Spinal muscular atrophy is a pediatric neuromuscular disorder caused by mutation in the survival of motor neuron 1 (SMN1) gene. Kariya et al. explored the temporal requirement for survival motoneuron (SMN) proteins using an inducible deletion strategy in mice. Their findings suggest that SMN is critical during the maturation and repair of neuromuscular junctions and have important implications for emerging therapeutic strategies. In an accompanying Commentary, Kathryn Swoboda discusses the importance of these elegant genetic studies and the translational implications for emerging therapeutic strategies to optimally restore SMN in SMA patients. The cover image shows a transverse section through the mouse spinal cord stained for SMN (green), choline acetyltransferase (red), and nuclei (DAPI).
In the latest Conversations with Giants in Medicine, the JCI talks with Sir Marc Feldmann. Over the last 30 years, his research has focused on the understanding of autoimmune disease, specifically the treatment of rheumatoid arthritis (RA). Sir Marc, now at the Kennedy Institute of Rheumatology at Oxford University, championed the importance of antigen presentation and cytokines in autoimmunity, a concept that led to TNF-α blockade. This idea was considered heretical in the 1980s until he and Sir Ravinder Maini led clinical trials showing that blocking TNF-α effectively treated rheumatoid arthritis refractory to previous therapy. The TNF-α antibodies Remicade, Humira, and Enbrel are now the cornerstone of a $25 billion industry. For stories about getting Pharma to speed delivery to patients and the power of persistence. The full interview can be seen on the JCI website, along with all of the JCI‘s Conversations with Giants in Medicine.
Current therapies aimed at limiting tumor angiogenesis are based on our understanding of factors that regulate blood vessel sprouting during growth and development. For example, inhibition of the pro-angiogenic VEGF pathway can successfully inhibit growth of some tumors; however, many forms of cancer are not responsive to anti-VEGF therapies. Gabriela D’Amico and colleagues determined that endothelium-specific deletion of Tie1, which encodes an orphan receptor that interacts with the angiopoietin receptor Tie2, inhibited tumor angiogenesis and growth without disrupting normal vasculature. Furthermore, lack of Tie1 delayed developmental angiogenesis in the eye via enhanced Notch signaling. This study indicates that targeting Tie1 has therapeutic potential to limit tumor angiogenesis and growth. The accompanying image shows the localization of Tie1 (green) within tumor vasculature (red) and nuclei stained with DAPI (blue).
A key characteristic of cancer cells is the presence of genome alterations, including changes in epigenetic modifications that can profoundly impact gene expression and cellular function. Regulators of DNA methylation and histone modification can thus be considered as potential therapeutic targets in oncology. In recent years, DNA methyltransferase inhibitors and histone deacetylase inhibitors have shown efficacy in treating some hematological malignancies. Intense efforts are underway to develop the next generation of inhibitors, including targeting additional epigenetic regulators, and further to test treatment of solid tumors. The reviews in this series explore advances in cancer epigenetics driven by high-throughput sequencing studies, the clinical use of DNA methyltransferase inhibitors, the development of inhibitors targeting histone modifying enzymes, biomarkers of drug efficacy, and aging-related changes in the epigenome. In his overview, series editor Peter Jones highlights ongoing basic and clinical efforts as well as future challenges in translating epigenetic research to patient therapy.
Alveolar rhabdomyosarcoma (aRMS) is an aggressive childhood cancer that is frequently associated with the PAX3-FOXO1 fusion gene. On page 285, Crose et al. uncover a mechanism for how PAX3-FOXO1bypasses cellular senescence in aRMS. Their findings show that PAX3-FOXO1 upregulates expression of the Ras-association domain family member 4 (RASSF4), which in turn acts to suppress signaling through the Hippo pathway.
A pharmacological approach to reversing aniridia
Nonsense mutations that lead to PAX6 haploinsufficiency cause congenital aniridia, a panocular condition that results in severe vision defects. Cheryl Gregory-Evans and colleagues hypothesized that suppression of nonsense mutations could increase PAX6 levels and prevent post-natal eye damage. They developed a topical formulation of ataluren that not only inhibited disease progression, but also reversed ocular malformations and restored retinal responses in Pax6-deficient mice.
Watch the video: Author’s take-episode 19
Multiple tools have been established to readily evaluate the carcinogenic potential of environmental agents; however, few options are available to examine the ability of an environmental agent to accelerate molecular aging. Expression of p16INK4a is associated with cellular senescence and increases with age and in age-related diseases. Jessica Sorrentino and colleagues took advantage of a recently developed mouse strain (p16LUC mice), in which luciferase production correlates with transcription of p16INK4a, to evaluate potential age accelerating compounds (gerontogens). Several candidate gerontogens were tested in p16LUC mice, including arsenic, a high-fat diet, UV light, and cigarette smoke. The authors found that a high fat diet did not enhance or accelerate p16INK4a expression, arsenic produced a moderate increase of p16INK4a transcription, while exposure to either UV light or cigarette smoke dramatically increased p16INK4a expression. This study demonstrates the usefulness of p16LUC mice for evaluating the age-promoting potential of environmental agents and suggests that DNA damaging agents are strong gerontogens. The above image is a representative luciferase-detecting scan of 24 week old p16LUC mice exposed to ambient air (left 2 animals), 24 week old control mice (center), and 24 week old p16LUC mice exposed to cigarette smoke (right 2 animals).
Metabolic changes within the tumor microenvironment include increased glycolysis; however, it not clear if enhanced glycolytic activity is the result of tumorigenesis or an oncogenic-driving event. Using a 3-dimensional cell culture system (lrECM) to evaluate the role of aerobic glycolysis in breast cancer cells, Yasuhito Onodera, Jin-Min Nam, and Mina Bissell revealed that increased sugar uptake by mammary cells promotes oncogenesis, rather than being a cancer-induced metabolic change. Overexpression of glucose transporter 3 (GLUT3) in non-malignant human breast cells activated known oncogenic pathways, resulting in a loss of tissue polarity, and increased cell replication. In contrast, reduction of glucose uptake in malignant breast cancer cells restored tissue organization and suppressed oncogenic signaling. Furthermore, the authors revealed that glucose-dependent upregulation of EPAC/RAP1 and O-linked N-acetylglucosamine pathways drive cancer-associated phenotypes. In the accompanying image, non-malignant S1 cells (top left) and malignant T4-2 cells (top right) show no difference in organization when cultured in 2D; however, S1 cells cultured in lrECM (bottom left) exhibit a polarized structure, while T4-2 cells cultured in lrECM exhibit a disorganized structure as seen with staining for alpha-6 integrin (green), beta-actin (red) and DAPI (blue).
Maintaining T cell polyfunctionality
In order to protect the body from viruses and cancer, T cells must perform multiple functions, a feature that is often lost during chronic infection. Jonathan Schneck and colleagues examined the molecular mechanisms that maintain T cell polyfunctionality. They found that MAPK/ERK signaling was upregulated in polyfunctional T cells and that activation of this pathway was altered in response to different levels of antigen. Importantly, high levels of antigen increased levels of sprouty-2 (SPRY2), a negative regulator of MAPK/ERK signaling. High levels of SPRY2 were observed in HIV-specific T cells and inhibition of SPRY2 expression increased polyfunctional responses to HIV. These findings suggest that SPRY2 could be targeted to increase T cell polyfunctionality in the context of chronic viral infections.
Watch the video: http://www.youtube.com/watch?v=sqYJm7mg_5U
Read the article: http://www.jci.org/articles/view/70510
In the latest Conversations with Giants in Medicine, the JCI speaks with Thomas Südhof of Stanford University. In 2013, Dr. Südhof was a co-recipient of the Nobel Prize in Physiology or Medicine and the Albert Lasker Basic Medical Research Award for his contribution to the understanding of the molecular mechanisms of neurotransmission in synaptic signaling. The full interview between Ushma Neill and Thomas Südhof can be seen on the JCI website, along with all of the JCI‘s Conversations with Giants in Medicine.