Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.

Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases

Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets

Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations. Through the temporal dissection of aberrations, we identified driver mutations specifically associated with steps in the progression of prostate cancer, establishing, for example, loss of CHD1 and BRCA2 as early events in cancer development of ETS fusion-negative cancers. Computational chemogenomic (canSAR) analysis of prostate cancer mutations identified 11 targets of approved drugs, 7 targets of investigational drugs, and 62 targets of compounds that may be active and should be considered candidates for future clinical trials

Mutational signatures of ionizing radiation in second malignancies

Ionizing radiation is a potent carcinogen, inducing cancer through DNA damage. The signatures of mutations arising in human tissues following in vivo exposure to ionizing radiation have not been documented. Here, we searched for signatures of ionizing radiation in 12 radiation-associated second malignancies of different tumour types. Two signatures of somatic mutation characterize ionizing radiation exposure irrespective of tumour type. Compared with 319 radiation-naive tumours, radiation-associated tumours carry a median extra 201 deletions genome-wide, sized 1-100 base pairs often with microhomology at the junction. Unlike deletions of radiation-naive tumours, these show no variation in density across the genome or correlation with sequence context, replication timing or chromatin structure. Furthermore, we observe a significant increase in balanced inversions in radiation-associated tumours. Both small deletions and inversions generate driver mutations. Thus, ionizing radiation generates distinctive mutational signatures that explain its carcinogenic potential.This work was supported by funding from the Wellcome Trust (grant reference 077012/Z/05/Z), Skeletal Cancer Action Trust, Rosetrees Trust UK, Bone Cancer Research Trust, the RNOH NHS Trust, the National Institute for Health Research Health Protection Research Unit in Chemical and Radiation Hazards and Threats at Newcastle University in partnership with Public Health England. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health or Public Health England. Tissue was obtained from the RNOH Musculoskeletal Research Programme and Biobank, co-ordinated by Mrs Deidre Brooking and Mrs Ru Grinnell, Biobank staff, RNOH. Support was provided to AMF by the National Institute for Health Research, UCLH Biomedical Research Centre, and the CRUK UCL Experimental Cancer Centre. S.N.Z. and S.B. are personally funded through Wellcome Trust Intermediate Clinical Research Fellowships, P.J.C. through a Wellcome Trust Senior Clinical Research Fellowship

Optimizing the Protection of Cattle against Escherichia coli O157: H7 Colonization through Immunization with Different Combinations of H7 Flagellin, Tir, Intimin-531 or EspA

Enterohemorrhagic Escherichia coli (EHEC) are important human pathogens, causing hemorrhagic colitis and hemolytic uraemic syndrome in humans. E. coli O157:H7 is the most common serotype associated with EHEC infections worldwide, although other non-O157 serotypes cause life-threatening infections. Cattle are a main reservoir of EHEC and intervention strategies aimed at limiting EHEC excretion from cattle are predicted to lower the risk of human infection. We have previously shown that immunization of calves with recombinant versions of the type III secretion system (T3SS)-associated proteins EspA, intimin and Tir from EHEC O157:H7 significantly reduced shedding of EHEC O157 from experimentally-colonized calves, and that protection could be augmented by the addition of H7 flagellin to the vaccine formulation. The main aim of the present study was to optimize our current EHEC O157 subunit vaccine formulations by identifying the key combinations of these antigens required for protection. A secondary aim was to determine if vaccine-induced antibody responses exhibited cross-reactive potential with antigens from other EHEC serotypes. Immunization with EspA, intimin and Tir resulted in a reduction in mean EHEC O157 shedding following challenge, but not the mean proportion of calves colonized. Removal of Tir resulted in more prolonged shedding compared with all other groups, whereas replacement of Tir with H7 flagellin resulted in the highest levels of protection, both in terms of reducing both mean EHEC O157 shedding and the proportion of colonized calves. Immunization of calves with recombinant EHEC O157 EspA, intimin and Tir resulted in the generation of antibodies capable of cross-reacting with antigens from non-O157 EHEC serotypes, suggesting that immunization with these antigens may provide a degree of cross-protection against other EHEC serotypes. Further studies are now required to test the efficacy of these vaccines in the field, and to formally test the cross-protective potential of the vaccines against other non-O157 EHEC

Institutional entrepreneurship, governance, and poverty: Insights from emergency medical response servicesin India

We present an in-depth case study of GVK Emergency Management and Research Institute, an Indian public–private partnership (PPP), which successfully brought emergency medical response to remote and urban settings. Drawing insights from the case, we investigate how the organization established itself through institutional entrepreneurship using a process conceptualized as opportunity framing, entrenchment, and propagation. The case and context highlight the need for innovation in organizational design and governance modes to create a new opportunity that connects state actors, private healthcare providers, and the public at large. We consider the role of open innovation and novel business models in creating these service platforms. The implications of our findings for the literature on PPPs, institutional entrepreneurship, inclusive and open innovation, and organizational design in base of the pyramid contexts are discussed

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Institutions, organizations and markets for inclusive growth

This dissertation views the challenge of delivering new products and services in low-cost contexts as an organization design problem, a thesis explored in three interrelated studies. Study I examines opportunity enactment and inter-organizational design via an in-depth case study on emergency medical response services in India, a context characterised by poor access, resource constraints and institutional voids. The case and context highlight the need for innovation in organization design and governance modes to create a new opportunity that connects state actors, private healthcare providers, and the public at large. It considers the role of open innovation and novel organizational arrangements between public and private actors in creating these service platforms, before discussing their implications for literature on public-private partnerships and institutional entrepreneurship. Study II is a qualitative study on the delivery of prevention of mother-to-child transmission of HIV/AIDS services in three different states in India. Using archival data, fieldwork and interviews with healthcare professionals and front-line workers in the National AIDS Control Organization of India (NACO), it examines how work is coordinated in stigmatized client settings. It proposes a model for organization design and work integration in contexts where stigma is an antecedent to disenfranchisement. In addition, my findings highlight the interplay of formal design choices and informal coordinating practices in restoring the integrative conditions necessary for collective work. Study III is a comparative case study of two hybrid organizations. Combining stakeholder theory with organization design perspectives, it explores the prioritization of stakeholder preferences within two social enterprises. Specifically, how the demands of their most salient stakeholders influence internal governance and organization design arrangements. It demonstrates how salient preferences create complex trade-offs between coordination and agency costs associated with alternate governance choices. Their impact on the depth and breadth of social value creation are also discussed.Open Acces

Integration of ERG gene mapping and gene-expression profiling identifies distinct categories of human prostate cancer

To integrate the mapping of ERG alterations with the collection of expression microarray (EMA) data, as previous EMA analyses have failed to consider the genetic heterogeneity and complex patterns of ERG alteration frequently found in cancerous prostates