On the stability and spectrum of non-supersymmetric AdS(5) solutions of M-theory compactified on Kahler-Einstein spaces

Eleven-dimensional supergravity admits non-supersymmetric solutions of the form AdS(5)xM(6) where M(6) is a positive Kahler-Einstein space. We show that the necessary and sufficient condition for such solutions to be stable against linearized bosonic supergravity perturbations can be expressed as a condition on the spectrum of the Laplacian acting on (1,1)-forms on M(6). For M(6)=CP(3), this condition is satisfied, although there are scalars saturating the Breitenlohner-Freedman bound. If M(6) is a product S(2)xM(4) (where M(4) is Kahler-Einstein) then there is an instability if M(4) has a continuous isometry. We show that a potential non-perturbative instability due to 5-brane nucleation does not occur. The bosonic Kaluza-Klein spectrum is determined in terms of eigenvalues of operators on M(6).Comment: 21 pages. v2: Includes SU(4) quantum numbers for CP3 case, typos fixed, refs adde

Caged Gammarus fossarum (crustacea) as a robust tool for the characterization of bioavailable contamination levels in continental waters. Toward the determination of threshold values

We investigated the suitability of an active biomonitoring approach, using the ecologically relevant species Gammarus fossarum, to assess trends of bioavailable contamination in continental waters. Gammarids were translocated into cages at 27 sites, in the Rhône-Alpes region (France) during early autumn 2009. Study sites were chosen to represent different physico-chemical characteristics and various anthropic pressures. Biotic factors such as sex, weight and food availability were controlled in order to provide robust and comparable results. After one week of exposure, concentrations of 11 metals/metalloids (Cd, Pb, Hg, Ni, Zn, Cr, Co, Cu, As, Se and Ag) and 38 hydrophobic organic substances including polycyclic aromatic hydrocarbons (PAHs), polychlorobiphenyles (PCBs), pentabromodiphenylethers (PBDEs) and organochlorine pesticides, were measured in gammarids. All metals except Ag, and 33 organic substances among 38 were quantified in G. fossarum, showing that this species is relevant for chemical biomonitoring. The control of biotic factors allowed a robust and direct inter-site comparison of the bioavailable contamination levels. Overall, our results show the interest and robustness of the proposed methodological approach for assessing trends of bioavailable contamination, notably for metals and hydrophobic organic contaminants, in continental waters. Furthermore, we built threshold values of bioavailable contamination in gammarids, above which measured concentrations are expected to reveal a bioavailable contamination at the sampling site. Two ways to define such values were investigated, a statistical approach and a model fit. Threshold values were determined for almost all the substances investigated in this study and similar values were generally derived from the two approaches. Then, levels of contaminants measured in G. fossarum at the 27 study were compared to the threshold values obtained using the model fit. These threshold values could serve as a basis for further implementation of quality grids to rank sites according to the extent of the bioavailable contamination, with regard to the applied methodology

High immunoproteasome activity and sXBP1 in pediatric precursor B-ALL predicts sensitivity towards proteasome inhibitors

Proteasome inhibitors (PIs) are approved backbone treatments in multiple myeloma. More recently, inhibition of proteasome activity with the PI bortezomib has been clinically evaluated as a novel treatment strategy in pediatric acute lymphoblastic leukemia (ALL). However, we lack a marker that could identify ALL patients responding to PI-based therapy. By using a set of activity-based proteasome probes in conjunction with cytotoxicity assays, we show that B-cell precursor ALL (BCP-ALL), in contrast to T-ALL, demonstrates an increased activity of immunoproteasome over constitutive proteasome, which correlates with high ex vivo sensitivity to the PIs bortezomib and ixazomib. The novel selective PI LU015i-targeting immunoproteasome beta 5i induces cytotoxicity in BCP-ALL containing high beta 5i activity, confirming immunoproteasome activity as a novel therapeutic target in BCP-ALL. At the same time, cotreatment with beta 2-selective proteasome inhibitors can sensitize T-ALL to currently available PIs, as well as to beta 5i selective PI. In addition, levels of total and spliced forms of XBP1 differ between BCP-ALL and T-ALL, and only in BCP-ALL does high-spliced XBP1 correlate with sensitivity to bortezomib. Thus, in BCP-ALL, high immunoproteasome activity may serve as a predictive marker for PI-based treatment options, potentially combined with XBP1 analyses.Bio-organic Synthesi

Toric Kahler metrics and AdS_5 in ring-like co-ordinates

Stationary, supersymmetric supergravity solutions in five dimensions have Kahler metrics on the four-manifold orthogonal to the orbits of a time-like Killing vector. We show that an explicit class of toric Kahler metrics provide a unified framework in which to describe both the asymptotically flat and asymptotically AdS solutions. The Darboux co-ordinates used for the local description turn out to be ''ring-like.'' We conclude with an Ansatz for studying the existence of supersymmetric black rings in AdS.Comment: A new appendix derives the explicit co-ordinate transformation between the ``ring-like'' co-ordinates and the polar co-ordinates of global AdS. Also, references adde

Irreducible holonomy algebras of Riemannian supermanifolds

Possible irreducible holonomy algebras \g\subset\osp(p,q|2m) of Riemannian supermanifolds under the assumption that \g is a direct sum of simple Lie superalgebras of classical type and possibly of a one-dimensional center are classified. This generalizes the classical result of Marcel Berger about the classification of irreducible holonomy algebras of pseudo-Riemannian manifolds.Comment: 27 pages, the final versio

Some No-go Theorems for String Duals of Non-relativistic Lifshitz-like Theories

We study possibilities of string theory embeddings of the gravity duals for non-relativistic Lifshitz-like theories with anisotropic scale invariance. We search classical solutions in type IIA and eleven-dimensional supergravities which are expected to be dual to (2+1)-dimensional Lifshitz-like theories. Under reasonable ansaetze, we prove that such gravity duals in the supergravities are not possible. We also discuss a possible physical reason behind this.Comment: 18 pages, Latex, flux conditions clarified (v2), brief summary of results added (v3

Homogeneity and plane-wave limits

We explore the plane-wave limit of homogeneous spacetimes. For plane-wave limits along homogeneous geodesics the limit is known to be homogeneous and we exhibit the limiting metric in terms of Lie algebraic data. This simplifies many calculations and we illustrate this with several examples. We also investigate the behaviour of (reductive) homogeneous structures under the plane-wave limit.Comment: In memory of Stanley Hobert, 33 pages. Minor corrections and some simplification of Section 4.3.

De Sitter and Schwarzschild-De Sitter According to Schwarzschild and De Sitter

When de Sitter first introduced his celebrated spacetime, he claimed, following Schwarzschild, that its spatial sections have the topology of the real projective space RP^3 (that is, the topology of the group manifold SO(3)) rather than, as is almost universally assumed today, that of the sphere S^3. (In modern language, Schwarzschild was disturbed by the non-local correlations enforced by S^3 geometry.) Thus, what we today call "de Sitter space" would not have been accepted as such by de Sitter. There is no real basis within classical cosmology for preferring S^3 to RP^3, but the general feeling appears to be that the distinction is in any case of little importance. We wish to argue that, in the light of current concerns about the nature of de Sitter space, this is a mistake. In particular, we argue that the difference between "dS(S^3)" and "dS(RP^3)" may be very important in attacking the problem of understanding horizon entropies. In the approach to de Sitter entropy via Schwarzschild-de Sitter spacetime, we find that the apparently trivial difference between RP^3 and S^3 actually leads to very different perspectives on this major question of quantum cosmology.Comment: 26 pages, 8 figures, typos fixed, references added, equation numbers finally fixed, JHEP versio

Antitumor activity of lurbinectedin in second-line small cell lung cancer patients who are candidates for re-challenge with the first-line treatment

Introduction: The National Comprehensive Cancer Network guidelines recommend re-challenge with the first-line treatment for relapsed small cell lung cancer (SCLC) with chemotherapy-free interval (CTFI)=180 days. A phase II study (NCT02454972) showed remarkable antitumor activity in SCLC patients treated with lurbinectedin 3.2 mg/m2 1 -h intravenous infusion every 3 weeks as second-line therapy. We report results for the pre-planned subset of patients with CTFI = 180 days. Material and Methods: Twenty patients aged =18 years with pathologically proven SCLC diagnosis, pretreated with only one prior platinum-containing line, no CNS metastases, and with CTFI = 180 days were evaluated. The primary efficacy endpoint was the overall response rate (ORR) assessed by the Investigators according to RECIST v1.1. Results: ORR was 60.0 % (95 %CI, 36.1-86.9), with a median duration of response of 5.5 months (95 %CI, 2.9-11.2) and disease control rate of 95.0 % (95 %CI, 75.1-99.9). Median progression-free survival was 4.6 months (95 %CI, 2.6-7.3). With a censoring of 55.0 %, the median overall survival was 16.2 months (95 %CI, 9.6-upper level not reached). Of note, 60.9 % and 27.1 % of patients were alive at 1 and 2 years, respectively. The most common grade 3/4 adverse events and laboratory abnormalities were hematological disorders (neutropenia, 55.0 %; anemia; 10.0 % thrombocytopenia, 10.0 %), fatigue (10.0 %) and increased liver function tests (GGT, 10 %; ALT and AP, 5.0 % each). No febrile neutropenia was reported. Conclusion: Lurbinectedin is an effective treatment for platinum-sensitive relapsed SCLC, especially in patients with CTFI = 180 days, with acceptable safety and tolerability. These encouraging results suggest that lurbinectedin can be another valuable therapeutic option rather than platinum re-challenge

Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer

Activation of MAPK signaling via BRAF mutations may limit the activity of EGFR inhibitors in EGFR-mutant lung cancer patients. However, the impact of BRAF mutations on the selection and fitness of emerging resistant clones during anti-EGFR therapy remains elusive. We tracked the evolution of subclonal mutations by whole-exome sequencing and performed clonal analyses of individual metastases during therapy. Complementary functional analyses of polyclonal EGFR-mutant cell pools showed a dose-dependent enrichment of BRAF(V600E) and a loss of EGFR inhibitor susceptibility. The clones remain stable and become vulnerable to combined EGFR, RAF, and MEK inhibition. Moreover, only osimertinib/trametinib combination treatment, but not monotherapy with either of these drugs, leads to robust tumor shrinkage in EGFR-driven xenograft models harboring BRAF mutations. These data provide insights into the dynamics of clonal evolution of EGFR-mutant tumors and the therapeutic implications of BRAF(V600E) co-mutations that may facilitate the development of treatment strategies to improve the prognosis of these patients