Combined ATR and DNA-PK Inhibition Radiosensitizes Tumor Cells Independently of Their p53 Status.

Head and neck squamous cell carcinoma (HNSCC) is a significant cause of cancer deaths. Cisplatin-based chemoradiotherapy is a standard of care for locally advanced disease. ATR and DNA-PK inhibition (DNA-PKi) are actively being investigated in clinical trials with preclinical data supporting clinical translation as radiosensitizers. Here, we hypothesized that targeting both ATR and DNA-PK with small molecule inhibitors would increase radiosensitization of HNSCC cell lines. Radiosensitization was assessed by Bliss independence analysis of colony survival data. Strong cell cycle perturbing effects were observed with ATR inhibition reversing the G2/M arrest observed for radiation-DNA-PKi. Increased apoptosis in combination groups was measured by Sub-G1 DNA populations. DNA-PKi increased radiation-induced RAD51 and gamma-H2Ax foci, with the addition of ATR inhibition reducing levels of both. A sharp increase in nuclear fragmentation after aberrant mitotic transit appears to be the main driver of decreased survival due to irradiation and dual ATR/DNA-PKi. Dual inhibition of DNA-PK and ATR represents a novel approach in combination with radiation, with efficacy appearing to be independent of p53 status. Due to toxicity concerns, careful assessment is necessary in any future translation of single or dual radiosensitization approaches. Ongoing clinical trials into the ATR inhibitor AZD6738 plus radiation, and the phenotypically similar combination of AZD6738 and the PARP inhibitor olaparib, are likely to be key in ascertaining the toxicity profile of such combinations

Acute Kawasaki Disease: Not Just for Kids

Kawasaki Disease is a small-to-medium-vessel vasculitis that preferentially affects children. Kawasaki Disease can occur in adults, but the presentation may differ from that observed in children. Typical findings in both adults and children include fever, conjunctivitis, pharyngitis, and skin erythema progressing to a desquamating rash on the palms and soles. Adults more frequently present with cervical adenopathy (93% of adults vs. 15% of children), hepatitis (65% vs. 10%), and arthralgia (61% vs. 24–38%). In contrast, adults are less frequently affected by meningitis (10% vs. 34%), thrombocytosis (55% vs. 100%), and coronary artery aneurysms (5% vs. 18–25%). We report a case of acute Kawasaki Disease in a 24-year-old man who presented with rash, fever, and arthritis. He was successfully treated with high-dose aspirin and intravenous immunoglobulin (IVIG). Our case highlights the importance of considering Kawasaki Disease in adults presenting with symptoms commonly encountered in a general medical practice

Discursive positioning and planned change in organizations

This study uses discursive positioning theory to explore how planned change messages influence organizational members’ identity and the way they experienced organizational change. Based on an in-depth case study of a home healthcare and hospice organization that engaged in a multiyear planned change process, our analysis suggests that workers experienced salient change messages as constituting unfavorable identities, which were associated with the experiences of violation, recitation, habituation, or reservation. Our study also explores the way discursive and material contexts enabled and constrained the governing board’s change messages as they responded to external and internal audiences. We highlight the importance of viewing messaging as a process of information transfer as well as discursive construction, which has important implications for the way change agents approach issues of sense making, emotionality, resistance, and materiality during planned change processes.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Automatic radiographic quantification of hand osteoarthritis; accuracy and sensitivity to change in joint space width in a phantom and cadaver study

This is the final version of the article. Available from Springer Verlag via the DOI in this record.OBJECTIVE: To validate a newly developed quantification method that automatically detects and quantifies the joint space width (JSW) in hand radiographs. Repeatability, accuracy and sensitivity to changes in JSW were determined. The influence of joint location and joint shape on the measurements was tested. METHODS: A mechanical micrometer set-up was developed to define and adjust the true JSW in an acrylic phantom joint and in human cadaver-derived phalangeal joints. Radiographic measurements of the JSW were compared to the true JSW. Repeatability, systematic error (accuracy) and sensitivity (defined as the smallest detectable difference (SDD)) were determined. The influence of joint position on the JSW measurement was assessed by varying the location of the acrylic phantom on the X-ray detector with respect to the X-ray beam and the influence of joint shape was determined by using morphologically different human cadaver joints. RESULTS: The mean systematic error was 0.052 mm in the phantom joint and 0.210 mm in the cadaver experiment. In the phantom experiments, the repeatability was high (SDD = 0.028 mm), but differed slightly between joint locations (p = 0.046), and a change in JSW of 0.037 mm could be detected. Dependent of the joint shape in the cadaver hand, a change in JSW between 0.018 and 0.047 mm could be detected. CONCLUSIONS: The automatic quantification method is sensitive to small changes in JSW. Considering the published data of JSW decline in the normal and osteoarthritic population, the first signs of OA progression with this method can be detected within 1 or 2 years.This work was funded by the Dutch Arthritis Association (Reumafonds). The study sponsor had no involvement in study design, data collection, data analysis, or interpretation of the results

The influence of the accessory genome on bacterial pathogen evolution

Bacterial pathogens exhibit significant variation in their genomic content of virulence factors. This reflects the abundance of strategies pathogens evolved to infect host organisms by suppressing host immunity. Molecular arms-races have been a strong driving force for the evolution of pathogenicity, with pathogens often encoding overlapping or redundant functions, such as type III protein secretion effectors and hosts encoding ever more sophisticated immune systems. The pathogens’ frequent exposure to other microbes, either in their host or in the environment, provides opportunities for the acquisition or interchange of mobile genetic elements. These DNA elements accessorise the core genome and can play major roles in shaping genome structure and altering the complement of virulence factors. Here, we review the different mobile genetic elements focusing on the more recent discoveries and highlighting their role in shaping bacterial pathogen evolution

InterGEO: a digital platform for university education on geomorphological heritage

The project InterGEO was carried out with the objective to disseminate knowledge on geomorphological heritage by developing a digital learning platform. It aims at improving students' autonomy by the reduction of face-to-face teaching and increasing autonomous learning as well as promoting international interactions between students interested in geomorphological heritage. A completely free-access virtual course on geomorphosites was developed with the Learning Management System Moodle. The course is divided into 24 thematic chapters, each of them containing a short description, a list of references and selected publications, as well as other educational material (videos, virtual fieldtrips, etc.). In particular, several videos allow presenting in a dynamic way concepts and examples. The paper presents the tool and its use in academic programmes in six European universities, where it was tested, in various contexts (Bachelors' and Masters' programmes; students in geography or geology; general courses in geomorphology and specific courses on geoheritage and geoconservation), before discussing the advantages and challenges the tool is facing. The InterGEO platform is an easy-to-use and friendly educational tool, which allows developing blended learning activities; it is flexible and adaptable in various learning contexts.The coordination tasks (appointment of an assistant) and two workshops in Lausanne were financed by the University of Lausanne (Teaching Innovation Fund and Investment Fund of the Faculty of Geosciences and Environment, FGSE). The videos were designed and created with support of the universities of Lausanne (TIF) and Savoie Mont Blanc (IDEFI Promising and ReflexPro; LabEx ITEM)

Was Wright Right? The Canonical Genetic Code is an Empirical Example of an Adaptive Peak in Nature; Deviant Genetic Codes Evolved Using Adaptive Bridges

The canonical genetic code is on a sub-optimal adaptive peak with respect to its ability to minimize errors, and is close to, but not quite, optimal. This is demonstrated by the near-total adjacency of synonymous codons, the similarity of adjacent codons, and comparisons of frequency of amino acid usage with number of codons in the code for each amino acid. As a rare empirical example of an adaptive peak in nature, it shows adaptive peaks are real, not merely theoretical. The evolution of deviant genetic codes illustrates how populations move from a lower to a higher adaptive peak. This is done by the use of “adaptive bridges,” neutral pathways that cross over maladaptive valleys by virtue of masking of the phenotypic expression of some maladaptive aspects in the genotype. This appears to be the general mechanism by which populations travel from one adaptive peak to another. There are multiple routes a population can follow to cross from one adaptive peak to another. These routes vary in the probability that they will be used, and this probability is determined by the number and nature of the mutations that happen along each of the routes. A modification of the depiction of adaptive landscapes showing genetic distances and probabilities of travel along their multiple possible routes would throw light on this important concept

Tissue microarray analysis of eIF4E and its downstream effector proteins in human breast cancer

Correction to Kleiner HE, Krishnan P, Tubbs J, Smith M, Meschonat C, Shi R, Lowery-Nordberg M, Adegboyega P, Unger M, Cardelli J et al: Tissue microarray analysis of eIF4E and its downstream effector proteins in human breast cancer. J Exp Clin Cancer Res 2009, 28:5