The ACE2 receptor accelerates but is not biochemically required for SARS-CoV-2 membrane fusion.

The SARS-CoV-2 coronavirus infects human cells the ACE2 receptor. Structural evidence suggests that ACE2 may not just serve as an attachment factor but also conformationally activate the SARS-CoV-2 spike protein for membrane fusion. Here, we test that hypothesis directly, using DNA-lipid tethering as a synthetic attachment factor in place of ACE2.

Single-Virus Fusion Measurements Reveal Multiple Mechanistically Equivalent Pathways for SARS-CoV-2 Entry.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to cell surface receptors and is activated for membrane fusion and cell entry via proteolytic cleavage. Phenomenological data have shown that SARS-CoV-2 can be activated for entry at either the cell surface or in endosomes, but the relative roles in different cell types and mechanisms of entry have been debated. Here, we used single-virus fusion experiments and exogenously controlled proteases to probe activation directly.

Gerbode defect formation two decades after tetrology of fallot repair.

Although most intracardiac defects are congenital, a small fraction may be acquired during life. The Gerbode defect is an abnormal anatomical connection between the left ventricle and the right atrium. We describe herein a patient who initially underwent repair of tetralogy of Fallot (TOF).

OP449 inhibits breast cancer growth without adverse metabolic effects.

Hyperinsulinemia is associated with a decrease in breast cancer recurrence-free survival and overall survival. Inhibition of insulin receptor signaling is associated with glycemic dysregulation. SET is a direct modulator of PP2A, which negatively regulates the PI3K/AKT/mTOR pathway.

Silencing vimentin expression decreases pulmonary metastases in a pre-diabetic mouse model of mammary tumor progression.

Increased breast cancer risk and mortality has been associated with obesity and type 2 diabetes (T2D). Hyperinsulinemia, a key factor in obesity, pre-diabetes and T2D, has been associated with decreased breast cancer survival. In this study, a mouse model of pre-diabetes (MKR mouse) was used to investigate the mechanisms through which endogenous hyperinsulinemia promotes mammary tumor metastases.

Non-metabolisable insulin glargine does not promote breast cancer growth in a mouse model of type 2 diabetes.

Aims/hypothesis: Previous epidemiological studies have reported a potential link between insulin analogues and breast cancer; however, a prospective randomised controlled trial showed neutral effects of insulin glargine on cancer risk. Insulin glargine is metabolised in vivo to an M1 metabolite. A question remains whether a subset of individuals with slower rates of glargine metabolism or who are on high doses could, theoretically, have an increased risk of cancer progression if a tumour is already present.

The effect of dipeptidyl peptidase-IV inhibition on bone in a mouse model of type 2 diabetes.

Background: Individuals with type 2 diabetes (T2D) are at greater risk of bone fractures than those without diabetes. Certain oral diabetic medications may further increase the risk of fracture. Dipeptidyl peptidase-IV (DPP-IV) inhibitors are incretin-based therapies that are being increasingly used for the management of T2D.

Insulin receptor phosphorylation by endogenous insulin or the insulin analog AspB10 promotes mammary tumor growth independent of the IGF-I receptor.

Endogenous hyperinsulinemia and insulin receptor (IR)/IGF-I receptor (IGF-IR) phosphorylation in tumors are associated with a worse prognosis in women with breast cancer. In vitro, insulin stimulation of the IR increases proliferation of breast cancer cells. However, in vivo studies demonstrating that IR activation increases tumor growth, independently of IGF-IR activation, are lacking.

Hyperinsulinemia promotes metastasis to the lung in a mouse model of Her2-mediated breast cancer.

The Her2 oncogene is expressed in ∼25% of human breast cancers and is associated with metastatic progression and poor outcome. Epidemiological studies report that breast cancer incidence and mortality rates are higher in women with type 2 diabetes. Here, we use a mouse model of Her2-mediated breast cancer on a background of hyperinsulinemia to determine how elevated circulating insulin levels affect Her2-mediated primary tumor growth and lung metastasis.

Trends in Fidelis lead survival: transition from an exponential to linear pattern of lead failure over time.

Background: The Sprint Fidelis implantable cardioverter-defibrillator lead was recalled in 2007 because of an levated risk of lead fracture. Several studies have demonstrated an accelerating risk of lead failure over time. We sought to identify predictors and characterize trends of Fidelis lead failure.