Corrigendum: Homeobox regulator Wilms Tumour 1 is displaced by androgen receptor at cis-regulatory elements in the endometrium of PCOS patients.

[This corrects the article DOI: 10.3389/fendo.2024.1368494.].

Critical values for body mass index related to morbidity in high-volume low-complexity general surgery: a systematic review and meta-analysis.

INTRODUCTION: The aim of this study was to investigate the effect of body mass index (BMI, kg/m2) on outcomes of high-volume low-complexity (HVLC) general surgery procedures and to determine critical values for BMI when selecting patients into HVLC programmes. METHODS: A systematic review was conducted of studies looking at patients in different BMI categories undergoing HVLC general surgery procedures (laparoscopic cholecystectomy, inguinal hernia repair and umbilical or paraumbilical hernia repair), in accordance with the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. A comparison meta-analysis model was constructed to compare the outcomes using random-effects modelling. The QUIPS (Quality In Prognosis Studies) tool and GRADE (Grading of Recommendations Assessment, Development and Evaluation) system were used to assess bias. RESULTS: A total of 26 studies including 486,392 patients were examined. In laparoscopic cholecystectomy, BMI ≥40 was associated with higher conversion to open surgery (odds ratio [OR]: 1.33, p=0.040) but did not affect complications (OR: 0.69, p=0.400) or length of hospital stay (mean difference [MD]: -0.01 days, p=0.900). In inguinal hernia repair, BMI ≥35 was associated with longer operative time (MD: 18.00 minutes, p<0.00001), and higher risk of wound complications (OR: 3.01, p<0.00001) and hospital readmission (OR: 1.46, p=0.0008). In umbilical or paraumbilical hernia repair, BMI ≥30 was associated with higher risk of wound complications (OR: 6.45, p<0.0001) and hospital readmission (OR: 5.56, p<0.00001), and longer operative time (MD: 4.01 minutes, p=0.030). CONCLUSIONS: Obesity was associated with longer operative time (up to 23 minutes) and higher risk of postoperative morbidity (up to 4-fold) in HVLC procedures. BMI <40 (moderate GRADE certainty - laparoscopic cholecystectomy) and BMI <35 (moderate GRADE certainty - inguinal hernia) appear to represent optimal critical values for perioperative safety metrics.

Editorial: Open science and methods review for Child and Adolescent Mental Health.

This editorial introduces the journal's new open data policy for original articles using quantitative data. It discusses key opportunities from data and code sharing. It further briefly sets out the new methods review that articles which use quantitative analysis will automatically undergo. With both changes we hope to strengthen our review process and contribute to a better evidence base in the field.

Homeobox regulator Wilms Tumour 1 is displaced by androgen receptor at cis-regulatory elements in the endometrium of PCOS patients.

Decidualisation, the process whereby endometrial stromal cells undergo morphological and functional transformation in preparation for trophoblast invasion, is often disrupted in women with polycystic ovary syndrome (PCOS) resulting in complications with pregnancy and/or infertility. The transcription factor Wilms tumour suppressor 1 (WT1) is a key regulator of the decidualization process, which is reduced in patients with PCOS, a complex condition characterized by increased expression of androgen receptor in endometrial cells and high presence of circulating androgens. Using genome-wide chromatin immunoprecipitation approaches on primary human endometrial stromal cells, we identify key genes regulated by WT1 during decidualization, including homeobox transcription factors which are important for regulating cell differentiation. Furthermore, we found that AR in PCOS patients binds to the same DNA regions as WT1 in samples from healthy endometrium, suggesting dysregulation of genes important to decidualisation pathways in PCOS endometrium due to competitive binding between WT1 and AR. Integrating RNA-seq and H3K4me3 and H3K27ac ChIP-seq metadata with our WT1/AR data, we identified a number of key genes involved in immune response and angiogenesis pathways that are dysregulated in PCOS patients. This is likely due to epigenetic alterations at distal enhancer regions allowing AR to recruit cofactors such as MAGEA11, and demonstrates the consequences of AR disruption of WT1 in PCOS endometrium.

Sex-dependent interactions between prodromal intestinal inflammation and LRRK2 G2019S in mice promote endophenotypes of Parkinson's disease.

Gastrointestinal (GI) disruptions and inflammatory bowel disease (IBD) are commonly associated with Parkinson's disease (PD), but how they may impact risk for PD remains poorly understood. Herein, we provide evidence that prodromal intestinal inflammation expedites and exacerbates PD endophenotypes in rodent carriers of the human PD risk allele LRRK2 G2019S in a sex-dependent manner. Chronic intestinal damage in genetically predisposed male mice promotes α-synuclein aggregation in the substantia nigra, loss of dopaminergic neurons and motor impairment. This male bias is preserved in gonadectomized males, and similarly conferred by sex chromosomal complement in gonadal females expressing human LRRK2 G2019S. The early onset and heightened severity of neuropathological and behavioral outcomes in male LRRK2 G2019S mice is preceded by increases in α-synuclein in the colon, α-synuclein-positive macrophages in the colonic lamina propria, and loads of phosphorylated α-synuclein within microglia in the substantia nigra. Taken together, these data reveal that prodromal intestinal inflammation promotes the pathogenesis of PD endophenotypes in male carriers of LRRK2 G2019S, through mechanisms that depend on genotypic sex and involve early accumulation of α-synuclein in myeloid cells within the gut.

Malnutrition, sarcopenia and cachexia: exploring prevalence, overlap, and perceptions in older adults with cancer.

BACKGROUND: Older adults with cancer are a growing population requiring tailored care to achieve optimum treatment outcomes. Their care is complicated by under-recognised and under-treated wasting disorders: malnutrition, sarcopenia, and cachexia. We aimed to investigate the prevalence, overlap, and patients' views and experiences of malnutrition, sarcopenia, and cachexia, in older adults with cancer. METHODS: Mixed-methods study with cross-sectional study and qualitative interviews. Interviews were thematically analysed through a phenomenological lens, with feedback loop analysis investigating relationships between themes and findings synthesised using modified critical interpretative synthesis. FINDINGS: n = 30 were screened for malnutrition, sarcopenia, and cachexia, n = 8 completed semi-structured interviews. Eighteen (60.0%) were malnourished, 16 (53.3%) sarcopenic, and 17 (56.7%) cachexic. One or more condition was seen in 80%, and all three in 30%. In univariate analysis, Rockwood clinical frailty score (OR 2.94 [95% CI: 1.26-6.89, p = 0.013]) was associated with sarcopenia, reported percentage meal consumption (OR 2.28 [95% CI: 1.24-4.19, p = 0.008]), and visible wasting (OR 8.43 [95% CI: 1.9-37.3] p = 0.005) with malnutrition, and percentage monthly weight loss (OR 8.71 [95% CI: 1.87-40.60] p = 0.006) with cachexia. Screening tools identified established conditions rather than 'risk'. Nutritional and functional problems were often overlooked, overshadowed, and misunderstood by both patients and (in patients' perceptions) by clinicians; misattributed to ageing, cancer, or comorbidities. Patients viewed these conditions as both personal impossibilities, yet accepted inevitabilities. CONCLUSION: Perceptions, identification, and management of these conditions needs to improve, and their importance recognised by clinicians and patients so those truly 'at risk' are identified whilst conditions are more remediable to interventions.

Transcriptomic analysis reveals the anti-cancer effect of gestational mesenchymal stem cell secretome.

The environment created during embryogenesis contributes to reducing aberrations that drive structural malformations and tumorigenesis. In this study, we investigate the anti-cancer effect of mesenchymal stem cells (MSCs) derived from 2 different gestational tissues, the amniotic fluid (AF) and the chorionic villi (CV), with emphasis on their secretome. Transcriptomic analysis was performed on patient-derived AF- and CV-MSCs collected during prenatal diagnosis and identified both mRNAs and lncRNAs, involved in tissue homeostasis and inhibiting biological processes associated with the etiology of aggressive cancers while regulating immune pathways shown to be important in chronic disorders. Secretome enrichment analysis also identified soluble moieties involved in target cell regulation, tissue homeostasis, and cancer cell inhibition through the highlighted Wnt, TNF, and TGF-ß signaling pathways. Transcriptomic data were experimentally confirmed through in vitro assays, by evaluating the anti-cancer effect of the media conditioned by AF- and CV-MSCs and the exosomes derived from them on ovarian cancer cells, revealing inhibitory effects in 2D (by reducing cell viability and inducing apoptosis) and in 3D conditions (by negatively interfering with spheroid formation). These data provide molecular insights into the potential role of gestational tissues-derived MSCs as source of anti-cancer factors, paving the way for the development of therapeutics to create a pro-regenerative environment for tissue restoration following injury, disease, or against degenerative disorders.

Neutron source reconstruction using a generalized expectation-maximization algorithm on one-dimensional neutron images from the Z facility.

Magnetized Liner Inertial Fusion experiments have been performed at the Z facility at Sandia National Laboratories. These experiments use deuterium fuel, which produces 2.45 MeV neutrons on reaching thermonuclear conditions. To study the spatial structure of neutron production, the one-dimensional imager of neutrons diagnostic was fielded to record axial resolved neutron images. In this diagnostic, neutrons passing through a rolled edge aperture form an image on a CR-39-based solid state nuclear track detector. Here, we present a modified generalized expectation-maximization algorithm to reconstruct an axial neutron emission profile of the stagnated fusion plasma. We validate the approach by comparing the reconstructed neutron emission profile to an x-ray emission profile provided by a time-integrated pinhole camera.

The validity of the selection methods for recruitment to UK core psychiatry training: cohort study.

AIMS AND METHOD: Selection into core psychiatry training in the UK uses a computer-delivered Multi-Specialty Recruitment Assessment (MSRA; a situational judgement and clinical problem-solving test) and, previously, a face-to-face Selection Centre. The Selection Centre assessments were suspended during the COVID-19 pandemic. We aimed to evaluate the validity of this selection process using data on 3510 psychiatry applicants. We modelled the ability of the selection scores to predict subsequent performance in the Clinical Assessment of Skills and Competencies (CASC). Sensitivity to demographic characteristics was also estimated. RESULTS: All selection assessment scores demonstrated positive, statistically significant, independent relationships with CASC performance and were sensitive to demographic factors. IMPLICATIONS: All selection components showed independent predictive validity. Re-instituting the Selection Centre assessments could be considered, although the costs, potential advantages and disadvantages should be weighed carefully.

Validation of a real-time polymerase chain reaction for the detection and quantification of the nucleic acid of Histoplasma from equine clinical samples.

Histoplasma capsulatum var. farciminosum (HCF) is a dimorphic fungus that causes epizootic lymphangitis in equids. Current diagnostic approaches, including culture, microscopy, and clinical presentation, lack speed, sensitivity, and specificity when diagnosing clinical cases. In this study, equine blood and pus samples on Whatman FTA cards from Senegal (n = 3), The Gambia (n = 19), Ethiopia (n = 16), and Mali (n = 13) were tested using a real-time PCR (qPCR) protocol. The assay was optimized and tested for its suitability to detect and quantify HCF in blood and pus loaded onto Whatman FTA cards at sampling. Whatman FTA cards were tested for their suitability for use with qPCR and were found to recover DNA more efficiently than from direct extraction. Using TaqMan fluorescent probes and specific primers, the assay demonstrated 100% analytical specificity when detecting multiple strains of Histoplasma and no false positives with off-target organisms. The assay's diagnostic performance was measured against an existing nested internal transcribed spacer PCR protocol using a receiver operating characteristic curve. The test was found to have a diagnostic specificity and sensitivity of 100% and 71.4%, respectively, when analyzing pus samples using a cycle threshold (Ct) cutoff determined by Youden's index (27.75). Blood sample cutoff Ct value was proposed at 34.55. Further optimization is required to improve the performance of the protocol when applied to blood samples. This study has, for the first time, demonstrated the ability to detect and quantify the DNA of Histoplasma spp. in equine blood and pus samples with a high degree of accuracy, providing a platform to further investigate the pathogenesis and epidemiology of this disease. IMPORTANCE: Histoplasmosis is a neglected yet major cause of morbidity and mortality in both equids and people in resource-scarce settings. One of the major hindrances to the control of histoplasmosis is a lack of readily available diagnostic tests. Tests are needed to support clinical decision-making and to be applied in population-based research to further understand this disease in situ. This paper reports, for the first time, the validation and application of a qPCR to detect Histoplasma directly from equine clinical samples, bypassing the need to culture this notoriously difficult organism. We report and comment on the performance of the qPCR in comparison with our previously developed nested PCR.

New evidence on the validity of the selection methods for recruitment to general practice training: a cohort study.

BACKGROUND: Selection into UK-based GP training has used the Multi-Specialty Recruitment Assessment (MSRA) and a face-to-face selection centre (SC). The MSRA comprises of a situational judgement test and clinical problem-solving test. The SC was suspended during the COVID-19 pandemic. Evidence is needed to guide national and international selection policy. AIM: To evaluate the validity of GP training selection. DESIGN & SETTING: A retrospective cohort study using data from UK-based national recruitment to GP training, from 2015-2021. METHOD: Data were available for 32 215 GP training applicants. The ability of scores from the specialty selection process to predict subsequent performance in the Clinical Skills Assessment (CSA) of the Membership of the Royal College of General Practitioners examination was modelled using path analysis. The effect sizes for sex, professional family background, and world region of qualification were estimated. RESULTS: All component scores of the selection process demonstrated statistically significant independent relationships with CSA performance (P<0.001), thus establishing their predictive validity. All were sensitive to demographic factors. The SC scores had the weakest relationship with future CSA performance. However, for candidates with MSRA scores below the lowest quartile, the relative contribution of the SC scores to predicting CSA performance was similar to that observed for MSRA components. CONCLUSION: The MSRA has predictive validity in this context. Re-instituting an SC for those with relatively low MSRA scores should be considered. However, the relative costs and potential advantages and disadvantages should be carefully weighed.

p-tau Ser356 is associated with Alzheimer's disease pathology and is lowered in brain slice cultures using the NUAK inhibitor WZ4003.

Tau hyperphosphorylation and aggregation is a common feature of many dementia-causing neurodegenerative diseases. Tau can be phosphorylated at up to 85 different sites, and there is increasing interest in whether tau phosphorylation at specific epitopes, by specific kinases, plays an important role in disease progression. The AMP-activated protein kinase (AMPK)-related enzyme NUAK1 has been identified as a potential mediator of tau pathology, whereby NUAK1-mediated phosphorylation of tau at Ser356 prevents the degradation of tau by the proteasome, further exacerbating tau hyperphosphorylation and accumulation. This study provides a detailed characterisation of the association of p-tau Ser356 with progression of Alzheimer's disease pathology, identifying a Braak stage-dependent increase in p-tau Ser356 protein levels and an almost ubiquitous presence in neurofibrillary tangles. We also demonstrate, using sub-diffraction-limit resolution array tomography imaging, that p-tau Ser356 co-localises with synapses in AD postmortem brain tissue, increasing evidence that this form of tau may play important roles in AD progression. To assess the potential impacts of pharmacological NUAK inhibition in an ex vivo system that retains multiple cell types and brain-relevant neuronal architecture, we treated postnatal mouse organotypic brain slice cultures from wildtype or APP/PS1 littermates with the commercially available NUAK1/2 inhibitor WZ4003. Whilst there were no genotype-specific effects, we found that WZ4003 results in a culture-phase-dependent loss of total tau and p-tau Ser356, which corresponds with a reduction in neuronal and synaptic proteins. By contrast, application of WZ4003 to live human brain slice cultures results in a specific lowering of p-tau Ser356, alongside increased neuronal tubulin protein. This work identifies differential responses of postnatal mouse organotypic brain slice cultures and adult human brain slice cultures to NUAK1 inhibition that will be important to consider in future work developing tau-targeting therapeutics for human disease.

Life-Threatening Hematuria as Initial Presentation of a Complicated Transplant Renal Artery Pseudoaneurysm.

In this case report, we describe the clinical course of a complicated transplant renal artery (TRA) pseudoaneurysm, clinically featured by gross and massive hematuria one month after a kidney transplant was performed on a 50 year-old male patient. TRA pseudoaneurysm is a rare but potentially life-threatening complication that may result in bleeding, infection, graft dysfunction/loss, lower limb ischemia/loss, hemorrhagic shock, and death. TRA pseudoaneurysm treatment remains challenging as it needs to be tailored to the patient characteristics including hemodynamic stability, graft function, anatomy, presentation, and pseudoaneurysm features. This publication discusses the clinical scenario of massive gross hematuria that derived from a retroperitoneal hematoma which originated from an actively bleeding TRA pseudoaneurysm. This case highlights the combined approach of endovascular stent placement and subsequent transplant nephrectomy as a last resort in the management of intractable bleeding from a complicated TRA pseudoaneurysm. To the best of our knowledge, this is the first published case report of an actively bleeding TRA anastomotic pseudoaneurysm that caused a massive retroperitoneal bleed that in turn evacuated via the bladder after disrupting the ureter-to-bladder anastomosis. A temporizing hemostatic arterial stent placed percutaneously allowed for a safer and controlled emergency transplant nephrectomy.

Advanced data analysis in inertial confinement fusion and high energy density physics.

Bayesian analysis enables flexible and rigorous definition of statistical model assumptions with well-characterized propagation of uncertainties and resulting inferences for single-shot, repeated, or even cross-platform data. This approach has a strong history of application to a variety of problems in physical sciences ranging from inference of particle mass from multi-source high-energy particle data to analysis of black-hole characteristics from gravitational wave observations. The recent adoption of Bayesian statistics for analysis and design of high-energy density physics (HEDP) and inertial confinement fusion (ICF) experiments has provided invaluable gains in expert understanding and experiment performance. In this Review, we discuss the basic theory and practical application of the Bayesian statistics framework. We highlight a variety of studies from the HEDP and ICF literature, demonstrating the power of this technique. Due to the computational complexity of multi-physics models needed to analyze HEDP and ICF experiments, Bayesian inference is often not computationally tractable. Two sections are devoted to a review of statistical approximations, efficient inference algorithms, and data-driven methods, such as deep-learning and dimensionality reduction, which play a significant role in enabling use of the Bayesian framework. We provide additional discussion of various applications of Bayesian and machine learning methods that appear to be sparse in the HEDP and ICF literature constituting possible next steps for the community. We conclude by highlighting community needs, the resolution of which will improve trust in data-driven methods that have proven critical for accelerating the design and discovery cycle in many application areas.

Transcriptomic analysis of stem cells from chorionic villi uncovers the impact of chromosomes 2, 6 and 22 in the clinical manifestations of Down syndrome.

BACKGROUND: Down syndrome (DS) clinical multisystem condition is generally considered the result of a genetic imbalance generated by the extra copy of chromosome 21. Recent discoveries, however, demonstrate that the molecular mechanisms activated in DS compared to euploid individuals are more complex than previously thought. Here, we utilize mesenchymal stem cells from chorionic villi (CV) to uncover the role of comprehensive functional genomics-based understanding of DS complexity. METHODS: Next-generation sequencing coupled with bioinformatic analysis was performed on CV obtained from women carrying fetuses with DS (DS-CV) to reveal specific genome-wide transcriptional changes compared to their euploid counterparts. Functional assays were carried out to confirm the biological processes identified as enriched in DS-CV compared to CV (i.e., cell cycle, proliferation features, immunosuppression and ROS production). RESULTS: Genes located on chromosomes other than the canonical 21 (Ch. 2, 6 and 22) are responsible for the impairment of life-essential pathways, including cell cycle regulation, innate immune response and reaction to external stimuli were found to be differentially expressed in DS-CV. Experimental validation confirmed the key role of the biological pathways regulated by those genes in the etiology of such a multisystem condition. CONCLUSIONS: NGS dataset generated in this study highlights the compromised functionality in the proliferative rate and in the innate response of DS-associated clinical conditions and identifies DS-CV as suitable tools for the development of specifically tailored, personalized intervention modalities.

Product promotions in online supermarkets: prevalence of 'High Fat Sugar Salt' (HFSS) products and labelling characteristics.

OBJECTIVE: To evaluate the prevalence of 'High Fat Sugar Salt' (HFSS) products and front-of-pack nutrition labelling (FOPNL) characteristics across promoted products in UK online supermarkets. DESIGN: A cross-sectional survey conducted (December 2021-January 2022) on promoted products. Data on ingredients, nutritional composition and display of FOPNL were collected from product webpages. The UK's Nutrient Profiling Model and Multiple Traffic Light criteria were used to determine HFSS status and possession of inherent red traffic lights (iRTL), respectively. Data analysis determined the prevalence (i.e. percentage of products of the total number of products sampled) of HFSS; FOPNL and possession of iRTL. Chi-squared tests explored associations between these. SETTING: Three major UK online supermarket retailer websites. PARTICIPANTS: Product 'multibuy' and 'entrance' promotions, from selected product categories. RESULTS: Among the sampled 625 promoted products, the prevalence of HFSS was greater in entrance (73 %) compared with multibuy (41 %) promotions (χ2 (1) = 34, P < 0·05), with variations in the former across retailers (49-92 %). The prevalence of HFSS products in multibuy promotions offered by two retailers varied by category (i.e. Confectionery 94-97 %, Yogurts 20-20 %, Soft Drinks 16-33 %, Ready Meals 1·4-18 %). Not all promoted products displayed FOPNL on webpages (70 %) or images (52 %). A number of iRTL were found to be possessed by both HFSS and non-HFSS-promoted products. CONCLUSIONS: Prior to the 2022 implementation of Regulations restricting these, HFSS products were promoted in online supermarkets with varying display of FOPNL and possession of iRTL. Findings support future policy evaluation and mandatory digital FOPNL.

Mental health trajectories in university students across the COVID-19 pandemic: findings from the Student Wellbeing at Northern England Universities prospective cohort study.

Introduction: Psychological wellbeing in university students is receiving increased focus. However, to date, few longitudinal studies in this population have been conducted. As such, in 2019, we established the Student Wellbeing At Northern England Universities (SWANS) cohort at the University of York, United Kingdom aiming to measure student mental health and wellbeing every six months. Furthermore, the study period included the COVID-19 pandemic, giving an opportunity to track student wellbeing over time, including over the pandemic. Methods: Eligible participants were invited to participate via email. Data were collected, using Qualtrics, from September 2019 to April 2021, across five waves (W1 to W5). In total, n = 4,622 students participated in at least one wave of the survey. Data collection included sociodemographic, educational, personality measures, and mental health and wellbeing. Latent profile analyses were performed, exploring trajectories of student wellbeing over the study period for those who had completed at least three of the five waves of the survey (n = 765), as measured by the Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS). Results: Five latent profile trajectories of student wellbeing were identified. Of these, the two latent classes with initially higher wellbeing scores had broadly stable wellbeing across time (total n = 505, 66%). Two classes had lower initial scores, which lowered further across time (total n = 227, 30%). Additionally, a fifth class of students was identified who improved substantially over the study period, from a mean WEMWBS of 30.4 at W1, to 49.4 at W5 (n = 33, 4%). Risk factors for having less favourable wellbeing trajectories generally included identifying as LGBT+, self-declaring a disability, or previously being diagnosed with a mental health condition. Conclusion: Our findings suggest a mixed picture of the effect of the COVID-19 pandemic on student wellbeing, with a majority showing broadly consistent levels of wellbeing across time, a smaller but still substantial group showing a worsening of wellbeing, and a small group that showed a very marked improvement in wellbeing. Those from groups traditionally underrepresented in higher education were most at risk of poorer wellbeing. This raises questions as to whether future support for wellbeing should target specific student subpopulations.

Demonstration of improved laser preheat with a cryogenically cooled magnetized liner inertial fusion platform.

We report on progress implementing and testing cryogenically cooled platforms for Magnetized Liner Inertial Fusion (MagLIF) experiments. Two cryogenically cooled experimental platforms were developed: an integrated platform fielded on the Z pulsed power generator that combines magnetization, laser preheat, and pulsed-power-driven fuel compression and a laser-only platform in a separate chamber that enables measurements of the laser preheat energy using shadowgraphy measurements. The laser-only experiments suggest that ∼89% ± 10% of the incident energy is coupled to the fuel in cooled targets across the energy range tested, significantly higher than previous warm experiments that achieved at most 67% coupling and in line with simulation predictions. The laser preheat configuration was applied to a cryogenically cooled integrated experiment that used a novel cryostat configuration that cooled the MagLIF liner from both ends. The integrated experiment, z3576, coupled 2.32 ± 0.25 kJ preheat energy to the fuel, the highest to-date, demonstrated excellent temperature control and nominal current delivery, and produced one of the highest pressure stagnations as determined by a Bayesian analysis of the data.

In silico enhancer mining reveals SNS-032 and EHMT2 inhibitors as therapeutic candidates in high-grade serous ovarian cancer.

BACKGROUND: Epigenomic dysregulation has been linked to solid tumour malignancies, including ovarian cancers. Profiling of re-programmed enhancer locations associated with disease has the potential to improve stratification and thus therapeutic choices. Ovarian cancers are subdivided into histological subtypes that have significant molecular and clinical differences, with high-grade serous carcinoma representing the most common and aggressive subtype. METHODS: We interrogated the enhancer landscape(s) of normal ovary and subtype-specific ovarian cancer states using publicly available data. With an initial focus on H3K27ac histone mark, we developed a computational pipeline to predict drug compound activity based on epigenomic stratification. Lastly, we substantiated our predictions in vitro using patient-derived clinical samples and cell lines. RESULTS: Using our in silico approach, we highlighted recurrent and privative enhancer landscapes and identified the differential enrichment of a total of 164 transcription factors involved in 201 protein complexes across the subtypes. We pinpointed SNS-032 and EHMT2 inhibitors BIX-01294 and UNC0646 as therapeutic candidates in high-grade serous carcinoma, as well as probed the efficacy of specific inhibitors in vitro. CONCLUSION: Here, we report the first attempt to exploit ovarian cancer epigenomic landscapes for drug discovery. This computational pipeline holds enormous potential for translating epigenomic profiling into therapeutic leads.

Bromodomain inhibitor i-BET858 triggers a unique transcriptional response coupled to enhanced DNA damage, cell cycle arrest and apoptosis in high-grade ovarian carcinoma cells.

BACKGROUND: Ovarian cancer has a specific unmet clinical need, with a persistently poor 5-year survival rate observed in women with advanced stage disease warranting continued efforts to develop new treatment options. The amplification of BRD4 in a significant subset of high-grade serous ovarian carcinomas (HGSC) has led to the development of BET inhibitors (BETi) as promising antitumour agents that have subsequently been evaluated in phase I/II clinical trials. Here, we describe the molecular effects and ex vivo preclinical activities of i-BET858, a bivalent pan-BET inhibitor with proven in vivo BRD inhibitory activity. RESULTS: i-BET858 demonstrates enhanced cytotoxic activity compared with earlier generation BETis both in cell lines and primary cells derived from clinical samples of HGSC. At molecular level, i-BET858 triggered a bipartite transcriptional response, comprised of a 'core' network of genes commonly associated with BET inhibition in solid tumours, together with a unique i-BET858 gene signature. Mechanistically, i-BET858 elicited enhanced DNA damage, cell cycle arrest and apoptotic cell death compared to its predecessor i-BET151. CONCLUSIONS: Overall, our ex vivo and in vitro studies indicate that i-BET858 represents an optimal candidate to pursue further clinical validation for the treatment of HGSC.