The association between glycaemic control during hospitalization and risk of adverse events: A retrospective cohort study.

INTRODUCTION: Hyperglycaemia is common during hospitalization; glycaemic targets in non-critical care settings have not been well studied. We assessed associations between inpatient glycaemic control and adverse events. METHODS: We conducted a retrospective cohort study on non-critically ill medical patients hospitalized in a tertiary care hospital between 2015 and 2018. Mean glycaemia during the first four days of hospitalization was categorized as 4.0-7.0 mmol/L, 7.1-10.0 mmol/L and >10.0 mmol/L. The primary outcome was a composite of adverse events including mortality, infections, acute kidney injury, thromboembolic and cardiovascular events. The secondary outcome was hypoglycaemia, defined as any glycaemia <4.0 mmol/L. Logistic regression was used to assess adverse events, and a Cox proportional hazards model was used to estimate hypoglycaemia risk. RESULTS: Our cohort included 1,368 patients, of whom 407 (29.8%) experienced an adverse event. We did not find associations between glycaemia of 4.0-7.0 mmol/L (adjusted odds ratio [OR]: 0.88, 95% confidence interval [CI]: 0.63-1.23) or glycaemia of >10.0 mmol/L (adjusted OR: 0.98, 95% CI: 0.75-1.28) and the occurrence of adverse events, compared to a glycaemia of 7.1-10.0 mmol/L. Glycaemia of >10.0 mmol/L was associated with an increased risk of hypoglycaemia (adjusted hazard ratio [HR]: 1.72, 95% CI: 1.21-2.45). Hypoglycaemia was associated with adverse events (adjusted OR 1.85, 95% CI 1.31-2.60). CONCLUSIONS: Neither glycaemia of 4.0-7.0 mmol/L nor glycaemia of >10.0mmol/L during non-critical care hospitalization was associated with increased adverse events. Glycaemia of >10.0 mmol/L was associated with increased hypoglycaemia, likely due to aggressive glucose lowering. These findings highlight the need for further studies to discern optimal inpatient glycaemic targets.

MNK1/NODAL Signaling Promotes Invasive Progression of Breast Ductal Carcinoma In Situ.

The mechanisms by which breast cancers progress from relatively indolent ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) are not well understood. However, this process is critical to the acquisition of metastatic potential. MAPK-interacting serine/threonine-protein kinase 1 (MNK1) signaling can promote cell invasion. NODAL, a morphogen essential for embryogenic patterning, is often reexpressed in breast cancer. Here we describe a MNK1/NODAL signaling axis that promotes DCIS progression to IDC. We generated MNK1 knockout (KO) or constitutively active MNK1 (caMNK1)-expressing human MCF-10A-derived DCIS cell lines, which were orthotopically injected into the mammary glands of mice. Loss of MNK1 repressed NODAL expression, inhibited DCIS to IDC conversion, and decreased tumor relapse and metastasis. Conversely, caMNK1 induced NODAL expression and promoted IDC. The MNK1/NODAL axis promoted cancer stem cell properties and invasion in vitro. The MNK1/2 inhibitor SEL201 blocked DCIS progression to invasive disease in vivo. In clinical samples, IDC and DCIS with microinvasion expressed higher levels of phospho-MNK1 and NODAL versus low-grade (invasion-free) DCIS. Cumulatively, our data support further development of MNK1 inhibitors as therapeutics for preventing invasive disease. SIGNIFICANCE: These findings provide new mechanistic insight into progression of ductal carcinoma and support clinical application of MNK1 inhibitors to delay progression of indolent ductal carcinoma in situ to invasive ductal carcinoma.