Rare presentation of multisystem inflammatory syndrome in an adult associated with SARS-CoV-2 infection: unilateral neck swelling.

Multisystem inflammatory syndrome in adults (MIS-A) is a rare but often severe complication of SARS-CoV-2 infection. While several case reports about MIS-A in the setting of COVID-19 have been published since the term was first coined in June 2020, a clear description of the underlying pathophysiology and guideline-based recommendations on the diagnostic and therapeutic approach are lacking. What has been reported is that in the absence of severe respiratory illness, MIS-A can present with hypotension or shock, high-grade fever, abdominal pain, diarrhoea and severe weakness days to weeks after SARS-CoV-2 infection. Here, we present a case of a 28-year-old man who presented with a rarely described initial symptom: unilateral neck swelling. His presentation, disease progression and treatment course provide further information about MIS-A as a complication and in formulating diagnostic guidelines.

Functional Annotation of ESR1 Gene Fusions in Estrogen Receptor-Positive Breast Cancer.

RNA sequencing (RNA-seq) detects estrogen receptor alpha gene (ESR1) fusion transcripts in estrogen receptor-positive (ER+) breast cancer, but their role in disease pathogenesis remains unclear. We examined multiple ESR1 fusions and found that two, both identified in advanced endocrine treatment-resistant disease, encoded stable and functional fusion proteins. In both examples, ESR1-e6>YAP1 and ESR1-e6>PCDH11X, ESR1 exons 1-6 were fused in frame to C-terminal sequences from the partner gene. Functional properties include estrogen-independent growth, constitutive expression of ER target genes, and anti-estrogen resistance. Both fusions activate a metastasis-associated transcriptional program, induce cellular motility, and promote the development of lung metastasis. ESR1-e6>YAP1- and ESR1-e6>PCDH11X-induced growth remained sensitive to a CDK4/6 inhibitor, and a patient-derived xenograft (PDX) naturally expressing the ESR1-e6>YAP1 fusion was also responsive. Transcriptionally active ESR1 fusions therefore trigger both endocrine therapy resistance and metastatic progression, explaining the association with fatal disease progression, although CDK4/6 inhibitor treatment is predicted to be effective.

Dietary and genetic effects on age-related loss of gene silencing reveal epigenetic plasticity of chromatin repression during aging.

During aging, changes in chromatin state that alter gene transcription have been postulated to result in expression of genes that are normally silenced, leading to deleterious age-related effects on cellular physiology. Despite the prevalence of this hypothesis, it is primarily in yeast that loss of gene silencing with age has been well documented. We use a novel position effect variegation (PEV) reporter in Drosophila melanogaster to show that age-related loss of repressive heterochromatin is associated with loss of gene silencing in metazoans and is affected by Sir2, as it is in yeast. The life span-extending intervention, calorie restriction (CR), delays the age-related loss of gene silencing, indicating that loss of gene silencing is a component of normal aging. Diet switch experiments show that such flies undergo a rapid change in their level of gene silencing, demonstrating the epigenetic plasticity of chromatin during aging and highlighting the potential role of diet and metabolism in chromatin maintenance, Thus, diet and related interventions may be of therapeutic importance for age-related diseases, such as cancer.