The disease, which results from damaged or absent lymphatic vessels, may be inherited or may be a side-effect of the surgical removal of tumors. Lymphatic vessels normally remove fluid and proteins escaping from blood capillaries into surrounding tissues, and lymphedema is characterized by the disabling swelling of legs, and sometimes arms, that results when the lymphatic vessels are unable to clear the lymph from the tissues. The current study, has uncovered a fundamental mechanism of the formation of lymphatic vessels.

The LICR team, together with collaborators from the UK, Japan, USA and Austria, analyzed a hereditary form of lymphedema, known as Lymphedema Distichiasis (LD), which is caused by mutations in a gene called FOXC2. The team found that the lymphatic vessels of LD patients are abnormally shaped and covered with smooth muscle cells that are usually present only on blood vessels and on larger, collecting lymphatic vessels. In addition, mutations in Foxc2 led to a lack of lymphatic valves, which prevent the reflux of lymph. This is the first study that describes a gene critical for the formation of lymphatic valves, and regulation of the interaction between lymphatic endothelial cells and vascular smooth muscle cells.

According to Professor Kari Alitalo, the senior author of the study, the insights gleaned into FOXC2 function may be applicable in the development of therapies for several disorders that affect lymphatic vessel formation. We are currently working on approaches to stimulate the proper formation of lymphatic vessels in people who suffer from lymphedema. However, FOXC2 is produced in endothelial cells of both lymphatic and venous valves, so these results may also turn out to be important for the understanding and treatment of chronic venous insufficiency, which affects 5-25 % of the adult population.

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Their success in stimulating replication in latently infected cells "suggests that there may be additional new ways to manipulate HIV latency, and perhaps deplete latently infected reservoirs or even perhaps eliminate HIV infection," Zeichner said.

Zeichner's team also examined differences in gene expression between latently infected cells and actively infected cells, generating further possible therapeutic targets. They induced HIV replication in latently infected cells and monitored their gene expression patterns over time. A total of 1740 genes out of 9127 studied showed statistically significant differences in expression throughout this period. Genes involved in the MAPK signaling pathway, which promotes viral replication, were expressed at a higher level; genes preventing transcription of DNA were expressed at a lower level.

Some of the genes that were expressed differently in infected cells are genes that have been linked to some cancers, suggesting that HIV requires some of the same functions that are implicated in the development of cancer. Many of these genes are already the subject of drug development efforts directed at cancer and other disorders.

While Krishnan, the first author on the study, cautions that their data are far from clinical application, she believes "the results may provide an early hint at strategies for drugs that target cellular activity, rather than the virus itself." Unlike current AIDS drugs, such therapies "may be less likely to engender drug resistance by HIV."

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