Development of classical Hodgkin’s lymphoma in an adult with biallelic STXBP2 mutations

Experimental model systems have delineated an important role for cytotoxic lymphocytes in the immunosurveillance of cancer. In humans, perforin-deficiency has been associated with occurrence of hematologic malignancies. Here, we describe an Epstein-Barr virus-positive classical Hodgkin's lymphoma in a patient harboring biallelic mutations in STXBP2, a gene required for exocytosis of perforin-containing lytic granules and associated with familial hemophagocytic lymphohistocytosis. Cytotoxic T lymphocytes were found infiltrating the tumor, and a high frequency of Epstein-Barr virus-specific cytotoxic T lymphocytes were detected in peripheral blood. However, lytic granule exocytosis and cytotoxicity by cytotoxic T lymphocytes, as well as natural killer cells, were severely impaired in the patient. Thus, the data suggest a link between defective lymphocyte exocytosis and development of lymphoma in STXBP2-deficient patients. Therefore, with regards to treatment of familial hemophagocytic lymphohistocytosis patients with mutations in genes required for lymphocyte exocytosis, it is important to consider both the risks of hemophagocytic lymphohistocytosis and malignancy.Swedish Research CouncilSwedish Cancer FoundationSwedish Children’s Cancer FoundationHistiocytosis AssociationClas Groschinsky’s Memorial FundJeanssons FoundationÅke Olsson Foundation for Hematological ResearchÅke Wiberg FoundationKarolinska Institute Research FoundationStockholm County Council (ALF project)Publishe

Necessary Optimality Conditions for Higher-Order Infinite Horizon Variational Problems on Time Scales

We obtain Euler-Lagrange and transversality optimality conditions for higher-order infinite horizon variational problems on a time scale. The new necessary optimality conditions improve the classical results both in the continuous and discrete settings: our results seem new and interesting even in the particular cases when the time scale is the set of real numbers or the set of integers.Comment: This is a preprint of a paper whose final and definite form will appear in Journal of Optimization Theory and Applications (JOTA). Paper submitted 17-Nov-2011; revised 24-March-2012 and 10-April-2012; accepted for publication 15-April-201

Influence Diffusion in Social Networks under Time Window Constraints

We study a combinatorial model of the spread of influence in networks that generalizes existing schemata recently proposed in the literature. In our model, agents change behaviors/opinions on the basis of information collected from their neighbors in a time interval of bounded size whereas agents are assumed to have unbounded memory in previously studied scenarios. In our mathematical framework, one is given a network $G=(V,E)$, an integer value $t(v)$ for each node $v\in V$, and a time window size $\lambda$. The goal is to determine a small set of nodes (target set) that influences the whole graph. The spread of influence proceeds in rounds as follows: initially all nodes in the target set are influenced; subsequently, in each round, any uninfluenced node $v$ becomes influenced if the number of its neighbors that have been influenced in the previous $\lambda$ rounds is greater than or equal to $t(v)$. We prove that the problem of finding a minimum cardinality target set that influences the whole network $G$ is hard to approximate within a polylogarithmic factor. On the positive side, we design exact polynomial time algorithms for paths, rings, trees, and complete graphs.Comment: An extended abstract of a preliminary version of this paper appeared in: Proceedings of 20th International Colloquium on Structural Information and Communication Complexity (Sirocco 2013), Lectures Notes in Computer Science vol. 8179, T. Moscibroda and A.A. Rescigno (Eds.), pp. 141-152, 201

Transversality Conditions for Infinite Horizon Variational Problems on Time Scales

We consider problems of the calculus of variations on unbounded time scales. We prove the validity of the Euler-Lagrange equation on time scales for infinite horizon problems, and a new transversality condition.Comment: Submitted 6-October-2009; Accepted 19-March-2010 in revised form; for publication in "Optimization Letters"

The synthesized 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one (CHM-1) promoted G2/M arrest through inhibition of CDK1 and induced apoptosis through the mitochondrial-dependent pathway in CT-26 murine colorectal adenocarcinoma cells

In this study, we investigated the effects of 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one (CHM-1) on cell viability, cell cycle arrest and apoptosis in CT-26 murine colorectal adenocarcinoma cells. For determining cell viability, the MTT assay was used. CHM-1 promoted G2/M arrest by PI staining and flow cytometric analysis. Apoptotic cells were evaluated by DAPI staining. We used CDK1 kinase assay, Western blot analysis and caspase activity assays for examining the CDK1 activity and proteins correlated with apoptosis and cell cycle arrest. The in vivo anti-tumor effects of CHM-1-P were evaluated in BALB/c mice inoculated with CT-26 cells orthotopic model. CHM-1 induced CT-26 cell viability inhibition and morphologic changes in a dose-dependent and time-dependent manner and the approximate IC(50) was 742.36 nM. CHM-1 induced significant G2/M arrest and apoptosis in CT-26 cells. CHM-1 inhibited the CDK1 activity and decreased CDK1, Cyclin A, Cyclin B protein levels. CHM-1 induced apoptosis in CT-26 cells and promoted increasing of cytosolic cytochrome c, AIF, Bax, BAD, cleavage of pro-caspase-9, and -3. The significant reduction of caspase-9 and -3 activity and increasing the viable CT-26 cells after pretreated with caspase-9 and -3 inhibitor indicated that CHM-1-induced apoptosis was mainly mediated a mitochondria-dependent pathway. CHM-1-P improved mice survival rate, and enlargement of the spleen and liver metastasis were significantly reduced in groups treated with either 10 mg/kg and 30 mg/kg of CHM-1-P and 5-FU in comparison to these of CT-26/BALB/c mice. Taken together, CHM-1 acted against colorectal adenocarcinoma cells in vitro via G2/M arrest and apoptosis, and CHM-1-P inhibited tumor growth in vivo

SETD2 haploinsufficiency for microtubule methylation is an early driver of genomic instability in renal cell carcinoma

Loss of the short arm of chromosome 3 (3p) occurs early in >95% of clear cell renal cell carcinoma (ccRCC). Nearly ubiquitous 3p loss in ccRCC suggests haploinsufficiency for 3p tumor suppressors as early drivers of tumorigenesis. We previously reported methyltransferase SETD2, which trimethylates H3 histones on lysine 36 (H3K36me3) and is located in the 3p deletion, to also trimethylate microtubules on lysine 40 (aTubK40me3) during mitosis, with aTubK40me3 required for genomic stability. We now show that monoallelic, Setd2-deficient cells retaining H3K36me3, but not aTubK40me3, exhibit a dramatic increase in mitotic defects and micronuclei count, with increased viability compared with biallelic loss. In SETD2-inactivated human kidney cells, rescue with a pathogenic SETD2 mutant deficient for microtubule (aTubK40me3), but not histone (H3K36me3) methylation, replicated this phenotype. Genomic instability (micronuclei) was also a hallmark of patient-derived cells from ccRCC. These data show that the SETD2 tumor suppressor displays a haploinsufficiency phenotype disproportionately impacting microtubule methylation and serves as an early driver of genomic instability. Significance: Loss of a single allele of a chromatin modifier plays a role in promoting oncogenesis, underscoring the growing relevance of tumor suppressor haploinsufficiency in tumorigenesis

Search for B -> h(*) nu nubar Decays at Belle

We present a search for the rare decays B -> h(*) nu nubar, where h(*) stands for a light meson. A data sample of 535 million BBbar pairs collected with the Belle detector at the KEKB e+e- collider is used. Signal candidates are required to have an accompanying B meson fully reconstructed in a hadronic mode and signal-side particles consistent with a single h(*) meson. No significant signal is observed and we set upper limits on the branching fractions at 90% confidence level. The limits on B0 -> K*0 nu nubar and B+ -> K+ nu nubar decays are more stringent than the previous constraints, while the first searches for B0 -> K0 nu nubar, pi0 nu nubar, rho0 nu nubar, phi nu nubar and B+ -> K*+ nu nubar, rho+ nu nubar are reported.Comment: 6 pages, 2 figures, submit to PR

Automating Integration of Heterogeneous COTS Components

Abstract. Mismatches make COTS components difficult to be incorporated. In this paper, an approach is presented to eliminate mismatches among COTS components, which can truly consider COTS components as black boxes. In the approach, only the assembly description of components is required, based on which adaptors for resolving mismatches can be generated automatically. This paper also described an agent-based GUI implementation of the approach.

Constraints on Dark Matter Annihilation in Clusters of Galaxies with the Fermi Large Area Telescope

Nearby clusters and groups of galaxies are potentially bright sources of high-energy gamma-ray emission resulting from the pair-annihilation of dark matter particles. However, no significant gamma-ray emission has been detected so far from clusters in the first 11 months of observations with the Fermi Large Area Telescope. We interpret this non-detection in terms of constraints on dark matter particle properties. In particular for leptonic annihilation final states and particle masses greater than ~200 GeV, gamma-ray emission from inverse Compton scattering of CMB photons is expected to dominate the dark matter annihilation signal from clusters, and our gamma-ray limits exclude large regions of the parameter space that would give a good fit to the recent anomalous Pamela and Fermi-LAT electron-positron measurements. We also present constraints on the annihilation of more standard dark matter candidates, such as the lightest neutralino of supersymmetric models. The constraints are particularly strong when including the fact that clusters are known to contain substructure at least on galaxy scales, increasing the expected gamma-ray flux by a factor of ~5 over a smooth-halo assumption. We also explore the effect of uncertainties in cluster dark matter density profiles, finding a systematic uncertainty in the constraints of roughly a factor of two, but similar overall conclusions. In this work, we focus on deriving limits on dark matter models; a more general consideration of the Fermi-LAT data on clusters and clusters as gamma-ray sources is forthcoming.Comment: accepted to JCAP, Corresponding authors: T.E. Jeltema and S. Profumo, minor revisions to be consistent with accepted versio