Molecular biomarkers for preeclampsia

Preeclampsia is a sudden pregnancy complication that can interfere with the blood flow to the placenta and possibly to the fetus, it can lead to low birth weight, prematurity and death. It is also a leading cause of maternal mortality. A new Tel Aviv University study identifies novel molecular biomarkers of preeclampsia, signaling the potential for an early diagnostic blood test.

Research for the study was led by Dr. Noam Shomron and Prof. Moshe Hod and conducted by Liron Yoffe and other lab members, all affiliated with TAU's Sackler School of Medicine, and in collaboration with Prof. Kypros Nicolaides of King's College, London. Preeclampsia is a serious disease that endangers the health, sometimes even the lives, of the mother and the fetus.

The causes of  preeclampsia is unknown if caught in time it has a simple and proven remedy: low doses of aspirin administered from the 16th week until the end of pregnancy. Medical practitioners have assessed a woman's risk of preeclampsia by referring to previous pregnancies, blood pressure levels and other general symptoms. Blood test could predict preeclampsia and, in turn, allow doctors to provide treatment that would prevent the  onset of the disease.

Researchers examined the blood samples from thousands of pregnant women in their first trimester, the team then narrowed their focused to 75 specific blood samples: 35 taken from women who eventually contracted preeclampsia, and 40 taken from those who completed their pregnancies in full health. The researchers extracted the RNA molecules (snippets of molecular information present in human cells) from the plasma of the samples and sequenced these using Next Generation Sequencing (NGS).

The scientists discovered the new biomarkers by analyzing the data using computational methods that included statistical analyses and machine learning algorithms. They identified 25 small RNA molecules that were differentially expressed between the preeclampsia and the control groups. Based on those RNA molecules, they developed a model for the classification of preeclampsia samples.

These findings indicate the predictive value of circulating small RNA molecules in the first trimester, and lay the foundation for producing a novel early non-invasive diagnostic tool for preeclampsia, which could reduce the life-threatening risk for the mother and fetus.
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How liver responds to food

Minutes after eating, as nutrients rush into the bloodstream the body makes massive shifts in how it breaks down and stores fats and sugars. Within half an hour, the liver has made a complete switch  from burning fat for energy to storing as much glucose, or sugar, as possible. It's too short a time span for the liver's cells to activate genes and produce the RNA blueprints needed to assemble new proteins to guide metabolism.

Liver cells store up pre-RNA molecules involved in glucose and fat metabolism. ''The switch from fasting to feeding is a very quick switch and human physiology has to adapt to it in the right time frame," says Satchidananda Panda, a professor in the Salk Institute's Regulatory Biology Laboratory. It was known that a RNA-binding protein called NONO was implicated in regulating daily ("circadian") rhythms in the body.

Researchers analyzed levels of NONO in response to feeding and fasting in mice. After the animals ate, speckled clumps of NONO suddenly appeared in their liver cells, newly attached to RNA molecules. Within half an hour, the levels of corresponding proteins-those encoded by the NONO-bound RNA increased.

After mice eat, it looks as if NONO brings all these RNAs together and processes them so they can be used to make proteins. When mice lacked NONO, it took more than three hours for levels of the same proteins involved in processing glucose to increase. During that time lag, blood glucose levels shot up to unhealthy levels.

Since blood glucose levels are also heightened in diabetes, the researchers think that the mice without NONO may act as a model to study some forms of the disease. NONO has been found at high levels in the brain and muscle cells.
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Oestrogen changes neuroblastoma cells into neurons

The female sex hormone oestrogen can perform an important role in neuroblastoma, a form of cancer mainly affecting young children. In laboratory experiments, researchers at Karolinska Institutet in Sweden demonstrate that oestrogen treatment and overexpression of the oestrogen receptor cause malignant neuroblastoma cells to mature into neuron-like cells.

Neuroblastoma forms in the peripheral nervous system and is one of the most common forms of solid cancer in young children. The disease mainly affects babies and young children, and while in some cases the tumours can disappear of their own accord, the majority are aggressive, metastasising cancer tumours that are resistant to modern combinations of surgery, radiotherapy and intensive chemotherapy.

The most aggressive forms of neuroblastoma are often associated with a more active MYCN gene, which drives tumour cell growth and spread and inhibits the maturation of the cells. Researchers focus on the activity of this gene and how it relates to neuroblastoma. MYCN is often seen only as a marker for a poor prognosis, but it's critical to the disease and is a possible target for new drugs.

In a previous study, the group discovered that activation of MYCN results in the formation of specific microRNAs, which are relatively small RNA molecules that regulate proteins. Some of these microRNAs disable the oestrogen receptor ERalpha. The present study shows that the inhibition of these microRNA molecules or oestrogen therapy in combination with an overexpression of the oestrogen receptor can cause aggressive neuroblastoma cells with MYCN activation to mature into neuron-like cells which behave more like normal cells.

The researchers studied tumour tissue from patients, cultivated human tumour cells and tumours in mouse models for neuroblastoma. In the mice, the neuron-like cells did not grow as quickly as the original cancer cells, and analyses of the tumour tissue from patients show that those with a high level of the oestrogen receptor have a better survival rate than those with a low. Oestrogen could be a therapeutic method for patients who express high levels of the oestrogen receptor. Another therapy could involve deregulating MYCN or upregulating the oestrogen receptor and then treating with oestrogen.
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RNA molecules can kill cancer

Small RNA molecules developed as a tool to study gene function trigger a mechanism hidden in every cell that forces the cell to commit suicide.
The mechanism RNA suicide molecules can potentially be developed into a form of cancer therapy. Cancer cells treated with the RNA molecules never become resistant to them because they simultaneously eliminate multiple genes that cancer cells need for survival.

The inability of cancer cells to develop resistance to the molecules is a first, researchers discovered sequences in the human genome that when converted into small double-stranded RNA molecules trigger what they believe to be an ancient kill switch in cells to prevent cancer.

Testing a class of small RNAs, called small interfering (si)RNAs, researchers use to suppress gene activity. siRNAs are designed by taking short sequences of the gene to be targeted and converting them into double- stranded RNA. These siRNAs when introduced into cells suppress the expression of the gene they are derived from.

A large number of these small RNAs derived from certain genes did not, only suppress the gene they were designed against. They also killed all cancer cells. These special sequences are distributed throughout the human genome, embedded in multiple genes.
When converted to siRNAs, these sequences all act as highly trained super assassins.

They kill the cells by simultaneously eliminating the genes required for cell survival. By taking out these survivor genes, the assassin molecule activates multiple death cell pathways in parallel. The small RNA assassin molecules trigger a mechanism calls DISE, for Death Induced by Survival gene Elimination. Activating DISE in organisms with cancer might allow cancer cells to be eliminated.
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