Integrative analysis identifies candidate tumor microenvironment and intracellular signaling pathways that define tumor heterogeneity in NF1

Neurofibromatosis type 1 (NF1) is a monogenic syndrome that gives rise to numerous symptoms including cognitive impairment, skeletal abnormalities, and growth of benign nerve sheath tumors. Nearly all NF1 patients develop cutaneous neurofibromas (cNFs), which occur on the skin surface, whereas 40-60% of patients develop plexiform neurofibromas (pNFs), which are deeply embedded in the peripheral nerves. Patients with pNFs have a ~10% lifetime chance of these tumors becoming malignant peripheral nerve sheath tumors (MPNSTs). These tumors have a severe prognosis and few treatment options other than surgery. Given the lack of therapeutic options available to patients with these tumors, identification of druggable pathways or other key molecular features could aid ongoing therapeutic discovery studies. In this work, we used statistical and machine learning methods to analyze 77 NF1 tumors with genomic data to characterize key signaling pathways that distinguish these tumors and identify candidates for drug development. We identified subsets of latent gene expression variables that may be important in the identification and etiology of cNFs, pNFs, other neurofibromas, and MPNSTs. Furthermore, we characterized the association between these latent variables and genetic variants, immune deconvolution predictions, and protein activity predictions

Why business angels reject investment opportunities: Is it personal?

A major focus of research on business angels has examined their decision-making processes and investment criteria. As business angels reject most of the opportunities that they receive, this article explores the reasons informing such decisions. In view of angel heterogeneity, investment opportunities might be expected to be rejected for differing reasons. Two sources of data are used to examine this issue. Face-to-face interviews with 30 business angels in Scotland and Northern Ireland provided information on typical ‘deal killers’. This was complemented by an Internet survey of United Kingdom that attracted responses from 238 UK business angels. The findings confirm that the main reason for rejection relates to the entrepreneur/management team. However, angel characteristics do not explain the number of reasons given for opportunity rejection nor do they predict the reasons for rejecting investment opportunities. This could be related to the increasing trend for business angels to join organised groups which, in turn, leads to the development of a shared repertoire of investment approaches. We suggest the concept of ‘communities-of-practice’ as an explanation for this finding

Establishing comprehensive oral assessments for children with safeguarding concerns.

The dental profession is well placed to contribute important information in child protection cases but no previous research has been reported that assesses the volume or impact of this information. Comprehensive oral assessment clinics were introduced and established as an integral part of comprehensive medical assessments for children with welfare concerns in Greater Glasgow and Clyde. An assessment protocol and standardised paperwork for comprehensive oral assessments were developed to enhance information sharing and patient access to appropriate care. Two cases are presented and discussed to demonstrate the value of dental input

New Experimental Limits on Macroscopic Forces Below 100 Microns

Results of an experimental search for new macroscopic forces with Yukawa range between 5 and 500 microns are presented. The experiment uses 1 kHz mechanical oscillators as test masses with a stiff conducting shield between them to suppress backgrounds. No signal is observed above the instrumental thermal noise after 22 hours of integration time. These results provide the strongest limits to date between 10 and 100 microns, improve on previous limits by as much as three orders of magnitude, and rule out half of the remaining parameter space for predictions of string-inspired models with low-energy supersymmetry breaking. New forces of four times gravitational strength or greater are excluded at the 95% confidence level for interaction ranges between 200 and 500 microns.Comment: 25 Pages, 7 Figures: Minor Correction

The actions of methotrexate on endothelial cells are dependent on the shear stress-induced regulation of one carbon metabolism

Objectives: The disease-modifying anti-rheumatic drug methotrexate (MTX) is recognized to reduce cardiovascular risk in patients with systemic inflammatory diseases. However, the molecular basis for these cardioprotective effects remains incompletely understood. This study evaluated the actions of low-dose MTX on the vascular endothelium. Methods: Human endothelial cells (EC) were studied under in vitro conditions relevant to inflammatory arthritis. These included culture in a pro-inflammatory microenvironment and exposure to fluid shear stress (FSS) using a parallel plate model. Respectively treated cells were analyzed by RNA sequencing and quantitative real-time PCR for gene expression, by immunoblotting for protein expression, by phosphokinase activity arrays, by flow cytometry for cell cycle analyses and by mass spectrometry to assess folate metabolite levels. Results: In static conditions, MTX was efficiently taken up by EC and caused cell cycle arrest concurrent with modulation of cell signaling pathways. These responses were reversed by folinic acid (FA), suggesting that OCM is a predominant target of MTX. Under FSS, MTX did not affect cell proliferation or pro-inflammatory gene expression. Exposure to FSS downregulated endothelial one carbon metabolism (OCM) as evidenced by decreased expression of key OCM genes and metabolites. Conclusion: We found that FSS significantly downregulated OCM and thereby rendered EC less susceptible to the effects of MTX treatment. The impact of shear stress on OCM suggested that MTX does not directly modulate endothelial function. The cardioprotective actions of MTX likely reflect direct actions on inflammatory cells and indirect benefit on the vascular endothelium

Use of a sternocleidomastoid muscle flap to protect the carotid artery during laryngectomy.

ObjectivesThis paper describes a simple method of securing tissue coverage of the great vessels at the initial surgery by rotating the divided sternal heads of the sternocleidomastoid muscle, a routine step during laryngectomy, and approximating them to the prevertebral fascia. The paper presents an illustrated case example where this technique in a salvage laryngectomy repair resulted in a protected vascular axis following a salivary leak.ResultsSince utilising this technique, there has been a marked reduction in the requirement of subsequent flap procedures to protect vessels, and no episodes of threatened or actual carotid blowout

Associations between post-traumatic stress disorders and psychotic symptom severity in adult survivors of developmental trauma: a multisite cross-sectional study in the UK and South Korea

BACKGROUND: Childhood maltreatment is a risk factor for the development of post-traumatic stress disorders and psychosis. However, the association between post-traumatic stress disorder (PTSD), including complex PTSD, and psychotic symptoms is unknown. We investigated whether the presence of PTSD and complex PTSD was associated with psychotic symptom severity within survivors of developmental trauma. METHODS: As part of the Investigating Mechanisms underlying Psychosis Associated with Childhood Trauma (IMPACT) study, from Aug 20, 2020, to Jan 24, 2021, and from Sept 9, 2022, to Feb 21, 2023, using study advertisement on online platforms we recruited adult (≥18 years) participants who had experienced developmental trauma without a psychiatric diagnosis in the UK and South Korea. We measured whether participants met diagnostic thresholds for PTSD and complex PTSD using the self-reported International Trauma Questionnaire, and psychotic symptoms using the self-reported Community Assessment of Psychic Experiences. We used linear regression, adjusting for sociodemographic variables such as age, sex, ethnicity, educational attainment, and socioeconomic status, to examine whether there was an association between PTSD and complex PTSD and psychotic symptoms. The study is registered in the UK (University College London Research Ethics Committee [14317/001] and the National Health Service Research Ethics Committee [22/YH/0096]) and South Korea (Institutional Review Board of Seoul National University Bundang Hospital [B-2011-648-306]), and is ongoing. FINDINGS: Of the 2675 participants who took part in the study, 1273 had experienced developmental trauma and were included in the study in the UK (n=475) and South Korea (n=798), comprising 422 (33%) men and 851 (67%) women with a mean age of 26·9 years (SD 6, range 18-40), mostly of White British (n=328) or South Korean (n=798) ethnicity. We found no significant association between PTSD and psychotic symptom severity (total severity β=-2·40 [SE 3·28], p=0·47), compared with participants who did not meet PTSD or complex PTSD caseness. We found a significant relationship between complex PTSD and psychotic symptom severity (total severity β=22·62 [SE 1·65], p<0·0001), including for positive (β=12·07 [SE 0·99], p<0·0001) and negative symptoms (β=10·5 [SE 0·95], p<0·0001), compared with participants who did not meet PTSD or complex PTSD caseness. INTERPRETATION: Health systems must assess individuals with previous developmental trauma for complex PTSD and treat those affected. These individuals should also be assessed for psychotic symptoms, and if necessary, preventative measures should be taken to reduce risk of conversion. Further work should assess whether treating complex PTSD modifies the risk of conversion to psychosis. FUNDING: UKRI Future Leaders Fellowship, British Medical Association Margaret Temple Award for Schizophrenia Research, and the National Research Foundation of Korea-Korea Government

Use of mixed methods designs in substance research: a methodological necessity in Nigeria

The utility of mixed methods (qualitative and quantitative) is becoming increasingly accepted in health sciences, but substance studies are yet to substantially benefit from such utilities. While there is a growing number of mixed methods alcohol articles concerning developed countries, developing nations are yet to embrace this method. In the Nigerian context, the importance of mixed methods research is yet to be acknowledged. This article therefore, draws on alcohol studies to argue that mixed methods designs will better equip scholars to understand, explore, describe and explain why alcohol consumption and its related problems are increasing in Nigeria. It argues that as motives for consuming alcohol in contemporary Nigeria are multiple, complex and evolving, mixed method approaches that provide multiple pathways for proffering solutions to problems should be embraced

Knowledge Graph Exploration: A Usability Evaluation of Query Builders for Laypeople

SPARQL enables users to access and browse knowledge graphs in a precise way. However, using SPARQL requires knowledge that many casual users lack. To counter this, specific tools have been created that enable more casual users to browse and query results. This paper evaluates and compares the most prominent techniques, QueryVOWL, SPARKLIS and the Wikidata Query Service (WQS), through a usability evaluation, using a mixed-method evaluation based on usability metrics and heuristics, containing both quantitative and qualitative data. The findings show that while WQS achieved the best results, usability problems were encountered in all tools. Key aspects for usability, extracted from the evaluation, serve as important contributions for future query builders

When the target may know better: Effects of experience and information asymmetries on value from mergers and acquisitions

Ministry of Education, Singapore under its Academic Research Funding Tier