Clinical application of capsule sponge testing in symptomatic reflux disease: a national prospective cohort study.

Background: Capsule sponge testing, using an oesophageal cell collection device with biomarkers, was implemented nationally across Scotland in 2020 for symptomatic reflux patients referred to secondary care for non-urgent endoscopy. The aim was to use capsule sponge testing as a triage tool to reduce pressures on the endoscopy service during COVID-19, focus endoscopy resources on those most likely to have pathology and streamline the patient pathway. This prospective cohort study presents the first real-world results and evaluates the clinical application of capsule sponge testing in symptomatic reflux disease based on endoscopic biopsy results.

Multi-pollutant removal dynamics by aquatic plants in monoculture or mixed communities.

Much of our knowledge about the phytoremediation potential of floating treatment wetlands (FTWs) comes from studies focusing on the removal of single pollutants, often by a single plant species. Here, we quantify the potential of FTWs planted with varying proportions of the emergent monocots Typha latifolia, Glyceria maxima, and Phragmites australis to simultaneously remove a suite of eleven nutrient/metalloid pollutants. Pollutants most readily removed from water included total inorganic nitrogen (TIN), K and Mn, whilst P, Zn and Cu showed a moderate removal efficiency, and Mg, Ca, Na, Cr, and Fe were poorly removed.

Oesophageal cell collection device and biomarker testing to identify high-risk Barrett's patients requiring endoscopic investigation.

Background: Barrett's oesophagus surveillance places significant burden on endoscopy services yet is vital to detect early cancerous change. Oesophageal cell collection device (OCCD) testing was introduced across Scotland for Barrett's surveillance in response to the COVID-19 pandemic. This national pragmatic retrospective study presents the CytoSCOT programme results and evaluates whether OCCD testing is successfully identifying high-risk Barrett's patients requiring urgent endoscopy.

KIT ATP-Binding Pocket/Activation Loop Mutations in GI Stromal Tumor: Emerging Mechanisms of Kinase Inhibitor Escape.

Purpose: Imatinib resistance in GI stromal tumors (GISTs) is primarily caused by secondary mutations, and clonal heterogeneity of these secondary mutations represents a major treatment obstacle. KIT inhibitors used after imatinib have clinical activity, albeit with limited benefit. Ripretinib is a potent inhibitor of secondary KIT mutations in the activation loop (AL).

National adoption of an esophageal cell collection device for Barrett's esophagus surveillance: impact on delay to investigation and pathological findings.

High quality Barrett's esophagus surveillance is crucial to detect early neoplastic changes. An esophageal cell collection device (OCCD) was introduced as a triage tool for Barrett's surveillance. This study aims to evaluate whether the Scottish OCCD program (CytoSCOT) has reduced delays to Barrett's surveillance, and whether delayed surveillance negatively impacts endoscopic pathology.

Engineering aquatic plant community composition on floating treatment wetlands can increase ecosystem multifunctionality.

Phytoremediation using floating treatment wetlands (FTWs) is an emerging nature-based solution for freshwater restoration. However, the potential to design these systems by manipulating macrophyte community composition to provide multiple ecosystem services remains unexplored. Using a tank experiment, we simulated aquatic environments impacted by multiple pollutants and employed a comparative ecological approach to design emergent macrophyte communities using the trait of plant stature (plant height) to structure communities.

Targeting DNA-PK.

This chapter explores the multifaceted roles of DNA-PK with particular focus on its functions in non-homologous end-joining (NHEJ) DNA repair. DNA-PK is the primary orchestrator of NHEJ but also regulates other biologic processes. The growing understanding of varied DNA-PK biologic roles highlights new avenues for cancer treatment.

Shedding New Light: Novel Therapies for Common Disorders in Children with Neurofibromatosis Type I.

Neurofibromatosis type I (NF1) is a common dominantly inherited disorder, and one of the most common of the RASopathies. Most individuals with NF1 develop plexiform neurofibromas and cutaneous neurofibromas, nerve tumors caused by NF1 loss of function in Schwann cells. Cell culture models and mouse models of NF1 are being used to test drug efficacy in preclinical trials, which led to Food and Drug Administration approval for use of MEK inhibitors to shrink most inoperable plexiform neurofibromas.

SETDB1 tumour suppressor roles in near-haploid mesothelioma involve TP53.

Background: Mutational inactivation of the SETDB1 histone methyltransferase is found in a subset of mesothelioma, particularly in cases with near-haploidy and TP53 mutations. However, the tumourigenic consequences of SETDB1 inactivation are poorly understood.

Methods: In this study, we investigated SETDB1 tumour suppressor functions in mesothelioma and explored biologic relationships between SETDB1 and TP53.

No-biopsy strategy for coeliac disease is applicable in adult patients: a 'real-world' Scottish experience.

Objective: Emergency interim guidance from the British Society for Gastroenterology (BSG) states that a no-biopsy strategy is possible to diagnose coeliac disease (CD) in adults with elevated transglutaminase IgA antibody (TGA-IgA) levels. We aimed to determine if the suggested TGA-IgA ≥10× ULN is safe and robust in making the diagnosis in adult patients in Scotland. We also aimed to establish if any important co-diagnoses would be missed if no biopsy was performed.

Concurrent inhibition of CDK2 adds to the anti-tumour activity of CDK4/6 inhibition in GIST.

Background: Advanced gastrointestinal stromal tumour (GIST) is characterised by genomic perturbations of key cell cycle regulators. Oncogenic activation of CDK4/6 results in RB1 inactivation and cell cycle progression. Given that single-agent CDK4/6 inhibitor therapy failed to show clinical activity in advanced GIST, we evaluated strategies for maximising response to therapeutic CDK4/6 inhibition.

Strategies to inhibit FGFR4 V550L-driven rhabdomyosarcoma.

Background: Rhabdomyosarcoma (RMS) is a paediatric cancer driven either by fusion proteins (e.g., PAX3-FOXO1) or by mutations in key signalling molecules (e.

PRC2-Inactivating Mutations in Cancer Enhance Cytotoxic Response to DNMT1-Targeted Therapy via Enhanced Viral Mimicry.

Unlabelled: Polycomb repressive complex 2 (PRC2) has oncogenic and tumor-suppressive roles in cancer. There is clinical success of targeting this complex in PRC2-dependent cancers, but an unmet therapeutic need exists in PRC2-loss cancer. PRC2-inactivating mutations are a hallmark feature of high-grade malignant peripheral nerve sheath tumor (MPNST), an aggressive sarcoma with poor prognosis and no effective targeted therapy.

Phase II Study of Ponatinib in Advanced Gastrointestinal Stromal Tumors: Efficacy, Safety, and Impact of Liquid Biopsy and Other Biomarkers.

Purpose: The purpose of this study is to evaluate ponatinib for advanced gastrointestinal stromal tumors (GIST).

Patients And Methods: This single-arm phase II trial enrolled patients with metastatic and/or unresectable GIST with failure of prior tyrosine kinase inhibitor (TKI) treatment into two cohorts based on presence or absence of KIT exon 11 (ex11) primary mutations. Patients initially received ponatinib 45 mg once daily.

E3 ubiquitin ligase Atrogin-1 mediates adaptive resistance to KIT-targeted inhibition in gastrointestinal stromal tumor.

KIT/PDGFRA oncogenic tyrosine kinase signaling is the central oncogenic event in most gastrointestinal stromal tumors (GIST), which are human malignant mesenchymal neoplasms that often feature myogenic differentiation. Although targeted inhibition of KIT/PDGFRA provides substantial clinical benefit, GIST cells adapt to KIT/PDGFRA driver suppression and eventually develop resistance. The specific molecular events leading to adaptive resistance in GIST remain unclear.

E3 ligase MKRN3 is a tumor suppressor regulating PABPC1 ubiquitination in non-small cell lung cancer.

Central precocious puberty (CPP), largely caused by germline mutations in the MKRN3 gene, has been epidemiologically linked to cancers. MKRN3 is frequently mutated in non-small cell lung cancers (NSCLCs) with five cohorts. Genomic MKRN3 aberrations are significantly enriched in NSCLC samples harboring oncogenic KRAS mutations.

YWHAE-NUTM2 oncoprotein regulates proliferation and cyclin D1 via RAF/MAPK and Hippo pathways.

Endometrial stromal sarcoma (ESS) is the second most common subtype of uterine mesenchymal cancer, after leiomyosarcoma, and oncogenic fusion proteins are found in many ESS. Our previous studies demonstrated transforming properties and diagnostic relevance of the fusion oncoprotein YWHAE-NUTM2 in high-grade endometrial stromal sarcoma (HG-ESS) and showed that cyclin D1 is a diagnostic biomarker in these HG-ESS. However, YWHAE-NUTM2 mechanisms of oncogenesis and roles in cyclin D1 expression have not been characterized.

Relationships between highly recurrent tumor suppressor alterations in 489 leiomyosarcomas.

Background: Leiomyosarcoma (LMS) is the most common soft tissue and uterine sarcoma, but no standard therapy is available for recurrent or metastatic LMS. TP53, p16/RB1, and PI3K/mTOR pathway dysregulations are recurrent events, and some LMS express estrogen receptor (ER) and/or progesterone receptor (PR). To characterize relationships between these pathway perturbations, the authors evaluated protein expression in soft tissue and uterine nonprimary leiomyosarcoma (np-LMS), including local recurrences and distant metastases.

Loss of SFRP1 expression is a key progression event in gastrointestinal stromal tumor pathogenesis.

The mechanism of high-grade transformation in gastrointestinal stromal tumors (GISTs) remains to be clarified. We aim to discover the key progression events by studying biphasic GISTs. The study group included 101 GISTs.

AXL Inactivation Inhibits Mesothelioma Growth and Migration via Regulation of p53 Expression.

Malignant mesothelioma is a locally aggressive and highly lethal neoplasm. Dysregulation and activation of Gas6/AXL tyrosine kinase signaling are associated with mesothelioma progression, but the mechanisms of these AXL tumorigenic roles are poorly understood. p53 mutants in lung carcinoma upregulate AXL expression by binding and acetylating the promoter.

Resistance to Avapritinib in PDGFRA-Driven GIST Is Caused by Secondary Mutations in the PDGFRA Kinase Domain.

Gastrointestinal stromal tumors (GIST) harboring activating mutations of respond to imatinib, with the notable exception of the most common mutation, D842V. Avapritinib is a novel, potent KIT/PDGFRA inhibitor with substantial clinical activity in patients with the D842V genotype. To date, only a minority of -mutant patients treated with avapritinib have developed secondary resistance.