A Multicenter Phase 2 Study Incorporating High-Dose Rituximab into the CODOX-M/IVAC Regimen for Untreated Burkitt’s Lymphoma (BL): Examination of Correlative Serum and CSF Rituximab Levels

Background: Two-year survival rates for adult BL remain Methods: Twenty-five BL patients were enrolled. Patients had low-risk (LR) or high-risk (HR) disease; LR patients received 3 CODOX-M cycles, while HR had 4 alternating CODOX-M/IVAC cycles (Mead et al. Blood 2009). Rituximab (500mg/m2) was given x 2 doses each cycle. Correlative analyses of paired serum and CSF Rituximab levels were obtained for cycles 1+3 at 24+72 hours. Results: There were 20 HR and 5 LR patients and median age was 44 years (range, 23-70). 3 HR and 1 LR patient were HIV+, while 15% of HR patients had CNS disease. Additionally, 35% of HR patients had bulk \u3e10 cm and 40% had bone marrow involvement. Myelosuppression and mucositis appeared comparable with prior CODOX-M/IVAC data. The overall remission rate after 2 cycles was 100% with 67% complete remission. At 34-month median follow-up, 2-year PFS and OS rates for all patients were 86% and 86%, respectively (LR 2-year PFS and OS: both 100%; HR 2-year PFS and OS: both 82%). Further, the 2-year PFS and OS for HR, HIV-negative patients were 91% and 91%, respectively (disease-specific survival 100%). Two patients died from progressive disease (both HIV+ HR). The median serum and CSF rituximab levels for these patients were compared with patients without relapse (Table 1). Interestingly, cycle 1, 24-hour serum Rituximab levels were significantly higher among patients without relapse compared with the two patients who relapsed/died (P=0.042). Cycle 3, 24-hour Rituximab levels were of borderline significance (P=0.06). Conclusions: The integration of Rituximab into CODOX-M/IVAC was associated with excellent survival rates, especially for HIV-negative BL. Further investigation of the predictive value of serum Rituximab levels is warranted

National Security vs Criminal law. Perspectives, Doubts and Concerns on the Criminalisation of Organised Crime in England and Wales

This paper will interpret and critically analyse the new offence for organised crime in England and Wales (Section 45 of the Serious Crime Act 2015) from a criminological perspective in light of evidence found in research in the country. It will argue that changes in the law relate to changes in political narratives rather than to variations in the criminal panorama of organised crime. It will discuss these changes within three perspectives, which address various levels of concern: a narrative perspective, which reflects on the overlapping of meanings in the use of the words ‘organised crime’; an evolution perspective, which reflects on the origins of the new participation offences with reference to both national and international pressures; a management perspective, which reflects on some of the immediate effects of the new offences of organised crime on the criminal justice system. This paper will conclude that political narratives have indeed influenced criminal policy, while there is no significant change in the phenomenon of organised crime to justify such narratives

Gene expression changes and community turnover differentially shape the global ocean metatranscriptome

Ocean microbial communities strongly influence the biogeochemistry, food webs, and climate of our planet. Despite recent advances in understanding their taxonomic and genomic compositions, little is known about how their transcriptomes vary globally. Here, we present a dataset of 187 metatranscriptomes and 370 metagenomes from 126 globally distributed sampling stations and establish a resource of 47 million genes to study community-level transcriptomes across depth layers from pole-to-pole. We examine gene expression changes and community turnover as the underlying mechanisms shaping community transcriptomes along these axes of environmental variation and show how their individual contributions differ for multiple biogeochemically relevant processes. Furthermore, we find the relative contribution of gene expression changes to be significantly lower in polar than in non-polar waters and hypothesize that in polar regions, alterations in community activity in response to ocean warming will be driven more strongly by changes in organismal composition than by gene regulatory mechanisms

A Rigidifying Salt-Bridge Favors the Activity of Thermophilic Enzyme at High Temperatures at the Expense of Low-Temperature Activity

Although enzymes from thermophiles thriving in hot habitats are more stable than their mesophilic homologs, they are often less active at low temperatures. One theory suggests that extra stabilizing interactions found in thermophilic enzymes may increase their rigidity and decrease enzymatic activity at lower temperatures. We used acylphosphatase as a model to study how flexibility affects enzymatic activity. This enzyme has a unique structural feature in that an invariant arginine residue, which takes part in catalysis, is restrained by a salt-bridge in the thermophilic homologs but not in its mesophilic homologs. Here, we demonstrate the trade-offs between flexibility and enzymatic activity by disrupting the salt-bridge in a thermophilic acylphosphatase and introducing it in the mesophilic human homolog. Our results suggest that the salt-bridge is a structural adaptation for thermophilic acylphosphatases as it entropically favors enzymatic activity at high temperatures by restricting the flexibility of the active-site residue. However, at low temperatures the salt-bridge reduces the enzymatic activity because of a steeper temperature-dependency of activity

DNA methylation levels in candidate genes associated with chronological age in mammals are not conserved in a long-lived seabird

© 2017 De Paoli-Iseppi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Most seabirds do not have any outward identifiers of their chronological age, so estimation of seabird population age structure generally requires expensive, long-term banding studies. We investigated the potential to use a molecular age biomarker to estimate age in short-tailed shearwaters (Ardenna tenuirostris). We quantified DNA methylation in several A. tenuirostris genes that have shown age-related methylation changes in mammals. In birds ranging from chicks to 21 years of age, bisulphite treated blood and feather DNA was sequenced and methylation levels analysed in 67 CpG sites in 13 target gene regions. From blood samples, five of the top relationships with age were identified in KCNC3 loci (CpG66: R2 = 0.325, p = 0.019). In feather samples ELOVL2 (CpG42: R2 = 0.285, p = 0.00048) and EDARADD (CpG46: R2 = 0.168, p = 0.0067) were also weakly correlated with age. However, the majority of markers had no clear association with age (of 131 comparisons only 12 had a p-value < 0.05) and statistical analysis using a penalised lasso approach did not produce an accurate ageing model. Our data indicate that some age-related signatures identified in orthologous mammalian genes are not conserved in the long-lived short tailed shearwater. Alternative molecular approaches will be required to identify a reliable biomarker of chronological age in these seabirds

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M>70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0<e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM