A phase 1 trial of the herpes simplex virus HSV1716 in patients with high grade glioma plus an in vitro investigation of the interaction between HSV1716 and ionising radiation

HSV1716 is a mutant herpes simplex virus with a deletion in both copies of the RL1 gene, that encodes the protein ICP34.5, a specific determinant of virulence. Section one presents a phase I study in which it has been demonstrated that herpes simplex virus 1716 (HSV1716) does not generate toxicity following injection into brain adjacent to excised high-grade glioma, in patients who proceeded to receive further immunosuppressive radiotherapy or chemotherapy. The survival and imaging data, in addition to the lack of toxicity, were encouraging. Section two investigates the possibility of enhanced cell kill when ionising radiation is employed in conjunction with the ICP34.5 null mutant HSV1716 in a tissue culture model and the possible mechanisms responsible for enhanced cell kill. Using the MTS assay, experiments combining HSV1716 and ionising radiation demonstrated additional cell kill in 373 and MOG cells by day six compared to either modality in isolation. Isobologram analysis confirmed a synergistic relationship between ionising radiation and HSV1716 in 373 cells and an additive relationship in the MOG cell line when the cells were irradiated one hour prior to inoculation. Lastly, stable 3T6 cells expressing ICP34.5 were developed with the aim of elucidating the mechanism of action of the ICP34.5 in the replication cycle of HSV. Functional ICP34.5 and ICP34.5-GFP in the transfected 3T6 cells was detected and able to support the replication of HSV1716. These cells were analysed with respect to HSV1716 infection and were seen to support replication with the appearance of characteristic plaque morphology

Lung tumor 3D reconstruction from planar CT scans and registration to micro and macroscopic pathology imaging

The overall goal of this project is to ascertain whether a given PET radiotracer reliably and accurately identifies an active cancerous region within the gross tumour volume. The only means to assess it is to compare the PET signal with the gold standard of histopathology. To allow for this comparison both images need to be spatially aligned or registered. However, lung tissue undergoes several deformations following surgical resection and pathological processing. Therefore, these distortions need to be taken into account in order to obtain a truthful mapping. Moreover, PET signals are intrinsically 3D, whereas histopathology slices are planar images. In order to overcome this problem, 2D slices have to be stacked together to reconstruct the original volume prior to registration

Lung cancer symptom appraisal among people with chronic obstructive pulmonary disease: A qualitative interview study

© 2019 The Authors. Psycho-Oncology Published by John Wiley & Sons Ltd. Objective: The incidence of lung cancer is four times higher in people with chronic obstructive pulmonary disease (COPD) compared with the general population. Promotion of a shorter time from symptom onset to presentation is one potential strategy for earlier lung cancer diagnosis, but distinguishing respiratory symptoms can be difficult. We investigated how the experience of COPD influences symptom appraisal and help seeking for potential lung cancer symptoms. Methods: We conducted qualitative interviews with men (n = 17) and women (n = 23) aged 40 to 83 years with COPD. Topic guides drew on the integrated symptom-response framework and covered symptom experience, interpretation, action, recognition, help seeking, evaluation, and reevaluation. We used the framework method to analyse the data. Results: Participants said that they attributed chest symptoms to their COPD; no other cause was considered. Participants said that family/friends noticed changes in their symptoms and encouraged help seeking. Others felt isolated by their COPD because they could not get out, were fatigued, or were embarrassed. Participants visited health professionals frequently, but increased risk of lung cancer was not discussed. Conclusions: Our study provides insight into different levels of influence on symptom appraisal and targets for intervention. Greater awareness of increased lung cancer risk and support to act on symptom changes is essential and could be achieved through a concerted information campaign. Health professionals working with people with COPD could also optimise appointments to support symptom appraisal of potential lung cancer symptoms

From identification to validation to gene count

The current GENCODE gene count of ~ 30,000, including 21,727 protein-coding and 8,483 RNA genes, is significantly lower than the 100,000 genes anticipated by early estimates. Accurate annotation of protein-coding and non-coding genes and pseudogenes is essential in calculating the true gene count and gaining insight into human evolution. As part of the GENCODE Consortium, the HAVANA team produces high quality manual gene annotation, which forms the basis for the reference gene set being used by the ENCODE project and provides a rich annotation of alternative splice variants and assignment of functional potential. However, the protein-coding potential of some splice variants is uncertain and valid splice variants can remain unannotated if they are absent from current cDNA libraries. Recent technological developments in sequencing and mass spectrometry have created a vast amount of new transcript and protein data that facilitate the identification and validation of new and existing transcripts, while harboring their own limitations and problems

Driverless futures: Design for acceptance and adoption in urban environments

The driverless or autonomous car offers a range of challenges and opportunities – technical, economic and social – to the UK and the world. Harrow led the academic research for GATEway, an £8M Innovate UK project led for industry by the Transport Research Laboratory in which the RCA was the principal university. It created a world-leading test-bed for driverless cars that enabled automotive and software industries, local authorities, planners, insurers, Government ministers, policy makers and others to evaluate new vehicles and new technologies applied to existing vehicles, and to understand the human behaviours and attitudes emerging around these new forms of transport. The work is crucial to the future of mobility and to future cities, the connected digital economy, and future manufacturing. Harrow focused on design research, comprising stakeholder engagement, codesign with user groups, scenario building, studies of users through observation and interview, attitude discovery through traditional and digital means, and dissemination through multiple media. A key motivation was to use autonomous vehicles for social benefit especially for groups ill-served by current transport. The research led to new knowledge about vehicles, systems and behaviours, much of which was distilled into the RCA GATEway report. Additional dissemination included: peer-reviewed journal article in Municipal Engineer (2018); paper at 6th International Conference for Universal Design, Nagoya, Japan (2016); feature in exhibition and book NEW OLD: Designing for Our Future Selves, Design Museum, London (2017); book chapter for Institute of Civil Engineering Publishing (in press); keynote for Seoul Smart Mobility (29 September 2016) as a central part of Seoul Design Week

Stereotactic ablative radiotherapy for the comprehensive treatment of 4-10 oligometastatic tumors (SABR-COMET-10): Study protocol for a randomized phase III trial

Background: Stereotactic ablative radiotherapy (SABR) has emerged as a new treatment option for patients with oligometastatic disease. SABR delivers precise, high-dose, hypofractionated radiotherapy, and achieves excellent rates of local control for primary tumors or metastases. A recent randomized phase II trial evaluated SABR in a group of patients with a small burden of oligometastatic disease (mostly with 1-3 metastatic lesions), and found that SABR was associated with benefits in progression-free survival and overall survival. The goal of this phase III trial is to assess the impact of SABR in patients with 4-10 metastatic cancer lesions. Methods: One hundred and fifty-nine patients will be randomized in a 1:2 ratio between the control arm (consisting of standard of care palliative-intent treatments), and the SABR arm (consisting of standard of care treatment + SABR to all sites of known disease). Randomization will be stratified by two factors: histology (Group 1: prostate, breast, or renal; Group 2: all others), and type of pre-specified systemic therapy (Group 1: immunotherapy/targeted; Group 2: cytotoxic; Group 3: observation). SABR is to be completed within 2 weeks, allowing for rapid initiation of systemic therapy. Recommended SABR doses are 20 Gy in 1 fraction, 30 Gy in 3 fractions, or 35 Gy in 5 fractions, chosen to minimize risks of toxicity. The primary endpoint is overall survival, and secondary endpoints include progression-free survival, time to development of new metastatic lesions, quality of life, and toxicity. Translational endpoints include assessment of circulating tumor cells, cell-free DNA, and tumor tissue as prognostic and predictive markers, including assessment of immunological predictors of response and long-term survival. Discussion: This study will provide an assessment of the impact of SABR on clinical outcomes and quality of life, to determine if long-term survival can be achieved for selected patients with 4-10 oligometastatic lesions. Trial registration: Clinicaltrials.gov identifier: NCT03721341. Date of registration: October 26, 2018

Expert curation of the human and mouse olfactory receptor gene repertoires identifies conserved coding regions split across two exons.

BACKGROUND: Olfactory receptor (OR) genes are the largest multi-gene family in the mammalian genome, with 874 in human and 1483 loci in mouse (including pseudogenes). The expansion of the OR gene repertoire has occurred through numerous duplication events followed by diversification, resulting in a large number of highly similar paralogous genes. These characteristics have made the annotation of the complete OR gene repertoire a complex task. Most OR genes have been predicted in silico and are typically annotated as intronless coding sequences. RESULTS: Here we have developed an expert curation pipeline to analyse and annotate every OR gene in the human and mouse reference genomes. By combining evidence from structural features, evolutionary conservation and experimental data, we have unified the annotation of these gene families, and have systematically determined the protein-coding potential of each locus. We have defined the non-coding regions of many OR genes, enabling us to generate full-length transcript models. We found that 13 human and 41 mouse OR loci have coding sequences that are split across two exons. These split OR genes are conserved across mammals, and are expressed at the same level as protein-coding OR genes with an intronless coding region. Our findings challenge the long-standing and widespread notion that the coding region of a vertebrate OR gene is contained within a single exon. CONCLUSIONS: This work provides the most comprehensive curation effort of the human and mouse OR gene repertoires to date. The complete annotation has been integrated into the GENCODE reference gene set, for immediate availability to the research community

An international expert survey on the indications and practice of radical thoracic reirradiation for non-small cell lung cancer

Purpose: Thoracic re-irradiation for non-small cell lung cancer (NSCLC) with curative intent is potentially associated with severe toxicity. There are limited prospective data on the best method to deliver this treatment. We sought to develop expert consensus guidance on the safe practice of treating NSCLC with radiotherapy in the setting of prior thoracic irradiation. Methods and materials: Twenty-one thoracic radiation oncologists were invited to participate in an international Delphi consensus process. Guideline statements were developed and refined over four rounds on the definition of re-irradiation, appropriate patients and pre-treatment assessments, planning of radiotherapy, and cumulative dose constraints. Consensus was achieved once ≥75% of respondents agreed with a statement. Statements that did not reach consensus in the initial survey rounds were revised based on respondents’ comments and re-presented in subsequent rounds. Results: Fifteen radiation oncologists participated in the four surveys between September 2019 and March 2020. The first three rounds had a 100% response rate, and the final round was completed by 93% of participants. 33 out of 77 statements across all rounds achieved consensus. Key recommendations are: (1) appropriate patients should have a good performance status, can have locally relapsed disease or second primary cancers, and there are no absolute lung function values that preclude re-irradiation; (2) a full diagnostic work-up should be performed in patients with suspected local recurrence and; (3) any re-irradiation should be delivered using optimal image-guidance and highly conformal techniques. In addition, consensus cumulative dose for the organs at risk in the thorax are described. Conclusion: These consensus statements provide practical guidance on appropriate patient selection for re-irradiation, appropriate radiotherapy techniques, and cumulative dose constraints