Anti-Wolbachia therapy has been identified as a viable treatment for combating filarial diseases. Phenotypic screening revealed a series of pyrazolopyrimidine hits with potent anti-Wolbachia ...activity. This paper focuses on the exploration of the SAR for this chemotype, with improvement of metabolic stability and solubility profiles using medicinal chemistry approaches. Organic synthesis has enabled functionalization of the pyrazolopyrimidine core at multiple positions, generating a library of compounds of which many analogues possess nanomolar activity against Wolbachia in vitro with improved DMPK parameters. A lead compound, 15f, was selected for in vivo pharmacokinetics (PK) profiling in mice. The combination of potent anti-Wolbachia activity in two in vitro assessments plus the exceptional oral PK profiles in mice puts this lead compound in a strong position for in vivo proof-of-concept pharmacodynamics studies and demonstrates the strong potential for further optimization and development of this series for treatment of filariasis in the future.
Forty percent of breast cancers occur among older patients. Unfortunately, there is a lack of evidence for treatment guidelines for older breast cancer patients. The aim of this study is to compare ...treatment strategy and relative survival for operable breast cancer in the elderly between The Netherlands and Ireland.
From the Dutch and Irish national cancer registries, women aged ≥65 years with non-metastatic breast cancer were included (2001-2009). Proportions of patients receiving guideline-adherent locoregional treatment, endocrine therapy, and chemotherapy were calculated and compared between the countries by stage. Secondly, 5-year relative survival was calculated by stage and compared between countries.
Overall, 41,055 patients from The Netherlands and 5,826 patients from Ireland were included. Overall, more patients received guideline-adherent locoregional treatment in The Netherlands, overall (80% vs. 68%, adjusted p<0.001), stage I (83% vs. 65%, p<0.001), stage II (80% vs. 74%, p<0.001) and stage III (74% vs. 57%, P<0.001) disease. On the other hand, more systemic treatment was provided in Ireland, where endocrine therapy was prescribed to 92% of hormone receptor-positive patients, compared to 59% in The Netherlands. In The Netherlands, only 6% received chemotherapy, as compared 24% in Ireland. But relative survival was poorer in Ireland (5 years relative survival 89% vs. 83%), especially in stage II (87% vs. 85%) and stage III (61% vs. 58%) patients.
Treatment for older breast cancer patients differed significantly on all treatment modalities between The Netherlands and Ireland. More locoregional treatment was provided in The Netherlands, and more systemic therapy was provided in Ireland. Relative survival for Irish patients was worse than for their Dutch counterparts. This finding should be a strong recommendation to study breast cancer treatment and survival internationally, with the ultimate goal to equalize the survival rates for breast cancer patients across Europe.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Efficient Field-Sensitive Pointer Analysis of C PEARCE, David J; KELLY, Paul H. J; HANKIN, Chris
ACM transactions on programming languages and systems,
11/2007, Letnik:
30, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The subject of this article is flow- and context-insensitive pointer analysis. We present a novel approach for precisely modelling struct variables and indirect function calls. Our method emphasises ...efficiency and simplicity and is based on a simple language of set constraints. We obtain an
O
(
v
4
) bound on the time needed to solve a set of constraints from this language, where
v
is the number of constraint variables. This gives, for the first time, some insight into the hardness of performing field-sensitive pointer analysis of C. Furthermore, we experimentally evaluate the time versus precision trade-off for our method by comparing against the field-insensitive equivalent. Our benchmark suite consists of 11 common C programs ranging in size from 15,000 to 200,000 lines of code. Our results indicate the field-sensitive analysis is more expensive to compute, but yields significantly better precision. In addition, our technique has been integrated into the latest release (version 4.1) of the GNU Compiler GCC. Finally, we identify several previously unknown issues with an alternative and less precise approach to modelling struct variables, known as field-based analysis.
Contemporary chronic total occlusion (CTO) percutaneous coronary intervention (PCI) incorporates wire escalation and dissection/re-entry recanalisation strategies.
The purpose of the study was to ...investigate changes in collateral function after CTO PCI and to identify whether the mode of successful recanalisation influences collateral function regression.
Patients scheduled for elective CTO PCI with evidence of viability in the CTO territory by noninvasive imaging were included in this study. After successful CTO PCI, the aortic pressure (Pa) and distal coronary artery wedge pressure (Pw) during balloon occlusion were measured, both in a resting state and during infusion of intravenous adenosine, allowing the calculation of the pressure-derived collateral pressure index at rest and hyperaemia (CPI
and the collateral fractional flow reserve FFR
, respectively). Measurements were repeated 3 months later during angiographic follow-up.
Eighty-one patients had physiological measurements at baseline and follow-up. In the final cohort the mean age was 64 years and 82% were male. The mean maximal stent diameter and total stent length were 3.2±0.5 mm and 68±31 mm, respectively. Successful strategies were antegrade wiring (64.2%), antegrade dissection re-entry (8.6%), and retrograde dissection re-entry (27.1%). Between the index procedure and follow-up, wedge pressure decreased from 34±11 mmHg to 21±8.5 mmHg (p<0.01), respectively. FFR
changed from 0.34±0.11 to 0.19±0.09 (p<0.01) at follow-up and CPI
from 0.40±0.14 to 0.17±0.09 (p<0.01). Absolute maximum collateral flow decreased from 55±32 ml/min directly after PCI to 38±24 ml/min (p<0.01). There was no relation between the recanalisation technique and changes in FFR
.
There was a significant reduction in collateral flow over time, independent of the recanalisation technique.
We present a symbolic execution-based technique for cross-checking programs accelerated using SIMD or OpenCL against an unaccelerated version, as well as a technique for detecting data races in ...OpenCL programs. Our techniques are implemented in KLEE-CL, a tool based on the symbolic execution engine KLEE that supports symbolic reasoning on the equivalence between expressions involving both integer and floating-point operations. While the current generation of constraint solvers provide effective support for integer arithmetic, the situation is different for floating-point arithmetic, due to the complexity inherent in such computations. The key insight behind our approach is that floating-point values are only reliably equal if they are essentially built by the same operations. This allows us to use an algorithm based on symbolic expression matching augmented with canonicalisation rules to determine path equivalence. Under symbolic execution, we have to verify equivalence along every feasible control-flow path. We reduce the branching factor of this process by aggressively merging conditionals, if-converting branches into select operations via an aggressive phi-node folding transformation. To support the Intel Streaming SIMD Extension (SSE) instruction set, we lower SSE instructions to equivalent generic vector operations, which in turn are interpreted in terms of primitive integer and floating-point operations. To support OpenCL programs, we symbolically model the OpenCL environment using an OpenCL runtime library targeted to symbolic execution. We detect data races by keeping track of all memory accesses using a memory log, and reporting a race whenever we detect that two accesses conflict. By representing the memory log symbolically, we are also able to detect races associated with symbolically-indexed accesses of memory objects. We used KLEE-CL to prove the bounded equivalence between scalar and data-parallel versions of floating-point programs and find a number of issues in a variety of open source projects that use SSE and OpenCL, including mismatches between implementations, memory errors, race conditions and a compiler bug.
We study and systematically evaluate a class of composable code transformations that improve arithmetic intensity in local assembly operations, which represent a significant fraction of the execution ...time in finite element methods. Their performance optimization is indeed a challenging issue. Even though affine loop nests are generally present, the short trip counts and the complexity of mathematical expressions, which vary among different problems, make it hard to determine an optimal sequence of successful transformations. Our investigation has resulted in the implementation of a compiler (called COFFEE) for local assembly kernels, fully integrated with a framework for developing finite element methods. The compiler manipulates abstract syntax trees generated from a domain-specific language by introducing domain-aware optimizations for instruction-level parallelism and register locality. Eventually, it produces C code including vector SIMD intrinsics. Experiments using a range of real-world finite element problems of increasing complexity show that significant performance improvement is achieved. The generality of the approach and the applicability of the proposed code transformations to other domains is also discussed.
Summary
SPIRAL is an autotuning, program generation, and code synthesis system that offers a fully automatic generation of highly optimized target codes, customized for the specific execution ...platform at hand. Initially, SPIRAL was targeted at problem domains in digital signal processing, later also at basic linear algebra. We open SPIRAL up to a new, practically relevant and challenging domain: multigrid solvers. SPIRAL is driven by algebraic transformation rules. We specify a set of such rules for a simple multigrid solver with a Richardson smoother for a discretized square 2D Poisson equation with Dirichlet boundary conditions. We present the target code that SPIRAL generates in static single‐assignment form and discuss its performance. While this example required no changes of or extensions to the SPIRAL system, more complex multigrid solvers may require small adaptations.
Local charge and spin currents are evaluated from the solutions of fully relativistic quantum mechanical scattering calculations for systems that include temperature-induced lattice and spin disorder ...as well as intrinsic alloy disorder. This makes it possible to determine material-specific spin transport parameters at finite temperatures. Illustrations are given for a number of important materials and parameters at 300 K. The spin-flip diffusion length lsf of Pt is determined from the exponential decay of a spin current injected into a long length of thermally disordered Pt; we find lsfPt=5.3±0.4nm. For the ferromagnetic substitutional disordered alloy permalloy (Py), we inject currents that are fully polarized parallel and antiparallel to the magnetization and calculate lsf from the exponential decay of their difference; we find lsfPy=2.8±0.1nm. The transport polarization β is found from the asymptotic polarization of a charge current in a long length of Py to be β=0.75±0.01. The spin Hall angle ΘsH is determined from the transverse spin current induced by the passage of a longitudinal charge current in thermally disordered Pt; our best estimate is ΘsHPt=4.5±1% corresponding to the experimental room-temperature bulk resistivity ρ=10.8μΩcm.
In glioblastoma (GBM), heterogeneous expression of amplified and mutated epidermal growth factor receptor (EGFR) presents a substantial challenge for the effective use of EGFR-directed therapeutics. ...Here we demonstrate that heterogeneous expression of the wild-type receptor and its constitutively active mutant form, EGFRvIII, limits sensitivity to these therapies through an interclonal communication mechanism mediated by interleukin-6 (IL-6) cytokine secreted from EGFRvIII-positive tumor cells. IL-6 activates a NF-κB signaling axis in a paracrine and autocrine manner, leading to bromodomain protein 4 (BRD4)-dependent expression of the prosurvival protein survivin (BIRC5) and attenuation of sensitivity to EGFR tyrosine kinase inhibitors (TKIs). NF-κB and survivin are coordinately up-regulated in GBM patient tumors, and functional inhibition of either protein or BRD4 in in vitro and in vivo models restores sensitivity to EGFR TKIs. These results provide a rationale for improving anti-EGFR therapeutic efficacy through pharmacological uncoupling of a convergence point of NF-κB-mediated survival that is leveraged by an interclonal circuitry mechanism established by intratumoral mutational heterogeneity.
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