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News From The Journal Of Clinical Investigation: June 24, 2013

Gene dysregulation underlies preeclampsia

Preeclampsia is a medical condition affecting 4-8% of pregnancies that is characterized by high maternal blood pressure, excess protein in maternal urine, and reduced fetal growth. If left untreated, it can develop into eclampsia, which causes life threatening seizures. Apart from delivery, there is no known cure. In this issue of the Journal of Clinical Investigation, researchers led by Susan Fisher at the University of California, San Francisco, examined cytotrophoblast cells, which help to form the placenta, from women that developed preeclampsia and healthy controls. They found that the cytotrophoblasts from patients with preeclampsia exhibited changes in gene expression, particularly in the gene SEMA3B. Increased expression of SEMA3B in normal cytotrophoblasts recreated some of the features of the cytotrophoblasts from patients with preeclampsia. In the accompanying Attending Physician article, Roberto Romero of the National Institute of Child Health and Development discusses how these findings are our first insight into the pathogenesis of preeclampsia.

TITLE: Reversal of gene dysregulation in cultured cytotrophoblasts reveals possible causes of preeclampsia

ACCOMPANYING ATTENDING PHYSICIAN TITLE: Preeclampsia: a link between trophoblast dysregulation and an anti-angiogenic state

The inflammatory consequences of chronic cannabis use

Chronic cannabis use has been associated with defects in the regions of the brain that regulate motor control, but how the active component of the drug, THC, mediates these defects is incompletely understood. In this issue of the Journal of Clinical Investigation, Andres Ozaita and colleagues at Universitat Pompeu Fabra in Barcelona exposed mice to sub-chronic doses of THC and observed deficiencies in learning and coordination associated with brain inflammation and downregulation of the THC receptor CB1R. Furthermore, Ozaita and colleagues found that the defects in these animals could be prevented by treatment with an anti-inflammatory agent. This work suggests that brain inflammation resulting from decreased CB1R is directly related to the learning and motor coordination side effects associated with cannabis consumption. In the accompanying commentary, Nephi Stella at the Center for Human Development and Disability in Seattle points out that these findings raise questions about the safety of medicinal THC applications.

TITLE: Mechanisms underlying the cerebellar deficits produced by repeated cannabis exposure

ACCOMPANYING COMMENTARY TITLE: Chronic THC intake modifies fundamental cerebellar functions

Signal crossing in liver cancer

Many cancers rely on specific molecules, known as oncogenes, to mediate their initiation and growth; however, researcher have not identified oncogenes that drive hepatocellular carcinoma (HCC). This lack of specific targets makes it difficult to select therapies for HCC patients. In this issue of the Journal of Clinical Investigation, James Hsieh and colleagues at Memorial Sloan-Kettering Cancer Center found that the protein MLL, which is associated with mixed lineage leukemia and developmental disorders, is linked to the HGF-MET cell signaling pathway, which mediates metastasis in HCC. Using transgenic mice and HCC cell lines, Hsieh and colleagues demonstrated that HGF-MET signaling stabilizes MLL so that it can trigger the expression of genes required for HCC metastasis. In a companion commentary, Snorri Thorgeirsson at the National Cancer Institute discusses how future research can build on these findings and aid in the development of therapeutic strategies for HCC.

TITLE: HGF-MET signals via the MLL-ETS2 in hepatocellular carcinoma

ACCOMPANYING COMMENTARY TITLE: Linking MLL and the HGF-MET signaling pathway in liver cancer

Kidneys strike a balance in body pH

The body’s acid-base balance is modulated in part by the action of the kidney, where cells alter bodily pH by excreting acid or base into the urine in response to high levels of acid (acidosis) or base (alkaloidosis). It is unclear how these cells communicate with the rest of the kidney and participate in integrated physiological processes. In this issue of the Journal of Clinical Investigation, Dmitri Firsov and colleagues at the University of Lausanne found that a receptor known as OXGR1 in the kidney responds to levels of a metabolite, αKG, to coordinate the kidney’s response to acidosis and alkaloidosis. In the accompanying commentary, János Peti-Peterdi of UCLA points out that further research will be necessary to fully understand the systemic role of αKG.

TITLE: alpha-ketoglutarate regulates acid-base balance through an intra-renal paracrine mechanism

ACCOMPANYING COMMENTARY TITLE: Mitochondrial TCA-cycle intermediates regulate body fluid and acid-base balance

Targeting melanoma with modified dendritic cells

In this issue of the Journal of Clinical Investigation, researchers led by Scott Pruitt at Duke University and Merck Research Laboratories report on a human clinical trial in which modified dendritic cells, a component of the immune system, were tested in patients with melanoma. All cells express a complex known as the proteasome, which acts as the garbage disposal for the cell. There are two types of proteasomes: constitutive proteasomes (cPs), which are found in normal tissues, and immunoproteasomes (iPs), which are found in stressed or damaged cells. In a damaged cell, the iP generates protein fragments that are displayed on the surface of the distressed cells, triggering recognition by dendritic cells and subsequent destruction by the immune system. Most cancers, including melanoma, exclusively express cPs, making it impossible for them to express the protein fragments that are recognized by the immune system. To make it easier for the immune system to find cancer cells, Pruitt and colleagues engineered a specific type of immune cell, known as a dendritic cell, that recognizes protein fragments of cancer specific antigens made by cPs. The engineered dendritic cells were then injected into patients that were in remission from melanoma. The trial consisted of 4 patients that were vaccinated with regular dendritic cells, 3 patients that received cells that underwent a control treatment, and 5 patients that received dendritic cells that recognized cancer-made protein fragments. Vaccination with all three types of dendritic cells elicited an immune response, which peaked after 3-4 vaccinations with dendritic cells. Patients that received the specially modified dendritic cells had a longer lasting immune response and fewer circulating melanoma cells. Of the two patients that had active disease, treatment with modified dendritic cells resulted in a partial clinical response in one and a complete clinical response in the other. These results suggest that modification of dendritic cells so that they recognize cP-produced tumor antigens enhances immune recognition of melanoma cells.

This study was funded by Duke Clinical Research Institute/Duke Translational Medicine Institute, Duke Melanoma Consortium, and Duke University Department of Surgery. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

TITLE: Melanoma immunotherapy using mature DCs expressing the constitutive proteasome

Researchers identify a protein that hinders the immune response to severe bacterial infections

Clearance of invading pathogens is essential to prevent overwhelming inflammation and sepsis that are symptomatic of bacterial peritonitis, an infection of the abdominal cavity. Macrophages are immune cells that participate in the immune response by engulfing and digesting pathogens, a process called phagocytosis. Oxidized phospholipids (OxPL) are molecules generated in response to infection that can prevent bacterial clearance by phagocytosis. In this issue of the Journal of Clinical Investigation, Sylvia Knapp and colleagues at the Medical University of Vienna investigated how OxPL block macrophage activity. Using a mouse model of bacterial peritonitis, Knapp and colleagues found that the protein WAVE1 mediates the effects of OxPL in macrophages. Mice lacking WAVE1 survived longer than normal mice after bacterial infection. Additionally, peritoneal fluid from human patients with end-stage renal failure contained OxPL and inhibited phagocytosis via WAVE1. These data identify WAVE1 as an important mediator of bacterial pathogenicity and suggest that it could serve as a therapeutic target in severe bacterial infections.

TITLE:WAVE1 mediates suppression of phagocytosis by phospholipid-derived DAMPs

Modified immune cells reduce flu severity in mice

Influenza A viruses cause significant morbidity and mortality worldwide. Current treatment strategies are limited to antiviral medications; however, many forms of the virus have become resistant to these medications. In this issue of the Journal of Clinical Investigation, Kanta Subbarao and colleagues at the National Institute of Allergy and Infectious Disease describe a method to modify immune cells, known as dendritic cells, to enhance the immune response to influenza in mice. The modified dendritic cells decreased the severity of the disease in influenza A-infected mice, indicated that such a strategy could potentially be used to treat viral infections.

TITLE: Antigen-activated dendritic cells ameliorate influenza A infections


Journal of Clinical Investigation