Why Are Some Male Alcohol Misuse Disorder Patients High Utilisers of Emergency Health Services? An Asian Qualitative Study.

BACKGROUND: Certain alcohol misuse patients heavily utilise the Emergency Department (ED) and Emergency Medical Services (EMS) and may present with intoxication or long-term sequelae of alcohol misuse. Our study explored reasons for repeated ED/EMS utilisation and sought to understand perpetuating and protective factors for drinking. METHODS: Face-to-face semi-structured qualitative interviews were conducted. Participants were recruited from an ED in Singapore. Interviews were audio-recorded, transcribed verbatim and underwent manual thematic analysis. Emergent themes were independently reviewed for agreement. Data from medical records, interview transcripts, and field notes were triangulated for analysis. RESULTS: All participants were male (n = 20) with an average age of 55.6 years (SD = 8.86). Most were unemployed (75%), did not have tertiary education (75%), were divorced (55%), and had pre-existing psychiatric conditions (60%) and chronic cardiovascular conditions (75%). Reasons for utilisation included a perceived need due to symptoms, although sometimes it was bystanders who called the ambulance. ED/EMS was preferred due to the perceived higher quality and speed of care. Persistent drinking was attributed to social and environmental factors, and as a coping mechanism for stressors. Rehabilitation programs and meaningful activities reduced drinking tendencies. CONCLUSION: ED/EMS provide sought-after services for alcohol misuse patients, resulting in high utilisation. Social and medical intervention could improve drinking behaviours and decrease overall ED/EMS utilisation.

The Functional Landscape of Patient-Derived RNF43 Mutations Predicts Sensitivity to Wnt Inhibition.

A subset of Wnt-addicted cancers are sensitive to targeted therapies that block Wnt secretion or receptor engagement. RNF43 loss-of-function (LOF) mutations that increase cell surface Wnt receptor abundance cause sensitivity to Wnt inhibitors. However, it is not clear which of the clinically identified RNF43 mutations affect its function in vivo. We assayed 119 missense and 45 truncating RNF43 mutations found in human cancers using a combination of cell-based reporter assays, genome editing, flow cytometry, and immunofluorescence microscopy. Five common germline variants of RNF43 exhibited wild-type activity. Cancer-associated missense mutations in the RING ubiquitin ligase domain and a subset of mutations in the extracellular domain hyperactivate Wnt/ß-catenin signaling through formation of inactive dimers with endogenous RNF43 or ZNRF3. RNF43 C-terminal truncation mutants, including the common G659fs mutant are LOF specifically when endogenous mutations are examined, unlike their behavior in transient transfection assays. Patient-derived xenografts and cell lines with C-terminal truncations showed increased cell surface Frizzled and Wnt/ß-catenin signaling and were responsive to porcupine (PORCN) inhibition in vivo, providing clear evidence of RNF43 impairment. Our study provides potential guidelines for patient assignment, as virtually all RNF43 nonsense and frameshift mutations, including those in the C-terminal domain and a large number of patient-associated missense mutations in the RING domain and N-terminal region compromise its activity, and therefore predict response to upstream Wnt inhibitors in cancers without microsatellite instability. This study expands the landscape of actionable RNF43 mutations, extending the benefit of these therapies to additional patients. SIGNIFICANCE: Systematic examination of patient-derived RNF43 mutations identifies rules to guide patient selection, including that truncation or point mutations in well-defined functional domains sensitize cancers to PORCN inhibitors.

A functional network of gastric-cancer-associated splicing events controlled by dysregulated splicing factors.

Comprehensive understanding of aberrant splicing in gastric cancer is lacking. We RNA-sequenced 19 gastric tumor-normal pairs and identified 118 high-confidence tumor-associated (TA) alternative splicing events (ASEs) based on high-coverage sequencing and stringent filtering, and also identified 8 differentially expressed splicing factors (SFs). The TA ASEs occurred in genes primarily involved in cytoskeletal organization. We constructed a correlative network between TA ASE splicing ratios and SF expression, replicated it in independent gastric cancer data from The Cancer Genome Atlas and experimentally validated it by knockdown of the nodal SFs (PTBP1, ESRP2 and MBNL1). Each SF knockdown drove splicing alterations in several corresponding TA ASEs and led to alterations in cellular migration consistent with the role of TA ASEs in cytoskeletal organization. We have therefore established a robust network of dysregulated splicing associated with tumor invasion in gastric cancer. Our work is a resource for identifying oncogenic splice forms, SFs and splicing-generated tumor antigens as biomarkers and therapeutic targets.