Abdominal Noncontrast Computed Tomography Scanning to Screen for Kidney Cancer and Other Abdominal Pathology Within Community-based Computed Tomography Screening for Lung Cancer: Results of the Yorkshire Kidney Screening Trial.

BACKGROUND AND OBJECTIVE: The Yorkshire Kidney Screening Trial (YKST) assessed the feasibility of adding abdominal noncontrast computed tomography (NCCT) to lung cancer screening to screen for kidney cancer and other abdominal pathology. METHODS: A prospective diagnostic study offered abdominal NCCT to 55-80-yr-old ever-smokers attending a UK randomised lung cancer screening trial (May 2021 to October 2022). The exclusion criteria were dementia, frailty, previous kidney/lung cancer, and computed tomography (CT) of the abdomen and thorax within previous 6 and 12 mo, respectively. Six-month follow-up was undertaken. KEY FINDINGS AND LIMITATIONS: A total of 4438 people attended lung screening, of whom 4309 (97%) were eligible for and 4019 (93%) accepted abdominal NCCT. Only 3.9% respondents regretted participating. The additional time to conduct the YKST processes was 13.3 min. Of the participants, 2586 (64%) had a normal abdominal NCCT, whilst 787 (20%) required an abdominal NCCT imaging review but no further action and 611 (15%) required further evaluation (investigations and/or clinic). Of the participants, 211 (5.3%) had a new serious finding, including 25 (0.62%) with a renal mass/complex cyst, of whom ten (0.25%) had histologically proven kidney cancer; ten (0.25%) with other cancers; and 60 (1.5%) with abdominal aortic aneurysms (AAAs). Twenty-five (0.62%) participants had treatment with curative intent. Of the participants, 1017 (25%) had nonserious findings, most commonly benign renal cysts (727 [18%]), whereas only 259 (6.4%) had nonserious findings requiring further tests. The number needed to screen to detect one serious abdominal finding was 18; it was 93 to detect one suspicious renal lesion and 402 to detect one histologically confirmed renal cancer. Limitations of the cohort were fixed age range and being prior lung cancer screening attendees. CONCLUSIONS AND CLINICAL IMPLICATIONS: In this first prospective risk-stratified screening study of abdominal NCCT offered alongside CT thorax, uptake and participant satisfaction were high. The prevalence of serious findings, cancers, and AAAs, is in the range of established screening programmes such as bowel cancer. Longer-term outcomes and cost effectiveness should now be evaluated.

Acceptability of adding a non-contrast abdominal CT scan to screen for kidney cancer and other abdominal pathology within a community-based CT screening programme for lung cancer: A qualitative study.

OBJECTIVES: The Yorkshire Kidney Screening Trial (YKST) is a feasibility study of adding non-contrast abdominal CT scanning to screen for kidney cancer and other abdominal malignancies to community-based CT screening for lung cancer within the Yorkshire Lung Screening Trial (YLST). This study explored the acceptability of the combined screening approach to participants and healthcare professionals (HCPs) involved in the trial. METHODS: We conducted semi-structured interviews with eight HCPs and 25 participants returning for the second round of scanning within YLST, 20 who had taken up the offer of the additional abdominal CT scan and five who had declined. Transcripts were analysed using thematic analysis, guided by the Theoretical Framework of Acceptability. RESULTS: Overall, combining the offer of a non-contrast abdominal CT scan alongside the low-dose thoracic CT was considered acceptable to participants, including those who had declined the abdominal scan. The offer of the additional scan made sense and fitted well within the process, and participants could see benefits in terms of efficiency, cost and convenience both for themselves as individuals and also more widely for the NHS. Almost all participants made an instant decision at the point of initial invitation based more on trust and emotions than the information provided. Despite this, there was a clear desire for more time to decide whether to accept the scan or not. HCPs also raised concerns about the burden on the study team and wider healthcare system arising from additional workload both within the screening process and downstream following findings on the abdominal CT scan. CONCLUSIONS: Adding a non-contrast abdominal CT scan to community-based CT screening for lung cancer is acceptable to both participants and healthcare professionals. Giving potential participants prior notice and having clear pathways for downstream management of findings will be important if it is to be offered more widely.

Radiology and multi-scale data integration for precision oncology.

In this Perspective paper we explore the potential of integrating radiological imaging with other data types, a critical yet underdeveloped area in comparison to the fusion of other multi-omic data. Radiological images provide a comprehensive, three-dimensional view of cancer, capturing features that would be missed by biopsies or other data modalities. This paper explores the complexities and challenges of incorporating medical imaging into data integration models, in the context of precision oncology. We present the different categories of imaging-omics integration and discuss recent progress, highlighting the opportunities that arise from bringing together spatial data on different scales.

Management of severe ME/CFS in children and young people in the UK: a British Paediatric Surveillance Unit study.

OBJECTIVE: Severe myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) in children and young people (CYP) is a little-understood condition which significantly impacts education, development and quality of life. We used data from a population-wide surveillance study to explore the screening investigation, referral and management of suspected cases of paediatric severe ME/CFS. METHODS: A British Paediatric Surveillance Unit (BPSU) study reported cases of CYP with suspected severe ME/CFS between February 2018 and February 2019. Paediatricians reporting cases to BPSU and allied healthcare professionals in two large specialist paediatric ME/CFS centres were invited to complete questionnaires for CYP meeting the surveillance case definition. The study focused primarily on CYP with confirmed severe ME/CFS and the extent to which their care met NICE (The National Institute for Health and Care Excellence) recommendations but also considered separately those with probable or possible severe ME/CFS. RESULTS: This study includes a total of 92 CYP with suspected severe ME/CFS; 33 meeting criteria for severe ME/CFS and an additional 59 classified as probable or possible severe ME/CFS. For 16 possible cases, incomplete investigation to exclude alternative diagnoses prevented confirmation of a severe ME/CFS diagnosis. Only 21 of 33 (64%) confirmed severe ME/CFS cases had been referred to specialist services. The management provided varied considerably between patients and four received nothing at all. Of the management provided, the most frequent approaches were medication (67%), activity management (61%) and physiotherapy (61%). Domiciliary assessments and support, and social services referrals were received by 12% and 6% of confirmed severe cases. Similar proportions of management approaches were seen in probable/possible severe ME/CFS. CONCLUSION: Full investigation is frequently incomplete in CYP with suspected severe ME/CFS and recommendations for referral and management are poorly implemented, in particular the needs of CYP who are unable to leave their home might be poorly met.

Short-term psychosocial outcomes of adding a non-contrast abdominal computed tomography (CT) scan to the thoracic CT within lung cancer screening.

OBJECTIVES: To evaluate psychological, social, and financial outcomes amongst individuals undergoing a non-contrast abdominal computed tomography (CT) scan to screen for kidney cancer and other abdominal malignancies alongside the thoracic CT within lung cancer screening. SUBJECTS AND METHODS: The Yorkshire Kidney Screening Trial (YKST) is a feasibility study of adding a non-contrast abdominal CT scan to the thoracic CT within lung cancer screening. A total of 500 participants within the YKST, comprising all who had an abnormal CT scan and a random sample of one-third of those with a normal scan between 14/03/2022 and 24/08/2022 were sent a questionnaire at 3 and 6 months. Outcomes included the Psychological Consequences Questionnaire (PCQ), the short-form of the Spielberger State-Trait Anxiety Inventory, and the EuroQoL five Dimensions five Levels scale (EQ-5D-5L). Data were analysed using regression adjusting for participant age, sex, socioeconomic status, education, baseline quality of life (EQ-5D-5L), and ethnicity. RESULTS: A total of 380 (76%) participants returned questionnaires at 3 months and 328 (66%) at 6 months. There was no difference in any outcomes between participants with a normal scan and those with abnormal scans requiring no further action. Individuals requiring initial further investigations or referral had higher scores on the negative PCQ than those with normal scans at 3 months (standardised mean difference 0.28 sd, 95% confidence interval 0.01-0.54; P = 0.044). The difference was greater in those with anxiety or depression at baseline. No differences were seen at 6 months. CONCLUSION: Screening for kidney cancer and other abdominal malignancies using abdominal CT alongside the thoracic CT within lung cancer screening is unlikely to cause significant lasting psychosocial or financial harm to participants with incidental findings.

Severe myalgic encephalomyelitis/chronic fatigue syndrome in children and young people: a British Paediatric Surveillance Unit study.

OBJECTIVES: Primary objective: to determine the point prevalence and incidence rate of severe myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in children aged 5-16 years over 13 months. SECONDARY OBJECTIVES: to describe the demographic features, symptoms, impact on activities of daily living, school attendance and time to diagnosis. DESIGN: Prospective surveillance study conducted by the British Paediatric Surveillance Unit. Paediatricians was asked if they had assessed a child with severe ME/CFS (screening definition for prevalence and incidence: children (5-16 years) diagnosed with ME/CFS so severe that they are unable to attend school for more than 1 hour a week during the last 6 weeks of the school term). PARTICIPANTS: Patients 5-16 years of age, seen by paediatricians and two large ME/CFS specialist services across the UK and Ireland. OUTCOME MEASURES: Paediatrician-completed questionnaires describing demographics, symptoms, function and treatment, (applying National Institute for Health and Care Excellence (NICE)-recommended criteria to assess severity of ME/CFS). Diagnosis of severe, probable severe or possible severe ME/CFS was made only with evidence of NICE-recommended screening blood tests. RESULTS: 285 cases were reported, of which of which 33 were severe, 4 probable severe and 55 possible severe. Estimated prevalence was 3.2 per million children (95% CI 2.2 to 4.5). Including possible/probable severe ME/CFS gave 8.9 per million children (95% CI 7.2 to 11). The incidence rate was 0.90 per million children-years (95% CI 0.43 to 1.65) (1.97 per million children-years (95% CI 1.24 to 2.99)). Median age was 13 years and 58% of cases were female. Median time to diagnosis was 0.47 years. CONCLUSIONS: Although the incidence of children presenting with severe ME/CFS is low, all were very disabled. In addition, the majority receive little or no education. Paediatricians need to consider how to provide rehabilitation and education for these disabled young people.

The Yorkshire Kidney Screening Trial (YKST): protocol for a feasibility study of adding non-contrast abdominal CT scanning to screen for kidney cancer and other abdominal pathology within a trial of community-based CT screening for lung cancer.

INTRODUCTION: Kidney cancer (renal cell cancer (RCC)) is the seventh most common cancer in the UK. As RCC is largely curable if detected at an early stage and most patients have no symptoms, there is international interest in evaluating a screening programme for RCC. The Yorkshire Kidney Screening Trial (YKST) will assess the feasibility of adding non-contrast abdominal CT scanning to screen for RCC and other abdominal pathology within the Yorkshire Lung Screening Trial (YLST), a randomised trial of community-based CT screening for lung cancer. METHODS AND ANALYSIS: In YLST, ever-smokers aged 55-80 years registered with a general practice in Leeds have been randomised to a Lung Health Check assessment, including a thoracic low-dose CT (LDCT) for those at high risk of lung cancer, or routine care. YLST participants randomised to the Lung Health Check arm who attend for the second round of screening at 2 years without a history of RCC or abdominal CT scan within the previous 6 months will be invited to take part in YKST. We anticipate inviting 4700 participants. Those who consent will have an abdominal CT immediately following their YLST thoracic LDCT. A subset of participants and the healthcare workers involved will be invited to take part in a qualitative interview. Primary objectives are to quantify the uptake of the abdominal CT, assess the acceptability of the combined screening approach and pilot the majority of procedures for a subsequent randomised controlled trial of RCC screening within lung cancer screening. ETHICS AND DISSEMINATION: YKST was approved by the North West-Preston Research Ethics Committee (21/NW/0021), and the Health Research Authority on 3 February 2021. Trial results will be disseminated at clinical meetings, in peer-reviewed journals and to policy-makers. Findings will be made available to participants via the study website (www.YKST.org). TRIAL REGISTRATION NUMBERS: NCT05005195 and ISRCTN18055040.

TET1 and 5-Hydroxymethylation Preserve the Stem Cell State of Mouse Trophoblast.

The ten-eleven translocation factor TET1 and its conferred epigenetic modification 5-hydroxymethylcytosine (5hmC) have important roles in maintaining the pluripotent state of embryonic stem cells (ESCs). We previously showed that TET1 is also essential to maintain the stem cell state of trophoblast stem cells (TSCs). Here, we establish an integrated panel of absolute 5hmC levels, genome-wide DNA methylation and hydroxymethylation patterns, transcriptomes, and TET1 chromatin occupancy in TSCs and differentiated trophoblast cells. We show that the combined presence of 5-methylcytosine (5mC) and 5hmC correlates with transcriptional activity of associated genes. Hypoxia can slow down the global loss of 5hmC that occurs upon differentiation of TSCs. Notably, unlike in ESCs and epiblast cells, most TET1-bound regions overlap with active chromatin marks and TFAP2C binding sites and demarcate putative trophoblast enhancer regions. These chromatin modification and occupancy patterns are highly informative to identify novel candidate regulators of the TSC state.

A Critical Role of TET1/2 Proteins in Cell-Cycle Progression of Trophoblast Stem Cells.

The ten-eleven translocation (TET) proteins are well known for their role in maintaining naive pluripotency of embryonic stem cells. Here, we demonstrate that, jointly, TET1 and TET2 also safeguard the self-renewal potential of trophoblast stem cells (TSCs) and have partially redundant roles in maintaining the epithelial integrity of TSCs. For the more abundantly expressed TET1, we show that this is achieved by binding to critical epithelial genes, notably E-cadherin, which becomes hyper-methylated and downregulated in the absence of TET1. The epithelial-to-mesenchymal transition phenotype of mutant TSCs is accompanied by centrosome duplication and separation defects. Moreover, we identify a role of TET1 in maintaining cyclin B1 stability, thereby acting as facilitator of mitotic cell-cycle progression. As a result, Tet1/2 mutant TSCs are prone to undergo endoreduplicative cell cycles leading to the formation of polyploid trophoblast giant cells. Taken together, our data reveal essential functions of TET proteins in the trophoblast lineage.

The BioMart community portal: an innovative alternative to large, centralized data repositories.

The BioMart Community Portal (www.biomart.org) is a community-driven effort to provide a unified interface to biomedical databases that are distributed worldwide. The portal provides access to numerous database projects supported by 30 scientific organizations. It includes over 800 different biological datasets spanning genomics, proteomics, model organisms, cancer data, ontology information and more. All resources available through the portal are independently administered and funded by their host organizations. The BioMart data federation technology provides a unified interface to all the available data. The latest version of the portal comes with many new databases that have been created by our ever-growing community. It also comes with better support and extensibility for data analysis and visualization tools. A new addition to our toolbox, the enrichment analysis tool is now accessible through graphical and web service interface. The BioMart community portal averages over one million requests per day. Building on this level of service and the wealth of information that has become available, the BioMart Community Portal has introduced a new, more scalable and cheaper alternative to the large data stores maintained by specialized organizations.

Molecular basis of the interactions between the p73 N terminus and p300: effects on transactivation and modulation by phosphorylation.

The transcription factor p73 belongs to the p53 family of proteins and can transactivate a number of target genes in common with p53. Here, we characterized the interaction of the p73 N terminus with four domains of the transcriptional coactivator p300 and with the negative regulator Mdm2 by using biophysical and cellular measurements. We found that, like p53, the N terminus of p73 contained two distinct transactivation subdomains, comprising residues 10-30 and residues 46-67. The p73 N terminus bound weakly to the Taz1, Kix, and IBiD domains of p300 but with submicromolar affinity for Taz2, in contrast to previous reports. We found weaker binding of the p73 N terminus to the p300 domains in vitro correlated with a significant decrease in transactivation activity in a cell line for the QS and T14A mutants, and tighter binding of the phosphomimetic T14D in vitro correlated with an increase in vivo. Further, we found that phosphorylation of T14 increased the affinity of the p73 N terminus for Taz2 10-fold. The phosphomimetic p73alpha T14D caused increased levels of transactivation.

Structure of an unprecedented G-quadruplex scaffold in the human c-kit promoter.

The c-kit oncogene is an important target in the treatment of gastrointestinal tumors. A potential approach to inhibition of the expression of this gene involves selective stabilization of G-quadruplex structures that may be induced to form in the c-kit promoter region. Here we report on the structure of an unprecedented intramolecular G-quadruplex formed by a G-rich sequence in the c-kit promoter in K+ solution. The structure represents a new folding topology with several unique features. Most strikingly, an isolated guanine is involved in G-tetrad core formation, despite the presence of four three-guanine tracts. There are four loops: two single-residue double-chain-reversal loops, a two-residue loop, and a five-residue stem-loop, which contain base-pairing alignments. This unique structural scaffold provides a highly specific platform for the future design of ligands specifically targeted to the promoter DNA of c-kit.