Phase I dose-escalation and pharmacokinetic study of dasatinib in patients with advanced solid tumors

PURPOSE: To determine the maximum tolerated dose, dose-limiting toxicity (DLT), and recommended phase II dose of dasatinib in metastatic solid tumors refractory to standard therapies or for which no effective standard therapy exists. <br></br> EXPERIMENTAL DESIGN: In this phase I, open-label, dose-escalation study, patients received 35 to 160 mg of dasatinib twice daily in 28-day cycles either every 12 hours for 5 consecutive days followed by 2 nontreatment days every week (5D2) or as continuous, twice-daily (CDD) dosing. <br></br> RESULTS: Sixty-seven patients were treated (5D2, n = 33; CDD, n = 34). The maximum tolerated doses were 120 mg twice daily 5D2 and 70 mg twice daily CDD. DLTs with 160 mg 5D2 were recurrent grade 2 rash, grade 3 lethargy, and one patient with both grade 3 prolonged bleeding time and grade 3 hypocalcemia; DLTs with 120 mg twice daily CDD were grade 3 nausea, grade 3 fatigue, and one patient with both grade 3 rash and grade 2 proteinuria. The most frequent treatment-related toxicities across all doses were nausea, fatigue, lethargy, anorexia, proteinuria, and diarrhea, with infrequent hematologic toxicities. Pharmacokinetic data indicated rapid absorption, dose proportionality, and lack of drug accumulation. Although no objective tumor responses were seen, durable stable disease was observed in 16% of patients.<br></br> CONCLUSION: Dasatinib was well tolerated in this population, with a safety profile similar to that observed previously in leukemia patients, although with much less hematologic toxicity. Limited, although encouraging, preliminary evidence of clinical activity was observed. Doses of 120 mg twice daily (5D2) or 70 mg twice daily (CDD) are recommended for further studies in patients with solid tumors.<br></br&gt

Extra-dimensional cosmology with domain-wall branes

We show how to define a consistent braneworld cosmology in a model in which the brane is constructed as a field-theoretic domain wall of finite thickness. The Friedmann, Robertson-Walker metric is recovered in the region of the brane, but, remarkably, with scale factor that depends on particle energy and on particle species, constituting a breakdown of the weak equivalence principle on sufficiently small scales. This unusual effect comes from the extended nature of particles confined to a domain-wall brane, and the fact that they feel an "average" of the bulk spacetime. We demonstrate how to recover the standard results of brane cosmology in the infinitely-thin brane limit, and comment on how our results have the potential to place bounds on parameters such as the thickness of domain-wall braneworlds.Comment: 23 pages; v2 has additional references and reflects journal versio

Atomic X-ray Spectroscopy of Accreting Black Holes

Current astrophysical research suggests that the most persistently luminous objects in the Universe are powered by the flow of matter through accretion disks onto black holes. Accretion disk systems are observed to emit copious radiation across the electromagnetic spectrum, each energy band providing access to rather distinct regimes of physical conditions and geometric scale. X-ray emission probes the innermost regions of the accretion disk, where relativistic effects prevail. While this has been known for decades, it also has been acknowledged that inferring physical conditions in the relativistic regime from the behavior of the X-ray continuum is problematic and not satisfactorily constraining. With the discovery in the 1990s of iron X-ray lines bearing signatures of relativistic distortion came the hope that such emission would more firmly constrain models of disk accretion near black holes, as well as provide observational criteria by which to test general relativity in the strong field limit. Here we provide an introduction to this phenomenon. While the presentation is intended to be primarily tutorial in nature, we aim also to acquaint the reader with trends in current research. To achieve these ends, we present the basic applications of general relativity that pertain to X-ray spectroscopic observations of black hole accretion disk systems, focusing on the Schwarzschild and Kerr solutions to the Einstein field equations. To this we add treatments of the fundamental concepts associated with the theoretical and modeling aspects of accretion disks, as well as relevant topics from observational and theoretical X-ray spectroscopy.Comment: 63 pages, 21 figures, Einstein Centennial Review Article, Canadian Journal of Physics, in pres

Coset Space Dimensional Reduction and Wilson Flux Breaking of Ten-Dimensional N=1, E(8) Gauge Theory

We consider a N=1 supersymmetric E(8) gauge theory, defined in ten dimensions and we determine all four-dimensional gauge theories resulting from the generalized dimensional reduction a la Forgacs-Manton over coset spaces, followed by a subsequent application of the Wilson flux spontaneous symmetry breaking mechanism. Our investigation is constrained only by the requirements that (i) the dimensional reduction leads to the potentially phenomenologically interesting, anomaly free, four-dimensional E(6), SO(10) and SU(5) GUTs and (ii) the Wilson flux mechanism makes use only of the freely acting discrete symmetries of all possible six-dimensional coset spaces.Comment: 45 pages, 2 figures, 10 tables, uses xy.sty, longtable.sty, ltxtable.sty, (a shorter version will be published in Eur. Phys. J. C

Protocol for a multi-centre observational and mixed methods pilot study to identify factors predictive of poor functional recovery after major gastrointestinal surgery and strategies to enhance uptake of perioperative optimization. Optimizing the care and treatment pathways for older patients facing major gastrointestinal surgery (OCTAGON)

Introduction: National datasets report large variations in outcomes from older people (≥65 years) between different UK surgical units. This implies that not all patients receive the same level of care or access to resources, such as rehabilitation or allied health professional input. This might impact functional decline. Aims: Our aim is to evaluate the baseline status of older patients facing major gastrointestinal surgery and the impact of variation in perioperative assessment and provision of perioperative support on functional outcomes. Patients’ experiences and views of assessment and optimization will be explored via integrated qualitative semi-structured interviews. Methods and analysis: This multi-centre, pilot cohort study will include patients ≥65 years presenting via both elective and emergency pathways at three to five South Yorkshire NHS hospitals (Clinical Trials registration NCT04545125). The primary outcome is functional recovery measured using the World Health Organization Disability Assessment Schedule 2.0 at 6 weeks post-operation. Secondary outcomes include feasibility, quality of life, length of stay and complication rate. An opportunistic sample size of 120 has been estimated and will inform the design of a future, adequately powered study. For the qualitative study, 20–30 semi-structured patient interviews will be undertaken with patients from the cohort study to explore experiences of assessment and optimization. Interviews will be digitally recorded, transcribed verbatim and analysed according to the framework approach. Ethics and dissemination: This study has been approved by the National Health Service Research Ethics Committee and is registered centrally with Health Research Authority. It has been adopted by the National Institute for Health Research Portfolio scheme. Dissemination will be via international and national surgical and geriatric conferences

Cognitive performance and functional outcomes of carriers of pathogenic copy number variants: analysis of the UK Biobank

Background: Rare copy number variants (CNVs) are associated with risk of neurodevelopmental disorders characterised by varying degrees of cognitive impairment, including schizophrenia, autism spectrum disorder and intellectual disability. However, the effects of many individual CNVs in carriers without neurodevelopmental disorders are not yet fully understood, and little is known about the effects of reciprocal copy number changes of known pathogenic loci. Aims We aimed to analyse the effect of CNV carrier status on cognitive performance and measures of occupational and social outcomes in unaffected individuals from the UK Biobank. Method: We called CNVs in the full UK Biobank sample and analysed data from 420 247 individuals who passed CNV quality control, reported White British or Irish ancestry and were not diagnosed with neurodevelopmental disorders. We analysed 33 pathogenic CNVs, including their reciprocal deletions/duplications, for association with seven cognitive tests and four general measures of functioning: academic qualifications, occupation, household income and Townsend Deprivation Index. Results: Most CNVs (24 out of 33) were associated with reduced performance on at least one cognitive test or measure of functioning. The changes on the cognitive tests were modest (average reduction of 0.13 s.d.) but varied markedly between CNVs. All 12 schizophrenia-associated CNVs were associated with significant impairments on measures of functioning. Conclusions CNVs implicated in neurodevelopmental disorders, including schizophrenia, are associated with cognitive deficits, even among unaffected individuals. These deficits may be subtle but CNV carriers have significant disadvantages in educational attainment and ability to earn income in adult life

​​South Georgia marine productivity over the past 15 ka and implications for glacial evolution​

The subantarctic islands of South Georgia are located in the Southern Ocean, and they may be sensitive to future climate warming. However, due to a lack of well-dated subantarctic palaeoclimate archives, there is still uncertainty about South Georgia's response to past climate change. Here, we reconstruct primary productivity changes and infer Holocene glacial evolution by analysing two marine gravity cores: one near Cumberland Bay on the inner South Georgia shelf (GC673: ca. 9.5 to 0.3 cal. kyr BP) and one offshore of Royal Bay on the mid-shelf (GC666: ca. 15.2 cal. kyr BP to present). We identify three distinct benthic foraminiferal assemblages characterised by the dominance of Miliammina earlandi, Fursenkoina fusiformis, and Cassidulinoides parkerianus that are considered alongside foraminiferal stable isotopes and the organic carbon and biogenic silica accumulation rates of the host sediment. The M. earlandi assemblage is prevalent during intervals of dissolution in GC666 and reduced productivity in GC673. The F. fusiformis assemblage coincides with enhanced productivity in both cores. Our multiproxy analysis provides evidence that the latest Pleistocene to earliest Holocene (ca. 15.2 to 10.5 cal. kyr BP) was a period of high productivity associated with increased glacial meltwater discharge. The mid–late Holocene (ca. 8 to 1 cal. kyr BP), coinciding with a fall in sedimentation rates and lower productivity, was likely a period of reduced glacial extent but with several short-lived episodes of increased productivity from minor glacial readvances. The latest Holocene (from ca. 1 cal. kyr BP) saw an increase in productivity and glacial advance associated with cooling temperatures and increased precipitation which may have been influenced by changes in the southwesterly winds over South Georgia. We interpret the elevated relative abundance of F. fusiformis as a proxy for increased primary productivity which, at proximal site GC673, was forced by terrestrial runoff associated with the spring–summer melting of glaciers in Cumberland Bay. Our study refines the glacial history of South Georgia and provides a more complete record of mid–late Holocene glacial readvances with robust chronology. Our results suggest that South Georgia glaciers were sensitive to modest climate changes within the Holocene

A stochastic evolutionary model generating a mixture of exponential distributions

Recent interest in human dynamics has stimulated the investigation of the stochastic processes that explain human behaviour in various contexts, such as mobile phone networks and social media. In this paper, we extend the stochastic urn-based model proposed in \cite{FENN15} so that it can generate mixture models, in particular, a mixture of exponential distributions. The model is designed to capture the dynamics of survival analysis, traditionally employed in clinical trials, reliability analysis in engineering, and more recently in the analysis of large data sets recording human dynamics. The mixture modelling approach, which is relatively simple and well understood, is very effective in capturing heterogeneity in data. We provide empirical evidence for the validity of the model, using a data set of popular search engine queries collected over a period of 114 months. We show that the survival function of these queries is closely matched by the exponential mixture solution for our model

Measurement of the B0-anti-B0-Oscillation Frequency with Inclusive Dilepton Events

The $B^0$-$\bar B^0$ oscillation frequency has been measured with a sample of 23 million \B\bar B pairs collected with the BABAR detector at the PEP-II asymmetric B Factory at SLAC. In this sample, we select events in which both B mesons decay semileptonically and use the charge of the leptons to identify the flavor of each B meson. A simultaneous fit to the decay time difference distributions for opposite- and same-sign dilepton events gives $\Delta m_d = 0.493 \pm 0.012{(stat)}\pm 0.009{(syst)}$ ps$^{-1}$.Comment: 7 pages, 1 figure, submitted to Physical Review Letter