CDK1 is a synthetic lethal target for KRAS mutant tumours.

Activating KRAS mutations are found in approximately 20% of human cancers but no RAS-directed therapies are currently available. Here we describe a novel, robust, KRAS synthetic lethal interaction with the cyclin dependent kinase, CDK1. This was discovered using parallel siRNA screens in KRAS mutant and wild type colorectal isogenic tumour cells and subsequently validated in a genetically diverse panel of 26 colorectal and pancreatic tumour cell models. This established that the KRAS/CDK1 synthetic lethality applies in tumour cells with either amino acid position 12 (p.G12V, pG12D, p.G12S) or amino acid position 13 (p.G13D) KRAS mutations and can also be replicated in vivo in a xenograft model using a small molecule CDK1 inhibitor. Mechanistically, CDK1 inhibition caused a reduction in the S-phase fraction of KRAS mutant cells, an effect also characterised by modulation of Rb, a master control of the G1/S checkpoint. Taken together, these observations suggest that the KRAS/CDK1 interaction is a robust synthetic lethal effect worthy of further investigation

Networks or structures? : organizing cultural routes around heritage values : case studies from Poland

The most common way of managing cultural heritage recently takes form of cultural routes as they seem to offer a new model of participation in culture to their recipients; they are often a peculiar anchor point for inhabitants to let them understand their identity and form the future; they offer actual tours to enter into interaction with culture and history, to build together that creation of the heritage, which so is becoming not only a touristic product, but, first of all, the space for cultural, social and civic activity. Yet, so far, according to what we know, the research problem concerning the method of cultural route organization (points on the route) into solid structures or more of the networked nature, has not been deliberated. A question arises, what values are brought by routes and how to organize routes to be the carriers of the values important for communities, where routes are functioning. And, as a consequence, if, from the point of view of the values of local communities, organizing solid route structures or organizing more widely-spaced, network-based routes would bring effects and what those effects would be. Thus, the posed question is of course scientifically imprecise because a network is a type of structure but presents a given direction for the development of cultural route structures. Our objective here is to present a certain solidity and rigidity of structure with dynamic and smooth understanding of the network. The research presented in the article is based on 3 case studies. We have selected for this purpose the three largest cultural routes in Poland, organized to various degrees. The outcome of the research was referred also to other cultural route organization research

Circulating tumor cells criteria (CyCAR) versus standard RECIST criteria for treatment response assessment in metastatic colorectal cancer patients

The use of circulating tumor cells (CTCs) as indicators of treatment response in metastatic colorectal cancer (mCRC) needs to be clarified. The objective of this study is to compare the Response Evaluation Criteria in Solid Tumors (RECIST) with the Cytologic Criteria Assessing Response (CyCAR), based on the presence and phenotypic characterization of CTCs, as indicators of FOLFOX–bevacizumab treatment response. We observed a decrease of CTCs (42.8 vs. 18.2%) and VEGFR positivity (69.7% vs. 41.7%) after treatment. According to RECIST, 6.45% of the patients did not show any clinical benefit, whereas 93.55% patients showed a favorable response at 12 weeks. According to CyCAR, 29% had a non-favorable response and 71% patients did not. No significant differences were found between the response assessment by RECIST and CyCAR at 12 or 24 weeks. However, in the multivariate analysis, RECIST at 12 weeks and CyCAR at 24 weeks were independent prognostic factors for OS (HR: 0.1, 95% CI 0.02–0.58 and HR: 0.35, 95% CI 0.12–0.99 respectively). CyCAR results were comparable to RECIST in evaluating the response in mCRC and can be used as an alternative when the limitation of RECIST requires additional response analysis techniques.This work was supported by Roche Spain and a Ph.D. grant from the University of Granada

Factors Associated with Height Catch-Up and Catch-Down Growth Among Schoolchildren

In developed countries, children with intrauterine growth restriction (IUGR) or born preterm (PT) tend to achieve catch-up growth. There is little information about height catch-up in developing countries and about height catch-down in both developed and developing countries. We studied the effect of IUGR and PT birth on height catch-up and catch-down growth of children from two cohorts of liveborn singletons. Data from 1,463 children was collected at birth and at school age in Ribeirão Preto (RP), a more developed city, and in São Luís (SL), a less developed city. A change in z-score between schoolchild height z-score and birth length z-score≥0.67 was considered catch-up; a change in z-score≤−0.67 indicated catch-down growth. The explanatory variables were: appropriate weight for gestational age/PT birth in four categories: term children without IUGR (normal), IUGR only (term with IUGR), PT only (preterm without IUGR) and preterm with IUGR; infant's sex; maternal parity, age, schooling and marital status; occupation of family head; family income and neonatal ponderal index (PI). The risk ratio for catch-up and catch-down was estimated by multinomial logistic regression for each city. In RP, preterms without IUGR (RR = 4.13) and thin children (PI<10th percentile, RR = 14.39) had a higher risk of catch-down; catch-up was higher among terms with IUGR (RR = 5.53), preterms with IUGR (RR = 5.36) and children born to primiparous mothers (RR = 1.83). In SL, catch-down was higher among preterms without IUGR (RR = 5.19), girls (RR = 1.52) and children from low-income families (RR = 2.74); the lowest risk of catch-down (RR = 0.27) and the highest risk of catch-up (RR = 3.77) were observed among terms with IUGR. In both cities, terms with IUGR presented height catch-up growth whereas preterms with IUGR only had height catch-up growth in the more affluent setting. Preterms without IUGR presented height catch-down growth, suggesting that a better socioeconomic situation facilitates height catch-up and prevents height catch-down growth

Review of natural fibre-reinforced hybrid composites

Natural fibre-reinforced hybrid composites which contain one or more types of natural reinforcement are gaining increasing research interest. This paper presents a review of natural fibre-reinforced hybrid composites. Both thermoplastic and thermoset composites reinforced by hybrid/synthetic fibres or hybrid/hybrid fibres are reviewed. The properties of natural fibres, the properties and processing of composites are summarised

Tailor-Made Zinc-Finger Transcription Factors Activate FLO11 Gene Expression with Phenotypic Consequences in the Yeast Saccharomyces cerevisiae

Cys2His2 zinc fingers are eukaryotic DNA-binding motifs, capable of distinguishing different DNA sequences, and are suitable for engineering artificial transcription factors. In this work, we used the budding yeast Saccharomyces cerevisiae to study the ability of tailor-made zinc finger proteins to activate the expression of the FLO11 gene, with phenotypic consequences. Two three-finger peptides were identified, recognizing sites from the 5′ UTR of the FLO11 gene with nanomolar DNA-binding affinity. The three-finger domains and their combined six-finger motif, recognizing an 18-bp site, were fused to the activation domain of VP16 or VP64. These transcription factor constructs retained their DNA-binding ability, with the six-finger ones being the highest in affinity. However, when expressed in haploid yeast cells, only one three-finger recombinant transcription factor was able to activate the expression of FLO11 efficiently. Unlike in the wild-type, cells with such transcriptional activation displayed invasive growth and biofilm formation, without any requirement for glucose depletion. The VP16 and VP64 domains appeared to act equally well in the activation of FLO11 expression, with comparable effects in phenotypic alteration. We conclude that the functional activity of tailor-made transcription factors in cells is not easily predicted by the in vitro DNA-binding activity

Instruments to assess the perception of physicians in the decision-making process of specific clinical encounters: a systematic review

<p>Abstract</p> <p>Background</p> <p>The measurement of processes and outcomes that reflect the complexity of the decision-making process within specific clinical encounters is an important area of research to pursue. A systematic review was conducted to identify instruments that assess the perception physicians have of the decision-making process within specific clinical encounters.</p> <p>Methods</p> <p>For every year available up until April 2007, PubMed, PsycINFO, Current Contents, Dissertation Abstracts and Sociological Abstracts were searched for original studies in English or French. Reference lists from retrieved studies were also consulted. Studies were included if they reported a self-administered instrument evaluating physicians' perceptions of the decision-making process within specific clinical encounters, contained sufficient description to permit critical appraisal and presented quantitative results based on administering the instrument. Two individuals independently assessed the eligibility of the instruments and abstracted information on their conceptual underpinnings, main evaluation domain, development, format, reliability, validity and responsiveness. They also assessed the quality of the studies that reported on the development of the instruments with a modified version of STARD.</p> <p>Results</p> <p>Out of 3431 records identified and screened for evaluation, 26 potentially relevant instruments were assessed; 11 met the inclusion criteria. Five instruments were published before 1995. Among those published after 1995, five offered a corresponding patient version. Overall, the main evaluation domains were: satisfaction with the clinical encounter (n = 2), mutual understanding between health professional and patient (n = 2), mental workload (n = 1), frustration with the clinical encounter (n = 1), nurse-physician collaboration (n = 1), perceptions of communication competence (n = 2), degree of comfort with a decision (n = 1) and information on medication (n = 1). For most instruments (n = 10), some reliability and validity criteria were reported in French or English. Overall, the mean number of items on the modified version of STARD was 12.4 (range: 2 to 18).</p> <p>Conclusion</p> <p>This systematic review provides a critical appraisal and repository of instruments that assess the perception physicians have of the decision-making process within specific clinical encounters. More research is needed to pursue the validation of the existing instruments and the development of patient versions. This will help researchers capture the complexity of the decision-making process within specific clinical encounters.</p

The Epistatic Relationship between BRCA2 and the Other RAD51 Mediators in Homologous Recombination

RAD51 recombinase polymerizes at the site of double-strand breaks (DSBs) where it performs DSB repair. The loss of RAD51 causes extensive chromosomal breaks, leading to apoptosis. The polymerization of RAD51 is regulated by a number of RAD51 mediators, such as BRCA1, BRCA2, RAD52, SFR1, SWS1, and the five RAD51 paralogs, including XRCC3. We here show that brca2-null mutant cells were able to proliferate, indicating that RAD51 can perform DSB repair in the absence of BRCA2. We disrupted the BRCA1, RAD52, SFR1, SWS1, and XRCC3 genes in the brca2-null cells. All the resulting double-mutant cells displayed a phenotype that was very similar to that of the brca2-null cells. We suggest that BRCA2 might thus serve as a platform to recruit various RAD51 mediators at the appropriate position at the DNA–damage site

The role of dietary fibre in pig production, with a particular emphasis on reproduction

Abstract Fibres from a variety of sources are a common constituent of pig feeds. They provide a means to utilise locally-produced plant materials which are often a by-product of the food or drink industry. The value of a high fibre diet in terms of producing satiety has long been recognised. However the addition of fibre can reduce feed intake, which is clearly detrimental during stages of the production cycle when nutrient needs are high, for example in growing piglets and during lactation. More recently, fibre has been found to promote novel benefits to pig production systems, particularly given the reduction in antimicrobial use world-wide, concern for the welfare of animals fed a restricted diet and the need to ensure that such systems are more environmentally friendly. For example, inclusion of dietary fibre can alter the gut microbiota in ways that could reduce the need for antibiotics, while controlled addition of certain fibre types may reduce nitrogen losses into the environment and so reduce the environmental cost of pig production. Of particular potential value is the opportunity to use crude fibre concentrates as ‘functional’ feed additives to improve young pig growth and welfare. Perhaps the greatest opportunity for the use of high fibre diets is to improve the reproductive efficiency of pigs. Increased dietary fibre before mating improves oocyte maturation, prenatal survival and litter size; providing a consumer-acceptable means of increasing the amount of saleable meat produced per sow. The mechanisms responsible for these beneficial effects remain to be elucidated. However, changes in plasma and follicular fluid concentrations of key hormones and metabolites, as well as effects of the hypothalamic satiety centre on gonadotrophin secretion and epigenetic effects are strong candidates

Costs Associated with Low Birth Weight in a Rural Area of Southern Mozambique

BACKGROUND: Low Birth Weight (LBW) is prevalent in low-income countries. Even though the economic evaluation of interventions to reduce this burden is essential to guide health policies, data on costs associated with LBW are scarce. This study aims to estimate the costs to the health system and to the household and the Disability Adjusted Life Years (DALYs) arising from infant deaths associated with LBW in Southern Mozambique. METHODS AND FINDINGS: Costs incurred by the households were collected through exit surveys. Health system costs were gathered from data obtained onsite and from published information. DALYs due to death of LBW babies were based on local estimates of prevalence of LBW (12%), very low birth weight (VLBW) (1%) and of case fatality rates compared to non-LBW weight babies [for LBW (12%) and VLBW (80%)]. Costs associated with LBW excess morbidity were calculated on the incremental number of hospital admissions in LBW babies compared to non-LBW weight babies. Direct and indirect household costs for routine health care were 24.12 US$(CI 95$ (CI 95% 6.33; 10.72). Of the 3,322 live births that occurred in one year in the study area, health system costs associated to LBW (routine health care and excess morbidity) and DALYs were 169,957.61 US$ (CI 95% 144,900.00; 195,500.00) and 2,746.06, respectively. CONCLUSIONS: This first cost evaluation of LBW in a low-income country shows that reducing the prevalence of LBW would translate into important cost savings to the health system and the household. These results are of relevance for similar settings and should serve to promote interventions aimed at improving maternal care