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The information on candidate cancer driver alterations available from public databases is often descriptive and of limited mechanistic insight, which poses difficulties for reliable distinction between true driver and passenger events. To address this challenge, we performed in-depth analysis of whole-exome sequencing data from cell lines generated by a barrier bypass-clonal expansion (BBCE) protocol. The employed strategy is based on carcinogen-driven immortalization of primary mouse embryonic fibroblasts and recapitulates early steps of cell transformation. Among the mutated genes were almost 200 COSMIC Cancer Gene Census genes, many of which were recurrently affected in the set of 25 immortalized cell lines. The alterations affected pathways regulating DNA damage response and repair, transcription and chromatin structure, cell cycle and cell death, as well as developmental pathways. The functional impact of the mutations was strongly supported by the manifestation of several known cancer hotspot mutations among the identified alterations. We identified a new set of genes encoding subunits of the BAF chromatin remodeling complex that exhibited Ras-mediated dependence on PRC2 histone methyltransferase activity, a finding that is similar to what has been observed for other BAF subunits in cancer cells. Among the affected BAF complex subunits, we determined Smarcd2 and Smarcc1 as putative driver candidates not yet fully identified by large-scale cancer genome sequencing projects. In addition, Ep400 displayed characteristics of a driver gene in that it showed a mutually exclusive mutation pattern when compared with mutations in the Trrap subunit of the TIP60 complex, both in the cell line panel and in a human tumor data set. We propose that the information generated by deep sequencing of the BBCE cell lines coupled with phenotypic analysis of the mutant cells can yield mechanistic insights into driver events relevant to human cancer development.

Next-generation sequencing (NGS) technology has demonstrated that the cancer genomes are peppered with mutations. Although most somatic tumour mutations are unlikely to have any role in the cancer process per se, the spectra of DNA sequence changes in tumour mutation catalogues have the potential to identify the mutagens, and to reveal the mutagenic processes responsible for human cancer. Very recently, a novel approach for data mining of the vast compilations of tumour NGS data succeeded in separating and precisely defining at least 30 distinct patterns of sequence change hidden in mutation databases. At least half of these mutational signatures can be readily assigned to known human carcinogenic exposures or endogenous mechanisms of mutagenesis. A quantum leap in our knowledge of mutagenesis in human cancers has resulted, stimulating a flurry of research activity. We trace here the major findings leading first to the hypothesis that carcinogenic insults leave characteristic imprints on the DNA sequence of tumours, and culminating in empirical evidence from NGS data that well-defined carcinogen mutational signatures are indeed present in tumour genomic DNA from a variety of cancer types. The notion that tumour DNAs can divulge environmental sources of mutation is now a well-accepted fact. This approach to cancer aetiology has also incriminated various endogenous, enzyme-driven processes that increase the somatic mutation load in sporadic cancers. The tasks now confronting the field of molecular epidemiology are to assign mutagenic processes to orphan and newly discovered tumour mutation patterns, and to determine whether avoidable cancer risk factors influence signatures produced by endogenous enzymatic mechanisms. Innovative research with experimental models and exploitation of the geographical heterogeneity in cancer incidence can address these challenges.

Contribution of the work consists in creation of a mathematical model (algorithm) for prediction of technological parameters of the two-high rolling stand DUO 210 Sva and Q110 at change of the absolute reduction Δh, for example for a deep-drawing steel and of the brand KOHAL grade 697 and low carbon steel, as well as generally speaking for any rolled material. It is possible to identify and predict on the basis of this algorithm an instant state of surface topography in respect to variable technological conditions. On this basis it is then possible to calculate and plot individual main technological parameters.

Direct synthesis of lead iodide, a promising material for X-ray and γ detectors operating at room temperature, was developed and optimized. The influence of admixture of rare earth elements Ce, Ho, Gd, Yb, Er, and Tb in concentrations 0.05–0.5 at. % on the quality of prepared PbI2 was investigated. Zone melting was employed in order to increase the lead iodide purity. Electrical and optical properties of PbI2 samples were assessed on the basis of the measurement of electrical resistivity and low-temperature photoluminescence. The electrical resistivity of synthesized samples varied from 109 Ω cm to 1011 Ω cm and occasionally it was increased up to 1013 Ω cm.

InP single crystals were grown by liquid phase epitaxy on semi-insulating InP:Fe and n-type InP:Sn substrates with cerium, thulium and lutetium additions to the growth melt. Grown layers were examined by low-temperature photoluminescence spectroscopy and C-V measurements. Layers prepared with the addition of Ce and Tm exhibit the change of electrical conductivity from n to p, while those grown with Lu admixture remain n-type. Ce has been found to be incorporated into the InP lattice and sharp luminescence arising from 2F7/2 → 2F5/2 inner shell transitions of Ce3+ at 3600 nm was detected. The highest purifying effect due to RE addition has been found for Tm admixture, where the impurity concentration was decreased by three orders of magnitude and fine spectral features were revealed by photoluminescence spectroscopy. The addition of Tm into the growth melt enables to prepare thick and pure InP layers of p-type conductivity – a material promising in the context of semiconductor radiation detectors. (© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

The preparation and characterization of thick InP layers by Liquid Phase Epitaxy with admixture of Ce, Tb, Dy and Yb in the growth melt is reported. Measurement of temperature dependent Hall affect, C-V characteristics and low-temperature photoluminescence show the change of n®p type conductivity and considerable improvement of structural and electro-optical parameters for all studied rare-earth elements. Mn was identified as dominant acceptor impurity in the case of Tb and Dy addition. In the case of Ce and Yb the dominant acceptor was identified as isoelectronic Ce or Yb on the In site subjected to a strong electron-lattice interaction. The reported high quality thick p-type InP layers could well be used for the preparation of radiation detector structures.

The aim of this work is to study the new method of direct synthesis of lead and iodine as the input material of PbI2. This method has not been studied for this material till now, and seems to be one of the new methods for preparation of the input material. The photoluminescence measurement and measurement of resistivity has been done and compared with the measurements done by precipitation and zone purification.

Binary and ternary TeO2 based oxy-chloride glass systems have been prepared and characterised by absorption and low-temperature photoluminescence spectroscopy, and by the measurements of dc electrical conductivity. Prepared glasses exhibit transmittance 75-80% in a broad transmission range 0.3 – 6.5µm with modest shift of upper absorption edge to longer wavelength as heavier ions are introduced into the system. Electronic transitions between 4f-4f inner shells of Pr3+ ions embedded into the host glass have been investigated in a wide temperature range as a function of used precursors used for doping. The temperature dependence of dc electrical conductivity exhibits Arrhenius plots with the single activation energy. PACS codes 81.05.Kf, 78.20.Ci, 78.55.Hx

Copper doped InP crystals were synthesized by Bridgman method and further grown by Czochralski technique. Samples of as grown crystals were of n-type conductivity with the estimated concentration of copper smaller than 5 × 1015 cm–3. The electron mobility in these samples is largely reduced at low temperatures, which is attributed to a strong scattering of electrons on copper impurities similar to other atomic impurities with partly occupied 3d shells. The samples were converted to p-type semi-insulating state after annealing at 500 °C and quenched to room temperature. The energy of copper acceptor causing the semi-insulating state was determined by temperature dependent Hall measurements as 0.29 eV in agreement with the low temperature photoluminescence spectroscopy. (© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

We report the effect of f‐element addition (Er, Ho, Nd, Pr, Tb and Yb) during the liquid phase epitaxy (LPE) on the growth process and structural, electrical and optical properties of thick InP epitaxial layers for applications in ionizing radiation detector structures. The layers were grown by LPE from the melt containing, besides essential components, also rare‐earth (RE) elements admixture. The grown layers were examined by low‐temperature photoluminescence spectroscopy and temperature‐dependent Hall effect. We have demonstrated that the concentration of shallow donors was reduced effectively by up to three orders of magnitude. Room temperature Hall effect measurements revealed p‐type conductivity of the layers prepared from the melt containing Tb, Pr or Yb admixture exceeding certain limiting concentration. From among the studied RE elements Pr and Tb appear as the most promising candidates for the preparation of pure and thick (d ≥ 10 mm) InP layers with p‐type conductivity. These layers could readily be used for the preparation of α‐particles detectors, where detection will be mediated via the depletion layer of high quality Schottky contact.

ABSTRACT

Theoretical expression for tunnel current of MIS-Schottky tunnel junction, based on the WKB analytical formula for the tunnelling probability, is presented. The dependence of the position of the main minimum in conductance characteristic on the semiconductor Fermi degeneracy is calculated numerically and compared with our experimental data in Au-SiO2-pSi tunnel junctions.

Interstitial deletions of the long arm of chromosome 5 are common in a number of disorders of leukemic and preleukemic myeloid disorders. Although the limits of these deletions vary among patients, a region of cytogenetic overlap that includes band 5q31 is deleted consistently, suggesting loss of 5q31 loci critical for normal myeloid differentiation and leukemogenesis. An anonymous genomic DNA segment D5S89, previously mapped to 5q21–31, detects consistent loss of alleles in cases showing the 5q- chromosome at presentation or relapse. Analysis of a panel of natural-deletion somatic-cell hybrids in conjunction with irradiation hybrids containing fragments of human chromosome 5q shows that the D5S89 locus is telomeric to the interleukin (IL) genes (IL-3, IL-4, IL-5, IL-9, and granulocyte- macrophage colony-stimulating factor [GM-CSF]) and interferon response factor-1 (IRF-1) gene and centromeric to the early response transcription factor (early growth response gene-1 [EGR-1]) on 5q31. To further define the principal region of loss, we have isolated and characterized yeast artificial chromosomes (YACs) spanning D5S89. The presence of several CpG islands within the 300-kb YAC is suggestive of multiple transcription units. However, IL-4, IL-5, IRF-1, IL-3, GM-CSF, and EGR-1 genes were not detected in the YAC clone spanning D5S89, implying that none of these genes are in the vicinity of the D5S89 marker. Further characterization of these YACs should facilitate the isolation of novel candidate genes that may play a role in the evolution of the abnormal phenotype associated with 5q- chromosome.

Distal renal tubular acidosis (dRTA) is characterized by defective urinary acidification by the distal nephron. Cl-/HCO3- exchange mediated by the AE1 anion exchanger in the basolateral membrane of type A intercalated cells is thought to be an essential component of lumenal H+ secretion by collecting duct intercalated cells. We evaluated the AE1 gene as a possible candidate gene for familial dRTA. We found in three unrelated families with autosomal dominant dRTA that all clinically affected individuals were heterozygous for a single missense mutation encoding the mutant AE1 polypeptide R589H. Patient red cells showed approximately 20% reduction in sulfate influx of normal 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid sensitivity and pH dependence. Recombinant kidney AE1 R589H expressed in Xenopus oocytes showed 20-50% reduction in Cl-/Cl- and Cl-/HCO3- exchange, but did not display a dominant negative phenotype for anion transport when coexpressed with wild-type AE1. One apparently unaffected individual for whom acid-loading data were unavailable also was heterozygous for the mutation. Thus, in contrast to previously described heterozygous loss-of-function mutations in AE1 associated with red cell abnormalities and apparently normal renal acidification, the heterozygous hypomorphic AE1 mutation R589H is associated with dominant dRTA and normal red cells.

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