News From The Journal Of Clinical Investigation
June 11, 2017
Deletion of the transient receptor potential cation channel TRPV4 impairs bladder voiding
In a new study, Bernd Nilius and colleagues from Katholieke Universiteit Leuven, Belgium, have identified a role for the protein TRPV4 in normal bladder function in mice.
TRPV4 was shown to be expressed by specific cell types in the bladder of mice and mice lacking TRPV4 were found to be incontinent. Further analysis revealed that, compared with normal mice, TRPV4-deficient mice experienced fewer contractions of the bladder that resulted in urination (voiding contractions) and more contractions of the bladder that did not result in urination (nonvoiding contractions). As whole bladders isolated from TRPV4-deficient mice generated a smaller biochemical response to filling than whole bladders isolated from normal mice, the authors have suggested that TRPV4 has an important role in translating bladder filling to urination and that TRPV4 might provide a target for the development of therapeutics to treat human bladder disorders.
Title: Deletion of the transient receptor potential cation channel TRPV4 impairs murine bladder voiding
Author Contact:
Bernd Nilius
Katholieke Universiteit Leuven, Leuven, Belgium.
The power of prediction: 10 genes that predict outcome in one form of lung cancer
Lung cancer is the leading cause of death from cancer in the world. The prognosis for individuals with lung cancer depends on the stage at which their lung cancer is detected, with those caught at an early stage (stage I) having the best outlook. However, being able to predict prognosis would help doctors target treatments to patients more appropriately.
In a new study, Pier Paolo Di Fiore and colleagues at the Istituto FIRC di Oncologia Molecolare, Italy, have identified a signature of 10 genes that predicts survival for individuals with stage I lung adenocarcinomas (a common type of lung cancer). The level of expression of these genes was easily determined by a routine laboratory technique known as RT-PCR making it easy to use in clinical laboratories. The authors therefore have suggested that determining patient prognosis using this gene signature might identify individuals who require additional treatment after surgery to improve their prognosis.
Title: Survival prediction of stage I lung adenocarcinomas by expression of 10 genes
Author Contact:
Pier Paolo Di Fiore
Istituto FIRC di Oncologia Molecolare, Milan, Italy.
Blood vessel development a new score for Notch
New research by Jan Kitajewski and colleagues at the University of Columbia, New York, has identified a role for Notch proteins in regulating blood vessel development and has provided preliminary evidence of a role for these proteins in regulating the growth of lymphatic vessels in tumors, which is important for the spreading of a tumor from its primary site to the lymph nodes.
In the study, in vitro analysis of human endothelial cells, the cells that line blood and lymphatic vessels, and in vivo analysis in mice indicated that a complex of proteins including Notch induced the expression of the gene VEGFR-3. In this way, the endothelial cells became more responsive to VEGF-C, which promoted their survival. In addition, the Notch protein Notch 1 was found to be active in lymphatic endothelial cells in a form of aggressive human breast cancer that has a high propensity to spread to the lymph nodes. The authors therefore have suggested that if future studies can confirm a role for Notch signaling in the development of tumor lymphatic vessels it might be possible to block breast cancer metastasis to the lymph nodes using antagonists of Notch signaling.
Title: Notch alters VEGF responsiveness in human and murine endothelial cells by direct regulation of VEGFR-3 expression
Author Contact:
Jan Kitajewski
Columbia University Medical Center, New York, New York, USA.
The origin of one cancer
Malignant fibrous histiocytoma (MFH) is a soft tissue cancer commonly diagnosed in late adult life. New data generated by a team of researchers from Columbia University and Memorial Sloan-Kettering Cancer Center has provided insight into both the molecular mechanisms of MFH development and the cells from which the cancer originates.
In the study, a cell line derived from an individual with MFH was found to be genetically and immunohistochemically similar to undifferentiated human mesenchymal stem cells (MSCs) -- the cells that give rise to soft tissues. Further analysis revealed that proliferating MSCs and the MFH cell line expressed high levels of a protein known as DKK1, which inhibits signaling by a group of proteins known as Wnts. Sustained inhibition of Wnt signaling in MSCs prevented them from differentiating and they became cancerous, developing tumors similar to MFH when transplanted into mice. By contrast, restoring Wnt signaling in MFH cells caused them to differentiate and lose their cancerous characteristics. The authors therefore have suggested that MSCs are the apparent cells of origin of MFH and that reprogramming MFH cells to differentiate might provide a therapeutic strategy for treating individuals with MFH.
Title: Derivation of sarcomas from mesenchymal stem cells via inactivation of the Wnt pathway
Author Contact:
Igor Matushansky
Columbia University, New York, New York, USA.
Robert G. Maki
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Carlos Cordon-Cardo
Columbia University, New York, New York, USA.
IL-15R-alpha takes center stage in one immune response
Immune cells known as natural killer (NK) cells are an important part of the body's defense against attack by viruses. In a new study, Christian Münz and colleagues at Rockefeller University, New York, have provided insight into the requirements for optimal activation of human NK cells by another group of immune cells known as dendritic cells (DCs).
In in vitro studies, human resting NK cells were shown to interact rapidly with DCs matured for optimal NK cell activation. Many proteins localized to the zone of contact between the two cell types, the synapse, including several that transmitted activating signals to the NK cell. In addition, a protein known as IL-15R-alpha, which is the high affinity component of the receptor for IL-15, accumulated on NK cells at the center of the synapse. In this context, IL-15R-alpha was important for NK cell survival, as blockade or absence of this protein reduced NK cell survival. These data have characterized in vitro the synapse that forms between NK cells and DCs during immune responses.
Title: NK cell survival mediated through the regulatory synapse with human DCs requires IL-15R-alpha
Author Contact:
Christian Münz
Rockefeller University, New York, New York, USA.
Inherited and acquired genetic differences confer susceptibility to type 2 diabetes
The risk of developing type 2 diabetes increases with reduced physical activity, obesity, and age. However, not all individuals who are exposed to these risk factors develop the disease, indicating that genetic makeup has an influence on disease susceptibility.
A decrease in expression of a specific set of genes in skeletal muscle is associated with type 2 diabetes. To determine whether this decrease is an inherited or acquired component of susceptibility to type 2 diabetes Charlotte Ling and colleagues at Lund University, Sweden, analyzed the expression of one gene (NDUFB6) in muscle biopsies from young and elderly twins. As genetic and acquired (epigenetic and nongenetic) factors were found to influence NDUFB6 expression in human muscle the authors suggested that an interplay between genetic and epigenetic factors confers an age-dependent susceptibility to type 2 diabetes.
Title: Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle
Author Contact:
Charlotte Ling
Lund University, Malmö, Sweden.
Source: Karen Honey
Journal of Clinical Investigation