A role for SOX9 and Wnt-related proteins in endometrial adenocarcinoma

Introduction: Endometrial carcinoma is already the most common gynaecological malignancy in the developed world, and by 2015 the incidence is set to be twice that of 2005. Despite this, therapeutic options available for advanced disease are very limited. The canonical Wnt/β-catenin pathway is known to have a key role in homeostasis of normal endometrial cellular proliferation and differentiation, and is also implicated in endometrial proliferative conditions such as carcinogenesis. SOX9 is a postulated Wnt-regulator and may play a key role in establishment and maintenance of characteristic phenotypes of glandular cells during the menstrual cycle. The interaction of Wnt/β-catenin pathway and SOX9 in the endometrium is not known, neither are the effects of ovarian steroids on these pathways and proteins fully elucidated. The expression of a panel of Wnt-related proteins in endometrial cancer tissue samples was compared to normal pre- and post-menopausal endometrium. Further in vitro work investigated the effect of ovarian steroid hormones on SOX9 and steroid receptor expression in a well characterised, well differentiated endometrial carcinoma cell line Ishikawa. Methods: 51 primary endometrial samples (31 endometrial adenocarcinomas (EC), 10 normal proliferative phase (PP) and 10 normal post-menopausal (PM)) were assessed for the expression of SOX9, Ki67, β-catenin, SOX2, SFRS2, and NAP1L1 using immunohistochemistry. The Ishikawa cell line was maintained in phenol-free charcoal stripped media for 72 hours, and then treated with ovarian steroids: estradiol (E2), medroxyprogesterone acetate (MPA), E2 + MPA, basic fibroblast growth factor (FGF), and 5-alpha-dihydrotestosterone (DHT) for 72 hours. RT-PCR was performed for oestrogen receptor α (ER), progesterone receptor (PR), and SOX9. Statistical analysis used the Mann-Whitney and Spearman Rank tests. Results: Nuclear β-catenin was correlated with the Wnt-related proteins SOX2 (p=0.025), NAP1L1 (p=0.046) and SFRS2 (p=0.032). However, none of these proteins demonstrated significantly different expression across the groups. The expression of SOX9 was significantly lower in the proliferative tissues (PP and EC) than the atrophic PM (

Quantitation of amino acids in diverse mammalian cell culture media types with the REBEL at-line analyzer

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Cancer screening attendance rates in transgender and gender-diverse patients: a systematic review and meta-analysis

Objectives: To examine disparities in attendance rates at cancer screening services between transgender and gender-diverse (TGD) people in comparison with their cisgender (CG) counterparts, and to determine whether these differences were based on the anatomical organ screened. Design: Systematic review and meta-analysis. Data sources: PubMed, EMBASE [via Ovid], CINAHL Complete [via EBSCO], and Cochrane Library from inception to 30 September 2023. Methods: Studies for inclusion were case-control or cross-sectional studies with quantitative data investigated TGD adults attending any cancer screening service. Exclusion criteria were studies with participants who were ineligible for cancer screening or without samples from TGD individuals, qualitative data, and a cancer diagnosis from symptomatic presentation or incidental findings. A modified Newcastle-Ottawa Scale was used to assess risk of bias, during which seven reports were found incompatible with the inclusion criteria and excluded. Results were synthesised through random-effects meta-analysis and narrative synthesis. Results: We identified 25 eligible records, of which 18 were included in the analysis. These were cross-sectional studies, including retrospective chart reviews and survey analyses, and encompassed over 14.8 million participants. The main outcomes measured were up-to-date (UTD) and lifetime (LT) attendance. Meta-analysis found differences for UTD cervical (OR=0.37, 95% CI [0.23, 0.60], p<0.0001) and mammography (OR=0.41, 95% CI [0.20, 0.87], p=0.02) but not for prostate or colorectal screening. There were no meaningful differences seen in LT attendance based on quantitative synthesis. Narrative synthesis of the seven remaining articles mostly supported the meta-analysis. Reduced rates of screening engagement in TGD participants were found for UTD cervical and mammography screening, alongside LT mammography screening. Conclusions: Compared to their CG counterparts, TGD individuals had lower rates of utilising cervical and mammography screening at the recommended frequencies but displayed similar prevalences of LT attendance. The greatest disparity was seen in UTD cervical screening. Limitations of this review included high risk of bias within studies, high heterogeneity, and a lack of resources for further statistical testing. Bridging gaps in healthcare to improve cancer screening experiences and outcomes will require consolidated efforts including working with the TGD community. Funding: This work was supported by the INSPIRE grant generously awarded to the Hull York Medical School by the Academy of Medical Sciences through the Wellcome Trust [Ref: IR5\1018]. Systematic review registration: PROSPERO CRD42022368911

The role of maternal stress in early pregnancy in the aetiology of gastroschisis : An incident case control study

We wish to thank all the women who took the time to take part in this study, the research nurses who undertook interviews and data collection: Sandra Edwards-Fenton, Anne Chamberlain, Marit Bodley, Sharon Brown, Isobel Clegg, Catherine Collins and the British Isles Network of Congenital Anomaly Registers (BINOCAR) for their support in facilitating this study.Peer reviewedPublisher PD

Accuracy and utility of blood and urine biomarkers for the non-invasive diagnosis of endometriosis: a systematic literature review and meta-analysis

ObjectiveEndometriosis is a chronic, incurable condition associated with debilitating pain and subfertility affecting over 190 million women worldwide which has no reliable non-invasive diagnostic tool. We aimed to determine the state-of-the-art in non-invasive liquid biopsy biomarker detection and predict the most promising biomarkers for endometriosis detection.Evidence ReviewA systematic review of the literature following the PRISMA guidelines was conducted using the Pubmed, Medline, Scopus and Cochrane Library databases was conducted. Primary research studies examining blood or urine biomarkers in humans published in English up until August 2022 were included. Studies with more than 10 patients including clear methodology and surgical staging of endometriosis were included, whereas studies which included gynaecological malignancies or who did not perform laparoscopy in the control group were excluded. The articles were assessed for the risk of bias using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. One investigator extracted the data and two investigators checked the accuracy. Extracted data were analysed descriptively, Box-plots of pooled data were calculated using R-studio and likelihood ratios were determined.ResultsA total of 8244 and 3619 manuscripts for blood and urine biomarkers were identified. Following screening based on title, abstract, full-text and quality assurance, 18 of these studies assessing blood biomarkers and 15 examining urine biomarkers were eligible for data extraction. However, there were inconsistencies in the results indicating that standardised techniques would be essential for direct comparisons to be made in the future. In four of the eligible studies, the urinary biomarkers were juxtaposed with blood markers, but in most cases, the combination of blood and/or urine biomarkers resulted in an increase in the AUC value, sensitivity, and specificity. One study presented biomarkers with a likelihood ratio (LR) above 10. However, as yet, none of the biomarkers have been shown to be clinically useful, and further research is necessary in order to determine their utility in clinical practice.ConclusionThere are multiple biomarkers described here that provide exciting avenues for further study particularly as part of diagnostic panels, including the endometrial antigens TPM3, SLP2 and TMOD3, microRNAs and interleukins. There is a need for standardised protocols to be used in order to achieve consistent, reproducible results that will facilitate the development of a clinically applicable non-invasive test for endometriosis

Donating a kidney to a stranger : a review of the benefits and controversies of unspecified kidney donation

Summary of Background Data: Unspecified kidney donation (UKD) describes living donation of a kidney to a stranger. The practice is playing an increasingly important role within the transplant programme in the United Kingdom, where these donors are commonly used to trigger a chain of transplants; thereby amplifying the benefit derived from their donation. The initial reluctance to accept UKD was in part due to uncertainty about donor motivations and whether the practice was morally and ethically acceptable. Objectives: This article provides an overview of UKD and answers common questions regarding the ethical considerations, clinical assessment, and how UKD kidneys are used to maximize utility. Existing literature on outcomes after UKD is also discussed, along with current controversies. Conclusions: We believe UKD is an ethically acceptable practice which should continue to grow, despite its controversies. In our experience, these donors are primarily motivated by a desire to help others and utilization of their kidney as part of a sharing scheme means that many more people seek to benefit from their very generous donation

Microplastics in human urine: characterisation using µFTIR and sampling challenges using healthy donors and endometriosis participants.

Microplastics (MPs) are found in all environments, within the human food chain, and have been recently detected in several human tissues. The objective herein was to undertake an analysis of MP contamination in human urine samples, from healthy individuals and participants with endometriosis, with respect to their presence, levels, and the characteristics of any particles identified. A total of 38 human urine samples and 15 procedural blanks were analysed. MPs were characterised using μFTIR spectroscopy (size limitation of 5 μm) and SEM-EDX. In total, 123 MP particles consisting of 22 MP polymer types were identified within 17/29 of the healthy donor (10 mL) urine samples, compared with 232 MP particles of differing 16 MP polymer types in 12/19 urine samples from participants with endometriosis, with an unadjusted average of 2589 ± 2931 MP/L and 4724 ± 9710 MP/L respectively. Of the MPs detected, polyethylene (PE)(27%), polystyrene (PS)(16%), resin and polypropylene (PP)(both 12%) polymer types were most abundant in healthy donor samples, compared with polytetrafluoroethylene (PTFE) (59%), and PE (16%) in samples from endometriosis participants. The MP levels within healthy and endometriosis participant samples were not significantly different. However, the predominant polymer types varied, and the MPs from the metal catheter-derived endometriosis participant samples and healthy donors were significantly smaller than those observed in the procedural blanks. The procedural blank samples comprised 62 MP particles of 10 MP polymer types, mainly PP (27%), PE (21%), and PS (15%) with a mean ± SD of 17 ± 18, highlighting the unavoidable contamination inherent in measurement of MPs from donors. This is the first evidence of MP contamination in human urine with polymer characterisation and accounting for procedural blanks. These results support the phenomenon of transport of MPs within humans, specifically to the bladder, and their characterisation of types, shapes and size ranges identified therein

Experiences of completed and withdrawn unspecified kidney donor candidates in the UK : an inductive thematic analysis from the BOUnD study

Objectives: This study sheds light on some controversial aspects of unspecified kidney donation (UKD) as well as the ways in which potential donors are screened and prepared for the donation experience and its aftermath. The aim of this study was to qualitatively investigate the experiences of individuals involved in the United Kingdom (UK) UKD scheme, including those who complete the donation, are eventually medically withdrawn, or self-withdraw. Better insight into the different experiences of these groups will provide useful guidance to clinical teams on how to better address the differing psychological needs of completed donors as well as those who do not proceed to donation. Methods: A purposive sample was recruited through the Barriers and Outcomes in Unspecified Donation (BOUnD) study covering twenty-three transplant centres in the UK. Semi-structured interviews were audio-recorded and transcribed verbatim and subjected to inductive thematic analysis. Results: Participants consisted of 15 individuals who had donated, 11 who had been withdrawn by the transplant team and 9 who had self-withdrawn. The analysis resulted in 6 themes and 14 subthemes. The major themes were maximising and sharing benefits; risk-to-motivation analysis; support; self-actualisation / finding meaning; the donor as patient; and relationship with the transplant team. Conclusions: The data demonstrates that, although all donors enter the process with a similar level of commitment, those who did not proceed to donation expressed dissatisfaction and lingering emotional consequences linked to lack of follow-up from transplant teams. The implication for the UKD programme is that from the beginning there needs to be a strategic and consistent approach to managing expectations in order to prepare those who embark on the donation process for all possible outcomes and their associated emotional consequences

The lifetime of nitrogen oxides in an isoprene-dominated forest

The lifetime of nitrogen oxides (NO_x) affects the concentration and distribution of NO_x and the spatial patterns of nitrogen deposition. Despite its importance, the lifetime of NO_x is poorly constrained in rural and remote continental regions. We use measurements from a site in central Alabama during the Southern Oxidant and Aerosol Study (SOAS) in summer 2013 to provide new insights into the chemistry of NO_x and NO_x reservoirs. We find that the lifetime of NO_x during the daytime is controlled primarily by the production and loss of alkyl and multifunctional nitrates (ΣANs). During SOAS, ΣAN production was rapid, averaging 90 ppt h^(−1) during the day, and occurred predominantly during isoprene oxidation. Analysis of the ΣAN and HNO_3 budgets indicate that ΣANs have an average lifetime of under 2 h, and that approximately 45 % of the ΣANs produced at this site are rapidly hydrolyzed to produce nitric acid. We find that ΣAN hydrolysis is the largest source of HNO_3 and the primary pathway to permanent removal of NO_x from the boundary layer in this location. Using these new constraints on the fate of ΣANs, we find that the NO_x lifetime is 11 ± 5 h under typical midday conditions. The lifetime is extended by storage of NO_x in temporary reservoirs, including acyl peroxy nitrates and ΣANs