ENHANCING DNA-DAMAGING THERAPY THROUGH THE INHIBITION OF DNTP SYNTHESIS USING A SYNERGISTIC DRUG COMBINATION TO TREAT PANCREATIC NEUROENDOCRINE NEOPLASMS

Despite clinical advances, pancreatic neuroendocrine neoplasms (pNEN) remain a difficult clinical entity to treat and can carry a poor prognosis. Systemic therapy is used to treat pNENs which are not amenable to surgical resection. Peptide receptor radionuclide therapy, a form of radiation therapy (RT) and cisplatin are two different forms of DNA-damaging therapy in current use to treat pNENs. However, their efficacy remains poor as single agents. This study aimed to increase the sensitivity of pNENs to the DNA-damaging agents, RT and cisplatin, by inhibiting deoxynucleotide triphosphate (dNTP) synthesis. Triapine, a ribonucleotide reductase inhibitor (RNRi), and ataxia telangiectasia and Rad3-related protein inhibitors (ATRi) were used to block the de novo and salvage pathways for dNTP synthesis, respectively. Of the three orally bioavailable ATRi tested (VX-970, AZD-6738, and BAY1895344), BAY1895344 was the most cytotoxic with and without RT. BAY1895344 and triapine show synergistic potential with increased DNA damage, cell cycle arrest, and apoptosis compared to singular treatment, which is amplified when combined with either RT or cisplatin. Additionally, we identified synergism between cisplatin and BAY1895344 which further amplified their therapeutic effects on the pNEN cells. With triapine treatment alone, we identified strong activation of the ATR pathway which may represent a mechanism of resistance to this treatment which is subsequently blocked by the addition of BAY1895344. With direct quantification, we identified levels of phosphorylated deoxynucleotides increased with triapine treatment alone but were decreased with combination therapy of triapine and BAY1895344, supporting our hypothesis that this combination therapy blocks dNTP synthesis. A similar trend was observed when combined with radiation therapy. Our findings show inhibition of the de novo and salvage pathways for dNTP synthesis markedly sensitize pNENs to subsequent radiation therapy and cisplatin therapy. By capitalizing on the synergy of this combination, clinical efficacy may be achieved at lower doses and represents two potentially novel pNEN treatments

Estimating expansion of the range of oak processionary moth (Thaumetopoea processionea) in the UK from 2006 to 2019

1. The expansion of oak processionary moth (OPM) in South-East England continues despite ongoing efforts to control the pest since its introduction in 2006. 2. Using locations of OPM larval nests, supplied by the Forestry Commission and recorded as part of ongoing surveillance and control measures from 2006 onwards, we show that the expansion of the range of OPM in South-East England up to 2019 was biphasic with a higher rate of expansion from 2015 onwards. 3. The maximum rate of OPM range expansion in the United Kingdom from 2006 to 2014 was estimated as 1.66 km/year (95% CI = [1.22, 2.09]), whereas the 2015–2019 expansion rate was estimated as 6.17 km/year (95% CI = [5.49, 6.84]). This corresponds to an estimated species range distribution area of 7077 km2 in 2019. 4. To explain the faster expansion of OPM range from 2015 onwards, we discuss potential reasons that include: natural capability of species of both short- and long-distance dispersal; external factors such as environmental heterogeneity; a reduction of active control

Automatic test image generation using procedural noise

It is difficult to test programs that input images, due to the large number of (pixel) values that must be chosen and the complex ways these values interact. Typically, such programs are tested manually, using images that have known results. However, this is a laborious process and limited in the range of tests that can be applied. We introduce a new approach for testing programs that input images automatically, using procedural noise and spatial statistics to create inputs that are both realistic and can easily be tuned to have specific properties. The effectiveness of our approach is illustrated on an epidemiological simulation of a recently introduced tree pest in Great Britain: Oriental Chestnut Gall Wasp. Our approach produces images that match the real landscapes more closely than other techniques and can be used (alongside metamorphic relations) to detect smaller (artificially introduced) errors with greater accuracy.This work was supported by the University of Cambridge/Wellcome Trust Junior Interdisciplinary Fellowship “Making scientific software easier to understand, test and communicate through modern advances in software engineering.This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by IEEE

ReadDepth: A Parallel R Package for Detecting Copy Number Alterations from Short Sequencing Reads

Copy number alterations are important contributors to many genetic diseases, including cancer. We present the readDepth package for R, which can detect these aberrations by measuring the depth of coverage obtained by massively parallel sequencing of the genome. In addition to achieving higher accuracy than existing packages, our tool runs much faster by utilizing multi-core architectures to parallelize the processing of these large data sets. In contrast to other published methods, readDepth does not require the sequencing of a reference sample, and uses a robust statistical model that accounts for overdispersed data. It includes a method for effectively increasing the resolution obtained from low-coverage experiments by utilizing breakpoint information from paired end sequencing to do positional refinement. We also demonstrate a method for inferring copy number using reads generated by whole-genome bisulfite sequencing, thus enabling integrative study of epigenomic and copy number alterations. Finally, we apply this tool to two genomes, showing that it performs well on genomes sequenced to both low and high coverage. The readDepth package runs on Linux and MacOSX, is released under the Apache 2.0 license, and is available at http://code.google.com/p/readdepth/

MTSS1 and SCAMP1 cooperate to prevent invasion in breast cancer

Cell–cell adhesions constitute the structural “glue” that retains cells together and contributes to tissue organisation and physiological function. The integrity of these structures is regulated by extracellular and intracellular signals and pathways that act on the functional units of cell adhesion such as the cell adhesion molecules/adhesion receptors, the extracellular matrix (ECM) proteins and the cytoplasmic plaque/peripheral membrane proteins. In advanced cancer, these regulatory pathways are dysregulated and lead to cell–cell adhesion disassembly, increased invasion and metastasis. The Metastasis suppressor protein 1 (MTSS1) plays a key role in the maintenance of cell–cell adhesions and its loss correlates with tumour progression in a variety of cancers. However, the mechanisms that regulate its function are not well-known. Using a system biology approach, we unravelled potential interacting partners of MTSS1. We found that the secretory carrier-associated membrane protein 1 (SCAMP1), a molecule involved in post-Golgi recycling pathways and in endosome cell membrane recycling, enhances Mtss1 anti-invasive function in HER2+/ER−/PR− breast cancer, by promoting its protein trafficking leading to elevated levels of RAC1-GTP and increased cell–cell adhesions. This was clinically tested in HER2 breast cancer tissue and shown that loss of MTSS1 and SCAMP1 correlates with reduced disease-specific survival. In summary, we provide evidence of the cooperative roles of MTSS1 and SCAMP1 in preventing HER2+/ER−/PR− breast cancer invasion and we show that the loss of Mtss1 and Scamp1 results in a more aggressive cancer cell phenotype

Clinical practice guideline exercise and lifestyle in chronic kidney disease

Availability of data and materials: All data and material used in the production of this guideline can be found within the references.Supplementary Information: available at https://static-content.springer.com/esm/art%3A10.1186%2Fs12882-021-02618-1/MediaObjects/12882_2021_2618_MOESM1_ESM.docx - Additional file 1: Appendix HD1. Full search strategies for a review of recent systematic reviews and randomised controlled trial data. Physical activity and exercise guidelines for individuals with end-stage kidney disease (ESKD) receiving haemodialysis. Appendix HD2. Flow diagram of search results. Appendix TX1. Full search strategies for a review of reviews reporting on the importance of physical activity and exercise in renal transplant recipients. Appendix TX2. Full search strategies for meta-analysis investigating the evidence for the effect of exercise training interventions in adult kidney transplant recipients. Appendix TX3. Flow diagram of systematic search of literature and included studies (until January 2020). Appendix TX4. Table of characteristics of included studies. Appendix TX5. Forest plots. Appendix TX6. Risk of bias summary. Appendix TX7. ‘Leave-one-out’ sensitivity analysis. Appendix TX8. Funnel plots.Copyright © The Author(s) 2022. Background: The statement that ‘if exercise were a pill it would be one of the most widely prescribed and cost-effective drugs ever invented’ has been used many times, with many slightly different iterations and with good reason; because the evidence is compelling, and the message is clear that being active provides a foundation for a longer, healthier and happier life. Although other national and international kidney disease guideline documents include some basic recommendations for physical activity and lifestyle, at the time of publication this is the first document of its kind to set out the evidence for those people living with kidney disease, including those on haemodialysis and with a kidney transplant. The scope of these guidelines was agreed by a multi-professional group of healthcare experts, experienced in this field, over three separate meetings of the UK Kidney Research Consortium Clinical Study Group for Exercise and Lifestyle. The authors and guideline development group entirely accept that physical activity recommendations comprise the majority of this document; this is intentional to avoid duplicating expert evidence that can be found elsewhere. Throughout, these national and international resources have been signposted, where appropriate. Systematic literature searches were undertaken to identify all published clinical evidence relevant to the review questions and the exact parameters are outlined below. As well as pragmatic audit measures, we have included ‘Points for implementation’ which we hope will help to translate some of the recommendations into clinical practice in your units. The group would like to particularly highlight the contributions of Drs Baker, March and Wilkinson who led the evidence reviews for the CKD, haemodialysis and transplantation sections, respectively.Not applicable

Heritability and Phenotypic Variation of Canine Hip Dysplasia Radiographic Traits in a Cohort of Australian German Shepherd Dogs

Canine Hip Dysplasia (CHD) is a common, painful and debilitating orthopaedic disorder of dogs with a partly genetic, multifactorial aetiology. Worldwide, potential breeding dogs are evaluated for CHD using radiographically based screening schemes such as the nine ordinally-scored British Veterinary Association Hip Traits (BVAHTs). The effectiveness of selective breeding based on screening results requires that a significant proportion of the phenotypic variation is caused by the presence of favourable alleles segregating in the population. This proportion, heritability, was measured in a cohort of 13,124 Australian German Shepherd Dogs born between 1976 and 2005, displaying phenotypic variation for BVAHTs, using ordinal, linear and binary mixed models fitted by a Restricted Maximum Likelihood method. Heritability estimates for the nine BVAHTs ranged from 0.14–0.24 (ordinal models), 0.14–0.25 (linear models) and 0.12–0.40 (binary models). Heritability for the summed BVAHT phenotype was 0.30±0.02. The presence of heritable variation demonstrates that selection based on BVAHTs has the potential to improve BVAHT scores in the population. Assuming a genetic correlation between BVAHT scores and CHD-related pain and dysfunction, the welfare of Australian German Shepherds can be improved by continuing to consider BVAHT scores in the selection of breeding dogs, but that as heritability values are only moderate in magnitude the accuracy, and effectiveness, of selection could be improved by the use of Estimated Breeding Values in preference to solely phenotype based selection of breeding animals

Is organizational justice climate at the workplace associated with individual-level quality of care and organizational affective commitment?:A multi-level, cross-sectional study on dentistry in Sweden

Purpose The aim of this study is to investigate whether organizational justice climate at the workplace level is associated with individual staff members’ perceptions of carequality and affective commitment to the workplace.Methods The study adopts a cross-sectional multi-level design. Data were collected using an electronic survey and a response rate of 75% was obtained. Organizational justice climate and affective commitment to the workplace were measured by items from Copenhagen Psychosocial Questionnaire and quality of care by three self-developed items. Non-managerial staff working at dental clinics with at least five respondents (n = 900 from 68 units) was included in analyses. A set of Level-2 random intercept models were built to predict individual-level organizational affective commitment and perceived quality of care from unit-level organizational justice climate, controlling for potential confoundingby group size, gender, age, and occupation.Results The results of the empty model showed substantial between-unit variation for both affective commitment (ICC-1 = 0.17) and quality of care (ICC-1 = 0.12). The overall results showed that the shared perception of organizational justice climate at the clinical unit level was significantly associated with perceived quality of care and affective commitment to the organization (p < 0.001).Conclusions Organizational justice climate at work unit level explained all variation in affective commitment among dental clinics and was associated with both the individualstaff members’ affective commitment and perceived quality of care. These findings suggest a potential for that addressing organizational justice climate may be a way to promote quality of care and enhancing affective commitment. However, longitudinal studies are needed to support causality in the examined relationships. Intervention research is also recommended to probe the effectiveness of actions increasingunit-level organizational justice climate and test their impact on quality of care and affective commitment

The Contribution of Occult Precipitation to Nutrient Deposition on the West Coast of South Africa

The Strandveld mediterranean-ecosystem of the west coast of South Africa supports floristically diverse vegetation growing on mostly nutrient-poor aeolian sands and extending from the Atlantic Ocean tens of kilometers inland. The cold Benguela current upwelling interacts with warm onshore southerly winds in summer causing coastal fogs in this region. We hypothesized that fog and other forms of occult precipitation contribute moisture and nutrients to the vegetation. We measured occult precipitation over one year along a transect running inland in the direction of the prevailing wind and compared the nutrient concentrations with those in rainwater. Occult deposition rates of P, N, K, Mg, Ca, Na, Al and Fe all decreased with distance from the ocean. Furthermore, ratios of cations to Na were similar to those of seawater, suggesting a marine origin for these. In contrast, N and P ratios in occult precipitation were higher than in seawater. We speculate that this is due to marine foam contributing to occult precipitation. Nutrient loss in leaf litter from dominant shrub species was measured to indicate nutrient demand. We estimated that occult precipitation could meet the demand of the dominant shrubby species for annual N, P, K and Ca. Of these species, those with small leaves intercepted more moisture and nutrients than those with larger leaves and could take up foliar deposits of glycine, NO3-, NH4 + and Li (as tracer for K) through leaf surfaces. We conclude that occult deposition together with rainfall deposition are potentially important nutrient and moisture sources for the Strandveld vegetation that contribute to this vegetation being floristically distinct from neighbouring nutrient-poor Fynbos vegetation

EGFR T790M Mutation as a Possible Target for Immunotherapy; Identification of HLA-A*0201-Restricted T Cell Epitopes Derived from the EGFR T790M Mutation

Treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, has achieved high clinical response rates in patients with non–small cell lung cancers (NSCLCs). However, over time, most tumors develop acquired resistance to EGFR-TKIs, which is associated with the secondary EGFR T790M resistance mutation in about half the cases. Currently there are no effective treatment options for patients with this resistance mutation. Here we identified two novel HLA-A*0201 (A2)-restricted T cell epitopes containing the mutated methionine residue of the EGFR T790M mutation, T790M-5 (MQLMPFGCLL) and T790M-7 (LIMQLMPFGCL), as potential targets for EGFR-TKI-resistant patients. When peripheral blood cells were repeatedly stimulated in vitro with these two peptides and assessed by antigen-specific IFN-γ secretion, T cell lines responsive to T790M-5 and T790M-7 were established in 5 of 6 (83%) and 3 of 6 (50%) healthy donors, respectively. Additionally, the T790M-5- and T790M-7-specific T cell lines displayed an MHC class I-restricted reactivity against NSCLC cell lines expressing both HLA-A2 and the T790M mutation. Interestingly, the NSCLC patients with antigen-specific T cell responses to these epitopes showed a significantly less frequency of EGFR-T790M mutation than those without them [1 of 7 (14%) vs 9 of 15 (60%); chi-squared test, p = 0.0449], indicating the negative correlation between the immune responses to the EGFR-T790M-derived epitopes and the presence of EGFR-T790M mutation in NSCLC patients. This finding could possibly be explained by the hypothesis that immune responses to the mutated neo-antigens derived from T790M might prevent the emergence of tumor cell variants with the T790M resistance mutation in NSCLC patients during EGFR-TKI treatment. Together, our results suggest that the identified T cell epitopes might provide a novel immunotherapeutic approach for prevention and/or treatment of EGFR-TKI resistance with the secondary EGFR T790M resistance mutation in NSCLC patients