Superconducting phase transitions in disordered NbTiN films.

Suppression of superconductivity in disordered systems is a fundamental problem of condensed matter physics. Here we investigate superconducting niobium-titanium-nitride (Nb1-xTixN) thin films grown by the atomic layer deposition (ALD) with slightly different growth process parameters. We observe a smooth crossover from the disorder-driven superconductor-normal metal transition (SMT) to the superconductor-insulator transition (SIT) via the intermediate Bose metal state detected by the low-temperature saturation of the temperature dependence of the sheet resistance. We demonstrate that the SIT via the intervening Bose metal state occurs if the sheet resistance of the film in the maximum, Rmax prior to the superconducting drop of R(T), exceeds Rq = h/4e2.

Stimulated emission in the 2.8-3.5 µm wavelength range from Peltier cooled HgTe/CdHgTe quantum well heterostructures.

We report stimulated emission in the 2.8-3.5 µm wavelength range from HgTe/CdHgTe quantum well (QW) heterostructures at temperatures available with thermoelectric cooling. The structures were designed to suppress the Auger recombination by implementing narrow (1.5 - 2 nm wide) QWs. We conclude that Peltier cooled operation is feasible in lasers based on such structures, making them of interest for spectroscopy applications in the atmospheric transparency window from 3 to 5 µm.

Human EHMT2/G9a activates p53 through methylation-independent mechanism.

p53 is a critical tumor suppressor in humans. It functions mostly as a transcriptional factor and its activity is regulated by numerous post-translational modifications. Among different covalent modifications found on p53 the most controversial one is lysine methylation. We found that human G9a (hG9a) unlike its mouse orthologue (mG9a) potently stimulated p53 transcriptional activity. Both ectopic and endogenous hG9a augmented p53-dependent transcription of pro-apoptotic genes, including Bax and Puma, resulting in enhanced apoptosis and reduced colony formation. Significantly, shRNA-mediated knockdown of hG9a attenuated p53-dependent activation of Puma. On the molecular level, hG9a interacted with histone acetyltransferase, p300/CBP, resulting in increased histone acetylation at the promoter of Puma. The bioinformatics data substantiated our findings showing that positive correlation between G9a and p53 expression is associated with better survival of lung cancer patients. Collectively, this study demonstrates that depending on the cellular and organismal context, orthologous proteins may exert both overlapping and opposing functions. Furthermore, this finding has important ramifications on the use of G9a inhibitors in combination with genotoxic drugs to treat p53-positive tumors.

The cytoskeleton adaptor protein ankyrin-1 is upregulated by p53 following DNA damage and alters cell migration.

The integrity of the genome is maintained by a host of surveillance and repair mechanisms that are pivotal for cellular function. The tumour suppressor protein p53 is a major component of the DNA damage response pathway and plays a vital role in the maintenance of cell-cycle checkpoints. Here we show that a microRNA, miR-486, and its host gene ankyrin-1 (ANK1) are induced by p53 following DNA damage. Strikingly, the cytoskeleton adaptor protein ankyrin-1 was induced over 80-fold following DNA damage. ANK1 is upregulated in response to a variety of DNA damage agents in a range of cell types. We demonstrate that miR-486-5p is involved in controlling G1/S transition following DNA damage, whereas the induction of the ankyrin-1 protein alters the structure of the actin cytoskeleton and sustains limited cell migration during DNA damage. Importantly, we found that higher ANK1 expression correlates with decreased survival in cancer patients. Thus, these observations highlight ANK1 as an important effector downstream of the p53 pathway.

p53MutaGene: an online tool to estimate the effect of p53 mutational status on gene regulation in cancer.

p53MutaGene is the first online tool for statistical validation of hypotheses regarding the effect of p53 mutational status on gene regulation in cancer. This tool is based on several large-scale clinical gene expression data sets and currently covers breast, colon and lung cancers. The tool detects differential co-expression patterns in expression data between p53 mutated versus p53 normal samples for the user-specified genes. Statistically significant differential co-expression for a gene pair is indicative that regulation of two genes is sensitive to the presence of p53 mutations. p53MutaGene can be used in 'single mode' where the user can test a specific pair of genes or in 'discovery mode' designed for analysis of several genes. Using several examples, we demonstrate that p53MutaGene is a useful tool for fast statistical validation in clinical data of p53-dependent gene regulation patterns. The tool is freely available at http://www.bioprofiling.de/tp53.

Molecular profiling reveals primary mesothelioma cell lines recapitulate human disease.

Malignant mesothelioma (MM) is an aggressive, fatal tumor strongly associated with asbestos exposure. There is an urgent need to improve MM patient outcomes and this requires functionally validated pre-clinical models. Mesothelioma-derived cell lines provide an essential and relatively robust tool and remain among the most widely used systems for candidate drug evaluation. Although a number of cell lines are commercially available, a detailed comparison of these commercial lines with freshly derived primary tumor cells to validate their suitability as pre-clinical models is lacking. To address this, patient-derived primary mesothelioma cell lines were established and characterized using complementary multidisciplinary approaches and bioinformatic analysis. Clinical markers of mesothelioma, transcriptional and metabolic profiles, as well as the status of p53 and the tumor suppressor genes CDKN2A and NF2, were examined in primary cell lines and in two widely used commercial lines. Expression of MM-associated markers, as well as the status of CDKN2A, NF2, the 'gatekeeper' in MM development, and their products demonstrated that primary cell lines are more representative of the tumor close to its native state and show a degree of molecular diversity, thus capturing the disease heterogeneity in a patient cohort. Molecular profiling revealed a significantly different transcriptome and marked metabolic shift towards a greater glycolytic phenotype in commercial compared with primary cell lines. Our results highlight that multiple, appropriately characterised, patient-derived tumor cell lines are required to enable concurrent evaluation of molecular profiles versus drug response. Furthermore, application of this approach to other difficult-to-treat tumors would generate improved cellular models for pre-clinical evaluation of novel targeted therapies.

KMTase Set7/9 is a critical regulator of E2F1 activity upon genotoxic stress.

During the recent years lysine methyltransferase Set7/9 ((Su(var)-3-9, Enhancer-of-Zeste, Trithorax) domain containing protein 7/9) has emerged as an important regulator of different transcription factors. In this study, we report a novel function for Set7/9 as a critical co-activator of E2 promoter-binding factor 1 (E2F1)-dependent transcription in response to DNA damage. By means of various biochemical, cell biology, and bioinformatics approaches, we uncovered that cell-cycle progression through the G1/S checkpoint of tumour cells upon DNA damage is defined by the threshold of expression of both E2F1 and Set7/9. The latter affects the activity of E2F1 by indirectly modulating histone modifications in the promoters of E2F1-dependent genes. Moreover, Set7/9 differentially affects E2F1 transcription targets: it promotes cell proliferation via expression of the CCNE1 gene and represses apoptosis by inhibiting the TP73 gene. Our biochemical screening of the panel of lung tumour cell lines suggests that these two factors are critically important for transcriptional upregulation of the CCNE1 gene product and hence successful progression through cell cycle. These findings identify Set7/9 as a potential biomarker in tumour cells with overexpressed E2F1 activity.

DRUGSURV: a resource for repositioning of approved and experimental drugs in oncology based on patient survival information.

The use of existing drugs for new therapeutic applications, commonly referred to as drug repositioning, is a way for fast and cost-efficient drug discovery. Drug repositioning in oncology is commonly initiated by in vitro experimental evidence that a drug exhibits anticancer cytotoxicity. Any independent verification that the observed effects in vitro may be valid in a clinical setting, and that the drug could potentially affect patient survival in vivo is of paramount importance. Despite considerable recent efforts in computational drug repositioning, none of the studies have considered patient survival information in modelling the potential of existing/new drugs in the management of cancer. Therefore, we have developed DRUGSURV; this is the first computational tool to estimate the potential effects of a drug using patient survival information derived from clinical cancer expression data sets. DRUGSURV provides statistical evidence that a drug can affect survival outcome in particular clinical conditions to justify further investigation of the drug anticancer potential and to guide clinical trial design. DRUGSURV covers both approved drugs (∼1700) as well as experimental drugs (∼5000) and is freely available at http://www.bioprofiling.de/drugsurv.

PPISURV: a novel bioinformatics tool for uncovering the hidden role of specific genes in cancer survival outcome.

Multiple clinical studies have correlated gene expression with survival outcome in cancer on a genome-wide scale. However, in many cases, no obvious correlation between expression of well-known tumour-related genes (that is, p53, p73 and p21) and survival rates of patients has been observed. This can be mainly explained by the complex molecular mechanisms involved in cancer, which mask the clinical relevance of a gene with multiple functions if only gene expression status is considered. As we demonstrate here, in many such cases, the expression of the gene interaction partners (gene 'interactome') correlates significantly with cancer survival and is indicative of the role of that gene in cancer. On the basis of this principle, we have implemented a free online datamining tool (http://www.bioprofiling.de/PPISURV). PPISURV automatically correlates expression of an input gene interactome with survival rates on >40 publicly available clinical expression data sets covering various tumours involving about 8000 patients in total. To derive the query gene interactome, PPISURV employs several public databases including protein-protein interactions, regulatory and signalling pathways and protein post-translational modifications.

p73 regulates serine biosynthesis in cancer.

Activation of serine biosynthesis supports growth and proliferation of cancer cells. Human cancers often exhibit overexpression of phosphoglycerate dehydrogenase (PHGDH), the metabolic enzyme that catalyses the reaction that diverts serine biosynthesis from the glycolytic pathway. By refueling serine biosynthetic pathways, cancer cells sustain their metabolic requirements, promoting macromolecule synthesis, anaplerotic flux and ATP. Serine biosynthesis intersects glutaminolysis and together with this pathway provides substrates for production of antioxidant GSH. In human lung adenocarcinomas we identified a correlation between serine biosynthetic pathway and p73 expression. Metabolic profiling of human cancer cell line revealed that TAp73 activates serine biosynthesis, resulting in increased intracellular levels of serine and glycine, associated to accumulation of glutamate, tricarboxylic acid (TCA) anaplerotic intermediates and GSH. However, at molecular level p73 does not directly regulate serine metabolic enzymes, but transcriptionally controls a key enzyme of glutaminolysis, glutaminase-2 (GLS-2). p73, through GLS-2, favors conversion of glutamine in glutamate, which in turn drives the serine biosynthetic pathway. Serine and glutamate can be then employed for GSH synthesis, thus the p73-dependent metabolic switch enables potential response against oxidative stress. In knockdown experiment, indeed, TAp73 depletion completely abrogates cancer cell proliferation capacity in serine/glycine-deprivation, supporting the role of p73 to help cancer cells under metabolic stress. These findings implicate p73 in regulation of cancer metabolism and suggest that TAp73 influences glutamine and serine metabolism, affecting GSH synthesis and determining cancer pathogenesis.

miR-16 and miR-26a target checkpoint kinases Wee1 and Chk1 in response to p53 activation by genotoxic stress.

The tumour suppressor p53 is a crucial regulator of cell cycle arrest and apoptosis by acting as a transcription factor to regulate a variety of genes. At least in part, this control is exerted by p53 via regulating expression of numerous microRNAs. We identified two abundantly expressed microRNAs, miR-16 and miR-26a, whose expression is regulated by p53 during the checkpoint arrest induced by the genotoxic drug, doxorubicin. Importantly, among the targets of these miRs are two critical checkpoint kinases, Chk1 and Wee1. The p53-dependent augmentation of miR-16 and miR-26a expression levels led to the cell cycle arrest of tumour cells in G1/S and increased apoptosis. Strikingly, the bioinformatics analysis of survival times for patients with breast and prostate cancers has revealed that co-expression of mir-16 and miR-26a correlated with a better survival outcome. Collectively, our data provide a novel mechanism whereby p53 represses Chk1 and Wee1 expression, at least partially, via upregulation of miR-16 and miR-26a and thus sensitizes tumour cells to genotoxic therapies.

[Decision on the rational algorithm in treatment of kidney cysts].

The article presents an algorithm of diagnostics and treatment of renal cysts and other liquid neoplasms of the retroperitoneal space on an analysis of 270 case histories. The algorithm takes into account the achievements of modern medical technologies developed in the recent years. The application of the proposed algorithm must elevate efficiency of the diagnosis and quality of treatment of patients with renal cysts.

[Nephrectomy by an endovideosurgical access].

The results of nephrectomy for hydronephrosis and arteriolosclerotic kidney performed by open (30), laparoscopic (22) and lumboscopic (27) accesses were compared. The advantages of the endovideosurgical method of operation were statistically proved by the indices of invasiveness of surgery. No difference between the transperitoneal and retroperitoneal accesses in nephrectomy was found.

[Assessment of a risk to health as a way of reducing congenital and hereditary pathology in children].

Based on the data available in the literature and his own findings, the author determines the urgency of study of environment-dependent diseases in a poor ecological area. The analytical survey presents data available about the ecological situation in the town of Omsk, a center of chemical and oil-refining industries of Western Siberia from 1997 to 2003. Particular emphasis is laid on a child's responses to the combined exposure to unfavorable environmental factors. The signs characterizing ecopathology are considered and the main principles of the treatment and prevention of environment-dependent diseases are given.

[Gene typing of infectious tularemia strains isolated from the Stavropol and Krasnodar Territories]. / Genotipirovanie shtammov vozbutelia tuliaremii, vydelennykh na territoriiakh Stavropol'skogo i Krasnodarskogo Kraev.

The typing of F. tularensis strains by four variable number of tandem repeats (VNTR) loci has been carried out. Among the strains isolated in the Stavropol and Krasnodar Territories seven genotypes have been detected and their spread in different natural foci has been analyzed. The data thus obtained suggest that the VNTR analysis may become an important instrument for studying the structure of the natural foci of tularemia and evolutionary relationships between individual areas of these foci.

[Results of the bacteriological work of the specialized epidemic brigade of the Stavropol Research Institute for Plaque Control]. / Osnovnye itogi bakteriologicheskoi raboty spetsializirovannoi protivoépidemicheskoi brigady Stavropol'skogo Nauchno-Issledovatel'skogo Protivochumnogo Instituta.

The experience of use of efforts and resources by the bacteriological section of the specialized antiepidemic brigade of the Stavropol Research Institute for Plague Control in the Chechen Republic during the period of 1999-2000 under the conditions of the emergency situation, formed as the consequence of carrying out the antiterrorist operation, is summarized. The work load falling of the bacteriological section in different shifts, the structure of bacteriological investigations, as well as some problems arising in the process of work, were analyzed. The experience showed the necessity of the complete accommodation of the bacteriological laboratory in specialized motor-vehicle modules having all necessary equipment for investigation works, disinfection, sterilization. The brigade sent to its mission should be given concrete tasks with a view to ensure the adequate supply of the bacteriological section with diagnostic preparations, materials and equipment.

[The connection of adrenal function to nutritional factors and milk productivity in ruminant animals]. / Sviaz' funktsii nadpochechnikov s faktorami pitaniia i molochnoi produktivnost'iu u zhvachnykh zhivotnykh.

In this paper the literature and experimental data about ruminant's adrenal function in the connect with feeding level, ration structure and lactation are generalized and systematized. It is shown, that the adrenal secretion and either glucocorticoid, or katecholamine metabolism can be changed in the dependence on the alimentary factors. When the animals feeding is not adequate physiologically, increased cortisol secretion is necessary for supporting of glucose level in the normal value, what leads to increased loading to the adrenal cortex and is accompanied by redistribution of this hormone between plasma and erythrocytes. The hypothesis explaining the received results is advanced. The ability of the endocrine indexes utilization for the estimation of physiological adequately of rations is discussed. The role of adrenal hormones in the regulation of the mammary gland supplying with the milk precursors, and the mechanisms of these hormones action (either positive, or negative) to the organism lactation function are studying.