Structural and energetic determinants of adhesive binding specificity in type I cadherins.

Type I cadherin cell-adhesion proteins are similar in sequence and structure and yet are different enough to mediate highly specific cell-cell recognition phenomena. It has previously been shown that small differences in the homophilic and heterophilic binding affinities of different type I family members can account for the differential cell-sorting behavior. Here we use a combination of X-ray crystallography, analytical ultracentrifugation, surface plasmon resonance and double electron-electron resonance (DEER) electron paramagnetic resonance spectroscopy to identify the molecular determinants of type I cadherin dimerization affinities. Small changes in sequence are found to produce subtle structural and dynamical changes that impact relative affinities, in part via electrostatic and hydrophobic interactions, and in part through entropic effects because of increased conformational heterogeneity in the bound states as revealed by DEER distance mapping in the dimers. These findings highlight the remarkable ability of evolution to exploit a wide range of molecular properties to produce closely related members of the same protein family that have affinity differences finely tuned to mediate their biological roles.

Euglycemic Diabetic Ketoacidosis Presenting as Hypoglycemia in a Patient With Type 2 Diabetes and Von Gierke's Disease.

Von Gierke's disease (VGD) is rarely associated with type 2 diabetes mellitus (DM2). We present a case of VGD with DM2 that presented with hypoglycemia in the setting of diabetic ketoacidosis (DKA) in a young male with VGD using the sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin. The patient required resuscitation with fluids containing glucose prior to the administration of insulin for DKA protocol with significant clinical improvement. This case demonstrates a rare presentation of DKA with hypoglycemia.

Management of Locally Advanced Basal Cell Carcinoma with Sonic Hedgehog Pathway Targeted Therapy: A Case Report and Discussion.

Introduction: Basal cell carcinoma (BCC) is the most common skin malignancy in the world. While most lesions are treated using surgical methods, others may present as locally advanced or metastatic disease and are not amenable to surgical therapy alone. Treatment with sonic hedgehog pathway inhibitors (vismodegib, sonidegib) is designed to inhibit key signaling proteins and gene pathways involved with BCC to reduce the uncontrolled proliferation of basal cells in complicated disease and can be invaluable in treating patients with advanced disease. Case Presentation: We describe the course of a 68-year-old man who presented with a 7.2 × 6 cm exophytic and ulcerated locally invasive BCC of his upper back. The patient was started on daily vismodegib treatment with the goal of eventual surgical resection. After 11 weeks of therapy, he had significant improvement in both wound size and appearance. After 18 weeks of therapy, he had achieved a near complete clinical response of the central aspect of lesion with three remaining small peripheral lesions. These lesions were biopsied, and two were found to be negative for malignancy, while a small inferior nodule was positive for squamous cell carcinoma (SCC). Vismodegib therapy was discontinued after a total of 26 weeks of therapy. Excision of the SCC was performed, and the patient remains disease free at 2 years. Conclusion: This case report shows the efficacy of hedgehog pathway inhibitor therapy in the treatment of a locally advanced BCC with complete pathologic response, not requiring surgical intervention.

Senescence-associated tissue microenvironment promotes colon cancer formation through the secretory factor GDF15.

The risk of colorectal cancer (CRC) varies between people, and the cellular mechanisms mediating the differences in risk are largely unknown. Senescence has been implicated as a causative cellular mechanism for many diseases, including cancer, and may affect the risk for CRC. Senescent fibroblasts that accumulate in tissues secondary to aging and oxidative stress have been shown to promote cancer formation via a senescence-associated secretory phenotype (SASP). In this study, we assessed the role of senescence and the SASP in CRC formation. Using primary human colon tissue, we found an accumulation of senescent fibroblasts in normal tissues from individuals with advanced adenomas or carcinomas in comparison with individuals with no polyps or CRC. In in vitro and ex vivo model systems, we induced senescence using oxidative stress in colon fibroblasts and demonstrated that the senescent fibroblasts secrete GDF15 as an essential SASP factor that promotes cell proliferation, migration, and invasion in colon adenoma and CRC cell lines as well as primary colon organoids via the MAPK and PI3K signaling pathways. In addition, we observed increased mRNA expression of GDF15 in primary normal colon tissue from people at increased risk for CRC in comparison with average risk individuals. These findings implicate the importance of a senescence-associated tissue microenvironment and the secretory factor GDF15 in promoting CRC formation.