Synthesis of new derivants 11h-indeno[1,2-b] - quinoxaline as perspective inhibitors of JNK (C-Jun n-terminalnal kinase)

Various quinoxalines show biological activity and have such properties as antiviral, antibacterial, antimicrobial, anti-inflammatory, anticancer, antidepressant, vermicidal, and act as inhibitors of kinases [1]. JNK family enzymes (C-Jun N-terminal kinase) are involved in an embryonal heart development, a regulation of metabolism and normal functioning of a myocardium. Besides, they play an important role in the signaling pathways which lead to apoptosis and necrosis and, also, they regulate processes by which damage of brain neurons and cardiomyocytes during ischemia are depended on. In this regard, the development of specific inhibitors of JNK is a relevant objective of medical chemistry. Derivants with 11H-indeno[1,2-b]-quinoxaline system are described in literature, but there is not a lot of them. For example, it is known only 45 replaced (generally - methyl, nitro - alkoxy-, carboxyl groups) 11Hindeno[1,2-b]- quinoxaline-11-ones according to Reaxys base. For some of them provided data about inhibition of enzymes (glucosidase, SYK kinase) anticarcinogenic activity. Someone systematic researches on influence of the nature of the substituting group on activity and bioavailability of 11H-indeno [1,2-b]- quinoxalines are still unknown of carrying out. The expected results are urgent to from the fundamental and practical point of view. Methods of synthesis of new derivants of 11H-indeno[1,2-b] -quinoxaline will be developed, which will make a contribution to chemistry of the condensed heterocyclic systems. The obtained data will make a contribution to rational design of medicines for treatment of these diseases. Existence in synthesizable molecules of ionizable and biocompatible group does them by potentially more bioavailable and will give an opportunity for creation on their basis of pharmaceuticals

Исследование коррозионных свойств биосовместимых покрытий на основе титана, осажденных методом реактивного магнетронного распыления

В работе изучались свойства Ti-O-N покрытий, нанесенных на стальные подложки методом реактивного магнетронного напыления, такие как коррозионная стойкость, термическая устойчивость, а так же диффузионные процессы в физиологических растворах. Методами инфракрасной спектроскопии и атомно-эмиссионного анализа была установлена химическая инертность пленки, а так же потенциальная биологическая активность в виду обнаружения оксида азота в модельных растворах после контакта с покрытиями Ti-O-N.The properties of Ti-O-N coatings deposited on steel substrates by the method of reactive magnetron sputtering, such as corrosion resistance, thermal stability, as well as diffusion processes in physiological solutions were studied. By the methods of infrared spectroscopy and atomic emission analysis, the chemical inertness of the film was established, as well as the potential biological activity in the form of detection of nitrogen oxide in model solutions after contact with Ti-O-N coatings

Molecular profiling of signet ring cell colorectal cancer provides a strong rationale for genomic targeted and immune checkpoint inhibitor therapies

We would like to thank all patients whose samples were used in this study. We are also thankful to the Northern Ireland Biobank and Grampian Biorepository for providing us with tissue blocks and patient data; and Dr HG Coleman (Queen’s University Belfast) for her advice on statistical analyses. This work has been carried out with financial support from Cancer Research UK (grant: C11512/A18067), Experimental Cancer Medicine Centre Network (grant: C36697/A15590 from Cancer Research UK and the NI Health and Social Care Research and Development Division), the Sean Crummey Memorial Fund and the Tom Simms Memorial Fund. The Northern Ireland Biobank is funded by HSC Research and Development Division of the Public Health Agency in Northern Ireland and Cancer Research UK through the Belfast CRUK Centre and the Northern Ireland Experimental Cancer Medicine Centre; additional support was received from Friends of the Cancer Centre. The Northern Ireland Molecular Pathology Laboratory which is responsible for creating resources for the Northern Ireland Biobank has received funding from Cancer Research UK, Friends of the Cancer Centre and Sean Crummey Foundation.Peer reviewedPublisher PD

Entry, Exit, and the Determinants of Market Structure

This paper estimates a dynamic, structural model of entry and exit in an oligopolistic industry and uses it to quantify the determinants of market structure and long-run firm values for two U.S. service industries, dentists and chiropractors. Entry costs faced by potential entrants, fixed costs faced by incumbent producers, and the toughness of short-run price competition are all found to be important determinants of long-run firm values, firm turnover, and market structure. Estimates for the dentist industry allow the entry cost to differ for geographic markets that were designated as Health Professional Shortage Areas and in which entry was subsidized. The estimated mean entry cost is 11 percent lower in these markets. Using simulations, we compare entry-cost versus fixed-cost subsidies and find that entry-cost subsidies are less expensive per additional firm

Tele-branding in TVIII: the network as brand and the programme as brand

In the era of TVIII, characterized by deregulation, multimedia conglomeration, expansion and increased competition, branding has emerged as a central industrial practice. Focusing on the case of HBO, a particularly successful brand in TVIII, this article argues that branding can be understood not simply as a feature of television networks, but also as a characteristic of television programmes. It begins by examining how the network as brand is constructed and conveyed to the consumer through the use of logos, slogans and programmes. The role of programmes in the construction of brand identity is then complicated by examining the sale of programmes abroad, where programmes can be seen to contribute to the brand identity of more than one network. The article then goes on to examine programme merchandising, an increasingly central strategy in TVIII. Through an analysis of different merchandising strategies the article argues that programmes have come to act as brands in their own right, and demonstrates that the academic study of branding not only reveals the development of new industrial practices, but also offers a way of understanding the television programme and its consumption by viewers in a period when the texts of television are increasingly extended across a range of media platforms

Biological Misinterpretation of Transcriptional Signatures in Tumor Samples Can Unknowingly Undermine Mechanistic Understanding and Faithful Alignment with Preclinical Data

PURPOSE Precise mechanism-based gene expression signatures (GES) have been developed in appropriate in vitro and in vivo model systems, to identify important cancer-related signaling processes. However, some GESs originally developed to represent specific disease processes, primarily with an epithelial cell focus, are being applied to heterogeneous tumor samples where the expression of the genes in the signature may no longer be epithelial-specific. Therefore, unknowingly, even small changes in tumor stroma percentage can directly influence GESs, undermining the intended mechanistic signaling. EXPERIMENTAL DESIGN Using colorectal cancer as an exemplar, we deployed numerous orthogonal profiling methodologies, including laser capture microdissection, flow cytometry, bulk and multiregional biopsy clinical samples, single-cell RNA sequencing and finally spatial transcriptomics, to perform a comprehensive assessment of the potential for the most widely used GESs to be influenced, or confounded, by stromal content in tumor tissue. To complement this work, we generated a freely-available resource, ConfoundR; https://confoundr.qub.ac.uk/, that enables users to test the extent of stromal influence on an unlimited number of the genes/signatures simultaneously across colorectal, breast, pancreatic, ovarian and prostate cancer datasets. RESULTS Findings presented here demonstrate the clear potential for misinterpretation of the meaning of GESs, due to widespread stromal influences, which in-turn can undermine faithful alignment between clinical samples and preclinical data/models, particularly cell lines and organoids, or tumor models not fully recapitulating the stromal and immune microenvironment. CONCLUSIONS Efforts to faithfully align preclinical models of disease using phenotypically-designed GESs must ensure that the signatures themselves remain representative of the same biology when applied to clinical samples

All grown up? The fate after 15 years of a quarter of a million UK firms born in 1998

The theory of firm growth is in a rather unsatisfactory state. However, the analysis of large firm-level datasets which have become available in recent years allows us to begin building an evidence base which can, in turn, be used to underpin the development of more satisfactory theory. Here we study the 239 thousand UK private sector firms born in 1998 over their first 15 years of life. A first, and quite striking, finding is the extraordinary force of mortality. By age 15, 90% of the UK firms born in 1998 are dead, and, for those surviving to age 15, the hazard of death is still about 10% a year. The chance of death is related to the size and growth of firms in an interesting way. Whilst the hazard rate after 15 years is largely independent of size at birth, it is strongly affected by the current (age 14) size. In particular, firms with more than five employees are half as likely to die in the next year as firms with less than five employees. A second important finding is that most firms, even those which survive to age 15, do not grow very much. By age 15 more than half the 26,000 survivors still have less than five jobs. In other words, the growth paths – what we call the ‘growth trajectories’ – of most of the 26,000 survivors are pretty flat. However, of the firms that do grow, firms born smaller grow faster than those born larger. Another striking finding is that growth is heavily concentrated in the first five years. Whilst growth does continue, even up to age 15, each year after age five it involves only a relatively small proportion of firms. Finally, there are two groups of survivors which contribute importantly to job creation. Some are those born relatively large (with more than 20 jobs) although their growth rate is quite modest. More striking though, is a very small group of firms born very small with less than five jobs (about 5% of all survivors) which contribute a substantial proportion (more than one third) of the jobs added to the cohort total by age 15

Risk factor screening to identify women requiring oral glucose tolerance testing to diagnose gestational diabetes : a systematic review and meta-analysis and analysis of two pregnancy cohorts

BACKGROUND: Easily identifiable risk factors including: obesity and ethnicity at high risk of diabetes are commonly used to indicate which women should be offered the oral glucose tolerance test (OGTT) to diagnose gestational diabetes (GDM). Evidence regarding these risk factors is limited however. We conducted a systematic review (SR) and meta-analysis and individual participant data (IPD) analysis to evaluate the performance of risk factors in identifying women with GDM. METHODS: We searched MEDLINE, Medline in Process, Embase, Maternity and Infant Care and the Cochrane Central Register of Controlled Trials (CENTRAL) up to August 2016 and conducted additional reference checking. We included observational, cohort, case-control and cross-sectional studies reporting the performance characteristics of risk factors used to identify women at high risk of GDM. We had access to IPD from the Born in Bradford and Atlantic Diabetes in Pregnancy cohorts, all pregnant women in the two cohorts with data on risk factors and OGTT results were included. RESULTS: Twenty nine published studies with 211,698 women for the SR and a further 14,103 women from two birth cohorts (Born in Bradford and the Atlantic Diabetes in Pregnancy study) for the IPD analysis were included. Six studies assessed the screening performance of guidelines; six examined combinations of risk factors; eight evaluated the number of risk factors and nine examined prediction models or scores. Meta-analysis using data from published studies suggests that irrespective of the method used, risk factors do not identify women with GDM well. Using IPD and combining risk factors to produce the highest sensitivities, results in low specificities (and so higher false positives). Strategies that use the risk factors of age (>25 or >30) and BMI (>25 or 30) perform as well as other strategies with additional risk factors included. CONCLUSIONS: Risk factor screening methods are poor predictors of which pregnant women will be diagnosed with GDM. A simple approach of offering an OGTT to women 25 years or older and/or with a BMI of 25kg/m2 or more is as good as more complex risk prediction models. Research to identify more accurate (bio)markers is needed. Systematic Review Registration: PROSPERO CRD42013004608