The Open Pediatric Cancer Project.

Background: In 2019, the Open Pediatric Brain Tumor Atlas (OpenPBTA) was created as a global, collaborative open-science initiative to genomically characterize 1,074 pediatric brain tumors and 22 patient-derived cell lines. Here, we extend the OpenPBTA to create the Open Pediatric Cancer (OpenPedCan) Project, a harmonized open-source multi-omic dataset from 6,112 pediatric cancer patients with 7,096 tumor events across more than 100 histologies. Combined with RNA-Seq from the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA), OpenPedCan contains nearly 48,000 total biospecimens (24,002 tumor and 23,893 normal specimens). Findings: We utilized Gabriella Miller Kids First (GMKF) workflows to harmonize WGS, WXS, RNA-seq, and Targeted Sequencing datasets to include somatic SNVs, InDels, CNVs, SVs, RNA expression, fusions, and splice variants. We integrated summarized CPTAC whole cell proteomics and phospho-proteomics data, miRNA-Seq data, and have developed a methylation array harmonization workflow to include m-values, beta-vales, and copy number calls. OpenPedCan contains reproducible, dockerized workflows in GitHub, CAVATICA, and Amazon Web Services (AWS) to deliver harmonized and processed data from over 60 scalable modules which can be leveraged both locally and on AWS. The processed data are released in a versioned manner and accessible through CAVATICA or AWS S3 download (from GitHub), and queryable through PedcBioPortal and the NCI's pediatric Molecular Targets Platform. Notably, we have expanded PBTA molecular subtyping to include methylation information to align with the WHO 2021 Central Nervous System Tumor classifications, allowing us to create research- grade integrated diagnoses for these tumors. Conclusions: OpenPedCan data and its reproducible analysis module framework are openly available and can be utilized and/or adapted by researchers to accelerate discovery, validation, and clinical translation.

Malassezia responds to environmental pH signals through the conserved Rim/Pal pathway.

During mammalian colonization and infection, microorganisms must be able to rapidly sense and adapt to changing environmental conditions including alterations in extracellular pH. The fungus-specific Rim/Pal signaling pathway is one process that supports microbial adaptation to alkaline pH. This cascading series of interacting proteins terminates in the proteolytic activation of the highly conserved Rim101/PacC protein, a transcription factor that mediates microbial responses that favor survival in neutral/alkaline pH growth conditions, including many mammalian tissues. We identified the putative Rim pathway proteins Rim101 and Rra1 in the human skin colonizing fungus Malassezia sympodialis. Gene deletion by transconjugation and homologous recombination revealed that Rim101 and Rra1 are required for M. sympodialis growth at higher pH. Additionally, comparative transcriptional analysis of the mutant strains compared to wild-type suggested mechanisms for fungal adaptation to alkaline conditions. These pH-sensing signaling proteins are required for optimal growth in a murine model of atopic dermatitis, a pathological condition associated with increased skin pH. Together these data elucidate both conserved and phylum-specific features of microbial adaptation to extracellular stresses.

An overview and evaluation of the differential attainment champion role in the North West of England GP school.

BACKGROUND AND AIMS: In the Northwest of England, a national allocation of funding to minimise the effects of differential attainment has been used to support experienced GP educators to act as Differential Attainment Champions (DAC) since October 2021. An evaluation of the role's impact was undertaken. METHODS: The evaluation was designed to gather the views and experiences of DACs and their trainees via online semi-structured interviews during the first 12 months following establishment of the intervention programme. RESULTS: Thematic framework analysis identified three main themes: DACs' adaptive approach to support trainees; barriers to fulfilling the DAC role; and the positive impact of the DAC role on training. The following aspects of the DAC role worked well: the freedom to tailor support to the individual needs of the trainees; the targeted and proactive support early on in GP core training; the support of trainees in a wide range of areas including e-portfolio advice, examination preparation, and personal help. Trainees valued one-to-one support when needed. Reported improvements included: improved examination outcomes; portfolio engagement recognised in some cases by Annual Review of Competence Progression (ARCP) panels. CONCLUSIONS: The individualised and adaptive approach works well but it does mean it is difficult to quantify how many trainees can be supported by one DAC and their workload needs to be monitored.

Translation of culturally and contextually informed diabetes training for Aboriginal primary health care providers on Aboriginal client outcomes: Protocol of a cluster randomized crossover trial of effectiveness.

BACKGROUND: Indigenous populations globally have significantly high rates of type 2 diabetes compared to their non-Indigenous counterparts. This study aims to implement and evaluate the effectiveness of a culturally and contextually informed Aboriginal Diabetes Workforce Training Program on Aboriginal primary health care workforce knowledge, attitude, confidence, skill and practice relating to diabetes care. METHODS: A Cluster Randomised Crossover Control Trial with two arms (Group A and Group B) will be conducted with Aboriginal primary health care services in South Australia. These services primarily provide primary health care to Aboriginal and Torres Strait Islander people. All healthcare service sites will be randomised into groups A and B to receive the training program. The training program consists of three components: 1) Peer support network, 2) E-Learning modules and 3) onsite support. Aboriginal Health Workers of participating sites will be invited to participate in the monthly online peer support network and all chronic disease staff are eligible to participate in the E-Learning modules and onsite support. The Peer Support Network runs for the entirety of the study, 17 months. Training components 2 and 3 occur simultaneously and are 2.5 months in length, with a six-month washout period between the two randomised groups undertaking the training. All primary outcomes of the study relate to diabetes management in a primary health care settings and measure participants' knowledge, attitude, confidence, practice and skills. These will be collected at seven time points across the entire study. Secondary outcomes measure satisfaction of the peer support network using a survey, interviews to understand enablers and barriers to participation, health service systems characteristics through focus groups, and medical record review to ascertain diabetes patients' care received and their clinical outcomes up to 12 months post training intervention. DISCUSSION: The findings will explore the effectiveness of the training program on Aboriginal primary health care provider knowledge, attitude, confidence, skill and practice relating to diabetes care. The final findings will be published in 2027. TRIAL REGISTRATION: The study was prospectively registered in The Australian New Zealand Clinical Trials Registry (ANZCTR), with registration number ACTRN12623000749606 at ANZCTR - Registration. Universal Trial Number (UTN) U1111-1283-5257.

A prospective observational cohort study comparing the treatment effectiveness and safety of ciclosporin, dupilumab and methotrexate in adult and paediatric patients with atopic dermatitis: results from the UK-Irish A-STAR register.

BACKGROUND: The main conventional systemic atopic dermatitis (AD) treatments are methotrexate (MTX) and ciclosporin (CyA). Dupilumab was the first novel systemic agent to enter routine clinical practice. There are no head-to-head randomised controlled trials or real-world studies comparing these agents directly. Network meta-analyses provide indirect comparative efficacy and safety data and have shown strong evidence for dupilumab and CyA. OBJECTIVES: The aim of this study was to compare the real-world clinical effectiveness and safety of CyA, dupilumab and MTX in AD. METHODS: We compared the effectiveness and safety of these systemic agents in a prospective observational cohort study of adult and paediatric patients recruited into the UK-Irish Atopic eczema Systemic TherApy Register (A-STAR). Treatment effectiveness measures included Eczema Area and Severity Index (EASI), Patient-Oriented Eczema Measure (POEM), Peak Pruritus Numerical Rating Scale (PP-NRS), Dermatology Life Quality Index (DLQI) and children's DLQI (cDLQI). Minimum duration of treatment was 28 days and follow-up was 12 months. Adjusted Cox-regression was used to compare the hazards of achieving EASI-50, EASI-75 and EASI-90 over time, and linear mixed-effects models were used to estimate changes in efficacy scores. Treatment safety was assessed by examining adverse events (AEs) at follow-up visits. RESULTS: 488 patients (n=311 adults and n=177 children/adolescents) on dupilumab (n=282), methotrexate (n=149), or CyA (n=57) were included. CyA and MTX were primarily used first line, while dupilumab was mainly a second line systemic as per UK National Institute of Clinical and Care Excellence (NICE) recommendations. EASI-50, EASI-75 and EASI-90 were achieved more rapidly in the dupilumab and CyA groups compared to MTX. After adjustment for previous severity, the reduction in EASI, POEM, PP-NRS and DLQI was greater for patients treated with dupilumab compared to MTX. In severe patients the reduction in EASI, POEM, and PP-NRS was even greater with CyA. The incidence of AEs was similar across groups (734, 654 and 594 per 10,000 person-month on CyA, dupilumab and MTX respectively). CONCLUSIONS: This real-world comparison of CyA, dupilumab and MTX in AD suggests that dupilumab is consistently more effective than MTX and that CyA is most effective in very severe disease within one follow-up year.

Latent classification model for censored longitudinal binary outcome.

Latent classification model is a class of statistical methods for identifying unobserved class membership among the study samples using some observed data. In this study, we proposed a latent classification model that takes a censored longitudinal binary outcome variable and uses its changing pattern over time to predict individuals' latent class membership. Assuming the time-dependent outcome variables follow a continuous-time Markov chain, the proposed method has two primary goals: (1) estimate the distribution of the latent classes and predict individuals' class membership, and (2) estimate the class-specific transition rates and rate ratios. To assess the model's performance, we conducted a simulation study and verified that our algorithm produces accurate model estimates (ie, small bias) with reasonable confidence intervals (ie, achieving approximately 95% coverage probability). Furthermore, we compared our model to four other existing latent class models and demonstrated that our approach yields higher prediction accuracies for latent classes. We applied our proposed method to analyze the COVID-19 data in Houston, Texas, US collected between January first 2021 and December 31st 2021. Early reports on the COVID-19 pandemic showed that the severity of a SARS-CoV-2 infection tends to vary greatly by cases. We found that while demographic characteristics explain some of the differences in individuals' experience with COVID-19, some unaccounted-for latent variables were associated with the disease.

Arabidopsis PROTODERMAL FACTOR2 binds lysophosphatidylcholines and transcriptionally regulates phospholipid metabolism.

Plant homeodomain leucine zipper IV (HD-Zip IV) transcription factors (TFs) contain an evolutionarily conserved steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domain. While the START domain is required for TF activity, its presumed role as a lipid sensor is not clear. Here we used tandem affinity purification from Arabidopsis cell cultures to demonstrate that PROTODERMAL FACTOR2 (PDF2), a representative member that controls epidermal differentiation, recruits lysophosphatidylcholines (LysoPCs) in a START-dependent manner. Microscale thermophoresis assays confirmed that a missense mutation in a predicted ligand contact site reduces lysophospholipid binding. We additionally found that PDF2 acts as a transcriptional regulator of phospholipid- and phosphate (Pi) starvation-related genes and binds to a palindromic octamer with consensus to a Pi response element. Phospholipid homeostasis and elongation growth were altered in pdf2 mutants according to Pi availability. Cycloheximide chase experiments revealed a role for START in maintaining protein levels, and Pi starvation resulted in enhanced protein destabilization, suggesting a mechanism by which lipid binding controls TF activity. We propose that the START domain serves as a molecular sensor for membrane phospholipid status in the epidermis. Our data provide insights toward understanding how the lipid metabolome integrates Pi availability with gene expression.

Insights into breast health issues in women's rugby.

World RugbyTM supports dedicated women's welfare, injury surveillance and medical/technical interventions, yet breast health has received limited attention. This article aims to provide insights into breast health issues in rugby, including breast impacts and injuries. We discuss how breast anatomy and position may be problematic in rugby. Breast volume relates to body size, which may be increasing in women's rugby, suggesting increased breast surface area and mass, potentially increasing injury risk. Breast health issues in rugby have been reported previously, with 58% of contact footballers (including rugby) experiencing breast injuries. There are damaging effects related to these breast health issues, with breast impacts often causing pain and swelling. Breast impacts may lead to haematomas, cysts and fat necrosis which can calcify over time making them difficult to distinguish from breast carcinoma, causing further investigation and anxiety. In sport, poor bra fit and insufficient support are associated with pain, skin strain and performance decrements. This article reports the potential implications of these breast health issues on performance in rugby. Recent breast-related projects supported by rugby communities may address recommendations identified in the literature for robust breast injury classifications, updated injury surveillance systems and prospective data collection on breast injury prevalence, severity and impact in rugby. These data should inform breast injury care pathways and intervention research, including evidence-based bra design. Understanding the implications of breast impacts on tissue properties, health and wellbeing is vital. Finally, data should inform rugby-specific breast education, raising awareness of this aspect of athlete health.

Affective music during episodic memory recollection modulates subsequent false emotional memory traces: an fMRI study.

Music is a powerful medium that influences our emotions and memories. Neuroscience research has demonstrated music's ability to engage brain regions associated with emotion, reward, motivation, and autobiographical memory. While music's role in modulating emotions has been explored extensively, our study investigates whether music can alter the emotional content of memories. Building on the theory that memories can be updated upon retrieval, we tested whether introducing emotional music during memory recollection might introduce false emotional elements into the original memory trace. We developed a 3-day episodic memory task with separate encoding, recollection, and retrieval phases. Our primary hypothesis was that emotional music played during memory recollection would increase the likelihood of introducing novel emotional components into the original memory. Behavioral findings revealed two key outcomes: 1) participants exposed to music during memory recollection were more likely to incorporate novel emotional components congruent with the paired music valence, and 2) memories retrieved 1 day later exhibited a stronger emotional tone than the original memory, congruent with the valence of the music paired during the previous day's recollection. Furthermore, fMRI results revealed altered neural engagement during story recollection with music, including the amygdala, anterior hippocampus, and inferior parietal lobule. Enhanced connectivity between the amygdala and other brain regions, including the frontal and visual cortex, was observed during recollection with music, potentially contributing to more emotionally charged story reconstructions. These findings illuminate the interplay between music, emotion, and memory, offering insights into the consequences of infusing emotional music into memory recollection processes.

Workload as a predictor of radiographer preliminary image evaluation accuracy.

INTRODUCTION: Despite a demonstrated high accuracy and reported successful implementations, radiographer preliminary image evaluation (PIE) has been slow and infrequent in its rollout across Australia. A key barrier reported to hamper radiographer PIE service implementation is lack of adequate time to review radiographs and provide an accurate interpretation. This study sought to conduct a correlational analysis between radiographer imaging workload and PIE service accuracy. METHODS: A total of 45,373 exams and 1152 PIE comments evenly distributed each month from January 1, 2022, to December 31, 2022, were reviewed. PIE comments were assessed for consistency with the radiologist's report. The imaging workload (average exams completed per hour) was separated into three, eight-hour 'shifts' based on time of imaging. Correlational analysis was performed using linear regression models and assessed for normality using the Shapiro-Wilks test. RESULTS: The study reported no significant linear association between increasing average workload and reduced service accuracy (P = 0.136). It was however noted that when the average workload increased beyond 7 exams/hour, average service accuracy for PIE was always below 85%. CONCLUSION: This study has demonstrated that, although perceived, there is no statistically significant correlation between x-ray imaging workload and radiographer PIE service accuracy. Consideration of this correlation to be a significant barrier to participation in such a service was not reported at this site.

Training injuries in elite men's senior and academy (Super League) rugby league; an analysis of 224,000 exposure-hours.

OBJECTIVES: Report two-years of training injury data in senior and academy professional rugby league. DESIGN: Prospective cohort study. METHODS: Match and training time-loss injuries and exposure data were recorded from two-seasons of the European Super League competition. Eleven/12 (2021) and 12/12 (2022) senior and 8/12 (2021) and 12/12 (2022) academy teams participated. Training injuries are described in detail and overall match injuries referred to for comparison only. RESULTS: 224,000 training exposure hours were recorded with 293 injuries at the senior (mean [95 % confidence interval]; 3 [2-3] per 1000 h) and 268 academy level (2 [2-3] per 1000 h), accounting for 31 % and 40 % of all injuries (i.e., matches and training). The severity of training injuries (senior: 35 [30-39], academy: 36 [30-42] days-lost) was similar to match injuries. Lower-limb injuries had the greatest injury incidence at both levels (senior: 1.85 [1.61-2.12], academy: 1.28 [1.08-1.51] per 1000 h). Head injuries at the academy level had greater severity (35 [25-45] vs. 18 [12-14] days-lost; p < 0.01) and burden (17 [16-18] vs. 4 [4-5] days-lost per 1000 h; p = 0.02) than senior level. At the senior level, the incidence of contact injuries was lower than non-contact injuries (risk ratio: 0.29 [0.09-0.88], p = 0.02). CONCLUSIONS: Training injuries accounted for about a third of injuries, with similar injury severity to match-play. Within training there is a higher rate of non-contact vs. contact injuries. Whilst current injury prevention interventions target matches, these data highlight the importance of collecting high quality training injury data to develop and evaluate injury prevention strategies in training.

Declining glacier cover drives changes in aquatic macroinvertebrate biodiversity in the Cordillera Blanca, Perú.

Ongoing climate change threatens the biodiversity of glacier-fed river ecosystems worldwide through shifts in water availability and timing, temperature, chemistry, and channel stability. However, tropical glacier-fed rivers have received little attention compared to those in temperate and Arctic biomes, despite their unique biodiversity potentially responding differently due to additional stress from higher altitude locations thus lower oxygen availability, diurnal freeze-thaw cycles, and annual monsoon rainfall disturbances. However, tropical glacier-fed rivers have received little attention compared to those in temperate and Arctic biomes, despite their unique biodiversity potentially responding differently due to additional stress from higher altitude locations thus lower oxygen availability, diurnal freeze-thaw cycles, and annual monsoon rainfall disturbances. This study quantified aquatic biodiversity responses to decreasing glacier cover in the Cordillera Blanca range of the Peruvian Andes. Ten rivers were studied along a gradient of decreasing glacier cover in the Parón, Huaytapallana, and Llanganuco basins, with a specific focus on macroinvertebrates and physicochemical parameters in both the dry and wet seasons. We found higher temperatures, more stable and lower turbidity rivers as glacier cover decreased, which were related significantly to higher local diversity and lower ß-diversity. Analysis of similarity revealed significant differences in the macroinvertebrate community among rivers with high, medium, or low glacier cover, illustrating turnover from specialists to generalists as glacial influence decreased. Redundancy analysis demonstrated that there were more species found to prefer stable beds and water temperatures in medium and low glacier cover in a catchment rivers. However, certain taxa in groups such as Paraheptagyia, Orthocladiinae, Anomalocosmoecus, and Limonia may be adapted to high glacial influence habitats and at risk of glacier retreat. Although species composition was different to other biomes, the Cordillera Blanca rivers showed similar benthic macroinvertebrate biodiversity responses to glacier retreat, supporting the hypothesis that climate change will have predictable effects on aquatic biodiversity in mountain ranges worldwide.

Canada's approach to SARS-CoV-2 sero-surveillance: Lessons learned for routine surveillance and future pandemics.

SETTING: In Canada's federated healthcare system, 13 provincial and territorial jurisdictions have independent responsibility to collect data to inform health policies. During the COVID-19 pandemic (2020-2023), national and regional sero-surveys mostly drew upon existing infrastructure to quickly test specimens and collect data but required cross-jurisdiction coordination and communication. INTERVENTION: There were 4 national and 7 regional general population SARS-CoV-2 sero-surveys. Survey methodologies varied by participant selection approaches, assay choices, and reporting structures. We analyzed Canadian pandemic sero-surveillance initiatives to identify key learnings to inform future pandemic planning. OUTCOMES: Over a million samples were tested for SARS-CoV-2 antibodies from 2020 to 2023 but siloed in 11 distinct datasets. Most national sero-surveys had insufficient sample size to estimate regional prevalence; differences in methodology hampered cross-regional comparisons of regional sero-surveys. Only four sero-surveys included questionnaires. Sero-surveys were not directly comparable due to different assays, sampling methodologies, and time-frames. Linkage to health records occurred in three provinces only. Dried blood spots permitted sample collection in remote populations and during stay-at-home orders. IMPLICATIONS: To provide timely, high-quality information for public health decision-making, routine sero-surveillance systems must be adaptable, flexible, and scalable. National capability planning should include consortiums for assay design and validation, defined mechanisms to improve test capacity, base documents for data linkage and material transfer across jurisdictions, and mechanisms for real-time communication of data. Lessons learned will inform incorporation of a robust sero-survey program into routine surveillance with strategic sampling and capacity to adapt and scale rapidly as a part of a comprehensive national pandemic response plan.

RéSUMé: CONTEXTE: Au Canada, où le système de santé est fédéré, les 13 juridictions provinciales et territoriales ont la responsabilité individuelle de recueillir les données qui leur permettent d'élaborer leurs politiques de santé. Lors de la pandémie de COVID-19 (2020­2023), pour réaliser les enquêtes de séroprévalence à l'échelle régionale et nationale, les autorités ont principalement utilisé l'infrastructure existante pour pouvoir analyser les échantillons et recueillir des données rapidement, mais cela a également nécessité de la communication et de la coordination entre les différentes juridictions. INTERVENTION: Au Canada, il y a eu quatre enquêtes nationales et sept enquêtes régionales sur la séroprévalence du SARS-CoV-2 dans la population générale. Les méthodologies utilisées différaient selon la méthode de sélection des participants, le choix des tests d'analyses et les structures de rapports. Nous avons analysé la façon dont ces enquêtes avaient été réalisées afin d'en dégager des éléments essentiels qui permettront de planifier pour les futures pandémies. RéSULTATS: Entre 2020 et 2023, plus d'un million d'échantillons, répartis en 11 ensembles de données distincts, ont été analysés afin de rechercher la présence d'anticorps au SARS-CoV-2. Dans la plupart des enquêtes nationales, la taille de l'échantillon était insuffisante pour pouvoir estimer la prévalence à l'échelle régionale. La disparité des méthodologies utilisées a entravé la comparaison des enquêtes régionales. Seules quatre enquêtes fournissaient les données recueillies à partir des questionnaires. Il a été impossible de comparer les enquêtes entre elles en raison de la diversité des tests d'analyse utilisés, des méthodes d'échantillonnage et de la durée des enquêtes. Seules trois provinces avaient couplé leurs données avec les archives médicales. Pour réaliser les enquêtes dans les populations éloignées et lors des périodes de confinement, la méthode d'analyse sur gouttes de sang séché a été utilisée. CONCLUSION: Afin de pouvoir fournir, en temps et en heure, des données de haute qualité pour la prise de décisions en matière de santé publique, un système de sérosurveillance continuelle doit être adaptable, modulable et évolutif. En cas de pandémie, un plan national doit prévoir des consortiums pour la conception et la validation des tests d'analyse, des moyens d'amélioration de la capacité de dépistage, des documents de base pour le couplage des données, un mode de transfert du matériel entre les différentes juridictions et des moyens pour une communication en temps réel des données. Les leçons tirées de cette analyse permettront de mettre en place un solide programme d'enquêtes de séroprévalence au sein des systèmes de sérosurveillance continuelle, et que ce programme sera accompagné d'une stratégie d'échantillonnage et d'un plan d'intervention national, rapide et complet en cas de pandémie.

Characterizing drug-induced epidermal necrolysis in a pediatric cohort.

This study aims to characterize the timeline and clinical features of onset, progression, and management of drug-induced epidermal necrolysis in pediatric patients. Sixteen pediatric patients were retrospectively identified and selected if under age 18 years at admission with one identified culprit drug exposure. Culprit drugs were antiepileptics (12/16, 75%) and antibiotics (4/16, 25%). Notably, anti-epileptic drugs (AED) had delayed onset and reported dose escalations that precipitated symptom onset; thus, patients prescribed AED with or without planned dose escalations should be monitored for prodromal symptoms longer than the typical onset window.

Medullary Thyroid Cancer: Molecular Drivers and Immune Cellular Milieu of the Tumour Microenvironment-Implications for Systemic Treatment.

In this review, we explore the underlying molecular biology of medullary thyroid carcinoma (MTC) and its interplay with the host immune system. MTC is consistently driven by a small number of specific pathogenic variants, beyond which few additional genetic events are required for tumorigenesis. This explains the exceedingly low tumour mutational burden seen in most MTC, in contrast to other cancers. However, because of the low tumour mutational burden (TMB), there is a correspondingly low level of tumour-associated neoantigens that are presented to the host immune system. This reduces tumour visibility and vigour of the anti-tumour immune response and suggests the efficacy of immunotherapy in MTC is likely to be poor, acknowledging this inference is largely based on the extrapolation of data from other tumour types. The dominance of specific RET (REarranged during Transfection) pathogenic variants in MTC tumorigenesis rationalizes the observed efficacy of the targeted RET-specific tyrosine kinase inhibitors (TKIs) in comparison to multi-kinase inhibitors (MKIs). Therapeutic durability of pathway inhibitors is an ongoing research focus. It may be limited by the selection pressure TKI treatment creates, promoting survival of resistant tumour cell clones that can escape pathway inhibition through binding-site mutations, activation of alternate pathways, and modulation of the cellular and cytokine milieu of the tumour microenvironment (TME).

Factors Influencing Margin Clearance and the Number of Stages of Mohs Micrographic Surgery in Basal Cell Carcinoma: A Retrospective Chart Review.

How patient and tumor factors influence clearance margins and the number of Mohs Micrographic Surgery (MMS) stages when treating basal cell carcinoma (BCC) remains widely uncharacterized. It is important to elucidate these relationships, as surgical outcomes may be compared nationally between colleagues. Our objective is to evaluate the relationships between defect size and patient demographics, as well as between BCC subtypes and the number of MMS stages. Our second objective is to compare practice patterns and characteristics of patients requiring MMS at academic centers and private practices. A retrospective chart review was performed using data collected at academic centers (2015-2018) and private practices (2011-2018) of BCC patients older than 18 years old who underwent MMS. In total, 7651 patients with BCC requiring MMS were identified. Academic center adjusted analyses demonstrated clearance margins 0.1 mm higher for every year's increase in age (p < 0.0001) and 0.25 increase in MMS stages for high-risk BCC (p < 0.0001). Private practice adjusted analyses demonstrated clearance margins 0.04 mm higher for every year's increase in age (p < 0.0001). Clearance margins correlate with older age, and additional MMS stages correlate with high-risk BCC, suggesting the role patient and tumor factors may play in predicting tumor clearance and MMS stages.

Genotype-Phenotype Correlation in Neurofibromatosis Type 1: Evidence for a Mild Phenotype Associated with Splicing Variants Leading to In-Frame Skipping of NF1 Exon 24 [19a].

Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder caused by loss-of-function variants in the NF1 gene. As of 20 November 2023, over 5000 distinct pathogenic or likely pathogenic variants have been reported in public databases. However, only a few NF1 genotype-phenotype correlations have been established so far. In this study, we present findings on 40 individuals with NF1, comprising 26 unrelated probands and 14 affected relatives, who carry one of nine NF1 heterozygous pathogenic splicing variants, all of which result in the in-frame skipping of exon 24 [19a] (NM_000267.3:r.3114_3197del, p.Asn1039_Arg1066del). These variants include c.3114-2A>G, c.3114-1G>A, c.3196A>G, c.3197G>A, c.3197G>T, c.3197+1G>A, c.3197+1G>T, c.3197+2T>C, and c.3197+3A>T. Among individuals with these variants, none exhibit externally visible plexiform neurofibromas, histopathologically confirmed cutaneous or subcutaneous neurofibromas, symptomatic spinal neurofibromas, or symptomatic optic pathway gliomas. The most prevalent, and sometimes sole, clinical feature observed in this cohort is multiple café-au-lait macules, with or without skinfold freckles: 85% and 60.5% of the individuals display six or more café-au-lait macules and freckles, respectively. In comparison to established NF1 genotype-phenotype correlations, these patients demonstrate highly similar clinical presentations to those associated with the NF1 pathogenic variant c.2970_2972del (p.Met992del), known for resulting in the mildest clinical features. Despite the generally mild phenotype, cognitive impairment, developmental delay, and/or learning difficulties are still observed in 33.3% of these patients, suggesting that learning challenges remain a prominent aspect of the phenotypic presentation in these individuals and necessitate specialized care. This newly established genotype-phenotype correlation will assist clinicians in improving the management of patients harboring NF1 exon 24 [19a] skipping variants and provide a new therapeutic target for NF1 treatment.

Evaluation of the Immunomodulatory Effects of Radiation for Chimeric Antigen Receptor T Cell Therapy in Glioblastoma Multiforme.

Standard-of-care treatment for Glioblastoma Multiforme (GBM) is comprised of surgery and adjuvant chemoradiation. Chimeric Antigen Receptor (CAR) T cell therapy has demonstrated disease-modifying activity in GBM and holds great promise. Radiation, a standard-of-care treatment for GBM, has well-known immunomodulatory properties and may overcome the immunosuppressive tumor microenvironment (TME); however, radiation dose optimization and integration with CAR T cell therapy is not well defined. Murine immunocompetent models of GBM were treated with titrated doses of stereotactic radiosurgery (SRS) of 5, 10, and 20 Gray (Gy), and the TME was analyzed using Nanostring. A conditioning dose of 10 Gy was determined based on tumor growth kinetics and gene expression changes in the TME. We demonstrate that a conditioning dose of 10 Gy activates innate and adaptive immune cells in the TME. Mice treated with 10 Gy in combination with mCAR T cells demonstrated enhanced antitumor activity and superior memory responses to rechallenge with IL13Rα2-positive tumors. Furthermore, 10 Gy plus mCAR T cells also protected against IL13Rα2-negative tumors through a mechanism that was, in part, c-GAS-STING pathway-dependent. Together, these findings support combination conditioning with low-dose 10 Gy radiation in combination with mCAR T cells as a therapeutic strategy for GBM.