Bryan O’Sullivan-Murphy

Ultrasonography (renamed from the Journal of Korean Society of Ultrasound in Medicine in January 2014), the official English-language journal of the Korean Society of Ultrasound in Medicine (KSUM), is an international peer-reviewed academic journal dedicated to practice, research, technology, and education dealing with medical ultrasound, Aims and Scope:Ultrasonography (renamed from the Journal of Korean Society of Ultrasound in Medicine in January 2014), the official English-language journal of the Korean Society of Ultrasound in Medicine (KSUM), is an international peer-reviewed academic journal dedicated to practice, research, technology, and education dealing with medical ultrasound.It is published four times per year: January 1, April 1, July 1, and October 1. Original articles, topical reviews, pictorial essays, and notable case reports are published in Ultrasonography covering state-of-the-art content. Ultrasonography also serves as a medium for cooperation among physicians and specialists from around the world who are focusing on various ultrasound technology and disease problems.

PURPOSE: There is a need to identify cancer chemoprevention mechanisms. We reported previously that all-trans-retinoic acid (RA) prevented carcinogenic transformation of BEAS-2B immortalized human bronchial epithelial cells by causing G(1) arrest, permitting repair of genomic DNA damage. G(1) arrest was triggered by cyclin D1 proteolysis via ubiquitin-dependent degradation. This study investigated which chemopreventive agents activated this degradation program and whether cyclin E was also degraded. EXPERIMENTAL DESIGN: This study examined whether: (a) cyclin E protein was affected by RA treatment; (b) cyclin degradation occurred in derived BEAS-2B-R1 cells that were partially resistant to RA; and (c) other candidate chemopreventive agents caused cyclin degradation. RESULTS: RA treatment triggered degradation of cyclin E protein, and ALLN, a proteasomal inhibitor, inhibited this degradation. Induction of the retinoic acid receptor beta, growth suppression, and cyclin degradation were each inhibited in BEAS-2B-R1 cells. Transfection experiments in BEAS-2B cells indicated that RA treatment repressed expression of wild-type cyclin D1 and cyclin E, but ALLN inhibited this degradation. Mutation of threonine 286 stabilized transfected cyclin D1, and mutations of threonines 62 and 380 stabilized transfected cyclin E, despite RA treatment. Specific chemopreventive agents triggered cyclin degradation. Nonclassical retinoids (fenretinide and retinoid X receptor agonists) and a synthetic triterpenoid (2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid) each suppressed BEAS-2B growth and activated this degradation program. However, a vitamin D3 analog (RO-24-5531), a cyclooxygenase inhibitor (indomethacin), and a peroxisome proliferator-activated receptor gamma agonist (rosiglitazone) each suppressed BEAS-2B growth, but did not cause cyclin degradation. BEAS-2B-R1 cells remained responsive to nonclassical retinoids and to 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid. CONCLUSIONS: Specific chemopreventive agents activate cyclin proteolysis. Yet, broad resistance did not occur after acquired resistance to a single agent. This provides a therapeutic rationale for combination chemoprevention with agents activating non-cross-resistant pathways.

Gimap5 (GTPase of the immunity-associated protein 5) has been linked to the regulation of T cell survival, and polymorphisms in the human GIMAP5 gene associate with autoimmune disorders. The BioBreeding diabetes-prone (BBDP) rat has a mutation in the Gimap5 gene that leads to spontaneous apoptosis of peripheral T cells by an unknown mechanism. Because Gimap5 localizes to the endoplasmic reticulum (ER), we hypothesized that absence of functional Gimap5 protein initiates T cell death through disruptions in ER homeostasis. We observed increases in ER stress-associated chaperones in T cells but not thymocytes or B cells from Gimap5(-/-) BBDP rats. We then discovered that ER stress-induced apoptotic signaling through C/EBP-homologous protein (CHOP) occurs in Gimap5(-/-) T cells. Knockdown of CHOP by siRNA protected Gimap5(-/-) T cells from ER stress-induced apoptosis, thereby identifying a role for this cellular pathway in the T cell lymphopenia of the BBDP rat. These findings indicate a direct relationship between Gimap5 and the maintenance of ER homeostasis in the survival of T cells.

Type 1 diabetes is an autoimmune disease characterized by the destruction of pancreatic β-cells and an absolute deficiency of insulin. Patients with type 1 diabetes are insulin dependent for life and require multiple daily insulin injections or the use of an insulin pump. It has been considered that β-cell dysfunction and death in type 1 diabetes results from a combination of inflammation, autoimmunity, β-cell stress, and insulin resistance (1–5). Clinical and experimental evidence has indicated that defects in β-cell function precede the massive death of β-cells by severe infiltration of T cells into the islets and the clinical onset of type 1 diabetes (6–9). However, the mechanisms involved in β-cell dysfunction before the onset of clinical type 1 diabetes are unclear. In this issue of Diabetes , Tersey et al. (10) add a new dimension to the progression of type 1 diabetes by demonstrating that endoplasmic reticulum (ER) stress in β-cells precedes the clinical onset of type 1 diabetes. The ER performs a number of important cellular tasks, including protein folding, calcium regulation, redox regulation, and life or death decisions (11,12). Within the β-cell, insulin production and secretion depend on the processing capacity of the …