Tufts scientists have discovered a new gene mechanism that appears to protect some people against cardiovascular disease, especially if they eat more polyunsaturated fat. The findings contribute to efforts to develop diets that complement genetic makeup.

The authors, including first author Kris Richardson, a postdoctoral associate in the Jean Mayer USDA Human Nutrition Research Center on Aging’s Nutritional Genomics Laboratory, analysed data from more than 27,000 men and women enrolled in 10 epidemiological studies. They observed a type of microRNA that slows down production of the enzyme LPL, which helps metabolize triglycerides in the blood.

The researchers did not see this microRNA activity in the carriers of the gene variant, said senior author José Ordovás, director of the genomics laboratory and a professor at the Friedman School.

‘Without that interference, people with the variant would presumably have more LPL available to break down excess triglycerides and prevent them from being deposited in the arteries, which could eventually lead to atherosclerosis and other cardiovascular diseases,’ he said.

The authors noted lower triglyceride levels and higher concentrations of HDL, the ‘good’ cholesterol, in those who had the gene variant. Carriers tended to have even lower triglyceride levels if their diets contained more polyunsaturated fatty acids, which are considered a healthier fat. Tufts University

Significance: Understanding more about how the different types of cells in breast tissue develop improves our knowledge of breast cancer. TAZ represents a potential new target for drug therapies to treat aggressive types of breast cancer.

Background: In cancer, normal cells can become unpredictable or aggressive and thus difficult to treat with anti-cancer drugs. This is especially true in breast cancer. By identifying the genes responsible for this change in cells from breast tissue, researchers hope to identify a way to stop or reverse it.

In breast tissue, there are two main types of cells: luminal cells and basal cells. Normally luminal cells are ‘programmed’ by a particular class of proteins (transcription factors), which prevent them from becoming basal cells, and vice-versa.

Previous work led by Charlotte Kuperwasser, principal investigator, determined that some common forms of breast cancer originate from luminal cells while some rarer forms of breast cancer originate from basal cells.

Findings: The research team identified a gene, TAZ, which controls whether breast cells behave more like basal cells or more like luminal cells, information that might be important in understanding and potentially treating certain difficult-to-treat forms of breast cancer. TAZ helps to regulate how different genes operate in different cell types.

How the Study Was Conducted: The research team identified TAZ by testing the function of more than 1,000 genes to determine which were involved in ‘reprogramming’ luminal and basal cells, therefore reversing lineage commitment.

To further identify the role of TAZ, the research team studied breast tissue at different stages of development using two groups of mice: a control group with the TAZ gene and an experimental group of knock-out mice with the TAZ gene deleted. (Cells in breast tissue are renewed/developed during puberty, pregnancy, and nursing.)

The team also looked at the levels of the TAZ gene in tumours from women with either luminal or basal tumours.

Results: The research team found that the experimental group had an imbalance of cell populations in breast tissue: too many luminal and too few basal. The control group had a normal ratio of luminal to basal cells. In breast tissue from women with cancer, they found high levels of TAZ in basal but not luminal tumours.

Discussion: First author Adam Skibinski, M.D./Ph.D. student at Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts University:

‘We’ve known for a long time that breast cells can lose their normal identity when they become cancerous, but we are now realising that normal cells can change their characteristics as well in response to transcription factors like TAZ. This might be a factor in the development of breast cancer.’ Tufts University

UT Southwestern Medical Center researchers are developing a new predictive tool that could help patients with breast cancer and certain lung cancers decide whether follow-up treatments are likely to help.
Dr. Jerry Shay, Vice Chairman and Professor of Cell Biology at UT Southwestern, led a three-year study on the effects of irradiation in a lung cancer-susceptible mouse model. When his team looked at gene expression changes in the mice, then applied them to humans with early stage cancer, the results revealed a breakdown of which patients have a high or low chance of survival.

The findings offer insight into helping patients assess treatment risk. Radiation therapy and chemotherapy that can destroy tumours also can damage surrounding healthy tissue. So with an appropriate test, patients could avoid getting additional radiation or chemotherapy treatment they may not need, Dr. Shay said.

‘This finding could be relevant to the many thousands of individuals affected by these cancers and could prevent unnecessary therapy,’ said Dr. Shay, Associate Director for Education and Training for the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. ‘We’re trying to find better prognostic indicators of outcomes so that only patients who will benefit from additional therapy receive it.’

Dr. Shay’s study closely monitored lung cancer development in mice after irradiation. His group found some types of irradiation resulted in an increase in invasive, more malignant tumours. He examined the gene expression changes in mice well before some of them developed advanced cancers. The genes in the mouse that correlated with poor outcomes were then matched with human genes. When Dr. Shay’s team compared the predictive signatures from the mice with more than 700 human cancer patient signatures, the overall survivability of the patients correlated with his predictive signature in the mice. Thus, the classifier that predicted invasive cancer in mice also predicted poor outcomes in humans.

His study looked at adenocarcinoma, a type of lung cancer in the air sacks that afflicts both smokers and non-smokers. The findings also predicted overall survival in patients with early-stage breast cancer and thus offer the same helpful information to breast cancer patients; however the genes were not predictive of another type of lung cancer, called squamous cell carcinoma. Other types of cancers have yet to be tested.

Researchers have linked a species of intestinal bacteria known as Prevotella copri to the onset of rheumatoid arthritis, the first demonstration in humans that the chronic inflammatory joint disease may be mediated in part by specific intestinal bacteria. The new findings by laboratory scientists and clinical researchers in rheumatology at NYU School of Medicine add to the growing evidence that the trillions of microbes in our body play an important role in regulating our health.
Using sophisticated DNA analysis to compare gut bacteria from faecal samples of patients with rheumatoid arthritis and healthy individuals, the researchers found that P. copri was more abundant in patients newly diagnosed with rheumatoid arthritis than in healthy individuals or patients with chronic, treated rheumatoid arthritis. Moreover, the overgrowth of P. copri was associated with fewer beneficial gut bacteria belonging to the genera Bacteroides.
‘Studies in rodent models have clearly shown that the intestinal microbiota contribute significantly to the causation of systemic autoimmune diseases,’ says Dan R. Littman, MD, PhD, the Helen L. and Martin S. Kimmel Professor of Pathology and Microbiology and a Howard Hughes Medical Institute investigator.
‘Our own results in mouse studies encouraged us to take a closer look at patients with rheumatoid arthritis, and we found this remarkable and surprising association,’ says Dr. Littman, whose basic science laboratory at NYU School of Medicine’s Skirball Institute of Biomolecular Medicine collaborated with clinical investigators led by Steven Abramson, MD, senior vice president and vice dean for education, faculty, and academic affairs; the Frederick H. King Professor of Internal Medicine; chair of the Department of Medicine; and professor of medicine and pathology at NYU School of Medicine.
‘At this stage, however, we cannot conclude that there is a causal link between the abundance of P. copri and the onset of rheumatoid arthritis,’ Dr. Littman says. ‘We are developing new tools that will hopefully allow us to ask if this is indeed the case.’ NYU Langone Medical Center

Researchers at the Sahlgrenska Academy have identified a gene, which explains why certain patients with chronic hepatitis C do not experience relapse after treatment. The discovery may contribute to more effective treatment.
More than 100 million humans around the world are infected with hepatitis C virus. The infection gives rise to chronic liver inflammation, which may result in reduced liver function, liver cirrhosis and liver cancer. Even though anti-viral medications often efficiently eliminate the virus, the infection recurs in approximately one fifth of the patients.
Martin Lagging and co-workers at the Sahlgrenska Academy have studied an enzyme called inosine trifosfatase (ITPase), which normally prevents the incorporation of defective building blocks into RNA and DNA.
Unexpectedly they found that the gene encoding for ITPase (ITPA) had significance for the treatment outcome in chronic hepatitis C virus infection.
Earlier studies had shown that approximately one third of all people carry variants of the ITPA gene that result in reduced ITPase activity. The research team at the Sahlgrenska Academy showed that patients with these gene variants exhibited a more than a five times lower risk of experiencing relapse after treatment.
The study encompassed over 300 patients and was carried out in co-operation with hepatitis researchers in several Nordic countries.
Relapse after completed treatment is a significant problem in chronic hepatitis C, and the results may contribute to explaining why the infection recurs in many patients. Our hypothesis is that a low ITPase activity results in defective nucleotides being incorporated into the virus RNA, which makes the virus unstable, Martin Lagging said.
According to Martin Lagging, the discovery may also have significance for other virus infections.
A medication that interferes with the enzyme’s activity could have a broad antiviral effect, but this must be further investigated in future studies. University of Gothenburg