Novel Techniques in the Assessment of Sports-Related Traumatic Brain Injury

Mild traumatic brain injuries (mTBI) or concussions are a substantial health concern, particularly in collision and contact sports. Consequently, there is growing concern regarding the acute and chronic effects of repeated brain trauma. Traditional assessment of mTBI has been based on clinical or computed tomography (CT) assessments followed by a period of in-hospital observation in some cases. These may have significant time and cost implications while potentially exposing patients to ionizing radiation and providing a low sensitivity and specificity. Recent advancements have focused on novel modalities that may potentially predict early and long-term sequelae from mTBI with greater accuracy and provide the optimum personalized treatment plan in collaboration with the athlete. This chapter will outline state of the art in these modalities, from salivary and blood biomarkers imaging and neuropsychology assessments, and discuss their translational applicability to the clinical setting

ADAM22/LGI1 complex as a new actionable target for breast cancer brain metastasis

Background: Metastatic breast cancer is a major cause of cancer-related deaths in woman. Brain metastasis is a common and devastating site of relapse for several breast cancer molecular subtypes, including oestrogen receptor-positive disease, with life expectancy of less than a year. While efforts have been devoted to developing therapeutics for extra-cranial metastasis, drug penetration of blood–brain barrier (BBB) remains a major clinical challenge. Defining molecular alterations in breast cancer brain metastasis enables the identification of novel actionable targets.Methods: Global transcriptomic analysis of matched primary and metastatic patient tumours (n = 35 patients, 70 tumour samples) identified a putative new actionable target for advanced breast cancer which was further validated in vivo and in breast cancer patient tumour tissue (n = 843 patients). A peptide mimetic of the target's natural ligand was designed in silico and its efficacy assessed in in vitro, ex vivo and in vivo models of breast cancer metastasis.Results: Bioinformatic analysis of over-represented pathways in metastatic breast cancer identified ADAM22 as a top ranked member of the ECM-related druggable genome specific to brain metastases. ADAM22 was validated as an actionable target in in vitro, ex vivo and in patient tumour tissue (n = 843 patients). A peptide mimetic of the ADAM22 ligand LGI1, LGI1MIM, was designed in silico. The efficacy of LGI1MIM and its ability to penetrate the BBB were assessed in vitro, ex vivo and in brain metastasis BBB 3D biometric biohybrid models, respectively. Treatment with LGI1MIM in vivo inhibited disease progression, in particular the development of brain metastasis.Conclusion: ADAM22 expression in advanced breast cancer supports development of breast cancer brain metastasis. Targeting ADAM22 with a peptide mimetic LGI1MIM represents a new therapeutic option to treat metastatic brain disease

Ex vivo drug sensitivity screening predicts response to temozolomide in glioblastoma patients and identifies candidate biomarkers

Background: Patient-derived glioma stem-like cells (GSCs) have become the gold-standard in neuro-oncological research; however, it remains to be established whether loss of in situ microenvironment affects the clinically-predictive value of this model. We implemented a GSC monolayer system to investigate in situ-in vitro molecular correspondence and the relationship between in vitro and patient response to temozolomide (TMZ). Methods: DNA/RNA-sequencing was performed on 56 glioblastoma tissues and 19 derived GSC cultures. Sensitivity to TMZ was screened across 66 GSC cultures. Viability readouts were related to clinical parameters of corresponding patients and whole-transcriptome data. Results: Tumour DNA and RNA sequences revealed strong similarity to corresponding GSCs despite loss of neuronal and immune interactions. In vitro TMZ screening yielded three response categories which significantly correlated with patient survival, therewith providing more specific prediction than the binary MGMT marker. Transcriptome analysis identified 121 genes related to TMZ sensitivity of which 21were validated in external datasets. Conclusion:GSCs retain patient-unique hallmark gene expressions despite loss of their natural environment. Drug screening using GSCs predicted patient response to TMZ more specifically than MGMT status, while transcriptome analysis identified potential biomarkers for this response. GSC drug screening therefore provides a tool to improve drug development and precision medicine for glioblastoma.</p

Comparative analysis of the AIB1 interactome in breast cancer reveals MTA2 as a repressive partner which silences E-Cadherin to promote EMT and associates with a pro-metastatic phenotype

Funder: Breast Cancer Ireland GR 14-0883Abstract: Steroid regulated cancer cells use nuclear receptors and associated regulatory proteins to orchestrate transcriptional networks to drive disease progression. In primary breast cancer, the coactivator AIB1 promotes estrogen receptor (ER) transcriptional activity to enhance cell proliferation. The function of the coactivator in ER+ metastasis however is not established. Here we describe AIB1 as a survival factor, regulator of pro-metastatic transcriptional pathways and a promising actionable target. Genomic alterations and functional expression of AIB1 associated with reduced disease-free survival in patients and enhanced metastatic capacity in novel CDX and PDX ex-vivo models of ER+ metastatic disease. Comparative analysis of the AIB1 interactome with complementary RNAseq characterized AIB1 as a transcriptional repressor. Specifically, we report that AIB1 interacts with MTA2 to form a repressive complex, inhibiting CDH1 (encoding E-cadherin) to promote EMT and drive progression. We further report that pharmacological and genetic inhibition of AIB1 demonstrates significant anti-proliferative activity in patient-derived models establishing AIB1 as a viable strategy to target endocrine resistant metastasis. This work defines a novel role for AIB1 in the regulation of EMT through transcriptional repression in advanced cancer cells with a considerable implication for prognosis and therapeutic interventions

Comparative analysis of the AIB1 interactome in breast cancer reveals MTA2 as a repressive partner which silences E-Cadherin to promote EMT and associates with a pro-metastatic phenotype

Funder: Breast Cancer Ireland GR 14-0883Abstract: Steroid regulated cancer cells use nuclear receptors and associated regulatory proteins to orchestrate transcriptional networks to drive disease progression. In primary breast cancer, the coactivator AIB1 promotes estrogen receptor (ER) transcriptional activity to enhance cell proliferation. The function of the coactivator in ER+ metastasis however is not established. Here we describe AIB1 as a survival factor, regulator of pro-metastatic transcriptional pathways and a promising actionable target. Genomic alterations and functional expression of AIB1 associated with reduced disease-free survival in patients and enhanced metastatic capacity in novel CDX and PDX ex-vivo models of ER+ metastatic disease. Comparative analysis of the AIB1 interactome with complementary RNAseq characterized AIB1 as a transcriptional repressor. Specifically, we report that AIB1 interacts with MTA2 to form a repressive complex, inhibiting CDH1 (encoding E-cadherin) to promote EMT and drive progression. We further report that pharmacological and genetic inhibition of AIB1 demonstrates significant anti-proliferative activity in patient-derived models establishing AIB1 as a viable strategy to target endocrine resistant metastasis. This work defines a novel role for AIB1 in the regulation of EMT through transcriptional repression in advanced cancer cells with a considerable implication for prognosis and therapeutic interventions

Targeting the apoptosis pathway to treat tumours of the paediatric nervous system

New, more effective therapeutics are required for the treatment of paediatric cancers. Current treatment protocols of cytotoxic treatments including chemotherapy trigger cancer-cell death by engaging the apoptosis pathway, and chemotherapy efficacy is frequently impeded by apoptosis dysregulation. Apoptosis dysregulation, through genetic or epigenetic mechanisms, is a feature of many cancer types, and contributes to reduced treatment response, disease progression and ultimately treatment resistance. Novel approaches are required to overcome dysregulated apoptosis signalling, increase the efficacy of cancer treatment and improve patient outcomes. Here, we provide an insight into current knowledge of how the apoptosis pathway is dysregulated in paediatric nervous system tumours, with a focus on TRAIL receptors, the BCL-2 proteins and the IAP family, and highlight preclinical evidence demonstrating that pharmacological manipulation of the apoptosis pathway can restore apoptosis signalling and sensitise cancer cells to treatment. Finally, we discuss the potential clinical implications of these findings

Perceptions of Concussion and Associated Anxiety in Irish Collegiate Athletes

Background: Concussion nondisclosure and poor management after a concussion are a concern in Irish collegiate sports. How athletes perceive concussions and appraise their own concussion may affect their decisions and behaviors after a suspected concussion. However, this has yet to be examined in an Irish context. This study aimed to (1) establish concussion perceptions and associated anxiety in Irish collegiate athletes; (2) examine how sex, concussion, and mood disorder history influenced their perceptions; and (3) investigate factors associated with higher anxiety perceptions. Hypothesis: Irish collegiate athletes will display negative concussion perceptions and anxiety related to concussion, especially in female athletes and those without a concussion history. Study Design: Cross-sectional study. Level of Evidence: Level 3. Methods: Irish collegiate athletes [n = 268 (141 women,127 men), mean age = 21.5 ± 2.2 years] from high-risk sports completed a survey including the Perceptions of Concussion Inventory for Athletes (PCI-A), demographics, diagnosed concussion history, self-reported mood disorder history, and a concussion knowledge assessment. Differences in concussion perceptions by sex, concussion history, mood disorder history were examined using Mann-Whitney U tests, and factors associated with anxiety-related concussion perceptions were identified using multivariate logistic regression. Results: Over half (53.0%, n = 142) of participants reported concerns regarding concussion. The thoughts of sustaining a concussion made participants feel upset (63.4%, n = 170), fearful (47.7%, n = 128), and anxious (35.1%, n = 94). Women reported significantly higher anxiety (P \u3c 0.01, r = 0.23), effects (P = 0.04, r = 0.12), and clarity (P = 0.01, r = 0.16) perception scores. Participants with a diagnosed concussion history displayed greater symptom variability perception scores (P = 0.04, r = 0.12), but lower anxiety (P = 0.03, r = 0.13) and treatment (P \u3c 0.01, r = 0.19) beliefs on the PCI-A. No differences were observed for those with a history of a mood disorder (P \u3e 0.05). A significant multivariate model was established (χ2 = 55.44, P \u3c 0.01), with female sex [odds ratio (OR) = 1.53], concussion history (OR = 0.63), effects (OR = 1.31), and treatment (OR = 1.15) subscales associated with greater anxiety. Conclusion: Concerns about sustaining a concussion are prevalent in Irish collegiate athletes. Women displayed more negative perceptions and those with a concussion history displayed fewer perceived benefits of treatment. Clinical Relevance: The findings support the need for concussion awareness campaigns to provide accurate concussion information to mitigate anxiety-related concussion perceptions and injury belief misconceptions

<i>Clostridioides difficile</i> infection in neurosurgical patients in a national centre over 10 years: less common but associated with longer hospital stays

Background: Clostridioides difficile infection (CDI) is a leading cause of healthcare-associated (HA) diarrhoea, contributing to patient morbidity and prolonged length-of-stay (LOS). We retrospectively assessed CDI over a decade in a national neurosurgical centre, with a multi-disciplinary approach to CDI surveillance and antimicrobial stewardship, by comparing CDI patients with other patient groups.Methods: Data on CDI in neurosurgical inpatients between January 2012 and December 2021 were collated. Disease-specific variables were compared to other inpatients with CDI. Rates per 10,000 bed days used were calculated. Patient-specific differences were compared with neurosurgical patients without CDI. CDI rates by patient group were explored using odds ratio (OR) and χ2 analyses. Negative binomial regression was used to investigate CDI rates over time.Results: Of 50 neurosurgical patients with CDI, all were HA; the average age was 53 years (standard deviation (SD) 16.3 years), 49 were first-episode CDI, and three had severe CDI. The majority (76.7%) had received recent antimicrobials. Compared with non-neurosurgical CDI patients, neurosurgical CDI rates differed significantly (1.9 versus 3.6 per 10,000 bed days used, p C. difficile testing was more likely to be requested by neurosurgeons (OR 2.4; p ≤ 0.01), and the proportion of severe CDI was higher (6% versus 2%, OR 3.0, p = 0.07, confidence interval (CI) 0.54 to 11.3). Within the neurosurgical cohort, CDI patients had an average LOS four times that of other patients (CI 15.2 to 35.1; p Conclusion: CDI in neurosurgery patients differed from the wider hospital, with greater awareness of CDI testing. Longer LOS impacted bed utilisation with limited capacity. Robust surveillance supports proactive antimicrobial stewardship programmes in this vulnerable population.</p