Childhood environmental health concerns in Russia

Environmental Health Centre (EHC) is one of the few Russian organisations responsible for the development of environmental epidemiology and health risk assessment methodologies in Russia. Being a WELL resource centre network partner we considered the possibilities for environmental interventions to address major causes of child mortality and morbidity and environmental health concerns in Russia. It was based on the results of the preliminary scoping studies carried out by our Centre during May – October 2002. The scoping studies themselves were based on published and unpublished literature and on consultations with key stakeholders

Outcome with lenalidomide plus dexamethasone followed by early autologous stem cell transplantation in patients with newly diagnosed multiple myeloma on the ECOG-ACRIN E4A03 randomized clinical trial: long-term follow-up

In Eastern Cooperative Oncology Group-ACRIN E4A03, on completion of four cycles of therapy, newly diagnosed multiple myeloma patients had the option of proceeding to autologous peripheral blood stem cell transplant (ASCT) or continuing on their assigned therapy lenalidomide plus low-dose dexamethasone (Ld) or lenalidomide plus high-dose dexamethasone (LD). This landmark analysis compared the outcome of 431 patients surviving their first four cycles of therapy pursuing early ASCT to those continuing on their assigned therapy. Survival distributions were estimated using the Kaplan–Meier method and compared with log-rank test. Ninety patients (21%) opted for early ASCT. The 1-, 2-, 3-, 4- an

The holonomy of the supercovariant connection and Killing spinors

We show that the holonomy of the supercovariant connection for M-theory backgrounds with $N$ Killing spinors reduces to a subgroup of SL(32-N,\bR)\st (\oplus^N \bR^{32-N}). We use this to give the necessary and sufficient conditions for a background to admit $N$ Killing spinors. We show that there is no topological obstruction for the existence of up to 22 Killing spinors in eleven-dimensional spacetime. We investigate the symmetry superalgebras of supersymmetric backgrounds and find that their structure constants are determined by an antisymmetric matrix. The Lie subalgebra of bosonic generators is related to a real form of a symplectic group. We show that there is a one-one correspondence between certain bases of the Cartan subalgebra of sl(32, \bR) and supersymmetric planar probe M-brane configurations. A supersymmetric probe configuration can involve up to 31 linearly independent planar branes and preserves one supersymmetry. The space of supersymmetric planar probe M-brane configurations is preserved by an SO(32,\bR) subgroup of SL(32, \bR).Comment: 27 pages, a key reference was added. v3: minor change

Prognostic role of serum cytokeratin 19 fragments in advanced non-small-cell lung cancer: association of marker changes after two chemotherapy cycles with different measures of clinical response and survival

Prognostic implication of serum cytokeratin 19 fragments (CYFRA 21-1) was explored in 60 advanced NSCLC patients, whereas in 45 patients assessable for serological response a ⩾35% CYFRA 21-1 decline after two chemotherapy cycles was strongly associated with non-progression (NP), defined as a sum of objective response (OR)+stable disease (P<0.0001) and survival (P=0.0002). Association of OR with survival was not significant. In multivariate survival analysis, ⩾35% marker decline and radiological NP status were found as major determinants of prolonged survival with RR: 0.37 (P=0.01) and 0.63 (P=0.01), respectively. In advanced NSCLC patients, NP reflects therapeutic efficacy better than traditional OR. CYFRA 21-1 ⩾35% decline seems to be a reliable surrogate marker of treatment efficacy in terms of survival

All solutions of the localization equations for N=2 quantum black hole entropy

We find the most general bosonic solution to the localization equations describing the contributions to the quantum entropy of supersymmetric black holes in four-dimensional N=2 supergravity coupled to n_v vector multiplets. This requires the analysis of the BPS equations of the corresponding off-shell supergravity (including fluctuations of the auxiliary fields) with AdS2 \times S2 attractor boundary conditions. Our work completes and extends the results of arXiv:1012.0265 that were obtained for the vector multiplet sector, to include the fluctuations of all the fields of the off-shell supergravity. We find that, when the auxiliary SU(2) gauge field strength vanishes, the most general supersymmetric configuration preserving four supercharges is labelled by n_v+1 real parameters corresponding to the excitations of the conformal mode of the graviton and the scalars of the n_v vector multiplets. In the general case, the localization manifold is labelled by an additional SU(2) triplet of one-forms and a scalar function.Comment: 27 page

Spectrum of Chiral Operators in Strongly Coupled Gauge Theories

We analyze the large $N$ spectrum of chiral primary operators of three dimensional fixed points of the renormalization group. Using the space-time picture of the fixed points and the correspondence between anti-de Sitter compactifications and conformal field theories we are able to extract the dimensions of operators in short superconformal multiplets. We write down some of these operators in terms of short distance theories flowing to these non-trivial fixed points in the infrared.Comment: harvmac, 16 pages, one acknowledgement adde

Bulk vs. Boundary Dynamics in Anti-de Sitter Spacetime

We investigate the details of the bulk-boundary correspondence in Lorentzian signature anti-de Sitter space. Operators in the boundary theory couple to sources identified with the boundary values of non-normalizable bulk modes. Such modes do not fluctuate and provide classical backgrounds on which bulk excitations propagate. Normalizable modes in the bulk arise as a set of saddlepoints of the action for a fixed boundary condition. They fluctuate and describe the Hilbert space of physical states. We provide an explicit, complete set of both types of modes for free scalar fields in global and Poincar\'e coordinates. For \ads{3}, the normalizable and non-normalizable modes originate in the possible representations of the isometry group \SL_L\times\SL_R for a field of given mass. We discuss the group properties of mode solutions in both global and Poincar\'e coordinates and their relation to different expansions of operators on the cylinder and on the plane. Finally, we discuss the extent to which the boundary theory is a useful description of the bulk spacetime.Comment: Standard LaTeX, 28 pages, 2 postscript figures. v2: References added. Substantial revision in section 3 of treatment of global modes; non-normalizable modes have arbitrary time dependence. Revised discussion of low-mass modes and puzzle raised re: coupling of the dual boundary operators. v3: unwanted paragraph removed. v4: Sec. 5.2 correcte

The linker histone H1.0 generates epigenetic and functional intratumor heterogeneity

Tumors comprise functionally diverse subpopulations of cells with distinct proliferative potential. Here, we show that dynamic epigenetic states defined by the linker histone H1.0 determine which cells within a tumor can sustain the long-term cancer growth. Numerous cancer types exhibit high inter- and intratumor heterogeneity of H1.0, with H1.0 levels correlating with tumor differentiation status, patient survival, and, at the single-cell level, cancer stem cell markers. Silencing of H1.0 promotes maintenance of self-renewing cells by inducing derepression of megabase-sized gene domains harboring downstream effectors of oncogenic pathways. Self-renewing epigenetic states are not stable, and reexpression of H1.0 in subsets of tumor cells establishes transcriptional programs that restrict cancer cells’ long-term proliferative potential and drive their differentiation. Our results uncover epigenetic determinants of tumor-maintaining cells

Identification of markers that functionally define a quiescent multiple myeloma cell sub-population surviving bortezomib treatment

The mechanisms allowing residual multiple myeloma (MM) cells to persist after bortezomib (Bz) treatment remain unclear. We hypothesized that studying the biology of bortezomib-surviving cells may reveal markers to identify these cells and survival signals to target and kill residual MM cells.We used H2B-GFP label retention, biochemical tools and in vitro and in vivo experiments to characterize growth arrest and the unfolded protein responses in quiescent Bz-surviving cells. We also tested the effect of a demethylating agent, 5-Azacytidine, on Bz-induced quiescence and whether inhibiting the chaperone GRP78/BiP (henceforth GRP78) with a specific toxin induced apoptosis in Bz-surviving cells. Finally, we used MM patient samples to test whether GRP78 levels might associate with disease progression. Statistical analysis employed t-test and Mann-Whitney tests at a 95% confidence.We report that Bz-surviving MM cells in vitro and in vivo enter quiescence characterized by p21(CIP1) upregulation. Bz-surviving MM cells also downregulated CDK6, Ki67 and P-Rb. H2B-GFP label retention showed that Bz-surviving MM cells are either slow-cycling or deeply quiescent. The Bz-induced quiescence was stabilized by low dose (500nM) of 5-azacytidine (Aza) pre-treatment, which also potentiated the initial Bz-induced apoptosis. We also found that expression of GRP78, an unfolded protein response (UPR) survival factor, persisted in MM quiescent cells. Importantly, GRP78 downregulation using a specific SubAB bacterial toxin killed Bz-surviving MM cells. Finally, quantification of Grp78(high)/CD138+ MM cells from patients suggested that high levels correlated with progressive disease.We conclude that Bz-surviving MM cells display a GRP78(HIGH)/p21(HIGH)/CDK6(LOW)/P-Rb(LOW) profile, and these markers may identify quiescent MM cells capable of fueling recurrences. We further conclude that Aza + Bz treatment of MM may represent a novel strategy to delay recurrences by enhancing Bz-induced apoptosis and quiescence stability.Alfred Adomako, Veronica Calvo, Noa Biran, Keren Osman, Ajai Chari, James C Paton, Adrienne W Paton, Kateri Moore, Denis M Schewe, and Julio A Aguirre-Ghis

Pre-neoplastic alterations define CLL DNA methylome and persist through disease progression and therapy

Most human cancers converge to a deregulated methylome with reduced global levels and elevated methylation at select CpG islands. To investigate the emergence and dynamics of the cancer methylome, we characterized genome-wide DNA methylation in preneoplastic monoclonal B-cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL), including serial samples collected across disease course. We detected the aberrant tumor-associated methylation landscape at CLL diagnosis and found no significant differentially methylated regions in the high-count MBL-to-CLL transition. Patient methylomes showed remarkable stability with natural disease and posttherapy progression. Single CLL cells were consistently aberrantly methylated, indicating a homogeneous transition to the altered epigenetic state and a distinct expression profile together with MBL cells compared with normal B cells. Our longitudinal analysis reveals the cancer methylome to emerge early, which may provide a platform for subsequent genetically driven growth dynamics, and, together with its persistent presence, suggests a central role in disease onset. SigNifiCANCe: DNA methylation data from a large cohort of patients with MBL and CLL show that epigenetic transformation emerges early and persists throughout disease stages with limited subsequent changes. Our results indicate an early role for this aberrant landscape in the normal-to-preneoplastic transition that may reflect a pan-cancer mechanism