Ibrutinib in the Treatment of Refractory Chronic Lymphocytic Leukemia

Background & Aims. This paper presents the results of the observational study of ibrutinib in patients with chronic lymphocytic leukemia (CLL), conducted in SP Botkin Municipal Clinical Hospital. The main objective was the analysis of complications of ibrutinib and identification of factors, influencing the dosage regimen; the secondary objective was the estimation of the total response to treatment, event-free and overall survival. Materials & Methods. The study included 96 patients with CLL with indications for ibrutinib therapy. The median age was 64,9 years (range 32–91 years), the study population consisted of 69 (72 %) men and 27 (28 %) women. The condition of 25 (26 %) patients according to the ECOG scale was of > 3 points. The disease of stage C were diagnosed in 36 (37 %) patients . Deletion of 17p/TP53 mutations were detected in 29 (33 %) of 87 patients. Seventy patients had refractory CLL. The median of the number of the lines of the previous therapy was 3 (range 1–9). Adverse events were assessed in accordance with the CTCAE criteria, version 4.0; the bleeding severity was evaluated using ITP-specific bleeding score; hematological complications were classified according to the recommendations of IWCLL-2008. Results. Ibrutinib was administered at a dosage of 420 mg per day daily until progression or intolerable toxicity. The median duration of ibrutinib therapy was 10.3 months. Ibrutinib was shown to have moderate toxicity, mostly of grade I or II. The bleeding was the most frequent complication. Of the hematological complications, thrombocytopenia was the most common (35 %); neutropenia grade III) developed in 26 % of patients. The treatment response was assessed in 92 patients. The overall response to treatment was 89 %. Complete remission, partial remission and partial remission with lymphocytosis were achieved in 4 (4 %), 57 (62 %), and 21 (23 %) patients, respectively. The event-free survival and overall survival by the month 10 was 90 % and 91 %, respectively. For this observation period, ECOG status and the number of the lines of therapy prior to ibrutinib had the prognostic value. Conclusion. Ibrutinib was shown to have high efficiency in relapsed/refractory forms of CLL. The nature of the ibrutinib toxicity is fundamentally different from that of the conventional chemotherapy. The frequency of ibrutinib therapy complications and patients’ non-compliance depends on the intensity of the previous treatment of CLL. Despite a short observation period, it can be concluded that ibrutinib had the greatest impact on the patient’s quality of life when administered for the first relapse. The low toxicity of ibrutinib is likely to allow the combination with other antitumor agents

The stellar and sub-stellar IMF of simple and composite populations

The current knowledge on the stellar IMF is documented. It appears to become top-heavy when the star-formation rate density surpasses about 0.1Msun/(yr pc^3) on a pc scale and it may become increasingly bottom-heavy with increasing metallicity and in increasingly massive early-type galaxies. It declines quite steeply below about 0.07Msun with brown dwarfs (BDs) and very low mass stars having their own IMF. The most massive star of mass mmax formed in an embedded cluster with stellar mass Mecl correlates strongly with Mecl being a result of gravitation-driven but resource-limited growth and fragmentation induced starvation. There is no convincing evidence whatsoever that massive stars do form in isolation. Various methods of discretising a stellar population are introduced: optimal sampling leads to a mass distribution that perfectly represents the exact form of the desired IMF and the mmax-to-Mecl relation, while random sampling results in statistical variations of the shape of the IMF. The observed mmax-to-Mecl correlation and the small spread of IMF power-law indices together suggest that optimally sampling the IMF may be the more realistic description of star formation than random sampling from a universal IMF with a constant upper mass limit. Composite populations on galaxy scales, which are formed from many pc scale star formation events, need to be described by the integrated galactic IMF. This IGIMF varies systematically from top-light to top-heavy in dependence of galaxy type and star formation rate, with dramatic implications for theories of galaxy formation and evolution.Comment: 167 pages, 37 figures, 3 tables, published in Stellar Systems and Galactic Structure, Vol.5, Springer. This revised version is consistent with the published version and includes additional references and minor additions to the text as well as a recomputed Table 1. ISBN 978-90-481-8817-

Multiple populations in globular clusters. Lessons learned from the Milky Way globular clusters

Recent progress in studies of globular clusters has shown that they are not simple stellar populations, being rather made of multiple generations. Evidence stems both from photometry and spectroscopy. A new paradigm is then arising for the formation of massive star clusters, which includes several episodes of star formation. While this provides an explanation for several features of globular clusters, including the second parameter problem, it also opens new perspectives about the relation between globular clusters and the halo of our Galaxy, and by extension of all populations with a high specific frequency of globular clusters, such as, e.g., giant elliptical galaxies. We review progress in this area, focusing on the most recent studies. Several points remain to be properly understood, in particular those concerning the nature of the polluters producing the abundance pattern in the clusters and the typical timescale, the range of cluster masses where this phenomenon is active, and the relation between globular clusters and other satellites of our Galaxy.Comment: In press (The Astronomy and Astrophysics Review

GPR50 Interacts with TIP60 to Modulate Glucocorticoid Receptor Signalling

GPR50 is an orphan G-protein coupled receptor most closely related to the melatonin receptors. The physiological function of GPR50 remains unclear, although our previous studies implicate the receptor in energy homeostasis. Here, we reveal a role for GPR50 as a signalling partner and modulator of the transcriptional co-activator TIP60. This interaction was identified in a yeast-two-hybrid screen, and confirmed by co-immunoprecipitation and co-localisation of TIP60 and GPR50 in HEK293 cells. Co-expression with TIP60 increased perinuclear localisation of full length GPR50, and resulted in nuclear translocation of the cytoplasmic tail of the receptor, suggesting a functional interaction of the two proteins. We further demonstrate that GPR50 can enhance TIP60-coactiavtion of glucocorticoid receptor (GR) signalling. In line with in vitro results, repression of pituitary Pomc expression, and induction of gluconeogenic genes in liver in response to the GR agonist, dexamethasone was attenuated in Gpr50−/− mice. These results identify a novel role for GPR50 in glucocorticoid receptor signalling through interaction with TIP60

Glibenclamide—10-h Treatment Window in a Clinically Relevant Model of Stroke

Glibenclamide improves outcomes in rat models of stroke, with treatment as late as 6 h after onset of ischemia shown to be beneficial. Because the molecular target of glibenclamide, the sulfonylurea receptor 1 (Sur1)-regulated NCCa-ATP channel, is upregulated de novo by a complex transcriptional mechanism, and the principal pathophysiological target, brain swelling, requires hours to develop, we hypothesized that the treatment window would exceed 6 h. We studied a clinically relevant rat model of stroke in which middle cerebral artery occlusion (75% < reduction in LDF signal ≤90%) was produced using an intra-arterial occluder. Recanalization was obtained 4.5 h later by removing the occluder. At that time, we administered recombinant tissue plasminogen activator (rtPA; 0.9 mg/kg IV over 30 min). Immunolabeling showed modest expression of Sur1 5 h after onset of ischemia, with expression increasing 7- to 11-fold (P < 0.01) by 24 h. Rats were administered either vehicle or glibenclamide (10 μg/kg IP loading dose plus 200 ng/h by constant subcutaneous infusion) beginning 4.5 or 10 h after onset of ischemia. In rats treated at 4.5 or 10 h, glibenclamide significantly reduced hemispheric swelling at 24 h from (mean ± SEM) 14.7 ± 1.5% to 8.1 ± 1.6% or 8.8 ± 1.1% (both P < 0.01), respectively, and significantly reduced 48-h mortality from 53% to 17% or 12% (both P < 0.01), and improved Garcia scores at 48 h from 3.8 ± 0.62 to 7.6 ± 0.70 or 8.4 ± 0.74 (both P < 0.01). We conclude that, in a clinically relevant model of stroke, the treatment window for glibenclamide extends to 10 h after onset of ischemia

At-risk registers integrated into primary care to stop asthma crises in the UK (ARRISA-UK): study protocol for a pragmatic, cluster randomised trial with nested health economic and process evaluations

Background: Despite effective treatments and long-standing management guidelines, there are approximately 1400 hospital admissions for asthma weekly in the United Kingdom (UK), many of which could be avoided. In our previous research, a secondary analysis of the intervention (ARRISA) suggested an improvement in the management of at-risk asthma patients in primary care. ARRISA involved identifying individuals at risk of adverse asthma events, flagging their electronic health records, training practice staff to develop and implement practice-wide processes of care when alerted by the flag, plus motivational reminders. We now seek to determine the effectiveness and cost-effectiveness of ARRISA in reducing asthma-related crisis events. Methods: We are undertaking a pragmatic, two-arm, multicentre, cluster randomised controlled trial, plus health economic and process evaluation. We will randomise 270 primary care practices from throughout the UK covering over 10,000 registered patients with ‘at-risk asthma’ identified according to a validated algorithm. Staff in practices randomised to the intervention will complete two 45-min eLearning modules (an individually completed module giving background to ARRISA and a group-completed module to develop practice-wide pathways of care) plus a 30-min webinar with other practices. On completion of training at-risk patients’ records will be coded so that a flag appears whenever their record is accessed. Practices will receive a phone call at 4 weeks and a reminder video at 6 weeks and 6 months. Control practices will continue to provide usual care. We will extract anonymised routine patient data from primary care records (with linkage to secondary care data) to determine the percentage of at-risk patients with an asthma-related crisis event (accident and emergency attendances, hospitalisations and deaths) after 12 months (primary outcome). We will also capture the time to crisis event, all-cause hospitalisations, asthma control and any changes in practice asthma management for at-risk and all patients with asthma. Cost-effectiveness analysis and mixed-methods process evaluations will also be conducted. Discussion: This study is novel in terms of using a practice-wide intervention to target and engage with patients at risk from their asthma and is innovative in the use of routinely captured data with record linkage to obtain trial outcomes. Trial registration: ISRCTN95472706. Registered on 5 December 2014

Minimum information about an uncultivated virus genome (MIUVIG)

This is the final version. Available on open access from Nature Research via the DOI in this recordNOTE: the full list of funders and grants is in the acknowledgements section of the articleWe present an extension of the Minimum Information about any (x) Sequence (MIxS) standard for reporting sequences of uncultivated virus genomes. Minimum Information about an Uncultivated Virus Genome (MIUViG) standards were developed within the Genomic Standards Consortium framework and include virus origin, genome quality, genome annotation, taxonomic classification, biogeographic distribution and in silico host prediction. Community-wide adoption of MIUViG standards, which complement the Minimum Information about a Single Amplified Genome (MISAG) and Metagenome-Assembled Genome (MIMAG) standards for uncultivated bacteria and archaea, will improve the reporting of uncultivated virus genomes in public databases. In turn, this should enable more robust comparative studies and a systematic exploration of the global virosphere.Simons Foundation InternationalNatural Environment Research Council (NERC

Proliferation of hydrocarbon-degrading microbes at the bottom of the Mariana Trench

Background: The Mariana Trench is the deepest known site in the Earth’s oceans, reaching a depth of ~ 11,000m 20 at the Challenger Deep. Recent studies reveal that hadal waters harbor distinctive microbial planktonic communities. However, the genetic potential of microbial communities within the hadal zone is poorly understood. Results: Here, implementing both culture-dependent and culture-independent methods, we perform extensive analysis of microbial populations and their genetic potential at different depths in the Mariana Trench. Unexpectedly, we observed an abrupt increase in the abundance of hydrocarbon-degrading bacteria at depths > 10,400m in the Challenger Deep. Indeed, the proportion of hydrocarbon-degrading bacteria at > 10,400m is the highest observed in any natural environment on Earth. These bacteria were mainly Oleibacter, Thalassolituus, and Alcanivorax genera, all of which include species known to consume aliphatic hydrocarbons. This community shift towards hydrocarbon degraders was accompanied by increased abundance and transcription of genes involved in alkane degradation. Correspondingly, three Alcanivorax species that were isolated from 10,400m water supplemented with hexadecane were able to efficiently degrade n-alkanes under conditions simulating the deep sea, as did a reference Oleibacter strain cultured at atmospheric pressure. Abundant n-alkanes were observed in sinking particles at 2000, 4000, and 6000m (averaged 23.5 μg/gdw) and hadal surface sediments at depths of 10,908, 10,909, and 10,911m (averaged 2.3 μg/gdw). The δ2H values of n-C16/18 alkanes that dominated surface sediments at near 11,000-m depths ranged from − 79 to − 93‰, suggesting these alkanes may derive from an unknown biological source. Conclusions: These results reveal that hydrocarbon-degrading microorganisms are present in great abundance in the deepest seawater on Earth and shed a new light on potential biological processes in this extreme environment

Species Diversity and Phylogeographical Affinities of the Branchiopoda (Crustacea) of Churchill, Manitoba, Canada

The region of Churchill, Manitoba, contains a wide variety of habitats representative of both the boreal forest and arctic tundra and has been used as a model site for biodiversity studies for nearly seven decades within Canada. Much previous work has been done in Churchill to study the Daphnia pulex species complex in particular, but no study has completed a wide-scale survey on the crustacean species that inhabit Churchill's aquatic ecosystems using molecular markers. We have employed DNA barcoding to study the diversity of the Branchiopoda (Crustacea) in a wide variety of freshwater habitats and to determine the likely origins of the Churchill fauna following the last glaciation. The standard animal barcode marker (COI) was sequenced for 327 specimens, and a 3% divergence threshold was used to delineate potential species. We found 42 provisional and valid branchiopod species from this survey alone, including several cryptic lineages, in comparison with the 25 previously recorded from previous ecological works. Using published sequence data, we explored the phylogeographic affinities of Churchill's branchiopods, finding that the Churchill fauna apparently originated from all directions from multiple glacial refugia (including southern, Beringian, and high arctic regions). Overall, these microcrustaceans are very diverse in Churchill and contain multiple species complexes. The present study introduces among the first sequences for some understudied genera, for which further work is required to delineate species boundaries and develop a more complete understanding of branchiopod diversity over a larger spatial scale