Early biomarkers related to secondary primary cancer risk in radiotherapy treated prostate cancer patients: IMRT versus IMAT

AbstractPurposeTo investigate whether rotational techniques (Volumetric Modulated Arc Therapy – VMAT) are associated with a higher risk for secondary primary malignancies compared to step-and-shoot Intensity Modulated Radiation Therapy (ss-IMRT). To this end, radiation therapy (RT) induced DNA double-strand-breaks and the resulting chromosomal damage were assessed in peripheral blood T-lymphocytes of prostate cancer (PCa) patients applying γH2AX foci and G0 micronucleus (MN) assays.Methods and materialsThe study comprised 33PCa patients. A blood sample was taken before start of therapy and after the 1st and 3rd RT fraction to determine respectively the RT-induced γH2AX foci and MN. The equivalent total body dose (DETB) was calculated based on treatment planning data.ResultsA linear dose response was obtained for γH2AX foci yields versus DETB while MN showed a linear-quadratic dose response. Patients treated with large volume (LV) VMAT show a significantly higher level of induced γH2AX foci and MN compared to IMRT and small volume (SV) VMAT (p<0.01). Assuming a linear-quadratic relationship, a satisfactory correlation was found between both endpoints (R2 0.86).ConclusionsBiomarker responses were governed by dose and irradiated volume of normal tissues. No significant differences between IMRT and rotational therapy inherent to the technique itself were observed

Use of probabilistic phrases in a coordination game: human versus GPT-4

English speakers use probabilistic phrases such as likely to communicate information about the probability or likelihood of events. Communication is successful to the extent that the listener grasps what the speaker means to convey and, if communication is successful, individuals can potentially coordinate their actions based on shared knowledge about uncertainty. We first assessed human ability to estimate the probability and the ambiguity (imprecision) of twenty-three probabilistic phrases in a coordination game in two different contexts, investment advice and medical advice. We then had GPT4 (OpenAI), a Large Language Model, complete the same tasks as the human participants. We found that the median human participant and GPT4 assigned probability estimates that were in good agreement (proportions of variance accounted for close to .90). GPT4's estimates of probability both in the investment and Medical contexts were as close or closer to that of the human participants as the human participants' estimates were to one another. Estimates of probability for both the human participants and GPT4 were little affected by context. In contrast, human and GPT4 estimates of ambiguity were not in such good agreement.Comment: Corrected typos, extended discussion, added reference

Structure of an Hsp90-Cdc37-Cdk4 complex

Activation of many protein kinases depends on their interaction with the Hsp90 molecular chaperone system. Recruitment of protein kinase clients to the Hsp90 chaperone system is mediated by the cochaperone adaptor protein Cdc37, which acts as a scaffold, simultaneously binding protein kinases and Hsp90. We have now expressed and purified an Hsp90-Cdc37-Cdk4 complex, defined its stoichiometry, and determined its 3D structure by single-particle electron microscopy. Comparison with the crystal structure of Hsp90 allows us to identify the locations of Cdc37 and Cdk4 in the complex and suggests a mechanism by which conformational changes in the kinase are coupled to the Hsp90 ATPase cycle

Phosphorylation-dependent assembly and coordination of the DNA damage checkpoint apparatus by Rad4TopBP1

The BRCT-domain protein Rad4(TopBP1) facilitates activation of the DNA damage checkpoint in Schizosaccharomyces pombe by physically coupling the Rad9-Rad1-Hus1 clamp, the Rad3(ATR) -Rad26(ATRIP) kinase complex, and the Crb2(53BP1) mediator. We have now determined crystal structures of the BRCT repeats of Rad4(TopBP1), revealing a distinctive domain architecture, and characterized their phosphorylation-dependent interactions with Rad9 and Crb2(53BP1). We identify a cluster of phosphorylation sites in the N-terminal region of Crb2(53BP1) that mediate interaction with Rad4(TopBP1) and reveal a hierarchical phosphorylation mechanism in which phosphorylation of Crb2(53BP1) residues Thr215 and Thr235 promotes phosphorylation of the noncanonical Thr187 site by scaffolding cyclin-dependent kinase (CDK) recruitment. Finally, we show that the simultaneous interaction of a single Rad4(TopBP1) molecule with both Thr187 phosphorylation sites in a Crb2(53BP1) dimer is essential for establishing the DNA damage checkpoint

Ультрадисперсные порошки на основе железа как катализаторы синтеза жидких углеводородов из СО и Н[2]

International audienceTo date, uniparental disomy (UPD) with phenotypic relevance is described for different chromosomes and it is likely that additional as yet unidentified UPD phenotypes exist. Due to technical difficulties and limitations of time and resources, molecular analyses for UPD using microsatellite markers are only performed in cases with specific phenotypic features. In this study, we carried out a whole genome UPD screening based on a microarray genotyping technique. Six patients with the diagnosis of both complete or segmental UPD including Prader-Willi syndrome (PWS; matUPD15), Angelman syndrome (AS; patUPD15), Silver-Russell syndrome (SRS; matUPD7), Beckwith-Wiedemann syndrome (BWS; patUPD11p), pseudohypoparathyroidism (PHP; patUPD20q) and a rare chromosomal rearrangement (patUPD2p, matUPD2q), were genotyped using the GeneChip Human Mapping 10K Array. Our results demonstrate the presence of UPD in the patients with high efficiency and reveal clues about the mechanisms of UPD formation. We thus conclude that array based SNP genotyping is a fast, cost-effective, and reliable approach for whole genome UPD screening

International randomised controlled trial for the treatment of newly diagnosed EWING sarcoma family of tumours - EURO EWING 2012 Protocol

[Background] Although there have been multiple randomised trials in newly diagnosed Ewing sarcoma family of tumours (ESFT) and these have been conducted over many years and involved many international cooperative groups, the outcomes for all stages of disease have plateaued. Internationally, the standard treatment of ESFT is not defined, and there is a need to add new agents other than conventional chemotherapy to improve outcomes. This trial will compare two different induction/consolidation chemotherapy regimens: (1) vincristine, ifosfamide, doxorubicin and etoposide (VIDE) induction and vincristine, actinomycin D, ifosfamide or cyclophosphamide, or busulfan and mephalan (VAI/VAC/BuMel) consolidation and (2) vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide (VDC/IE) induction and ifosfamide and etoposide, vincristine and cyclophosphamide, vincristine, actinomycin D and ifosfamide, or busulfan and mephalan (IE/VC/VAI/BuMel) consolidation (randomisation 1, or R1). A second randomisation (R2) will determine whether the addition of zoledronic acid to consolidation chemotherapy, as assigned at R1, is associated with improved clinical outcome.[Methods] EURO EWING 2012 is an international, multicentre, phase III, open-label randomised controlled trial. There are two randomisations: R1 and R2. Patients are randomly assigned at two different time points: at entry to the trial (R1) and following local control therapy (R2). The primary outcome measure is event-free survival. The secondary outcome measures include overall survival, adverse events and toxicity, histological response of the primary tumour, response of the primary tumour, regional lymph nodes or metastases (or both), and achievement of local control at the end of treatment.[Discussion] This study will establish which is the “standard regimen” of chemotherapy, taking into account both clinical outcomes and toxicity. This will form the chemotherapy backbone for future interventional studies where we may want to add new targeted agents. It will also determine the role of zoledronic acid in conjunction with the separate EE2008 trial. Any trial in ESFT needs to take into account the rarity of the tumour and consider that international cooperation is needed to provide answers in a timely manner.[Trial registration] Registered with EudraCT number 2012-002107-17 on 26 February 2012. Registered with ISRCTN number 92192408 on 4 November 2013.This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement n°602856. The NCC in France, CLB, receives additional funding from SFCE and Ligue contre le cancer. The coordinating sponsor (the University of Birmingham, Birmingham, UK) is funded by Cancer Research UK (grant award reference C5952/A14745)

Clinical practice guideline recommendations to improve the mental health of adult trauma patients:protocol for a systematic review

Introduction Mental disorders are common in adult patients with traumatic injuries. To limit the burden of poor psychological well-being in this population, recognised authorities have issued recommendations through clinical practice guidelines (CPGs). However, the uptake of evidence-based recommendations to improve the mental health of trauma patients has been low until recently. This may be explained by the complexity of optimising mental health practices and interpretating CGPs scope and quality. Our aim is to systematically review CPG mental health recommendations in the context of trauma care and appraise their quality. Methods and analysis We will identify CPG through a search strategy applied to Medline, Embase, CINAHL, PsycINFO and Web of Science databases, as well as guidelines repositories and websites of trauma associations. We will target CPGs on adult and acute trauma populations including at least one recommendation on any prevention, screening, assessment, intervention, patient and family engagement, referral or follow-up procedure related to mental health endorsed by recognised organisations in high-income countries. No language limitations will be applied, and we will limit the search to the last 15 years. Pairs of reviewers will independently screen titles, abstracts, full texts, and carry out data extraction and quality assessment of CPGs using the Appraisal of Guidelines Research and Evaluation (AGREE) II. We will synthesise the evidence on recommendations for CPGs rated as moderate or high quality using a matrix based on the Grading of Recommendations Assessment, Development and Evaluation quality of evidence, strength of recommendation, health and social determinants and whether recommendations were made using a population-based approach. Ethics and dissemination Ethics approval is not required, as we will conduct secondary analysis of published data. The results will be disseminated in a peer-reviewed journal, at international and national scientific meetings. Accessible summary will be distributed to interested parties through professional, healthcare quality and persons with lived experience associations.</p

Clinical practice guideline recommendations to improve the mental health of adult trauma patients:protocol for a systematic review

Introduction Mental disorders are common in adult patients with traumatic injuries. To limit the burden of poor psychological well-being in this population, recognised authorities have issued recommendations through clinical practice guidelines (CPGs). However, the uptake of evidence-based recommendations to improve the mental health of trauma patients has been low until recently. This may be explained by the complexity of optimising mental health practices and interpretating CGPs scope and quality. Our aim is to systematically review CPG mental health recommendations in the context of trauma care and appraise their quality. Methods and analysis We will identify CPG through a search strategy applied to Medline, Embase, CINAHL, PsycINFO and Web of Science databases, as well as guidelines repositories and websites of trauma associations. We will target CPGs on adult and acute trauma populations including at least one recommendation on any prevention, screening, assessment, intervention, patient and family engagement, referral or follow-up procedure related to mental health endorsed by recognised organisations in high-income countries. No language limitations will be applied, and we will limit the search to the last 15 years. Pairs of reviewers will independently screen titles, abstracts, full texts, and carry out data extraction and quality assessment of CPGs using the Appraisal of Guidelines Research and Evaluation (AGREE) II. We will synthesise the evidence on recommendations for CPGs rated as moderate or high quality using a matrix based on the Grading of Recommendations Assessment, Development and Evaluation quality of evidence, strength of recommendation, health and social determinants and whether recommendations were made using a population-based approach. Ethics and dissemination Ethics approval is not required, as we will conduct secondary analysis of published data. The results will be disseminated in a peer-reviewed journal, at international and national scientific meetings. Accessible summary will be distributed to interested parties through professional, healthcare quality and persons with lived experience associations.</p

UKRN Institutional tasks implied by the UK Open Research Data Concordat

This UKRN working paper outlines the tasks that are either explicitly or implicitly proposed for research institutions by the UK Open Research Data Concordat (2016). It also reflects on how those tasks are relevant to the recommendations from the 2018 report issued by the UK Government from the Open Research Data Task Force. The aim of this paper is to describe more clearly what UK research institutions might be expected to do to support open research data, which may be a helpful basis for sector-wide discussion on both those expectations and how they are being met. The tasks are grouped under the headings of organisational support, infrastructure, recognition, restrictions on open data, costs, and strategy