Phase I pharmacokinetic and pharmacodynamic study of the prenyl transferase inhibitor AZD3409 in patients with advanced cancer

AZD3409 is an orally active double prodrug that was developed as a novel dual prenyltransferase inhibitor. The formation of the active metabolite AZD3409 acid is mediated by esterases in plasma and cells. The aim of this phase I study was to determine the maximum tolerated dose, toxicities, pharmacokinetics and pharmacodynamics of AZD3409. AZD3409 was administered orally to patients with advanced solid malignancies using an interpatient dose-escalation scheme starting at 500 mg AZD3409 once daily. Twenty-nine patients were treated at seven dose levels. The MTD of part A was defined as 750 mg b.i.d. in the fasted state. Adverse events were mainly gastrointestinal and the severity was on average mild to moderate and reversible. The dose-limiting toxicities were vomiting, diarrhoea and uncontrolled nausea. Pharmacokinetic studies of the prodrug and the active metabolite indicated dose proportionality. Pharmacodynamic studies showed that farnesyltransferase (FTase) was inhibited at all dose levels. In conclusion, chronic oral dosing with AZD3409 is feasible and results in significant inhibition of FTase activity. Pharmacodynamic studies revealed that the maximal FTase inhibition, estimated at 49±11%, appeared to be reached at AZD3409 acid plasma concentrations at which the occurrence of drug-related toxicity was low. This study supports the rationale to implement biological effect studies in clinical trials with biologically active anticancer drugs to define optimal dosing regimens

Psychosocial factors during the first year after a coronary heart disease event in cases and referents. Secondary Prevention in Uppsala Primary Health Care Project (SUPRIM)

<p>Abstract</p> <p>Background</p> <p>A large number of studies have reported on the psychosocial risk factor pattern prior to coronary heart disease events, but few have investigated the situation during the first year after an event, and none has been controlled. We therefore performed a case-referent study in which the prevalence of a number of psychosocial factors was evaluated.</p> <p>Methods</p> <p>Three hundred and forty-six coronary heart disease male and female cases no more than 75 years of age, discharged from hospital within the past 12 months, and 1038 referents from the general population, matched to the cases by age, sex and place of living, received a postal questionnaire in which information on lifestyle, psychosocial and quality of life measures were sought.</p> <p>Results</p> <p>The cases were, as expected, on sick leave to a larger extent than the referents, reported poorer fitness, poorer perceived health, fewer leisure time activities, but unexpectedly reported better social support, and more optimistic views of the future than the referents. There were no significant case-referent differences in everyday life stress, stressful life events, vital exhaustion, depressive mood, coping or life orientation test. However, women reported less favourable situations than men regarding stressful life events affecting others, vital exhaustion, depressive mood, coping, self-esteem, sleep, and symptom reporting, and female cases reported the most unfavourable situation of all groups.</p> <p>Conclusion</p> <p>In this first controlled study of the situation during the first year after a CHD event disease and gender status both appeared to be determinants of psychological well-being, with gender status apparently the strongest. This may have implications for cardiac rehabilitation programmes.</p

Microbial catabolic activities are naturally selected by metabolic energy harvest rate

The fundamental trade-off between yield and rate of energy harvest per unit of substrate has been largely discussed as a main characteristic for microbial established cooperation or competition. In this study, this point is addressed by developing a generalized model that simulates competition between existing and not experimentally reported microbial catabolic activities defined only based on well-known biochemical pathways. No specific microbial physiological adaptations are considered, growth yield is calculated coupled to catabolism energetics and a common maximum biomass-specific catabolism rate (expressed as electron transfer rate) is assumed for all microbial groups. Under this approach, successful microbial metabolisms are predicted in line with experimental observations under the hypothesis of maximum energy harvest rate. Two microbial ecosystems, typically found in wastewater treatment plants, are simulated, namely: (i) the anaerobic fermentation of glucose and (ii) the oxidation and reduction of nitrogen under aerobic autotrophic (nitrification) and anoxic heterotrophic and autotrophic (denitrification) conditions. The experimentally observed cross feeding in glucose fermentation, through multiple intermediate fermentation pathways, towards ultimately methane and carbon dioxide is predicted. Analogously, two-stage nitrification (by ammonium and nitrite oxidizers) is predicted as prevailing over nitrification in one stage. Conversely, denitrification is predicted in one stage (by denitrifiers) as well as anammox (anaerobic ammonium oxidation). The model results suggest that these observations are a direct consequence of the different energy yields per electron transferred at the different steps of the pathways. Overall, our results theoretically support the hypothesis that successful microbial catabolic activities are selected by an overall maximum energy harvest rate

Genetics of Type A Behavior in Two European Countries: Evidence for Sibling Interaction

Young male twins in The Netherlands and England completed the Jenkins Activity Survey (Dutch and English versions, respectively), a measure of Type A behavior. Separate model fitting analysis revealed a similar pattern of variance estimates and associated goodness of fit across the two countries. The data were then analyzed concurrently, with a scalar parameter included to account for differences in variance due to the disparity of the measurement scales. A model including additive genetic and individual environmental effects gave a good explanation to the data. The heritability estimate was 0.28. Models of social interaction and dominance explained the data even better, the former being preferred. The twins' parents were included in the analysis to examine population variation for Type A behavior intergenerationally. There was evidence for individual environmental experiences having a greater influence on Type A behavior in the older generation. © 1991 Plenum Publishing Corporation

Capturing wheat phenotypes at the genome level

Recent technological advances in next-generation sequencing (NGS) technologies have dramatically reduced the cost of DNA sequencing, allowing species with large and complex genomes to be sequenced. Although bread wheat (Triticum aestivum L.) is one of the world’s most important food crops, efficient exploitation of molecular marker-assisted breeding approaches has lagged behind that achieved in other crop species, due to its large polyploid genome. However, an international public–private effort spanning 9 years reported over 65% draft genome of bread wheat in 2014, and finally, after more than a decade culminated in the release of a gold-standard, fully annotated reference wheat-genome assembly in 2018. Shortly thereafter, in 2020, the genome of assemblies of additional 15 global wheat accessions was released. As a result, wheat has now entered into the pan-genomic era, where basic resources can be efficiently exploited. Wheat genotyping with a few hundred markers has been replaced by genotyping arrays, capable of characterizing hundreds of wheat lines, using thousands of markers, providing fast, relatively inexpensive, and reliable data for exploitation in wheat breeding. These advances have opened up new opportunities for marker-assisted selection (MAS) and genomic selection (GS) in wheat. Herein, we review the advances and perspectives in wheat genetics and genomics, with a focus on key traits, including grain yield, yield-related traits, end-use quality, and resistance to biotic and abiotic stresses. We also focus on reported candidate genes cloned and linked to traits of interest. Furthermore, we report on the improvement in the aforementioned quantitative traits, through the use of (i) clustered regularly interspaced short-palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated gene-editing and (ii) positional cloning methods, and of genomic selection. Finally, we examine the utilization of genomics for the next-generation wheat breeding, providing a practical example of using in silico bioinformatics tools that are based on the wheat reference-genome sequence

Alendronate Inhibits VEGF Expression in Growth Plate Chondrocytes by Acting on the Mevalonate Pathway

Bisphosphonates decrease chondrocyte turnover at the growth plate and impact bone growth. Likewise vascular endothelial growth factor (VEGF) plays an important role in endochondral bone elongation by influencing chondrocyte turnover at the growth plate. To investigate whether the action of bisphosphonate on the growth plate works through VEGF, VEGF protein expression and isoform transcription in endochondral chondrocytes isolated from growing mice and treated with a clinically used bisphosphonate, alendronate, were assessed. Alendronate at 10µM and 100µM concentrations decreased secreted VEGF protein expression but not cell associated protein. Bisphosphonates are known to inhibit the mevalonate intracellular signaling pathway used by VEGF. Addition of the mevalonate pathway intermediates farnesol (FOH) and geranylgeraniol (GGOH) interacted with the low concentration of alendronate to further decrease secreted VEGF protein whereas FOH partially restored VEGF protein secretion when combined with the high alendronate. Similar to the protein data, the addition of alendronate decreased VEGF mRNA isoforms. VEGF mRNA levels were rescued by the GGOH mevalonate pathway intermediate at the low alendronate dose whereas neither intermediate consistently restored the VEGF mRNA levels at the high alendronate dose. Thus, the bisphophonate alendronate impairs growth plate chondrocyte turnover by down-regulating the secreted forms of VEGF mRNA and protein by inhibiting the mevalonate pathway

Where’s WALY? : A proof of concept study of the ‘wellbeing adjusted life year’ using secondary analysis of cross-sectional survey data

Background The Quality-Adjusted Life Year (QALY) is a measure that combines life extension and health improvement in a single score, reflecting preferences around different types of health gain. It can therefore be used to inform decision-making around allocation of health care resources to mutually exclusive options that would produce qualitatively different health benefits. A number of quality-of-life instruments can be used to calculate QALYs. The EQ-5D is one of the most commonly used, and is the preferred option for submissions to NICE (https://www.nice.org.uk/process/pmg9/). However, it has limitations that might make it unsuitable for use in areas such as public and mental health where interventions may aim to improve well-being. One alternative to the QALY is a Wellbeing-Adjusted Life Year. In this study we explore the need for a Wellbeing-Adjusted Life Year measure by examining the extent to which a measure of wellbeing (the Warwick-Edinburgh Mental Well-being Scale) maps onto the EQ-5D-3L. Methods Secondary analyses were conducted on data from the Coventry Household Survey in which 7469 participants completed the EQ-5D-3L, Warwick-Edinburgh Mental Well-being Scale, and a measure of self-rated health. Data were analysed using descriptive statistics, Pearson’s and Spearman’s correlations, linear regression, and receiver operating characteristic curves. Results Approximately 75 % of participants scored the maximum on the EQ-5D-3L. Those with maximum EQ-5D-3L scores reported a wide range of levels of mental wellbeing. Both the Warwick-Edinburgh Mental Well-being Scale and the EQ-5D-3L were able to detect differences between those with higher and lower levels of self-reported health. Linear regression indicated that scores on the Warwick-Edinburgh Mental Well-being Scale and the EQ-5D-3L were weakly, positively correlated (with R2 being 0.104 for the index and 0.141 for the visual analogue scale). Conclusion The Warwick-Edinburgh Mental Well-being Scale maps onto the EQ-5D-3L to only a limited extent. Levels of mental wellbeing varied greatly amongst participants who had the maximum score on the EQ-5D-3L. To evaluate the relative effectiveness of interventions that impact on mental wellbeing, a new measure – a Wellbeing Adjusted Life Year – is needed

Entrepreneurs’ achieved success: developing a multi-faceted measure

Firm performance is typically measured via objective financial indicators. However, researchers increasingly acknowledge that entrepreneurs do not measure their success solely in financial terms but that a range of often subjective indicators matter to them. This article contributes to the debate on entrepreneurial performance by studying how entrepreneurs assess their achieved success. ‘Entrepreneurs’ achieved success’ was conceptualized as a multi-faceted construct that includes entrepreneurs’ self-reported achievement of firm performance, workplace relationships, personal fulfilment, community impact, and personal financial rewards. It was measured via the Subjective Entrepreneurial Success–Achievement Scale (SES-AS). Over the course of three studies (N = 390) the factorial structure of ‘entrepreneurs’ achieved success’ was established and largely replicated in two cultures. Based on a nomological network, we documented relationships among ‘entrepreneurs’ achieved success’, quasi-objective indicators of firm performance, and entrepreneurs’ financial satisfaction, creativity, and health. Based on our research, we propose a new conceptual framework to study performance in the context of entrepreneurship. This framework acknowledges both the success criteria that entrepreneurs wish to achieve and those that they actually achieve, and extends our understanding of firm performance

Clinical trials update: endocrine and biological therapy combinations in the treatment of breast cancer

A greater understanding of the biological mechanisms responsible for de novo and acquired endocrine resistance has led to the rational design of clinical trials exploring the benefit of combining hormonal therapies with novel biological agents in an effort to enhance the efficacy of ER+ breast cancer treatment. These studies are increasingly including parallel biological analyses to elucidate the molecular characteristics of those tumors that are most likely to respond to specific targeted/endocrine combinations in an effort to develop a tailored approach to the management of individual patients. Unfortunately despite encouraging preclinical data, some of these combinations have yielded disappointing results in the clinical setting. This article will review the results of clinical trials of endocrine/biological combinations conducted in early and advanced breast cancer as well as provide an update on ongoing studies

New Insights into the Organization, Recombination, Expression and Functional Mechanism of Low Molecular Weight Glutenin Subunit Genes in Bread Wheat

The bread-making quality of wheat is strongly influenced by multiple low molecular weight glutenin subunit (LMW-GS) proteins expressed in the seeds. However, the organization, recombination and expression of LMW-GS genes and their functional mechanism in bread-making are not well understood. Here we report a systematic molecular analysis of LMW-GS genes located at the orthologous Glu-3 loci (Glu-A3, B3 and D3) of bread wheat using complementary approaches (genome wide characterization of gene members, expression profiling, proteomic analysis). Fourteen unique LMW-GS genes were identified for Xiaoyan 54 (with superior bread-making quality). Molecular mapping and recombination analyses revealed that the three Glu-3 loci of Xiaoyan 54 harbored dissimilar numbers of LMW-GS genes and covered different genetic distances. The number of expressed LMW-GS in the seeds was higher in Xiaoyan 54 than in Jing 411 (with relatively poor bread-making quality). This correlated with the finding of higher numbers of active LMW-GS genes at the A3 and D3 loci in Xiaoyan 54. Association analysis using recombinant inbred lines suggested that positive interactions, conferred by genetic combinations of the Glu-3 locus alleles with more numerous active LMW-GS genes, were generally important for the recombinant progenies to attain high Zeleny sedimentation value (ZSV), an important indicator of bread-making quality. A higher number of active LMW-GS genes tended to lead to a more elevated ZSV, although this tendency was influenced by genetic background. This work provides substantial new insights into the genomic organization and expression of LMW-GS genes, and molecular genetic evidence suggesting that these genes contribute quantitatively to bread-making quality in hexaploid wheat. Our analysis also indicates that selection for high numbers of active LMW-GS genes can be used for improvement of bread-making quality in wheat breeding