número de estabelecimentos pertencentes a estratos diferenciados de autoconsumo, e pouco nos tipos de alimentos produzidos para este fim, observando-se uma homogeneidade dos hábitos alimentares

Datalog-Based program analysis with BES and RWL

This paper describes two techniques for Datalog query evaluation and their application to object-oriented program analysis. The first technique transforms Datalog programs into an implicit Boolean Equation System (Bes) that can then be solved by using linear-time complexity algorithms that are available in existing, general purpose verification toolboxes such as Cadp. In order to improve scalability and to enable analyses involving advanced meta-programming features, we develop a second methodology that transforms Datalog programs into rewriting logic (Rwl) theories. This method takes advantage of the preeminent features and facilities that are available within the high-performance system Maude, which provides a very efficient implementation of Rwl. We provide evidence of the practicality of both approaches by reporting on some experiments with a number of real-world Datalog-based analyses. © 2011 Springer-Verlag.This work has been partially supported by the eu(feder), the Spanish mec/micinn under grants tin2007-68093-C02 and tin2010-21062-C02-02, and the Generalitat Valenciana under grant Emergentes gv/2009/024. M.A.Feliu was partially supported by the Spanish mec fpu grant AP2008-00608.Alpuente Frasnedo, M.; Feliú Gabaldón, MA.; Joubert, C.; Villanueva García, A. (2011). Datalog-Based program analysis with BES and RWL. En Datalog Reloaded. Springer Verlag (Germany). 6702:1-20. https://doi.org/10.1007/978-3-642-24206-9_1S1206702Afrati, F.N., Ullman, J.D.: Optimizing joins in a map-reduce environment. In: Manolescu, I., Spaccapietra, S., Teubner, J., Kitsuregawa, M., Léger, A., Naumann, F., Ailamaki, A., Özcan, F. (eds.) EDBT. ACM International Conference Proceeding Series, vol. 426, pp. 99–110. 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