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The MITF and SOX10 transcription factors regulate the expression of genes important for melanoma proliferation, invasion and metastasis. Despite growing evidence of the contribution of long noncoding RNAs (lncRNAs) in cancer, including melanoma, their functions within MITF-SOX10 transcriptional programmes remain poorly investigated. Here we identify 245 candidate melanoma associated lncRNAs whose loci are co-occupied by MITF-SOX10 and that are enriched at active enhancer-like regions. Our work suggests that one of these, Disrupted In Renal Carcinoma 3 (DIRC3), may be a clinically important MITF-SOX10 regulated tumour suppressor. DIRC3 depletion in human melanoma cells leads to increased anchorage-independent growth, a hallmark of malignant transformation, whilst melanoma patients classified by low DIRC3 expression have decreased survival. DIRC3 is a nuclear lncRNA that activates expression of its neighbouring IGFBP5 tumour suppressor through modulating chromatin structure and suppressing SOX10 binding to putative regulatory elements within the DIRC3 locus. In turn, DIRC3 dependent regulation of IGFBP5 impacts the expression of genes involved in cancer associated processes and is needed for DIRC3 control of anchorage-independent growth. Our work indicates that lncRNA components of MITF-SOX10 networks are an important new class of melanoma regulators and candidate therapeutic targets that can act not only as downstream mediators of MITF-SOX10 function but as feedback regulators of MITF-SOX10 activity.

Background/ObjectivesTo evaluate the outcomes of orbital evisceration with primary implant placement in acutely infected/inflamed eyes, using implant exposure/extrusion as a surrogate of success. To contextualise this with previously published literature.Subjects/MethodsA retrospective case series of all patients with acutely infected/inflamed eyes undergoing urgent orbital evisceration with primary implants, at a British tertiary centre between January 2006 and August 2018. A systematic literature review of orbital eviscerations with primary implant placement in acute endophthalmitis/infection and recent trauma.ResultsTwenty-six eyes were eviscerated in the context of acute infection/inflammation. Twenty-four eyes had primary orbital implants. Indications for evisceration included endophthalmitis (18/26, 69%), microbial keratitis with corneal perforation (4/26, 15%), non-infectious corneal perforation (3/26, 12%), and recent trauma (1/26, 4.8%). The implants used were acrylic (15/24, 63%), MEDPOR (5/24, 21%), and silicone (4/24, 17%). The follow-up period was 15 months to 14 years. Implant exposure occurred in two (8.3%), managed with implant exchange and scleral reformation in one, and implant removal with dermis fat grafting in the other. One patient (4.2%) had conjunctival wound dehiscence with spontaneous healing. Six (25%) required further surgery for minor complications as follows: conjunctival prolapse, upper lid ptosis with slight sulcus loss, lower lid entropion with shortened fornix, and lower lid ectropion. The systematic literature review showed that the mean rate of orbital implant exposure/extrusion in this subset of patients was 7.8% (95% CI: 2.7%, 12.9%, SD 8.0%), range 0–27%.ConclusionsIn acutely infected/inflamed eyes, the implant exposure/extrusion rate following orbital evisceration with primary implant placement is acceptable.

Pervasive enhancer transcription is at the origin of more than half of all long noncoding RNAs in humans. Transcription of enhancer-associated long noncoding RNAs (elncRNA) contribute to their cognate enhancer activity and gene expression regulation in cis . Recently, splicing of elncRNAs was shown to be associated with elevated enhancer activity. However, whether splicing of elncRNA transcripts is a mere consequence of accessibility at highly active enhancers or if elncRNA splicing directly impacts enhancer function, remains unanswered. We analysed genetically driven changes in elncRNA splicing, in humans, to address this outstanding question. We showed that splicing related motifs within multi-exonic elncRNAs evolved under selective constraints during human evolution, suggesting the processing of these transcripts is unlikely to have resulted from transcription across spurious splice sites. Using a genome-wide and unbiased approach, we used nucleotide variants as independent genetic factors to directly assess the causal relationship that underpin elncRNA splicing and their cognate enhancer activity. We found that the splicing of most elncRNAs is associated with changes in chromatin signatures at cognate enhancers and target mRNA expression. We provide evidence that efficient and conserved processing of enhancer-associated elncRNAs contributes to enhancer activity.

ObjectiveTo evaluate the incidence and management of recurrent periocular sebaceous gland carcinoma at a tertiary ocular oncology service in the United Kingdom.MethodsThis was a retrospective cohort study of 62 patients with sebaceous gland carcinoma treated between 2004 and 2017. A total of 10 eyes were treated for local recurrence. The following variables were recorded: age and sex of patient; tumour location, histological subtype; recurrence type; treatment and outcome.ResultsOf the 62 cases with eyelid SGC, 10 (16%) had recurrences during the study period and satisfied inclusion criteria. There were six (60%) females and four males in the recurrent group. The mean time interval between initial excision and tumour recurrence was 37 months (median 23 months; range 4 to 84 months). Four patients received cryotherapy to the lids and conjunctiva to control recurrent disease and two patients were treated with topical or intralesional chemotherapy. Four patients (40%) underwent orbital exenteration during the study period. Metastasis occurred in 20% over a mean follow-up of 113 months (median 106; range 47–184 months).ConclusionsThe risk factors for local recurrence of SGC after wide excision with paraffin section control were reported, and an approach to these recurrent lesions was proposed. The results of this study will help guide surgeons dealing with the medical and surgical conundrum of recurrent disease. The risk of recurrence is highest in the first 2 years after initial excision.

Hyperpolarised magnetic resonance imaging (HP- 13 C-MRI) has shown promise as a clinical tool for detecting and characterising prostate cancer. Here we use a range of spatially resolved histological techniques to identify the biological mechanisms underpinning differential [1- 13 C]lactate labelling between benign and malignant prostate, as well as in tumours containing cribriform and non-cribriform Gleason pattern 4 disease. Here we show that elevated hyperpolarised [1- 13 C]lactate signal in prostate cancer compared to the benign prostate is primarily driven by increased tumour epithelial cell density and vascularity, rather than differences in epithelial lactate concentration between tumour and normal. We also demonstrate that some tumours of the cribriform subtype may lack [1- 13 C]lactate labelling, which is explained by lower epithelial lactate dehydrogenase expression, higher mitochondrial pyruvate carrier density, and increased lipid abundance compared to lactate-rich non-cribriform lesions. These findings highlight the potential of combining spatial metabolic imaging tools across scales to identify clinically significant metabolic phenotypes in prostate cancer. Metabolic imaging offers promise for improving the characterisation of prostate cancer phenotypes of varying clinical significance. Here, the authors show distinct metabolic features of cribriform and non-cribriform lesions using a variety of imaging techniques across scales.

Context Patient reported outcome measures (PROMs) are useful tools in paediatric endocrinology to gauge health status in children, especially since they are often unable to clearly communicate it themselves. We aimed to systematically search and appraise all available PROMs relevant to paediatric endocrinology and provide a curated resource for health professionals to utilise. Evidence acquisition We identified PROMs in paediatric endocrinology by systematically searching the Cochrane Library, MEDLINE, World Health Organisation International Clinical Trials Registry Platform, and the Cumulative Index to Nursing and Allied Health Literature on May 20, 2022. Additional studies were located through hand searching and content area expert contributions. We assessed the quality of each PROM using the COSMIN risk of bias checklist. Evidence synthesis We identified 5003 papers in the initial search. After applying exclusion criteria we included seven PROMs in the review. Six PROMs were specific to Type I Diabetes and one to Hypothyroidism. We gave all studies an overall COSMIN score of ‘inadequate’ due to poorly detailed PROM development. Conclusion The scope and quality of PROMs in paediatric endocrinology is limited. Further research and development of PROM tools are required in paediatric endocrinology to allow for improved patient care.

Extant research has long documented the association between domestic violence and homelessness. Yet, there appear to be few interventions to address the housing needs of survivors of domestic violence, and none on a digital platform. Our primary objective is to determine the feasibility of a full-scale intervention trial of a web-based tool that screens and educates survivors of domestic violence on affordable housing programs in New York City. Our secondary objectives are to assess the perceived usability and acceptability of the tool. The study will take place in a community-based domestic violence center in New York City. Treatment will consist of study participants not using (SC) or using (SC+) the tool, in or outside of private meetings with a case manager to discuss housing and other benefits. The frequency of the meetings will vary depending on the participant's needs. The study will measure changes in housing knowledge, housing self-efficacy, and staff trust through two electronic surveys, administered at times 0 and 2 weeks. Following a historical cohort control group design, we will sequentially recruit participants, starting with SC and followed by SC+. After data collection for SC+ ends, we will invite staff from the partner site to individual, web-based interviews to share their experiences of and recommendations for implementing the tool. Recruitment for the SC arm commenced in March 2022 and was completed in April 2023. After a year, 23 participants completed the study: 75 were screened, 44 were deemed eligible, 35 enrolled, and in the end, 23 participants completed baseline and follow-up surveys. Given the length of time it took to recruit for SC and the limited time overall that we had for the study, the study team decided to follow an expedited recruitment timeline for SC+. Recruitment for SC+ commenced in January 2024 and is anticipated to end by May 2024. Recruitment for the staff interviews will take place in June 2024. We expect to complete the study and be ready to compile the results by the end of June 2024. The protocol describes a feasibility study that can inform future research on housing or digital tools for a similar study population. Data from the study will also be used to inform revisions to the tool. DERR1-10.2196/63162.

Recent developments in spatially resolved -omics have enabled the joint study of gene expression, metabolite levels and tissue morphology, offering greater insights into biological pathways. Integrating these modalities from matched tissue sections to probe spatially-coordinated processes, however, remains challenging. Here we introduce MAGPIE, a framework for co-registering spatially resolved transcriptomics, metabolomics, and tissue morphology from the same or consecutive sections. We show MAGPIE’s generalisability and scalability on spatial multi-omics data from multiple tissues, combining Visium with MALDI and DESI mass spectrometry imaging. MAGPIE was also applied to new multi-modal datasets generated with a specialised sampling strategy to characterise the metabolic and transcriptomic landscape in an in vivo model of drug-induced pulmonary fibrosis and to link small-molecule co-detection with endogenous lung responses. MAGPIE demonstrates the refined resolution and enhanced interpretability that spatial multi-modal analyses provide for studying tissue injury especially in pharmacological contexts, and delivers a modular, accessible workflow for data integration. MAGPIE is a computational framework for co-registering spatially-resolved transcriptomics, metabolomics and tissue morphology for integrated downstream analysis. Case studies across lung, brain and breast reveal coordinated cross-modality molecular changes.

Recent research on Critical Discourse Analysis (CDA) has focused on the identity construction of agents within discourse. This study delves into intercultural communication through the lens of multiculturality and interraciality. Employing the CDA framework, the research investigates how online Filipino Chinese writers construct their identities and those of their readers, examining the dynamics of dominance and subordination in selected intercultural discourse. The study is guided by three central questions: how online intercultural writers position themselves in terms of their social identities, how the relationship between the writer and readers is linguistically realized, and how the representations and relationships of the writer and reader manifest in terms of discursive strategies. By concentrating on identity construction through the analysis of linguistic items, the study offers critical discourse analysts an alternative method for unveiling power and dominance in written texts. Furthermore, the examination of discursive strategies allows this CDA study to perceive texts as dual in nature, serving not only as a means for writers to influence their readers but also as instruments to endorse ostensibly positive values. In conclusion, the study presents an approach for analyzing intercultural discourse, enriching the field of CDA with a nuanced understanding of the complex interplay between writer, reader, and text within the rich tapestry of intercultural communication.