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"Behrens, A"
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ATM signalling and cancer
ATM, the protein kinase mutated in the rare human disease ataxia telangiectasia (A-T), has been the focus of intense scrutiny over the past two decades. Initially this was because of the unusual radiosensitive phenotype of cells from A-T patients, and latterly because investigating ATM signalling has yielded valuable insights into the DNA damage response, redox signalling and cancer. With the recent explosion in genomic data,
ATM
alterations have been revealed both in the germline as a predisposing factor for cancer and as somatic changes in tumours themselves. Here we review these findings, as well as advances in the understanding of ATM signalling mechanisms in cancer and ATM inhibition as a strategy for cancer treatment.
Journal Article
A vaccine targeting mutant IDH1 in newly diagnosed glioma
Mutated isocitrate dehydrogenase 1 (
IDH1
) defines a molecularly distinct subtype of diffuse glioma
1
–
3
. The most common
IDH1
mutation in gliomas affects codon 132 and encodes IDH1(R132H), which harbours a shared clonal neoepitope that is presented on major histocompatibility complex (MHC) class II
4
,
5
. An IDH1(R132H)-specific peptide vaccine (IDH1-vac) induces specific therapeutic T helper cell responses that are effective against IDH1(R132H)
+
tumours in syngeneic MHC-humanized mice
4
,
6
–
8
. Here we describe a multicentre, single-arm, open-label, first-in-humans phase I trial that we carried out in 33 patients with newly diagnosed World Health Organization grade 3 and 4 IDH1(R132H)
+
astrocytomas (Neurooncology Working Group of the German Cancer Society trial 16 (NOA16), ClinicalTrials.gov identifier NCT02454634). The trial met its primary safety endpoint, with vaccine-related adverse events restricted to grade 1. Vaccine-induced immune responses were observed in 93.3% of patients across multiple MHC alleles. Three-year progression-free and death-free rates were 0.63 and 0.84, respectively. Patients with immune responses showed a two-year progression-free rate of 0.82. Two patients without an immune response showed tumour progression within two years of first diagnosis. A mutation-specificity score that incorporates the duration and level of vaccine-induced IDH1(R132H)-specific T cell responses was associated with intratumoral presentation of the IDH1(R132H) neoantigen in pre-treatment tumour tissue. There was a high frequency of pseudoprogression, which indicates intratumoral inflammatory reactions. Pseudoprogression was associated with increased vaccine-induced peripheral T cell responses. Combined single-cell RNA and T cell receptor sequencing showed that tumour-infiltrating CD40LG
+
and CXCL13
+
T helper cell clusters in a patient with pseudoprogression were dominated by a single IDH1(R132H)-reactive T cell receptor.
A phase 1 clinical trial provides evidence that a vaccine against mutant IDH1 is safe and produces a T helper immune response in patients with glioma.
Journal Article
Trust-building in temporary public health partnerships: a qualitative study of the partnership formation process of a Covid-19 test, trace and protect service
Background
Public health initiatives require coordinated efforts from healthcare, social services and other service providers. Organisational theory tells us that trust is essential for reaching collaborative effectiveness. This paper explores the drivers for initiating and sustaining trust in a temporary public health partnership, in response to a sudden health threat.
Methods
This qualitative study analysed the formation process of a multisector partnership for a Covid-19 contact tracing service. Data was collected through 12 interviews, two focus groups, one feedback workshop, and an online survey with workforce members from all seven partner organisations. Purposive maximum variation sampling was used to capture the reflections and experiences of workforce members from all seven partner organisations. A deductive code scheme was used to identify drivers for building and sustaining trust in inter-organisational collaboration.
Results
Relational mechanisms emanating from the commitment to the common aim, shared norms and values, and partnership structures affected trust-building. Shared values and the commitment to the common aim appeared to channel partners’ behaviour when interacting, resulting in being perceived as a fair, reliable and supportive partner. Shared values were congruent with the design of the partnership in terms of governance structure and communication lines reflecting flat hierarchies and shared decision-making power. Tensions between partner organisations arose when shared values were infringed.
Conclusions
When managing trust in a collaboration, partners should consider structural components like governance structure, organisational hierarchy, and communication channels to ensure equal power distribution. Job rotation, recruitment of candidates with the desired personality traits and attitudes, as well as training and development, encourage inter-organisational networking among employees, which is essential for building and strengthening relationships with partner organisations. Partners should also be aware of managing relational dynamics, channelling behaviours through shared values, objectives and priorities and fostering mutual support and equality among partner organisations.
Journal Article
Exploring teamwork in fluid multiteam systems (MTS): a qualitative analysis of team effectiveness in public health emergent response teams in Wales, UK
Objectives The research aims to understand key contributors to multiteam system (MTS) effectiveness by qualitatively exploring team members’ experiences working in a fluid MTS, their ability to effectively collaborate with component teams, and the effect of social dynamics on collaboration and cooperation.DesignIn-depth qualitative case study with semi-structured interviews, focus group discussions and open-ended answers from an online survey. Thematic analysis was applied.SettingA COVID-19 Test, Trace and Protect Service in the UK was formed as a partnership between a local health board, Public Health Wales and public sector organisations.ParticipantsSenior managers from different partner organisations, as well as current and former staff members from various positions and teams, were recruited via the service’s project management office.ResultsThe study identifies a strong influence of situational strength on team functioning, whereby the pandemic situation fuelled the teams’ commitment to the common purpose and promoted a shared identity across the teams. Further, the study highlights the key role of leadership in enabling MTS effectiveness through the establishment of effective governance structures, role-modelling (supporting that all voices are heard), and enhancing a psychologically safe working climate. Lastly, the study demonstrates the impact of social dynamics on team functioning, whereby team commitment, engagement and a shared team identity appeared to promote mutual support, communication and cooperation across component teams.ConclusionResults hold lessons for managers tasked with leading fluid MTS: communication of a clearly defined overarching purpose and aim, alignment of individual team contributions to the overarching aim alongside feedback cycles and acknowledgement of individual team efforts, selecting team members with the ability to cope with volatile, uncertain and ambiguous circumstances; selecting team leaders with inclusive and compassionate leadership styles, the establishment of collaborative governance structures and the introduction of staff well-being measures for coping with work stressors.
Journal Article
Biomechanical comparison of a new expandable intramedullary nail and conventional intramedullary nails for femoral osteosynthesis in dogs
Intramedullary nailing of diaphyseal femoral fractures is a commonly used treatment method in dogs because of its biological and biomechanical advantages compared to bone plating. To achieve adequate resistance of the intramedullary nail against torsional and axial compressive forces, additional application of transcortical screws is needed. As these interlocking screws represent a frequent cause of post-operative complications, a new expandable intramedullary nail (EXPN) was developed, which was designed to provide adequate fracture stabilisation without the need for transcortical fixation. The evaluation of the biomechanical properties of the new EXPN with regard to torsional, compressive and bending stability as well as direct comparison to the biomechanical properties of conventional Steinmann (STMN)- and interlocking (ILN) nails was carried out with different biomechanical test arrangements. No significant statistical differences regarding the torsional and bending resistance between the EXPN and ILN group were seen, which indicates that rotatory as well as bending stability of the innovative EXPN is similar to the conventional ILN. Nevertheless, the percentage deviation between the attempted and successfully reached physiological compressive forces was significantly higher (p = 0.045) in the EXPN group compared to the ILN group, which indicates that the compressive stability of the innovative EXPN might be weaker compared to the ILN. In summary, the new EXPN represents an interesting alternative to conventional intramedullary nails. However, in direct comparison to conventional interlocking nails, the EXPN has shown weaknesses in the neutralization of axial compressive forces, which indicates that at least biomechanically the interlocking nail seems advantageous. Further in-vitro and in-vivo investigations are required before clinical use can be recommended.
Journal Article
Strategies for residual stress adjustment in bulk metal forming
The family of bulk forming technologies comprises processes characterised by a complex three-dimensional stress and strain state. Besides shape and material properties, also residual stresses are modified during a bulk metal forming process. The state of residual stresses affects important properties, like fatigue behaviour and corrosion resistance. An adjustment of the residual stresses is possible through subsequent process steps such as heat treatments or mechanical surface modification technologies, like shot peening and deep rolling. However, these additional manufacturing steps involve supplementary costs, longer manufacturing times and harmful effects on the product quality. Therefore, an optimized strategy consists in a targeted introduction of residual stresses during the forming processes. To enable this approach, a fundamental understanding of the underlying mechanisms of residual stress generation in dependence of the forming parameters is necessary. The current state of the art is reviewed in this paper. Strategies for the manipulation of the residual stresses in different bulk forming processes are classified according to the underlying principles of process modification.
Journal Article
DMAP1 is an essential regulator of ATM activity and function
The hereditary autosomal recessive disease ataxia telangiectasia (A-T) is caused by mutation in the DNA damage kinase ATM. ATM’s main function is to orchestrate DNA repair, thereby maintaining genomic stability. ATM activity is increased in response to several stimuli, including ionising radiation (IR) and hypotonic stress. DNMT1-associated protein 1 (DMAP1) is a member of the TIP60-p400 histone acetyl transferase (HAT) complex, which acetylates histone H4 at lysine 16 (H4K16) to affect chromatin relaxation and modulate ATM activation. Here we demonstrate that DMAP1 is required for both modes of ATM activation. Knockdown of DMAP1 impaired IR-induced ATM activation and consequently resulted in radiosensitivity and impaired the G2/M checkpoint. Moreover, DMAP1 was also required for efficient ATM signalling in response to hypotonic stress. Overexpression of DMAP1 increased IR-induced ATM substrate phosphorylation, suggesting that DMAP1 function is rate limiting for ATM signalling. DMAP1 associated with TIP60-dependent HAT activity, and depletion of DMAP1 reduced H4K16 acetylation in response to DNA damage. Treatment with histone deacetylase inhibitors rescued IR-induced ATM signalling in
Dmap1
-depleted cells. These results suggest that DMAP1 is a critical regulator of ATM activity and function.
Journal Article
Sex chromosomes in the tribe Cyprichromini (Teleostei: Cichlidae) of Lake Tanganyika
Sex determining loci have been described on at least 12 of 22 chromosomes in East African cichlid fishes, indicating a high rate of sex chromosome turnover. To better understand the rates and patterns of sex chromosome replacement, we used new methods to characterize the sex chromosomes of the cichlid tribe
Cyprichromini
from Lake Tanganyika. Our k-mer based methods successfully identified sex-linked polymorphisms without the need for a reference genome. We confirm the three previously reported sex chromosomes in this group. We determined the polarity of the sex chromosome turnover on LG05 in
Cyprichromis
as ZW to XY. We identified a new ZW locus on LG04 in
Paracyprichromis brieni.
The LG15 XY locus in
Paracyprichromis nigripinnis
was not found in other
Paracyprichromis
species, and the sample of
Paracyprichromis sp. “tembwe
” is likely to be of hybrid origin. Although highly divergent sex chromosomes are thought to develop in a stepwise manner, we show two cases (LG05-ZW and LG05-XY) in which the region of differentiation encompasses most of the chromosome, but appears to have arisen in a single step. This study expands our understanding of sex chromosome evolution in the Cyprichromini, and indicates an even higher level of sex chromosome turnover than previously thought.
Journal Article
Targeted adjustment of residual stresses in hot-formed components by means of process design based on finite element simulation
The aim of this work is to generate an advantageous compressive residual stress distribution in the surface area of hot-formed components by intelligent process control with tailored cooling. Adapted cooling is achieved by partial or temporal instationary exposure of the specimens to a water–air spray. In this way, macroscopic effects such as local plastification caused by inhomogeneous strains due to thermal and transformation-induced loads can be controlled in order to finally customise the surface-near residual stress distribution. Applications for hot-formed components often require special microstructural properties, which guarantee a certain hardness or ductility. For this reason, the scientific challenge of this work is to generate different residual stress distributions on components surfaces, while the geometric as well as microstructural properties of AISI 52100 alloy stay the same. The changes in the residual stresses should therefore not result from the mentioned changed component properties, but solely from the targeted process control. Within the scope of preliminary experimental studies, tensile residual stresses in a martensitic microstructure were determined on reference components, which had undergone a simple cooling in water (from the forming heat), or low compressive stresses in pearlitic microstructures were determined after simple cooling in atmospheric air. Numerical studies are used to design two tailored cooling strategies capable of generating compressive stresses in the same components. The developed processes with tailored cooling are experimentally realised, and their properties are compared to those of components manufactured involving simple cooling. Based on the numerical and experimental analyses, this work demonstrates that it is possible to influence and even invert the sign of the residual stresses within a component by controlling the macroscopic effects mentioned above.
Journal Article