EDITOR'S PICK An inside look at how the elite control HIV
In the years since the AIDS epidemic began, it has become clear that there is substantial variation in the way that individuals respond to HIV infection. Although most progress quickly from initial infection to immunodeficiency, a small subset survive for long periods without developing symptoms. These patients, dubbed elite controllers, display undetectable levels of viral replication, but the mechanism that explains how their immune systems effectively control the virus is not understood.
In this paper, Mathias Lichterfeld and colleagues, at Massachusetts General Hospital in Boston, describe that the T cells from elite controllers are relatively resistant to infection with HIV because they upregulate a protein called p21, which in turn inhibits an enzyme required for the virus to replicate. In addition, blocking p21 increased the expression of viral genes. The researchers hope that this finding may inform the design and development of treatment strategies for patients who are more susceptible to the virus' tragic effects
CD4+ T cells from elite controllers resist HIV-1 infection by selective upregulation of p21
Massachusetts General Hospital, Boston, MA, USA
Phone: 617-726-3167; Fax: ; E-mail: firstname.lastname@example.org
View this article at: http://www.jci.org/articles/view/44539?key=2a386ca6b649875591bc
EDITOR'S PICK New mouse model explains common pediatric brain tumor
Pilocytic astrocytoma (PA) is the most common pediatric brain tumor, and there are few medical therapies available to those patients for whom surgery is not curative. However, it has been difficult to design targeted PA therapies because the cellular mechanisms that lead to the cancer are incompletely understood, and there is no animal model of the disease.
Recent work has suggested that activation of a particular cell signaling pathway may be required for PA formation, and mutations in one gene in that pathway, a kinase called BRAF, are found in more than half of all PA cases. In this paper, Peter Lichter and colleagues at the German Cancer Research Center, in Heidelberg, Germany investigated how BRAF protein contributes to PA formation. They found that expression of just part of the BRAF protein in mice was sufficient to induce the formation of brain tumors that closely resembled the human disease. They are hopeful that this new animal model helps define the molecular processes that lead to PA, and may be useful in the design and testing of new therapeutics.
TITLE: An activated mutant BRAF kinase domain is sufficient to induce pilocytic astrocytoma in mice
German Cancer Research Center, Heidelberg, DEU
Phone: 49-6221424609; Fax: ; E-mail: email@example.com
View this article at: http://www.jci.org/articles/view/44656?key=6fc5f3671026c2e3de26
ONCOLOGY A new target to prevent lung cancer metastasis?
Lung cancer is the most common cause of cancer-related death in Western countries, and most often, lung cancer patients die due to metastasis. The ability of tumor cells to metastasize is thought to be related to their propensity to lose their cell-cell contacts and gain an ability to invade other tissues, a process called epithelial-to-mesenchymal transition (EMT). The factors that promote EMT are negatively regulated by a family of microRNAs called miR-200, and thus regulation of miR-200 may be a critical determinant of whether isolated tumors become metastatic cancer. In new research, Jonathan Kurie and his team, at the MD Anderson Cancer Center in Houston, Texas, investigated the extracellular cues that promote metastasis in a mouse model of lung cancer. They found that activation of the Notch intracellular signaling pathway decreased the expression of miR-200, and thus increased EMT and made tumor cells more prone to metastasize. The scientists are hopeful that these findings suggest that therapies that inhibit the Notch pathway might prevent metastasis in lung cancer patients.
TITLE: The Notch Ligand Jagged2 Promotes Lung Adenocarcinoma Metastasis Through a miR-200-dependent Pathway in Mice
M. D. Anderson Cancer Center, Houston, TX, USA
Phone: 713-792-6363; Fax: 713-796-8655; E-mail: firstname.lastname@example.org
View this article at: http://www.jci.org/articles/view/42579?key=94785b90de89c56ad3a4
NEUROBIOLOGY Hope for hearing impairment in Huntington Disease
Huntington Disease (HD) is an incurable neurodegenerative genetic disorder associated with the development of uncontrollable movements. Recent studies of HD patients have also shown that many of them develop hearing deficits in the late stages of the disease, but the mechanism that explains this defect is not understood. However, there is increasing evidence that some of the symptoms of HD are related to defects in cellular energy levels. The enzyme brain-type creatine kinase (CKB) helps control the supply of energy to certain kinds of cells, including the hair cells of the inner ear (cochlea), and CKB is known to be dysregulated in the brains of HD patients.
In this paper, Yijuang Chern of the Institute of Biomedical Sciences, Academia Sinica, and Chih-Hung Wang, of Tri-Service General Hospital in Taipei, Taiwan and colleagues assessed the hearing of HD patients, and confirmed that a hearing deficit was associated with increasing disease severity. They also determined that in a mouse model of HD, development of an auditory deficit preceded the development of motor symptoms, and HD mice had reduced levels of CKB in their cochlea. Remarkably, adding creatine to the diets of HD mice elevated the level of CKB and reduced the extent of hearing loss. The team hopes that their findings indicate that a promising therapy to treat the hearing loss in HD patients might be right around the corner.
TITLE: Dysregulated brain-type creatine kinase is associated with hearing impairment in mice with Huntington disease
Institute of Biomedical Sciences, Academia Sinica, Taipei, UNK, TWN
Phone: 886-2-26523913; Fax: 886-2-27829143; E-mail: email@example.com
View this article at: http://www.jci.org/articles/view/43220?key=27d256ef5f24287b3cca
METABOLISM A new method to predict diabetes risk
As the obesity epidemic has grown, so has the incidence of diabetes, a chronic condition that currently affects almost 8% of US adults. Recent work has suggested that obese individuals and those with high amounts of lipid (fat) in their blood are more susceptible to developing diabetes, but it is still difficult to determine which individuals are most at risk. In new research, Robert E. Gerszten and colleagues, at Massachusetts General Hospital in Boston, carefully analyzed the lipid content of blood from a number of patients who had developed diabetes, and compared them to individuals who remained healthy. They found that modifications of a specific kind of lipid called triacylglycerols were reliable markers of relative diabetes risk. The scientists hope that this work might allow physicians to identify the patients most in need of interventional measures for diabetes prevention.
TITLE: Lipid Profiling Identifies a Triacylglycerol Signature of Insulin Resistance and Improves Diabetes Prediction in Humans
Massachusetts General Hospital, Charlestown, MA, USA
Phone: 617-724-8322; Fax: 617-726-1544; E-mail: RGERSZTEN@PARTNERS.ORG
View this article at: http://www.jci.org/articles/view/44442?key=2db0a8efbc938e79f05b
IMMUNOLOGY Virus sensors help prevent type 1 diabetes
Type 1 diabetes (T1D) is a failure to maintain normal blood sugar levels due to death of the insulin-producing pancreatic β cells, most often resulting from autoimmune T cell-mediated attack. Multiple genetic variants have been found to be associated with the disease, and recent studies have also suggested that viral infection may contribute to the development of T1D. However, it is unclear whether viral infection of β cells results in direct damage, or whether the immune response to the virus initiates a T cell-mediated β cell killing.
In this paper, Marco Colonna and colleagues, at Washington University School of Medicine in St. Louis, Missouri, investigated the role of the immune response in a mouse model of virally-induced T1D. They found that two genes involved in helping cells recognize invading viruses, toll like receptor 3 (Tlr3) and melanoma differentiation-associated gene 5 (Mda5), were important in protecting infected mice from developing T1D. In mice lacking those genes, the virus was better able to infect and kill β cells. The researchers believe that these findings suggest that the immune system can both promote and prevent T1D, depending on the underlying pathology in the patient.
TITLE: RNA sensorinduced type I IFN prevents diabetes caused by a β celltropic virus in mice
Washington University, School of Medicine, St. Louis, MO, USA
Phone: 314-362-0367; Fax: 314-362-4096; E-mail: firstname.lastname@example.org
View this article at: http://www.jci.org/articles/view/44005?key=c5f31cc0776eeafb49e8
IMMUNOLOGY Understanding how to use the immune system to fight cancer
Bone marrow transplants have become a standard of care in treating patients suffering from leukemia, but despite high success rates, some patients eventually relapse. In recent years, relapsing patients have been treated with infusions of white blood cells from the individual who originally donated the bone marrow, a process called donor leukocyte infusion (DLI). The goal of this treatment is to allow the patient to develop antibodies that recognize and kill tumor cells, but the mechanism behind this process is not completely understood.
In new research, Yu Lin, Catherine Wu and colleagues, at the Dana-Farber Cancer Institute in Boston, Massachusetts, investigated the immune stimulatory properties of plasma from DLI-treated patients. The plasma stimulated the activity of cultured immune cells in part by activating innate immune responses, suggesting that it contained nucleic acids, which are known to have this property. Indeed, the group determined that nucleic acids were required to induce an effective anti-tumor response. The researchers hope that their findings will be useful in the design of anti-tumor vaccines.
TITLE: Effective posttransplant antitumor immunity is associated with TLR-stimulating nucleic acidimmunoglobulin complexes in humans
Dana Farber Cancer Institute, Boston, MA, USA
Phone: 6176888855; Fax: ; E-mail: email@example.com
View this article at: http://www.jci.org/articles/view/44581?key=f61057fe9d33f827c5df
NEUROBIOLOGY New understanding of the brain lesions and seizures in Tuberous Sclerosis Complex
Tuberous Sclerosis Complex (TSC) is a genetic disorder that causes benign tumors (called tubers) to form in all of the major organ systems, including the heart, kidney, and brain. Tubers in the cortex area of the brain are associated with epileptic seizures, and it is estimated that 90% of TSC patients suffer from seizures at some point in their lifetime. Although the genetic causes of TSC have been identified, the mechanisms that result in cortex tuber formation and seizures are not well understood, in part because existing animal models of the disease do not recapitulate these phenotypes.
In new research, Anglique Bordey and colleagues, at Yale University School of Medicine in New Haven, Connecticut, utilized an innovative strategy to delete one of the causative genes (Tsc1) in mice in selected neuronal populations during embryonic development. The resulting mice developed tuber-like cortical lesions and were more susceptible to seizures. The researchers believe that their findings are the first to demonstrate that deletion of two copies of Tsc1 is required for the generation of cortical lesions, and they are hopeful that this model will allow further investigation of the pathogenesis of TSC.
TITLE: Single-cell Tsc1 knockout during corticogenesis generates tuber-like lesions and reduces seizure threshold in mice.
Yale University School of Medicine, New Haven, CT, USA
Phone: 203-737-2515; Fax: ; E-mail: firstname.lastname@example.org
View this article at: http://www.jci.org/articles/view/44909?key=d7aeab152f2f21067bcb
ONCOLOGY Cop1 polices cancer growth by regulating c-Jun
Cancer growth occurs due to uncontrolled cell division, which can result from the loss of proteins that repress cell cycle progression (tumor suppressors) or by increases in the amount or activity of proteins that promote cell cycle progression (oncogenes). In many cancers, loss of the tumor suppressor p53 activity is an important contributing factor to the uncontrolled cell growth. Thus, identifying the factors that contribute to controlling p53 levels has been of interest to cancer researchers. In cultured cancer cells, the protein Cop1 has been shown to target p53 for degradation, and thus there has been interest in developing inhibitors of Cop1 as cancer therapeutics.
In this paper, Jean-Christophe Marine at the Laboratory For Molecular Cancer Biology Leuven, Belgium developed a series of mouse models that demonstrate that in contrast to predictions, loss of Cop1 does not affect p53 levels or activity. Rather, Cop1 targets for degradation a protein that promotes cell cycle progression called c-Jun, and loss of Cop1 resulted in spontaneous cancer formation in the mice. The researchers believe that these findings suggest that Cop1 itself acts as a tumor suppressor, and that c-Jun, rather than p53, is its primary target in this context. In the accompanying commentary, Wenyi Wei of Beth Israel Deaconess Medical Center and William Kaelin, from Dana Farber Cancer Institute, in Boston, Massachusetts, stress that these findings suggest that inhibitors of Cop1 are unlikely to be effective cancer therapeutics, and may even enhance tumor growth.
TITLE: Cop1 constitutively regulates c-Jun protein stability and functions as a tumor suppressor in mice
VIB-KULeuven, Leuven, BEL
Phone: 003216330368; Fax: ; E-mail: JeanChristophe.Marine@cme.vib-kuleuven.be
View this article at: http://www.jci.org/articles/view/45784?key=a4414bd730c3fc66b388
TITLE: Good COP1 or bad COP1? In vivo veritas
William G. Kaelin, Jr.
Dana Farber Cancer Institute, Boston, MA, USA
Phone: 617-632-3975; Fax: 617-632-4760; E-mail: email@example.com
View this article at: http://www.jci.org/articles/view/57080?key=30faa1bf640753209238
|Contact: Kathryn Claiborn|
Journal of Clinical Investigation