RNA Therapy for Oncogenic NRAS-Driven Nevi Induces Apoptosis.

RAS proteins regulate cell division, differentiation, and apoptosis through multiple downstream effector pathways. Oncogenic RAS variants are the commonest drivers in cancers; however, they also drive many benign lesions predisposing to malignancy, such as melanocytic nevi, thyroid nodules, and colonic polyps. Reversal of these benign lesions could reduce cancer incidence; however, the effects of oncogenic RAS have been notoriously difficult to target with downstream pathway inhibitors. In this study, we show effective suppression of oncogenic and currently undruggable NRASQ61K in primary cells from melanocytic nevi using small interfering RNA targeted to the recurrent causal variant. This results in striking reduction in expression of ARL6IP1, a known inhibitor of endoplasmic reticulum stress-induced apoptosis not previously linked to NRAS. We go on to show that a single dose of small interfering RNA in primary cells triggers an apoptotic cascade, in contrast to treatment with a MAPK/extracellular signal-regulated kinase kinase inhibitor. Protective packaging of the targeted small interfering RNA into lipid nanoparticles permits successful delivery into a humanized mouse model of melanocytic nevi and results in variant NRAS knockdown in vivo. These data show that RAS-induced protection from apoptosis is involved in persistence of NRAS-driven melanocytic nevi and anticipate that targeted small interfering RNA could form the basis of clinical trials for RAS-driven benign tumors.

An experimental investigation of the influence of loneliness on changes in belongingness and desire to escape.

OBJECTIVE: Loneliness is a well-established risk factor for suicide in young adults, but the mechanisms involved are still unclear. Drawing on the Interpersonal Theory of Suicide, the Evolutionary Model of Loneliness, and Prospect Theory, we examined if high and low levels of loneliness are associated with different patterns of response to losses or gains of belongingness. METHODS: A sample of 188 students completed the UCLA-Loneliness scale (version 3) and measures of suicide risk. Participants in the top and bottom tertiles of loneliness scores completed a computerized task designed to induce changes (gains, losses) or consistency in risk factors for suicide (belongingness, burdensomeness) over time, and examined the effect on desire to quit the task. RESULTS: The results showed that the high loneliness group exhibited a larger magnitude of effect on desire to quit from gaining belongingness than for losing belongingness. In contrast, the low loneliness group showed a larger change in desire to quit from losing belongingness than gaining belongingness. CONCLUSION: The findings provide preliminary experimental support for distinct profiles of suicide risk based on prevailing levels of loneliness. The findings are discussed in relation to a need for increased precision in theoretical models of suicide and loneliness.

Unacceptably high: an audit of Kimberley self-harm data 2014-2018.

OBJECTIVE: To explore the rates and characteristics of self-harm across the Kimberley region of Western Australia. METHOD: Retrospective, cross-sectional audit. We obtained and descriptively analysed routinely collected self-harm data from the Kimberley District of the Western Australia Police Force (2014-2018) and the Emergency Department Data Collection (June 2017-December 2018). Variables included age, sex, Indigenous status, time of incident, and alcohol and drug use. RESULTS: The rate of emergency department attendance for self-harm was three times higher in the Kimberley than the rest of Western Australia. Both emergency department and police data showed a disproportionately high percentage of incidents involving Aboriginal people, with highest rates in the 15-19 and 20-24 year age groups. Almost 80% of self-harm events recorded by police involving individuals aged 25-50 years involved alcohol. Many self-harm incidents occurred in the evening and at night. CONCLUSIONS: The rates of self-harm across the Kimberley region from 2014-2018 are unacceptably high. Increased funding and alignment of services to meet regional need are required as part of a holistic effort to reduce regional rates of self-harm.

The Functional Influence of Breast Implant Outer Shell Morphology on Bacterial Attachment and Growth.

BACKGROUND: The introduction of texture to the outer shell of breast implants was aimed at increasing tissue incorporation and reducing capsular contracture. It has also been shown that textured surfaces promote a higher growth of bacteria and are linked to the development of breast implant-associated anaplastic large cell lymphoma. METHODS: The authors aimed to measure the surface area and surface roughness of 11 available implants. In addition, the authors aimed to subject these implant shells to an in vitro bacterial attachment assay with four bacterial pathogens (Staphylococcus epidermidis, S. aureus, Pseudomonas aeruginosa, and Ralstonia pickettii) and study the relationship among surface area, surface roughness, and bacterial growth. RESULTS: Surface area measurement showed grouping of implants into high, intermediate, low, and minimal. Surface roughness showed a correlation with surface area. The in vitro assay showed a significant linear relationship between surface area and bacterial attachment/growth. The high surface area/roughness implant texture grew significantly more bacteria at 24 hours, whereas the minimal surface area/roughness implant textures grew significantly fewer bacteria of all types at 24 hours. For implants with intermediate and low surface areas, some species differences were observed, indicating possible affinity of specific bacterial species to surface morphology. CONCLUSIONS: Implant shells should be reclassified using surface area/roughness into four categories (high, intermediate, low, and minimal). This classification is superior to the use of descriptive terms such as macrotexture, microtexture, and nanotexture, which are not well correlated with objective measurement and/or functional outcomes.

Inference of random walk models to describe leukocyte migration.

While the majority of cells in an organism are static and remain relatively immobile in their tissue, migrating cells occur commonly during developmental processes and are crucial for a functioning immune response. The mode of migration has been described in terms of various types of random walks. To understand the details of the migratory behaviour we rely on mathematical models and their calibration to experimental data. Here we propose an approximate Bayesian inference scheme to calibrate a class of random walk models characterized by a specific, parametric particle re-orientation mechanism to observed trajectory data. We elaborate the concept of transition matrices (TMs) to detect random walk patterns and determine a statistic to quantify these TM to make them applicable for inference schemes. We apply the developed pipeline to in vivo trajectory data of macrophages and neutrophils, extracted from zebrafish that had undergone tail transection. We find that macrophage and neutrophils exhibit very distinct biased persistent random walk patterns, where the strengths of the persistence and bias are spatio-temporally regulated. Furthermore, the movement of macrophages is far less persistent than that of neutrophils in response to wounding.