Programmed death-1 pathway in cancer and autoimmunity.

Programmed death-1 (PD-1) is a co-receptor that is expressed predominantly by T cells. The binding of PD-1 to its ligands, PD-L1 or PD-L2, is vital for the physiologic regulation of the immune system. A major functional role of the PD-1 signaling pathway is the inhibition of self-reactive T cells, which serve to protect against autoimmune diseases. Elimination of the PD-1 pathway can therefore result in the breakdown of immune tolerance that can ultimately lead to the development of pathogenic autoimmunity. Conversely, tumor cells can at times co-opt the PD-1 pathway to escape from immunosurveillance mechanisms. Therefore, blockade of the PD-1 pathway has become an attractive target in cancer therapy. Recent clinical trials have shown that anti-PD-1 agents have profound effects on solid tumor regression. Current approaches include six agents that are either PD-1 and PD-L1 targeted neutralizing antibodies or fusion proteins. More than forty clinical trials are underway to better define the role of PD-1 blockade in variety of tumor types. In this review we will highlight the basic biology of the PD-1 system and discuss its potential roles in both autoimmunity and cancer. We propose that future research on PD-1 may lead to the translation of fundamental regulatory pathways into the development of practical new approaches for the treatment of autoimmune diseases and cancer.

Advancing the Understanding of Vitamin D Status in Post-Thyroidectomy Hypocalcemia.

BACKGROUND: Post-thyroidectomy hypocalcemia is the most common complication after total thyroidectomy. Studies to examine the role of low vitamin D in increasing post-thyroidectomy hypocalcemia incidence have produced varying results. This study aimed to assess whether vitamin D deficiency increases the risk of post-thyroidectomy hypocalcemia. METHODS: This retrospective study involved 244 patients who underwent total thyroidectomy between 2014 and 2019. Patients were divided into two groups based on pre-operative vitamin D levels. Group A and Group B had pre-operative vitamin D (25-hydroxyvitamin D) levels of ≥20 ng/ml and <20 ng/ml (reference range for vitamin D is 30-100 ng/dl). The effect of vitamin D, gender, body mass index (BMI), and ethnicity on post-operative calcium and PTH levels was analyzed. RESULTS: Post-operative calcium levels for Group A were not statistically different compared to Group B (8.52 ± 0.64 mg/dl vs. 8.45 ± 0.58 mg/dl (mean ± S.D.; p value = 0.352). The average post-operative PTH of the two groups did not differ significantly (Group A: 32.4 ± 27.5 pg/ml; Group B: 34.4 ± 41.7 pg/ml; p value = 0.761). CONCLUSION: Pre-operative vitamin D levels are not predictive of post-thyroidectomy hypocalcemia.

Static adhesion assay for the study of integrin activation in T lymphocytes.

T lymphocyte adhesion is required for multiple T cell functions, including migration to sites of inflammation and formation of immunological synapses with antigen presenting cells. T cells accomplish regulated adhesion by controlling the adhesive properties of integrins, a class of cell adhesion molecules consisting of heterodimeric pairs of transmembrane proteins that interact with target molecules on partner cells or extracellular matrix. The most prominent T cell integrin is lymphocyte function associated antigen (LFA)-1, composed of subunits αL and ß2, whose target is the intracellular adhesion molecule (ICAM)-1. The ability of a T cell to control adhesion derives from the ability to regulate the affinity states of individual integrins. Inside-out signaling describes the process whereby signals inside a cell cause the external domains of integrins to assume an activated state. Much of our knowledge of these complex phenomena is based on mechanistic studies performed in simplified in vitro model systems. The T lymphocyte adhesion assay described here is an excellent tool that allows T cells to adhere to target molecules, under static conditions, and then utilizes a fluorescent plate reader to quantify adhesiveness. This assay has been useful in defining adhesion-stimulatory or inhibitory substances that act on lymphocytes, as well as characterizing the signaling events involved. Although described here for LFA-1 - ICAM-1 mediated adhesion; this assay can be readily adapted to allow for the study of other adhesive interactions (e.g. VLA-4 - fibronectin).