Frequent k- ras -2 mutations and p16INK4Amethylation in hepatocellular carcinomas in workers exposed to vinyl chloride

Vinyl chloride (VC) is a know animal and human carcinogen associated with liver angiosarcomas (LAS) and hepatocellular carcinomas (HCC). In VC-associated LAS mutations of the K- ras -2 gene have been reported; however, no data about the prevalence of such mutations in VC associated HCCs are available. Recent data indicate K- ras -2 mutations induce P16 methylation accompanied by inactivation of the p16 gene. The presence of K- ras -2 mutations was analysed in tissue from 18 patients with VC associated HCCs. As a control group, 20 patients with hepatocellular carcinoma due to hepatitis B (n = 7), hepatitis C (n = 5) and alcoholic liver cirrhosis (n = 8) was used. The specific mutations were determined by direct sequencing of codon 12 and 13 of the K- ras -2 gene in carcinomatous and adjacent non-neoplastic liver tissue after microdissection. The status of p16 was evaluated by methylation-specific PCR (MSP), microsatellite analysis, DNA sequencing and immunohistochemical staining. All patients had a documented chronic quantitated exposure to VC (average 8883 ppmy, average duration: 245 months). K- ras -2 mutations were found in 6 of 18 (33%) examined VC-associated HCCs and in 3 cases of adjacent non-neoplastic liver tissue. There were 3 G → A point mutations in the tumour tissue. All 3 mutations found in non-neoplastic liver from VC-exposed patients were also G → A point mutations (codon 12- and codon 13-aspartate mutations). Hypermethylation of the 5′ CpG island of the p16 gene was found in 13 of 18 examined carcinomas (72%). Of 6 cancers with K- ras -2 mutations, 5 specimens also showed methylated p16. Within the control group, K- ras -2 mutation were found in 3 of 20 (15%) examined HCC. p16 methylation occurred in 11 out of 20 (55%) patients. K- ras -2 mutations and p16 methylation are frequent events in VC associated HCCs. We observed a K- ras -2 mutation pattern characteristic of chloroethylene oxide, a carcinogenic metabolite of VC. Our results strongly suggest that K- ras -2 mutations play an important role in the pathogenesis of VC-associated HCC. © 2001 Cancer Research Campaignhttp://www.bjcancer.co

Physical Computation, P/poly and P/log*

In this paper we give a framework for describing how abstract systems can be used to compute if no randomness or error is involved. Using this we describe a class of classical "physical" computation systems whose computational capabilities in polynomial time are equivalent to P/poly. We then extend our framework to describe how measurement and transformation times may vary depending on their input. Finally we describe two classes of classical "physical" computation systems in this new framework whose computational capabilities in polynomial time are equivalent to P/poly and P/log*

Quantitative Coding and Complexity Theory of Compact Metric Spaces

Specifying a computational problem requires fixing encodings for input and output: encoding graphs as adjacency matrices, characters as integers, integers as bit strings, and vice versa. For such discrete data, the actual encoding is usually straightforward and/or complexity-theoretically inessential (up to polynomial time, say); but concerning continuous data, already real numbers naturally suggest various encodings with very different computational properties. With respect to qualitative computability, Kreitz and Weihrauch (1985) had identified ADMISSIBILITY as crucial property for 'reasonable' encodings over the Cantor space of infinite binary sequences, so-called representations [doi:10.1007/11780342_48]: For (precisely) these does the sometimes so-called MAIN THEOREM apply, characterizing continuity of functions in terms of continuous realizers. We rephrase qualitative admissibility as continuity of both the representation and its multivalued inverse, adopting from [doi:10.4115/jla.2013.5.7] a notion of sequential continuity for multifunctions. This suggests its quantitative refinement as criterion for representations suitable for complexity investigations. Higher-type complexity is captured by replacing Cantor's as ground space with Baire or any other (compact) ULTRAmetric space: a quantitative counterpart to equilogical spaces in computability [doi:10.1016/j.tcs.2003.11.012]

Mechanism of Preconditioning by Isoflurane in Rabbits: A Direct Role for Reactive Oxygen Species

LARGE quantities of reactive oxygen species (ROS) released during reperfusion after coronary artery occlusion damage proteins responsible for intracellular homeostasis, produce tissue injury, depress contractile function, and increase myocardial infarct size. In contrast, small quantities of ROS may exert beneficial effects during ischemia and reperfusion when released before a prolonged ischemic event. ROS derived from mitochondria during a brief ischemic episode produce preconditioning. Free radical scavengers administered during ischemic preconditioning (IPC) markedly attenuate the protective effect of the preconditioning stimulus on infarct size. These data suggest that IPC is mediated in part by small quantities of ROS released during preconditioning. Volatile anesthetics protect myocardium against infarction through a signal transduction pathway that includes adenosine type 1 receptors, protein kinase C, inhibitory guanine regulatory proteins, and mitochondrial and sarcolemmal adenosine triphosphate-regulated potassium (KATP) channels. A recent investigation by Müllenheim et al . provides compelling evidence that ROS also mediate myocardial protection produced by volatile anesthetics. We sought to confirm and extend these important results by examining the hypothesis that ROS scavengers inhibit isoflurane-induced protection against irreversible ischemic injury. We further tested the hypothesis that isoflurane directly generates ROS in rabbit ventricular myocardium in vivo using a confocal microscopic technique combined with the superoxide anion-specific fluorescent probe dihydroethidium

Computing domains of attraction for planar dynamics

In this note we investigate the problem of computing the domain of attraction of a ow on R2 for a given attractor. We consider an operator that takes two inputs, the description of the ow and a cover of the attractors, and outputs the domain of attraction for the given attractor. We show that: (i) if we consider only (structurally) stable systems, the operator is (strictly semi-)computable; (ii) if we allow all systems de ned by C1-functions, the operator is not (semi-)computable. We also address the problem of computing limit cycles on these systems

Radiofrequency applicator concepts for thermal magnetic resonance of brain tumors at 297 MHz (7.0 Tesla)

PURPOSE: Thermal intervention is a potent sensitizer of cells to chemo- and radiotherapy in cancer treatment. Glioblastoma multiforme (GBM) is a potential clinical target, given the cancer's aggressive nature and resistance to current treatment options. The annular phased array (APA) technique employing electromagnetic waves in the radiofrequency (RF) range allows for localized temperature increase in deep seated target volumes (TVs). Reports on clinical applications of the APA technique in the brain are still missing. Ultrahigh field magnetic resonance (MR) employs higher frequencies than conventional MR and has potential to provide focal temperature manipulation, high resolution imaging and noninvasive temperature monitoring using an integrated RF applicator (ThermalMR). This work examines the applicability of RF applicator concepts for ThermalMR of brain tumors at 297 MHz (7.0 Tesla). METHODS: Electromagnetic field (EMF) simulations are performed for clinically realistic data based on GBM patients. Two algorithms are used for specific RF energy absorption rate based thermal intervention planning for small and large TVs in the brain, aiming at maximum RF power deposition or RF power uniformity in the TV for 10 RF applicator designs. RESULTS: For both TVs , the power optimization outperformed the uniformity optimization. The best results for the small TV are obtained for the 16 element interleaved RF applicator using an elliptical antenna arrangement with water bolus. The two row elliptical RF applicator yielded the best result for the large TV. DISCUSSION: This work investigates the capacity of ThermalMR to achieve targeted thermal interventions in model systems resembling human brain tissue and brain tumors

Reactive Oxygen Species Modulate Coronary Wall Shear Stress and Endothelial Function During Hyperglycemia

Hyperglycemia is associated with generation of reactive oxygen species (ROS), and this action may contribute to accelerated atherogenesis. We tested the hypothesis that hyperglycemia produces alterations in left anterior descending coronary artery (LAD) wall shear stress concomitant with endothelial dysfunction and ROS production in dogs (n = 12) instrumented for measurement of LAD blood flow, velocity, and diameter. Dogs were randomly assigned to receive vehicle (0.9% saline) or the superoxide dismutase mimetic 4- hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (tempol) and were administered intravenous infusions of d-glucose to achieve target blood glucose concentrations of 350 and 600 mg/dl (moderate and severe hyperglycemia, respectively). Endothelial function and ROS generation were assessed by coronary blood flow responses to acetylcholine (10, 30, and 100 ng/kg) and dihydroethidium fluorescence of myocardial biopsies, respectively. Indexes of wall shear stress were calculated with conventional fluid dynamics theory. Hyperglycemia produced dose-related endothelial dysfunction, increases in ROS production, and reductions in oscillatory shear stress that were normalized by tempol. The results suggest a direct association between hyperglycemia-induced ROS production, endothelial dysfunction, and decreases in oscillatory shear stress in vivo

Language, Life, Limits

In the context of second-order polynomial-time computability, we prove that there is no general function space construction. We proceed to identify restrictions on the domain or the codomain that do provide a function space with polynomial-time function evaluation containing all polynomial-time computable functions of that type. As side results we show that a polynomial-time counterpart to admissibility of a representation is not a suitable criterion for natural representations, and that the Weihrauch degrees embed into the polynomial-time Weihrauch degrees