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News From The Journal Of Clinical Investigation: Aug. 27, 2012

Vitamin B3 helps fight staph infections in mice

Staph infections are responsible for an increasing number of life threatening infections and the bacteria that cause these infections are widespread in the community and the healthcare system. The bacterium Staphylococcus aureus normally resides on skin and in noses and typically infects tissues through cuts or rashes. The infections can remain minor, but they can also lead to illnesses ranging from abscesses and boils to necrotizing skin infections, pneumonia, or blood stream infections.

Researchers at Cedars-Sinai Medical Center in Los Angeles have been working to identify immune system components that fight off bacterial infections. Humans that lack a molecule known as C/EBPε are missing an important bacteria-fighting component of their immune systems and are highly susceptible to bacterial infections, including staph.

In this issue of the Journal of Clinical Investigation, Dr. George Liu and colleagues demonstrate that C/EBPε -deficient mice are also highly susceptible to staph infections and increasing the expression of C/EBPε allowed the mice to clear the infection. Vitamin B3 has previously been shown to increase expression of C/EBPε. Pre-treating the mice with vitamin B3 resulted in significantly increased infection clearance, suggesting that vitamin B3 may help the immune system to kill bacteria and clear infections.

TITLE: C/EBPε mediates nicotinamide-enhanced clearance of Staphylococcus aureus in mice

http://www.jci.org/articles/view/62070?key=a39ce7efc2f764ede04b

TECHNICAL ADVANCE: New biomarkers allow researchers to track neurodegeneration in cerebrospinal fluid

Biomarkers are important tools for diagnosing and monitoring diseases and are useful in assessing patient responses to new therapies. Neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) are particularly difficult to monitor because the site of disease (the brain) isn’t readily accessible.

In this issue of the Journal of Clinical Investigation, researchers led by Patrizia Fanara of KineMed, Inc. in Emeryville, CA and Marc Hellerstein of the University of California, San Francisco report the development of a novel class of cerebrospinal fluid (CSF)-based kinetic biomarkers. The biomarkers measure axonal transport, a cellular process that is altered in PD, AD, Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). The researchers first analyzed the biomarkers in a mouse model of Parkinsons’ disease. Prior to the test, the mice drank “labeled” water, which was metabolized and incorporated into molecules that could then be measured in CSF. The study was then repeated in humans. Fanara and colleagues observed marked alterations in CSF from patients with PD compared to healthy subjects. In a companion piece, William Potter, a member of the National Institutes of Health Neuroscience Steering Committee, discusses the use of CSF as a biomarker source and the implications of this technology for the study of neurological diseases.

TITLE: Cerebrospinal fluid-based kinetic biomarkers of axonal transport in monitoring neurodegeneration

http://www.jci.org/articles/view/64575?key=2327e0ba88b87a685c83

ACCOMPANYING COMMENTARY TITLE: Mining the secrets of the CSF: developing biomarkers of neurodegeneration

http://www.jci.org/articles/view/65309?key=5a4cab61960e0a7afdba

Out-PHOXed: Mutation in PHOX2B underlies multiple pediatric developmental disorders

In the developing embryo, neural crest cells (NCCs) give rise to various cell types, including neural, endocrine, and craniofacial cells. Impairment of NCC development can lead to a wide spectrum of disorders known as neurocristopathies. Three neuroscristopathies, Hirschsprung’s disease (HSCR), central hypoventilation syndrome (CCHS), and neuroblastoma (NB) are some of the most common pediatric developmental disorders and frequently occur in the same patient. Despite being highly dis-similar disease states, affecting function of the bowel, control of breathing, and the development of pediatric brain cancer, all three are linked to mutations in the PHOX2B gene.

To gain a better understanding of the cellular and molecular origins of these diseases, researchers at the Riken Center for Developmental Biology in Kobe, Japan examined the effects of PHOX2B mutations in mice. In this issue of the Journal of Clinical Investigation, Hideki Enomoto and colleagues demonstrate that a particular PHOX2B mutation disrupts the formation of neural cells, autonomic ganglia, that are required for the function of the autonomic nervous system, impairs enervation of part of the bowel, and promotes tumor development. In a companion piece, Michael Gershon of Columbia University discusses the impact of this work on our understanding of neurocristopathies.

TITLE: Autonomic neurocristopathy-associated mutations in PHOX2B dysregulate Sox10 expression

http://www.jci.org/articles/view/63401?key=7531565bc275e1d289ac

ACCOMPANYING COMMENTARY TITLE: NPARM in PHOX2B: why some things just should not be expanded

http://www.jci.org/articles/view/63884?key=2281f71ea2c1879ebc35

Targeting inflammation to stop cancer

Chronic inflammation is frequently at the route of multiple cancers, particularly in colorectal cancers where ulcerative colitis increases the risk of developing colon cancer 20-fold. Patients with ulcerative colitis are often treated with NSAIDs to reduce inflammation, which can reduce their cancer risk by 50%. Molecules that drive inflammation may be attractive therapeutic targets to prevent and treat inflammation-driven cancers.

Chemokine receptors are one of the primary classes of molecules that regulate inflammation and many cancers express molecules that activate these receptors. Researchers at the University of Glasgow in Glasgow, Scotland recently demonstrated that the chemokine receptor CXCR2 is a critical mediator of inflammation-driven tumorigenesis. In this issue of the Journal of Clinical Investigation, Thomas Jamieson and colleagues show that mice lacking CXCR2 or mice that are treated with CXCR2 inhibitors are less susceptible to inflammation-driven colon and skin cancer. These studies indicate that CXCR2 inhibitors may have potential as a therapy to treat or prevent inflammation-driven cancers.

TITLE: Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis

http://www.jci.org/articles/view/61067?key=533354e1dda2f8b553e8

Partners in crime: T Follicular Helper Cells assist HIV in thwarting the immune system

Antibodies play an essential role in protecting against viral infection by preventing viral entry into host cells and eliminating cells infected with virus. A few viruses, including HIV and SIV, have developed mechanisms to evade the body’s antibody response, allowing the virus to persist and making it very difficult to develop effective vaccines. In this issue of the Journal of Clinical Investigation, two research groups report that accumulation of a type of immune cell known as T follicular helper (TFH) cells accumulate during HIV and SIV infection to help the viruses escape antibody-mediated immune responses.

Hendrick Streeck and his colleagues at Harvard Medical School found that there was significant increase in the number of TFH cells in patients with chronic HIV infections. The extra TFH cells were associated with alterations in the development of B cells, which are responsible for antibody production in response to viral infections. Constantinos Petrovas’s group at NIH discovered that the gene profile of TFH cells in SIV-infected rhesus macaques, demonstrating that TFH cells are highly susceptible to SIV infection. In a companion piece, Carola Vinuesa of the Australian National University in Canberra, AU discusses the implications of these findings for the development of new HIV therapies.

TITLE: Expansion of HIV-specific T follicular helper cells in chronic HIV infection

http://www.jci.org/articles/view/64314?key=b546b9def97fc4ece208

ACCOMPANYING ARTICLE TITLE: CD4 T follicular helper cell dynamics during SIV infection

http://www.jci.org/articles/view/63039?key=a057d5f97094afa35d8e

ACCOMPANYING COMMENTARY TITLE: HIV and T follicular helper cells: a dangerous relationship

http://www.jci.org/articles/view/65175?key=77d9ab61bfb939c8bd4a

Source

Journal of Clinical Investigation