Genetic testing in the management of inherited cardiac disorders : two cases of Filamin-C arrhythmogenic left ventricular cardiomyopathy

Background: Arrhythmogenic left ventricular cardiomyopathy (ALVC) is a left ventricle–dominant arrhythmogenic cardiomyopathy (ACM) subtype often associated with malignant ventricular arrhythmias, left ventricular (LV) scar and sudden cardiac death. Awareness about LV involvement is now on the rise. The diagnosis relies on structural abnormalities on cardiac magnetic resonance (CMR) imaging and known ACM-causing genetic mutations.Case summary: A 28-year-old lady (Case 1) was referred for cardiac screening after her father passed away suddenly. Her paternal uncle (Case 2) had been diagnosed with supposed dilated cardiomyopathy prior to referral. Both cases were worked up extensively with an electrocardiogram (ECG), 24-h ambulatory ECG monitor, exercise testing, and CMR imaging. Investigations of Case 1 showed T-wave inversion in the infero-lateral leads and a ventricular ectopic burden of 3% on ambulatory monitoring. Cardiac magnetic resonance imaging revealed moderately reduced LV systolic function (ejection fraction of 40%) with circumferential macroscopic fibrosis. Her uncle (Case 2) also had an impaired and dilated ventricle with extensive scar on CMR. Following the recent introduction of a cardiogenetic service in our unit, both were heterozygous for a pathogenic Filamin-C variant (c.7384+1G>A). Based on CMR findings and genetic results, the diagnosis of both patients was deemed to be ALVC. After years of surveillance, Patient 1 now has an implantable cardioverter defibrillator (ICD) indication.Discussion: The importance of diagnosing patients with ACM lies in the predisposition to sudden cardiac death. Gene-specific treatment algorithms in ACM may alter management strategies, including ICD implantation as primary prevention. An in-depth multidisciplinary discussion and respecting patient autonomy are key factors in any decision pertaining to ICD implantation.peer-reviewe

Functional analysis of aryl hydrocarbon receptor (AHR) polymorphisms in pituitary adenomas (PAs) in the presence of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)

BACKGROUND: PAs are the most frequent pituitary neoplasms, however molecular pathogenesis is largely unknown. The AHR is a ligand-activated transcription factor that regulates expression of various genes that mediate cellular response to xenobiotics. The exact functional role of two AHR single nucleotide polymorphisms (SNPs); Arginine554Lysine (Arg554Lys) and Valine570Isoleucine (Val570Ile) has not yet been established, however studies suggest that these mutations might increase risk of developing PAs. To date, functional analysis of regarding the significance of these AHR SNPs in pituitary pathophysiology has never been analysed.AIMS: • Elucidate the effect of wildtype and polymorphic AHR on GH3 cell proliferation and on AHR-transcriptional response in the presence and absence of TCDD. • Determine the allele frequency of the most common AHR SNP; the Arg554Lys in PA patients and in a small cohort of the Maltese population.METHOD: The two missense mutations were introduced within the AHR-expressing vector and transfected in GH3 cells by magnetofaction, followed by the exposure to TCDD. Cell viability of GH3 transfected cells was measured using the MTT assay. Functional analysis of GH3 transfected cells treated with TCDD was carried out using luciferase assay and real-time PCR to detect and quantify the AHR-transcriptional activity. Genotyping of the Arg554Lys was performed on PA patients and neonatal controls using allele specific PCR. The Mann-Whitney test was used to compare two groups and Kruskall-Wallis test was used to compare three groups or more.RESULTS: In the absence and presence of low TCDD concentrations (1 and 10 nM), over-expression of wildtype AHR (wtAHR) did not affect GH3 cell proliferation. GH3 cells transfected with the AHR mutants did not exhibit any significant differences in their proliferative ability when compared with the wtAHR, both in the presence and absence of TCDD. Luciferase reporter analysis showed that there was a significant difference between the treated and untreated wtAHR (P=0.016), however this difference was not observed between the treated and untreated AHR mutants. Statistically significant difference in Cyp1a1 gene expression analysis was detected between the treated and untreated wtAHR (P=0.021), Arg554Lys (P=0.005) and Val570Ile (P=0.054). Genotyping of the Arg554Lys in patients with PA gave a minor allele frequency (MAF) of 3% vs 0% in neonatal controls.CONCLUSION: Gene expression and quantification analyses of AHR-target genes suggests that these AHR mutants might interfere with AHR target gene expression. Genotyping results suggested that this mutation is quite rare and may be similar to the frequencies of other European populations.peer-reviewe

Navigating intimate trans citizenship while incarcerated in Australia and the United States

Trans women incarcerated throughout the world have been described as 'vulnerable populations' due to significant victimization, mistreatment, lack of gender-affirming care, and human rights violations, which confers greater risk of trauma, self-harm, and suicide compared with the general incarcerated population. Most incarceration settings around the world are segregated by the person’s sex characteristics (i.e., male or female) and governed by strong cis and gender normative paradigms. This analysis seeks to better understand and appreciate how the 'instructions' and the 'authorities' that regulate trans women’s corporeal representation, housing options and sense of self-determination implicate and affect their agency and actions in handling intimacies related to their personal life. Drawing upon lived incarcerated experiences of 24 trans women in Australia and the United States, and employing Ken Plummer’s notion of intimate citizenship, this analysis explores how trans women navigate choices and ways 'to do' gender, identities, bodies, emotions, desires and relationships while incarcerated in men’s prisons and governed by cis and gender normative paradigms. This critical analysis contributes to understanding how incarcerated trans women through grit, resilience, and ingenuity still navigate ways to embody, express and enact their intimate citizenship in innovative and unique ways

Copy Number Variations as Determinants of Colorectal Tumor Progression in Liquid Biopsies

Over the years, increasing evidence has shown that copy number variations (CNVs) play an important role in the pathogenesis and prognosis of Colorectal Cancer (CRC). Colorectal adenomas are highly prevalent lesions, but only 5% of these adenomas ever progress to carcinoma. This review summarizes the different CNVs associated with adenoma-carcinoma CRC progression and with CRC staging. Characterization of CNVs in circulating free-RNA and in blood-derived exosomes augers well with the potential of using such assays for patient management and early detection of metastasis. To overcome the limitations related to tissue biopsies and tumor heterogeneity, using CNVs to characterize tumor-derived materials in biofluids provides less invasive sampling methods and a sample that collectively represents multiple tumor sites in heterogeneous samples. Liquid biopsies provide a source of circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), tumor-derived exosomes (TDE), circulating free RNA, and non-coding RNA. This review provides an overview of the current diagnostic and predictive models from liquid biopsies

A Critical Discourse Analysis of an Australian Incarcerated Trans Woman’s Letters of Complaint and Self-Advocacy

This case study provides a critical discourse analysis of 121 letters of complaint and self-advocacy authored by Natasha Keating, a trans woman incarcerated in two Australian male correctional facilities from 2000 to 2007. During her incarceration, Natasha experienced victimization, misgendering, microaggression, and institutional discrimination. Despite this, Natasha embodied and 'fought' against the injustices she experienced, whilst seeking to speak for other trans incarcerated persons also silenced and treated with indifference, contributing to changes in the carceral system. This original case study analyzes the discursive strategies Natasha employed to construct and reclaim an affirming self-identity through a deliberate campaign to effect social change and policy concessions within a system designed to curtail self-determination. Through her empathic and impassioned letter-writing approach, leveraging a military metaphor, this novel analysis showcases the significant implications her activism/agentism and determination had in naming and seeking to dismantle the systems of oppression trans incarcerated women experience

Single-dose psilocybin for a treatment-resistant episode of major depression: Impact on patient-reported depression severity, anxiety, function, and quality of life

Background: COMP360 is a proprietary, synthetic formulation of psilocybin being developed for treatment-resistant depression (TRD), a burdensome, life-threatening illness with high global impact. Here, we expand upon the previous report of primary outcomes from a phase 2 study of COMP360 in individuals with TRD—the largest randomised controlled clinical trial of psilocybin—to discuss findings of the exploratory efficacy endpoints. Methods: In this phase 2, double-blind trial, 233 participants with TRD were randomised to receive a single dose of psilocybin 25 mg, 10 mg, or 1 mg (control), administered alongside psychological support from trained therapists. Efficacy measures assessed patient-reported depression severity, anxiety, positive and negative affect, functioning and associated disability, quality of life, and cognitive function. Results: At Week 3, psilocybin 25 mg, compared with 1 mg, was associated with greater improvements from Baseline total scores in all measures. The 10 mg dose produced smaller effects across these measures. Limitations: Interpretation of this trial is limited by the absence of an active comparator and the possibility of functional unblinding in participants who received a low dose of psilocybin. Conclusions: Three weeks after dosing, psilocybin 25 mg and, to a lesser degree, 10 mg improved measures of patient-reported depression severity, anxiety, affect, and functioning. These results extend the primary findings from the largest randomised clinical trial of psilocybin for TRD to examine other outcomes that are of importance to patients