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

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]

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*

Making big steps in trajectories

We consider the solution of initial value problems within the context of hybrid systems and emphasise the use of high precision approximations (in software for exact real arithmetic). We propose a novel algorithm for the computation of trajectories up to the area where discontinuous jumps appear, applicable for holomorphic flow functions. Examples with a prototypical implementation illustrate that the algorithm might provide results with higher precision than well-known ODE solvers at a similar computation time

A CDCL-style calculus for solving non-linear constraints

In this paper we propose a novel approach for checking satisfiability of non-linear constraints over the reals, called ksmt. The procedure is based on conflict resolution in CDCL style calculus, using a composition of symbolical and numerical methods. To deal with the non-linear components in case of conflicts we use numerically constructed restricted linearisations. This approach covers a large number of computable non-linear real functions such as polynomials, rational or trigonometrical functions and beyond. A prototypical implementation has been evaluated on several non-linear SMT-LIB examples and the results have been compared with state-of-the-art SMT solvers.Comment: 17 pages, 3 figures; accepted at FroCoS 2019; software available at <http://informatik.uni-trier.de/~brausse/ksmt/

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

Comparative Approach to Define Increased Regulatory T Cells in Different Cancer Subtypes by Combined Assessment of CD127 and FOXP3

In recent years an increase of functional CD4+CD25+ regulatory T cells (Treg cells) has been established for patients with solid tumors, acute leukemias, and lymphomas. We have reported an expanded pool of CD4+CD25high Treg cells in patients with chronic lymphatic leukemia (CLL), multiple myeloma (MM) as well as its premalignant precursor monoclonal gammopathy of undetermined significance (MGUS). In healthy individuals, low-level expression of CD127 on T cells in addition to the expression of FOXP3 has been associated with Treg cells. Here, we demonstrate that the expanded FOXP3+ T-cell population in patients with colorectal cancer, CLL, MGUS, MM, follicular lymphoma, and Hodgkin's disease are exclusively CD127low Treg cells and were strongly suppressive. A significant portion of CD127lowFOXP3+ Treg cells expressed only low levels of CD25 suggesting that the previously reported expansion of CD25+ Treg cells underestimates the true expansion. The assessment of CCR7 and CD45RA expression on the expanded CD4+CD127lowFOXP3+ Treg cells revealed an increase of both naïve as well as central and effector memory Treg cells in peripheral blood. Our data strongly support superiority of combined CD127 and FOXP3 analysis in comparison to CD25 and FOXP3 assessment for further quantification of Treg cells in malignant diseases