A phase II study of vorinostat (MK-0683) in patients with polycythaemia vera and essential thrombocythaemia

Inhibition of histone deacetylases may be an important target in patients with myeloproliferative neoplasms. This investigator-initiated, non-randomized, open-label phase II multi-centre study included 63 patients (19 essential thrombocythaemia, 44 polycythaemia vera) from 15 centres. The primary objective was to evaluate if vorinostat was followed by a decline in clonal myeloproliferation as defined by European Leukaemia Net. Thirty patients (48%) completed the intervention period (24 weeks of therapy). An intention-to-treat response rate of 35% was identified. Pruritus was resolved [19% to 0% (P = 0·06)] and the prevalence of splenomegaly was lowered from 50% to 27% (P = 0·03). Sixty-five per cent of the patients experienced a decrease in JAK2 V617F allele burden (P = 0·006). Thirty-three patients (52% of patients) discontinued study drug before end of intervention due to adverse events (28 patients) or lack of response (5 patients). In conclusion, vorinostat showed effectiveness by normalizing elevated leucocyte and platelet counts, resolving pruritus and significantly reducing splenomegaly. However, vorinostat was associated with significant side effects resulting in a high discontinuation rate. A lower dose of vorinostat in combination with conventional and/or novel targeted therapies may be warranted in future studies.

Circulating YKL-40 in patients with essential thrombocythemia and polycythemia vera treated with the novel histone deacetylase inhibitor vorinostat

YKL-40 regulates vascular endothelial growth factors and induces tumor proliferation. We investigated YKL-40 before and after treatment with vorinostat in 31 polycythemia vera (PV) and 16 essential thrombocythemia (ET) patients. Baseline PV patient levels were 2 times higher than in healthy controls (P < 0.0001) and 1.7 times higher than in ET (P = 0.02). A significant correlation between YKL-40 at baseline and neutrophils, CRP, LDH, JAK2V617F and platelets in PV patients was observed, as well as a significantly greater reduction of YKL-40 levels in PV patients responding to therapy. YKL-40 might be a novel marker of disease burden and progression in myeloproliferative neoplasms.

A highly potent and specific MET therapeutic protein antagonist with both ligand-dependent and ligand-independent activity

Activation of the MET oncogenic pathway has been implicated in the development of aggressive cancers that are difficult to treat with current chemotherapies. This has led to an increased interest in developing novel therapies that target the MET pathway. However, most existing drug modalities are confounded by their inability to specifically target and/or antagonize this pathway. Anticalins, a novel class of monovalent small biologics, are hypothesized to be "fit for purpose" for developing highly specific and potent antagonists of cancer pathways. Here, we describe a monovalent full MET antagonist, PRS-110, displaying efficacy in both ligand-dependent and ligand-independent cancer models. PRS-110 specifically binds to MET with high affinity and blocks hepatocyte growth factor (HGF) interaction. Phosphorylation assays show that PRS-110 efficiently inhibits HGF-mediated signaling of MET receptor and has no agonistic activity. Confocal microscopy shows that PRS-110 results in the trafficking of MET to late endosomal/lysosomal compartments in the absence of HGF. In vivo administration of PRS-110 resulted in significant, dose-dependent tumor growth inhibition in ligand-dependent (U87-MG) and ligand-independent (Caki-1) xenograft models. Analysis of MET protein levels on xenograft biopsy samples show a significant reduction in total MET following therapy with PRS-110 supporting its ligand-independent mechanism of action. Taken together, these data indicate that the MET inhibitor PRS-110 has potentially broad anticancer activity that warrants evaluation in patients.

Transatlantic distribution of the Alaskan White River Ash

Volcanic ash layers preserved within the geologic record represent precise time markers that correlate disparate depositional environments and enable the investigation of synchronous and/or asynchronous behaviors in Earth system and archaeological sciences. However, it is generally assumed that only exceptionally powerful events, such as supereruptions (≥450 km3 of ejecta as dense-rock equivalent; recurrence interval of ∼105 yr), distribute ash broadly enough to have an impact on human society, or allow us to address geologic, climatic, and cultural questions on an intercontinental scale. Here we use geochemical, age, and morphological evidence to show that the Alaskan White River Ash (eastern lobe; A.D. 833–850) correlates to the “AD860B” ash (A.D. 846–848) found in Greenland and northern Europe. These occurrences represent the distribution of an ash over 7000 km, linking marine, terrestrial, and ice-core records. Our results indicate that tephra from more moderate-size eruptions, with recurrence intervals of ∼100 yr, can have substantially greater distributions than previously thought, with direct implications for volcanic dispersal studies, correlation of widely distributed proxy records, and volcanic hazard assessment.

High-precision ultra-distal Holocene tephrochronology in North America

Far-travelled volcanic ashes (tephras) from Holocene eruptions in Alaska and the Pacific northwest have been traced to the easternmost extent of North America, providing the basis for a new high-precision geochronological framework throughout the continent through tephrochronology (the dating and correlation of tephra isochrons in sedimentary records). The reported isochrons are geochemically distinct, with seven correlated to documented sources in Alaska and the Cascades, including the Mazama ash from Oregon (w7600 years old) and the eastern lobe of the White River Ash from Alaska (~1150 years old). These findings mark the beginning of a tephrochronological framework of enhanced precision across North America, with applications in palaeoclimate, surface process and archaeological studies. The particle travel distances involved (up tow7000 km) also demonstrate the potential for continent-wide or trans-Atlantic socio-economic disruption from similar future eruptions.

Integrated care pathways for airway diseases (AIRWAYS-ICPs)

The objective of Integrated Care Pathways for Airway Diseases (AIRWAYS-ICPs) is to launch a collaboration to develop multi-sectoral care pathways for chronic respiratory diseases in European countries and regions. AIRWAYS-ICPs has strategic relevance to the European Union Health Strategy and will add value to existing public health knowledge by: 1) proposing a common framework of care pathways for chronic respiratory diseases, which will facilitate comparability and trans-national initiatives; 2) informing cost-effective policy development, strengthening in particular those on smoking and environmental exposure; 3) aiding risk stratification in chronic disease patients, using a common strategy; 4) having a significant impact on the health of citizens in the short term (reduction of morbidity, improvement of education in children and of work in adults) and in the long-term (healthy ageing); 5) proposing a common simulation tool to assist physicians; and 6) ultimately reducing the healthcare burden (emergency visits, avoidable hospitalisations, disability and costs) while improving quality of life. In the longer term, the incidence of disease may be reduced by innovative prevention strategies. AIRWAYSICPs was initiated by Area 5 of the Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing. All stakeholders are involved (health and social care, patients, and policy makers).

Retrieving Regions of Interest for User Exploration

We consider an application scenario where points of interest (PoIs) each have a web presence and where a web user wants to iden- tify a region that contains relevant PoIs that are relevant to a set of keywords, e.g., in preparation for deciding where to go to conve- niently explore the PoIs. Motivated by this, we propose the length- constrained maximum-sum region (LCMSR) query that returns a spatial-network region that is located within a general region of in- terest, that does not exceed a given size constraint, and that best matches query keywords. Such a query maximizes the total weight of the PoIs in it w.r.t. the query keywords. We show that it is NP- hard to answer this query. We develop an approximation algorithm with a (5 + ǫ) approximation ratio utilizing a technique that scales node weights into integers. We also propose a more efficient heuris- tic algorithm and a greedy algorithm. Empirical studies on real data offer detailed insight into the accuracy of the proposed algorithms and show that the proposed algorithms are capable of computingresults efficiently and effectively.

Exceptionally Long Distance Transport of Volcanic Ash: Implications for Stratigraphy, Hazards and the Sourcing of Distal Tephra Deposits

Cryptotephras (tephra not visible to the naked eye) form the foundation of the tephrostratigraphic frameworks used in Europe to date and correlate widely distributed geologic, paleoenvironmental and archaeological records. Pyne-O'Donnell et al. (2012) established the potential for developing a similar crypto-tephrostratigraphy across eastern North America by identifying multiple tephra, including the White River Ash (east; WRAe), St. Helens We and East Lake, in a peat core located in Newfoundland. Following on from this work, several ongoing projects have examined additional peat cores from Michigan, New York State, Maine, Nova Scotia and Newfoundland to build a tephrostratigraphic framework for this region. Using the precedent set by recent research by Jensen et al.(in press) that correlated the Alaskan WRAe to the European cryptotephra AD860B, unknown tephras identified in this work were not necessarily assumed to be from "expected" source areas (e.g. the Cascades). Here we present several examples of the preservation of tephra layers with an intercontinental distribution (i.e. WRAe and Ksudach 1), from relatively small magnitude events (i.e. St. Helens layer T, Mono Crater), and the first example of a Mexican ash in the NE (Volcan Ceboruco, Jala pumice). There are several implications of the identification of these units. These far-travelled ashes: (1) highlight the need to consider "ultra" distal source volcanoes for unknown cryptotephra deposits,. (2) present an opportunity for physical volcanologists to examine why some eruptions have an exceptional distribution of ash that is not necessarily controlled by the magnitude of the event. (3) complicate the idea of using tephrostratigraphic frameworks to understand the frequency of eruptions towards aiding hazard planning and prediction (e.g. Swindles et al., 2011). (4) show that there is a real potential to link tropical and mid to high-latitude paleoenvironmental records. Jensen et al. (in press) Transatlantic correlation of the Alaskan White River Ash. Geology. Pyne-O'Donnell et al. (2012). High-precision ultra-distal Holocene tephrochronology in North America. Quaternary Science Reviews, 52, 6-11. Swindles et al. (2011). A 7000 yr perspective on volcanic ash clouds affecting northern Europe. Geology, 39, 887-890.

Timing and climate forcing of volcanic eruptions for the past 2,500 years

Volcanic eruptions contribute to climate variability, but quantifying these contributions has been limited by inconsistencies in the timing of atmospheric volcanic aerosol loading determined from ice cores and subsequent cooling from climate proxies such as tree rings. Here we resolve these inconsistencies and show that large eruptions in the tropics and high latitudes were primary drivers of interannual-to-decadal temperature variability in the Northern Hemisphere during the past 2,500 years. Our results are based on new records of atmospheric aerosol loading developed from high-resolution, multi-parameter measurements from an array of Greenland and Antarctic ice cores as well as distinctive age markers to constrain chronologies. Overall, cooling was proportional to the magnitude of volcanic forcing and persisted for up to ten years after some of the largest eruptive episodes. Our revised timescale more firmly implicates volcanic eruptions as catalysts in the major sixth-century pandemics, famines, and socioeconomic disruptions in Eurasia and Mesoamerica while allowing multi-millennium quantification of climate response to volcanic forcing.

Efficient Processing of Spatial Group Keyword Queries

With the proliferation of geo-positioning and geo-tagging techniques, spatio-textual objects that possess both a geographical location and a textual description are gaining in prevalence, and spatial keyword queries that exploit both location and textual description are gaining in prominence. However, the queries studied so far generally focus on finding individual objects that each satisfy a query rather than finding groups of objects where the objects in a group together satisfy a query.

We define the problem of retrieving a group of spatio-textual objects such that the group's keywords cover the query's keywords and such that the objects are nearest to the query location and have the smallest inter-object distances. Specifically, we study three instantiations of this problem, all of which are NP-hard. We devise exact solutions as well as approximate solutions with provable approximation bounds to the problems. In addition, we solve the problems of retrieving top-k groups of three instantiations, and study a weighted version of the problem that incorporates object weights. We present empirical studies that offer insight into the efficiency of the solutions, as well as the accuracy of the approximate solutions.