Selectin Inhibitors and Their Proposed Role in Ischemia and Reperfusion

The selectin family of cellular adhesion molecules plays an important role in the cellular infiltration and molecular signaling associated with ischemia/reperfusion (I/R). Selectins are essential in the recruitment and infiltration of leukocytes to sites of inflammation, and consequently, selectin blockade represents an important area of current research in the potential alleviation of the cell-mediated injury associated with I/R. Previously, treatments targeted at only a single selectin have proven ineffective, due to compensation by uninhibited cell-adhesion molecules. However, pan-selectin antagonists—those inhibitors capable of blocking the actions of all three selectins—have demonstrated great potential in blocking the initial events in the leukocyte-endothelium adhesion cascade. A number of therapeutics have been developed, with the most promising results demonstrated by a class of non-oligosaccharide, small-molecule selectin antagonists. TB-1269 and OC-229 are two of the most promising of inhibitors in this class—they are capable of binding all three selectins, they have been demonstrated to reduce neutrophil infiltration following ischemia/reperfusion, and they have been associated with reduced tissue damage in experimental animal models of ischemia/reperfusion involving the liver, the heart, the kidneys, and the whole body. Furthermore, TBC-1269 has recently undergone successful phase I and phase IIa clinical trials for asthma and psoriasis. Though the timing of selectin inhibition is essential in attenuating leukocyte infiltration and cell-mediated injury, the transient blockade of selectin function, in a well-controlled setting, could be an extremely beneficial intervention in ischemia/reperfusion injury.     

A liquid biopsy for head and neck cancers

Head and neck cancer patients often present with advanced metastatic disease resulting in a poor 5-year survival. Therefore, there is a need for non-invasive diagnostic tools that could complement conventional imaging to inform clinicians of patient outcomes and treatment responses. A liquid biopsy addresses this unmet clinical need; a simple peripheral blood draw could provide information about the disseminated disease in terms of circulating tumor cells and circulating tumor DNA. Moreover, detectable tumor DNA in the saliva of head and neck cancer patients could signify the early signs of the disease and present an opportunity for clinical intervention. This review provides an overview of the current literature with regard to the feasibility of such a test in the head and neck cancer field and highlights the need for such a test.     

Fully Integrated Artificial Pancreas in Type 1 Diabetes: Modular Closed-Loop Glucose Control Maintains Near Normoglycemia

Integrated closed-loop control (CLC), combining continuous glucose monitoring (CGM) with insulin pump (continuous subcutaneous insulin infusion [CSII]), known as artificial pancreas, can help optimize glycemic control in diabetes. We present a fundamental modular concept for CLC design, illustrated by clinical studies involving 11 adolescents and 27 adults at the Universities of Virginia, Padova, and Montpellier. We tested two modular CLC constructs: standard control to range (sCTR), designed to augment pump plus CGM by preventing extreme glucose excursions; and enhanced control to range (eCTR), designed to truly optimize control within near normoglycemia of 3.9-10 mmol/L. The CLC system was fully integrated using automated data transfer CGM→algorithm→CSII. All studies used randomized crossover design comparing CSII versus CLC during identical 22-h hospitalizations including meals, overnight rest, and 30-min exercise. sCTR increased significantly the time in near normoglycemia from 61 to 74%, simultaneously reducing hypoglycemia 2.7-fold. eCTR improved mean blood glucose from 7.73 to 6.68 mmol/L without increasing hypoglycemia, achieved 97% in near normoglycemia and 77% in tight glycemic control, and reduced variability overnight. In conclusion, sCTR and eCTR represent sequential steps toward automated CLC, preventing extremes (sCTR) and further optimizing control (eCTR). This approach inspires compelling new concepts: modular assembly, sequential deployment, testing, and clinical acceptance of custom-built CLC systems tailored to individual patient needs.