A Phase I/II first-line study of R-CHOP plus B-cell receptor/NF-κB-double-targeting to molecularly assess therapy response

The ImbruVeRCHOP trial is an investigator-initiated, multicenter, single-arm, open label Phase I/II study for patients 61-80 years of age with newly diagnosed CD20+ diffuse large B-cell lymphoma and a higher risk profile (International Prognostic Index ≥2). Patients receive standard chemotherapy (CHOP) plus immunotherapy (Rituximab), a biological agent (the proteasome inhibitor Bortezomib) and a signaling inhibitor (the Bruton's Tyrosine Kinase-targeting therapeutic Ibrutinib). Using an all-comers approach, but subjecting patients to another lymphoma biopsy acutely under first-cycle immune-chemo drug exposure, ImbruVeRCHOP seeks to identify an unbiased molecular responder signature that marks diffuse large B-cell lymphoma patients at risk and likely to benefit from this regimen as a double, proximal and distal B-cell receptor/NF-κB-co-targeting extension of the current R-CHOP standard of care. EudraCT-Number: 2015-003429-32; ClinicalTrials.gov identifier: NCT03129828

The persistent dynamic secrets of senescence

While the beneficial versus detrimental implications of the senescence-associated secretome remain an issue of debate, time-resolved analyses of its composition, regulatory mechanisms and functional consequences have been largely missing. The dynamic activity of NOTCH is now shown to direct two distinct senescence phenotypes, by first promoting a pro-senescent TGF-{beta}1-dependent secretome, followed by a second wave of pro-inflammatory, senescence-clearing cytokines

e-MERLIN and VLBI observations of the luminous infrared galaxy IC883: a nuclear starburst and an AGN candidate revealed

The high star formation rates of luminous infrared galaxies (LIRGs) make them ideal places for core-collapse supernova (CCSN) searches. At radio frequencies, free from dust extinction, it is possible to detect compact components within the innermost LIRG nuclear regions, such as SNe and SN remnants, as well as AGN buried deep in the LIRG nuclei. We studied the LIRG IC883 aiming at: (i) investigating its (circum-)nuclear regions using the e-EVN at 5GHz, and e-MERLIN at 6.9GHz, complemented by archival VLBI data; (ii) detecting at radio frequencies the two recently reported circumnuclear SNe 2010cu and 2011hi, which were discovered by near-IR (NIR) adaptive optics observations of IC883; and (iii) further investigating the nature of SN2011hi at NIR by means of observations with Gemini-North. The circumnuclear regions traced by e-MERLIN at 6.9GHz have an extension of ~1kpc, and show a striking double-sided structure, which very likely corresponds to a warped rotating ring, in agreement with previous studies. Our e-EVN observations at 5GHz and complementary archival VLBI data at 5GHz and 8.4GHz, reveal the presence of various milliarcsec compact components in the nucleus of IC883. A single compact source, an AGN candidate, dominates the emission at both nuclear and circumnuclear scales, as imaged with the e-EVN and e-MERLIN, respectively. The other milliarcsec components are very suggestive of ongoing nuclear CCSN activity. Our e-EVN observations also resulted in upper limits to the radio luminosity of the two SNe in IC883 recently discovered at NIR. We refine the classification of SN2011hi as a Type IIP SN according to our latest Gemini-North epoch from 2012, in agreement with a low-luminosity radio SN nature. We estimate a CCSN rate lower limit of 1.1_{-0.6}^{+1.3} yr^{-1} for the entire galaxy, based on three nuclear radio SNe and the circumnuclear SNe 2010cu and 2011hi. (abridged)Comment: 9 pages, 5 figures and 2 tables. Accepted for publication in A&

The Herschel Reference Survey: Dust in Early-Type Galaxies and Across the Hubble Sequence

We present Herschel observations of 62 Early-Type Galaxies (ETGs), including 39 galaxies morphologically classified as S0+S0a and 23 galaxies classified as ellipticals using SPIRE at 250, 350 and 500 microns (and PACS 100 and 160 microns for 19 sources) as part of the volume-limited Herschel Reference Survey. We detect dust emission in 24% of the ellipticals and 62% of the S0s. The mean temperature of the dust is 23.9+/-0.8 K, warmer than that found for late-type galaxies in the Virgo Cluster. Including the non-detections, the mean dust mass is log(Mdust) = 5.9+/-0.1 and 5.2+/-0.1 Msun for the S0s and elliptical galaxies respectively. The mean dust-to-stellar mass is log(Mdust/Mstar) = -4.4+/-0.1 (S0s) and -5.8+/-0.1 (ellipticals). Virtually all the galaxies lie close to the red sequence yet the large number of detections of cool dust, the gas-to-dust ratios and the ratios of far-infrared to radio emission all suggest that many ETGs contain a cool interstellar medium similar to that in late-type galaxies. The mean dust-to-stellar mass ratio for S0s is approximatly a factor of ten less than for early-type spirals and the sizes of the dust sources in the S0s are also much smaller. We show that the difference cannot be explained by either the different bulge-to-disk ratios or environmental effects such as ram-pressure stripping. The wide range in the dust-to-stellar mass ratio for ETGs and the lack of a correlation between dust mass and optical luminosity suggest that much of the dust in the ETGs detected by Herschel has been acquired as the result of gravitational interactions; these interactions are unlikely to have had a major effect on the stellar masses of the ETGs. The Herschel observations tentatively suggest that in the most massive ETGs, the mass of the interstellar medium is unconnected to the evolution of the stellar populations.Comment: 28 Pages, 12 Figures. Submitted to ApJ December 2011; accepted January 201

Cellular Senescence: Defining a Path Forward.

Cellular senescence is a cell state implicated in various physiological processes and a wide spectrum of age-related diseases. Recently, interest in therapeutically targeting senescence to improve healthy aging and age-related disease, otherwise known as senotherapy, has been growing rapidly. Thus, the accurate detection of senescent cells, especially in vivo, is essential. Here, we present a consensus from the International Cell Senescence Association (ICSA), defining and discussing key cellular and molecular features of senescence and offering recommendations on how to use them as biomarkers. We also present a resource tool to facilitate the identification of genes linked with senescence, SeneQuest (available at http://Senequest.net). Lastly, we propose an algorithm to accurately assess and quantify senescence, both in cultured cells and in vivo

FUS Phase Separation Is Modulated by a Molecular Chaperone and Methylation of Arginine Cation-π Interactions.

Reversible phase separation underpins the role of FUS in ribonucleoprotein granules and other membrane-free organelles and is, in part, driven by the intrinsically disordered low-complexity (LC) domain of FUS. Here, we report that cooperative cation-π interactions between tyrosines in the LC domain and arginines in structured C-terminal domains also contribute to phase separation. These interactions are modulated by post-translational arginine methylation, wherein arginine hypomethylation strongly promotes phase separation and gelation. Indeed, significant hypomethylation, which occurs in FUS-associated frontotemporal lobar degeneration (FTLD), induces FUS condensation into stable intermolecular β-sheet-rich hydrogels that disrupt RNP granule function and impair new protein synthesis in neuron terminals. We show that transportin acts as a physiological molecular chaperone of FUS in neuron terminals, reducing phase separation and gelation of methylated and hypomethylated FUS and rescuing protein synthesis. These results demonstrate how FUS condensation is physiologically regulated and how perturbations in these mechanisms can lead to disease

Hypoxia-Inducible Factor 1α Determines Gastric Cancer Chemosensitivity via Modulation of p53 and NF-κB

BACKGROUND: Reduced chemosensitivity of solid cancer cells represents a pivotal obstacle in clinical oncology. Hence, the molecular characterization of pathways regulating chemosensitivity is a central prerequisite to improve cancer therapy. The hypoxia-inducible factor HIF-1alpha has been linked to chemosensitivity while the underlying molecular mechanisms remain largely elusive. Therefore, we comprehensively analysed HIF-1alpha's role in determining chemosensitivity focussing on responsible molecular pathways. METHODOLOGY AND PRINCIPAL FINDINGS: RNA interference was applied to inactivate HIF-1alpha or p53 in the human gastric cancer cell lines AGS and MKN28. The chemotherapeutic agents 5-fluorouracil and cisplatin were used and chemosensitivity was assessed by cell proliferation assays as well as determination of cell cycle distribution and apoptosis. Expression of p53 and p53 target proteins was analyzed by western blot. NF-kappaB activity was characterized by means of electrophoretic mobility shift assay. Inactivation of HIF-1alpha in gastric cancer cells resulted in robust elevation of chemosensitivity. Accordingly, HIF-1alpha-competent cells displayed a significant reduction of chemotherapy-induced senescence and apoptosis. Remarkably, this phenotype was completely absent in p53 mutant cells while inactivation of p53 per se did not affect chemosensitivity. HIF-1alpha markedly suppressed chemotherapy-induced activation of p53 and p21 as well as the retinoblastoma protein, eventually resulting in cell cycle arrest. Reduced formation of reactive oxygen species in HIF-1alpha-competent cells was identified as the molecular mechanism of HIF-1alpha-mediated inhibition of p53. Furthermore, loss of HIF-1alpha abrogated, in a p53-dependent manner, chemotherapy-induced DNA-binding of NF-kappaB and expression of anti-apoptotic NF-kappaB target genes. Accordingly, reconstitution of the NF-kappaB subunit p65 reversed the increased chemosensitivity of HIF-1alpha-deficient cells. CONCLUSION AND SIGNIFICANCE: In summary, we identified HIF-1alpha as a potent regulator of p53 and NF-kappaB activity under conditions of genotoxic stress. We conclude that p53 mutations in human tumors hold the potential to confound the efficacy of HIF-1-inhibitors in cancer therapy

Search for squarks and gluinos in events with isolated leptons, jets and missing transverse momentum at s√=8 TeV with the ATLAS detector

The results of a search for supersymmetry in final states containing at least one isolated lepton (electron or muon), jets and large missing transverse momentum with the ATLAS detector at the Large Hadron Collider are reported. The search is based on proton-proton collision data at a centre-of-mass energy s√=8 TeV collected in 2012, corresponding to an integrated luminosity of 20 fb−1. No significant excess above the Standard Model expectation is observed. Limits are set on supersymmetric particle masses for various supersymmetric models. Depending on the model, the search excludes gluino masses up to 1.32 TeV and squark masses up to 840 GeV. Limits are also set on the parameters of a minimal universal extra dimension model, excluding a compactification radius of 1/R c = 950 GeV for a cut-off scale times radius (ΛR c) of approximately 30

Single hadron response measurement and calorimeter jet energy scale uncertainty with the ATLAS detector at the LHC

The uncertainty on the calorimeter energy response to jets of particles is derived for the ATLAS experiment at the Large Hadron Collider (LHC). First, the calorimeter response to single isolated charged hadrons is measured and compared to the Monte Carlo simulation using proton-proton collisions at centre-of-mass energies of sqrt(s) = 900 GeV and 7 TeV collected during 2009 and 2010. Then, using the decay of K_s and Lambda particles, the calorimeter response to specific types of particles (positively and negatively charged pions, protons, and anti-protons) is measured and compared to the Monte Carlo predictions. Finally, the jet energy scale uncertainty is determined by propagating the response uncertainty for single charged and neutral particles to jets. The response uncertainty is 2-5% for central isolated hadrons and 1-3% for the final calorimeter jet energy scale.Comment: 24 pages plus author list (36 pages total), 23 figures, 1 table, submitted to European Physical Journal

Measurement of χ c1 and χ c2 production with s√ = 7 TeV pp collisions at ATLAS

The prompt and non-prompt production cross-sections for the χ c1 and χ c2 charmonium states are measured in pp collisions at s√ = 7 TeV with the ATLAS detector at the LHC using 4.5 fb−1 of integrated luminosity. The χ c states are reconstructed through the radiative decay χ c → J/ψγ (with J/ψ → μ + μ −) where photons are reconstructed from γ → e + e − conversions. The production rate of the χ c2 state relative to the χ c1 state is measured for prompt and non-prompt χ c as a function of J/ψ transverse momentum. The prompt χ c cross-sections are combined with existing measurements of prompt J/ψ production to derive the fraction of prompt J/ψ produced in feed-down from χ c decays. The fractions of χ c1 and χ c2 produced in b-hadron decays are also measured