Prostate cancer has variable manifestations, ranging from relatively benign localized tumors to widespread life-threatening metastases. The origin of most prostate cancer metastases can be traced back to the primary tumor; therefore, understanding the mutations in the primary tumor that promote cancer spread is of great interest.
In this issue of the Journal of Clinical Investigation, Srinivasan Yegnasubramanian and colleagues at Johns Hopkins University track the development of lethal prostate cancer in a patient. Using tissue samples taken throughout the progression of the cancer, the authors identified the origin of the lethal clone. Surprisingly, in this case the lethal clone originated from a small, low-grade foci in the primary tumor and not from the larger high-grade region of the tumor.
In the accompanying commentary, Rose Brannon and Charles Sawyers of Memorial Sloan-Kettering Cancer Center discuss the importance of individual case studies and how a comprehensive database of such studies is needed to identify common patterns in cancer progression.
Tracking the clonal origin of lethal prostate cancer, http://www.jci.org/articles/view/70354?key=4f436390394081ee2a50
Reduction of reactive oxygen species in diabetes-associated nephrology
Diabetes-associated complications, including retinopathy, neuropathy, and nephropathy are associated with increased glucose levels, but it is not understood how glucose drives these manifestations. There is evidence that cultured cells exposed to high levels of glucose produce reactive oxygen species (ROS); however it is unknown if ROS contributes directly to diabetes complications. In this issue of the Journal of Clinical Investigation, Kumar Sharma and colleagues at the University of California, San Diego determined that ROS production was actually reduced in kidneys of diabetic mice, and this decrease was associated with lowered activity of the major energy-sensing enzyme, AMPK. Furthermore, AMPK activity was also reduced in kidneys of diabetic patients. Treatment of diabetic mice with a compound that increased AMPK activity reduced kidney-associated symptoms, including fibrosis and albuminuria. In the companion commentary, Dwight Towler of the Sanford-Burnham Medical Institute discusses how this view of ROS in diabetes will require a new look at therapeutic approaches for relieving diabetes complications.
TITLE: AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function
AUTHOR CONTACT:Kumar Sharma UCSD, La Jolla, CA, USA Phone: 858-822-0870; Fax: 858-822-7483; E-mail: kusharma@ucsd.edu
View this article at: http://www.jci.org/articles/view/66218?key=5fad8f958699794ef103
ACCOMPANYING COMMENTARY
TITLE: Mitochondrial ROS deficiency and diabetic complications: AMP[K]-lifying the adaptation to hyperglycemia
AUTHOR CONTACT: Dwight Towler Sanford-Burnham Medical Research Institute, orlando, , USA Phone: 407-745-2079; E-mail: dtowler@sanfordburnham.org
View this article at: http://www.jci.org/articles/view/72326?key=dcdae15a08a5b61c4555
Synthetic vitamin D receptor ligands reduce murine kidney fibrosis
Vitamin D deficiency has been associated with kidney disease including fibrosis. Some studies have even suggested that treatment with vitamin D or vitamin D analogs can reduce renal fibrosis; however, the pathways targeted by vitamin D therapy are not completely understood. In this issue of the Journal of Clinical Investigation, Junn Yanagisawa and colleagues at the University of Tsukuba found that vitamin D binding to its receptor inhibited the TGF-β/SMAD signaling pathway and prevented renal fibrosis in mice. The authors then generated a synthetic ligand of the vitamin D receptor that, like vitamin D, reduced renal fibrosis; however, unlike vitamin D, this synthetic ligand did not promote hypercalcemia. In the accompanying commentary Joseph Bonventre suggests that synthetic ligands of the vitamin D receptor should be further studied as therapeutics for patients with fibrotic diseases.
TITLE: A nonclassical vitamin D receptor pathway suppresses renal fibrosis
AUTHOR CONTACT: Junn Yanagisawa University of Tsukuba, Tsukuba, , JPN Phone: 81-29-853-7320; E-mail: junny@agbi.tsukuba.ac.jp
View this article at: http://www.jci.org/articles/view/67804?key=e9b75812c32074994393
ACCOMPANYING COMMENTARY
TITLE: Antifibrotic vitamin D analogs
AUTHOR CONTACT: Joseph V. Bonventre Brigham and Women's Hospital, Boston, MA, USA Phone: 617-525-5966; Fax: 617-525-5965; E-mail: joseph_bonventre@hms.harvard.edu
View this article at: http://www.jci.org/articles/view/72748?key=c9aa266738ffedbb76ab
Itch maintains regulatory T cell stability
Regulatory T cells (Tregs) function to suppress immune responses of other cells, and their dysfunction has been associated with development of immune disorders. Recent studies suggest that Tregs maintain plasticity even after differentiation, and can be influenced to change their regulatory profile. In this issue of the Journal of Clinical Investigation, Yun-Cai Liu and colleagues at the La Jolla Institute for Allergy and Immunology identified the E3 ubiquitin ligase Itch as a regulator of Tregs stability. The authors found that in the absence of Itch, Tregs took on a Th2 phenotype, which promoted the development of severe antigen-induced airway inflammation, skin lesion formation and other inflammatory characteristics in mice. In a companion commentary, WanJun Chen of the National Institutes of Health discusses the implications of this study on our understanding of allergy and asthma development.
TITLE: Itch expression by Treg cells controls Th2 inflammatory responses
AUTHOR CONTACT: Yun-Cai Liu La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA Phone: 858-752-6810; Fax: 858-752-6985; E-mail: yuncail@liai.org
View this article at: http://www.jci.org/articles/view/69355?key=34db86acfb334e362aa5