3 days popular7 days popular1 month popular3 months popular

News From The Journal Of Clinical Investigation: Dec. 3, 2012

Researchers inhibit plaque formation in a mouse model of Alzheimer’s disease

Alzheimer’s disease is characterized by the accumulation of protein plaques in the brain. The plaques are generated by BACE1-mediated cleavage of the β-amyloid precursor protein. In this issue of the , researchers led by Weihong Song at the University of British Columbia, demonstrate that the cellular signaling protein GSK3β promoted BACE1 expression and increased cleavage of the β-amyloid precursor protein. Inhibition of GSK3β blocked the formation of plaques in the brains of mice with a genetically engineered form of Alzheimer’s disease and improved their performance in memory tasks. These results suggest that drugs targeting GSK3β might be effective in treating Alzheimer’s disease.

TITLE: Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes


Tempering inflammation to treat the flu

Infection with the influenza virus induces an immune response to fight the virus; however, this natural defense sometimes results in excessive inflammation that can damage the lungs. In this issue of the Journal of Clinical Investigation, researchers led by Béatrice Riteau at the University of Lyon in Lyon, France, found that mice infected with influenza A had increased PAR1 activity, a protein that attracts inflammatory cells to the site of infection. To determine if PAR1 plays a role in the damaging inflammation caused by the influenza virus, Riteau and colleagues generated mice that lacked PAR1 or treated them with a drug that blocks PAR1 activity. Interestingly, both groups of mice were protected from influenza virus A infection. This study suggests that drugs that block PAR1 activity might be useful in treating influenza.

TITLE: PAR1 contributes to influenza A virus pathogenicity in mice


Lysosomal disruption targets cells

Acute myeloid leukemia (), a cancer that originates in the bone marrow, is the most common form of leukemia in adults. The disease is very difficult to treat and many patients experience relapses that are likely caused by the presence of chemotherapy-resistant leukemia initiating cells. In this issue of the Journal of Clinical Investigation, researchers led by Mahadeo Sukhai and Aaron Schimmer at the Princess Margaret Hospital in Toronto, Ontario, screened 100 common drugs to identify agents that could kill leukemia cells. They found that the malaria drug mefloquine selectively killed human AML cells and leukemia initiating cells by targeting a portion of the cell known as the lysosome. These results suggest that drugs which target the lysosome maybe useful in treating AML.

TITLE: Lysosomal disruption preferentially targets acute myeloid leukemia cells and progenitors


Researchers identify key gene transcription changes in acute myeloid leukemia

Abnormal gene transcription contributes to the pathogenesis of many cancers. CDX2 is a transcriptional regulatory protein that is expressed in the leukemic cells of 90% of acute myeloid leukemia (AML) patients, but the genes that it targets have not been defined. In this issue of the Journal of Clinical Investigation, researchers led by Stefan Fröhling at the German Cancer Research Center in Heidelberg, Germany, report that CDX2-mediated leukemogenesis is dependent on the protein KLF4. Interestingly, the effects of CDX2 on KLF4 are tissue-dependent. CDX2 repressed the expression of KLF4 in AML, but not in other forms of cancer. Additionally, Fröhling and colleagues identified signaling pathways that reactivate expression of KLF4, countering the effects of CDX2. These studies suggest that regulation of KLF4 expression could provide a new therapeutic target in the treatment of AML.

TITLE: Leukemogenesis by CDX2 involves KLF4 repression and deregulated PPARγ signaling


Gene transcription mediates the production of inflammatory factors during sepsis

Septic shock is a severe systemic infection that frequently results in multiple organ failure. The bacteria that cause the infection drive a sustained inflammatory response that can cause further damage. TNFα is an inflammatory factor that is induced in the liver and is a key determinant of liver failure during septic shock. In this issue of the Journal of Clinical Investigation, researchers led by Guadalupe Sabio at the Centro Nacional de Investigaciones Cardiovasculares Carlos III in Madrid, Spain, examined the regulation of TNFα gene transcription in a mouse model of bacterially-induced liver inflammation. They found that a stress response pathway regulated the activity of the protein that mediates TNFα transcription. These data demonstrate that inflammatory responses can be mediated by gene transcription and suggest that these factors are potential targets for the treatment of liver disease.

TITLE: Eukaryotic elongation factor 2 controls TNF-α translation in LPS-induced hepatitis



Journal of Clinical Investigation