EDITOR'S PICK: The biggest isn't always best when it comes to treating cancer
Developing immunotherapeutic approaches to treat individuals with cancer is an area of intensive investigation. One such approach being developed is the generation of cancer vaccines containing peptides that mimic tumor antigens (known as mimotopes) to induce potent tumor-specific T cell responses. However, previous studies have indicated that the magnitude of a tumor antigen–specific T cell response in vitro does not always correlate with tumor regression in vivo.
Now, in a study appearing online on August 24 in advance of publication in the September print issue of the Journal of Clinical Investigation, Jill Slansky and colleagues from the University of Colorado have shown that mice vaccinated with mimotopes that induce in vitro T cell responses of intermediate magnitude are protected against tumor growth. By contrast, mimotopes that induce in vitro T cell responses of high magnitude do not protect mice from tumor growth. Both types of mimotope caused T cells to infiltrate the tumors, but only the T cells activated by mimotopes inducing in vitro T cell responses of intermediate magnitude produced the soluble factor interferon-gamma, which is important for effective tumor-specific T cell responses. This study has important implications for the further development of cancer vaccines containing mimotopes, as many current studies have used the magnitude of a tumor-specific T cell response to identify the best mimotope for the vaccine.
TITLE: Relating TCR-peptide-MHC affinity to immunogenicity for the design of tumor vaccines
AUTHOR CONTACT: Jill E. Slansky University of Colorado at Denver and Health Sciences Center, Denver, Colorado, USA. Phone: (303) 398-1887; Fax: (303) 398-1396; E-mail: Jill.Slansky@UCHSC.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=26936
EDITOR'S PICK: An irregular heartbeat makes exercise deadly
The results of a study in mice that was conducted by researchers from Vanderbilt University has provided a potential explanation for why the heartbeat of humans lacking the protein cardiac calsequestrin (CASQ2) is irregular, and potentially fatal, only during exercise and not at other times.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a life-threatening disease characterized by an irregular heartbeat during exercise. CPVT can be caused by mutations in the gene encoding CASQ2, which is a Ca2+-binding protein found in the Ca2+ storage facility of the muscle cells of the heart. Paradoxically, although CASQ2 is thought to have a crucial role in regulating contraction of the heart, individuals lacking both copies of CASQ2 and whose hearts contract relatively normally have been identified. In a study that appears online on August 24 in advance of publication in the September print issue of the Journal of Clinical Investigation, Björn Knollmann and colleagues generated Casq2-deficient mice to help explain this paradox. Similar to humans lacking CASQ2, Casq2-deficient mice showed normal heart contraction under basal conditions, but both exercise and exposure to catecholamines (which are chemicals such as epinephrine made by the body during exercise and stress) induced an irregular heartbeat. The authors found that the lack of Casq2 was compensated for in several ways, including a substantial increase in the volume of the Ca2+ storage facility in the muscle cells of the heart, such that under basal conditions the heartbeat was regular. However, when exposed to catecholamines, a lack of Casq2 caused Ca2+ to spontaneously leak from its storage facility and trigger an inappropriate heartbeat. This study identifies the mechanisms behind the irregular heartbeats caused by a lack of Casq2, and might explain why the hearts of humans lacking CASQ2 beat relatively normally, but can beat irregularly and put these individuals at risk of sudden death when they exercise.
TITLE: Casq2 deletion causes sarcoplasmic reticulum volume increase, premature Ca2+ release, and catecholaminergic polymorphic ventricular tachycardia
AUTHOR CONTACT: Björn C. Knollman Vanderbilt University Medical Center, Nashville, Tennessee, USA. Phone: (615) 343-6493; Fax: (615) 343-4522; E-mail: bjorn.knollmann@vanderbilt.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=29128
ENDOCRINOLOGY: Individuals with a genetic deficiency can blame it on their hormones
Impaired development of the eyes is currently the main characteristic of humans lacking one copy of the SOX2 gene. However, some individuals also have other developmental defects, including defects in growth and male fertility, which are the defects observed in mice expressing only one copy of Sox2. In a study appearing online on August 24 in advance of publication in the September print issue of the Journal of Clinical Investigation, Mehul Dattani and colleagues from Great Ormond Street Hospital for Children in London now explain why growth and male fertility are impaired in mice and humans lacking one copy of Sox2 and SOX2, respectively. Abnormal development of the pituitary gland -- which secretes the hormones that regulate growth and fertility, such as growth hormone -- was observed in mice expressing only one copy of Sox2. Similar defects in the production of hormones secreted by the pituitary gland were observed in newly identified individuals with only one copy of SOX2. Defects in growth hormones and the hormones that regulate male fertility can be treated. So, this new understanding of the effects of having a single copy of SOX2 should allow individuals with this genetic defect to be treated and thereby avoid the many long-term problems associated with these hormone deficiencies.
TITLE: Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans
AUTHOR CONTACT: Mehul T. Dattani Institute of Child Health and Great Ormond Street Hospital for Children, London, United Kingdom. Phone: 44-20-7905-2657; Fax: 44-20-7404-6191; E-mail: mdattani@ich.ucl.ac.uk
View the PDF of this article at: https://www.the-jci.org/article.php?id=28658
CARDIOVASCULAR BIOLOGY: Arteriogenesis and angiogenesis: new tricks for BMX
The symptoms of coronary artery disease and peripheral arterial disease are caused by decreased blood flow, which is known as ischemia, to the heart muscles and/or other tissues, respectively. This in turn triggers local expansion of the lumen of blood vessels (arteriogenesis) and the growth of new blood vessels (angiogenesis), which together allow blood flow to the damaged tissue to be restored. Although previous studies have hinted at a role for a protein known as Bmx in angiogenesis, its function in vivo had remained unclear.
Now, in a study appearing online on August 24 in advance of publication in the September print issue of the Journal of Clinical Investigation, Wang Min and colleagues from Yale University have shown that Bmx has an important role in the arteriogenesis and angiogenesis induced by ischemic injury in the hind limbs of mice. Bmx-deficient mice showed impaired restoration of the blood flow to the limbs after ischemic injury, whereas mice expressing a constitutively active form of Bmx only in endothelial cells showed enhanced restoration of the blood flow to the limbs. This study highlights the importance of Bmx for arteriogenesis and angiogenesis after ischemia and suggests that Bmx might be a good target for the treatment of diseases caused by ischemia, such as coronary heart disease and peripheral arterial disease.
TITLE: Critical function of Bmx/Etk in ischemia-mediated arteriogenesis and angiogenesis
AUTHOR CONTACT: Wang Min Yale University School of Medicine, New Haven, Connecticut, USA. Phone : (203) 785-6047; Fax: (203) 737-2293; E-mail: wang.min@yale.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=28123
Journal
Journal of Clinical Investigation