New blood test developed that detects 94 percent of breast, bowel, ovary, skin and bile duct cancers with a false positive rate of just 2.5 percent and proved to be 65 percent accurate in detecting pancreas, kidney and brain cancers.

https://medicalxpress.com/news/2018-11-cancer-blood-based-dna-fragment.html

A cancer blood test based on DNA fragment size

November 8, 2018 by Bob Yirka, Medical Xpress report

A team of researchers from the U.K., Denmark, Poland, the Netherlands and Switzerland has developed a new way to test for cancer—by looking at the size of tumor DNA fragments circulating in the bloodstream. In their paper published in the journal Science Translational Medicine, the group describes their technique and how well it worked when tested on patients with different kinds of cancer. Ellen Heitzer and Michael Speicher, with Medical University of Graz, offer a Focus piece on the work done by the team in the same journal issue.

As Heitzer and Speicher note, human blood contains many small DNA fragments, most of them from white blood cells. But there are instances where other types are introduced, for instance, DNA from a fetus in the blood of pregnant women, or bits of DNA that break loose from cancerous tumors. In this new effort, the researchers discovered that DNA from tumors can be differentiated from other types of DNA in the blood by size—such fragments tend to be smaller than DNA fragments from other sources.

To take advantage of this finding, the researchers carefully studied DNA fragments in the blood from several types of cancer and found they could be classified by size. They then created a new metric of measurement for them based on size. They called it trimmed median absolute deviation from copy number neutrality (t-MAD). The team then tested their approach by introducing DNA fragments into a blood sample and then used a benchtop fluidic device to focus on the DNA fragments, which they assigned a t-MAD rating. Pleased with their findings, they further tested their approach by conducting similar tests with blood from actual cancer patients.

The researchers report that their testing showed the technique to be very reliable—it offered positive results for 94 percent of breast, bowel, ovary, skin and bile duct cancers with a false positive rate of just 2.5 percent. It also proved to be 65 percent accurate in detecting pancreas, kidney and brain cancers.

Heitzer and Speicher point out that there are still some questions regarding the technique, however. Chief among them is whether testing will be as accurate when used in a large multicenter clinical setting.

Journal article: Florent Mouliere et al. Enhanced detection of circulating tumor DNA by fragment size analysis, Science Translational Medicine (2018).

http://stm.sciencemag.org/content/10/466/eaat4921

Overweight patients sometimes respond better than other patients to powerful drugs that harness the immune system to fight tumors. Scientists figure out why.

In a paradox, obesity is a ‘net positive’ for cutting-edge anticancer drugs

By Jocelyn Kaiser Nov. 12, 2018 , 11:00 AM

Second only to smoking, obesity is a top risk factor for cancer. But cancer doctors have noticed something surprising: Overweight patients sometimes respond better than other patients to powerful drugs that harness the immune system to fight tumors. Now, researchers tracing the complex effects of obesity on cancer are glimpsing a possible explanation: Obesity weakens the immune system and favors tumor growth by boosting the very same molecules those drugs target.

“For the most part, everybody assumes obesity is always bad. But [with these drugs], there was a net positive,” says cancer immunologist William Murphy of the University of California (UC), Davis, who, with UC Davis oncologist Arta Monjazeb, led the work reported today in Nature Medicine. Murphy thinks the finding could point to ways to make the drugs more effective in all cancer patients.

Called checkpoint inhibitors, the drugs work by blocking the activation of PD-1, a protein on the surface of immune sentinels called T cells. The body naturally triggers PD-1 to dampen immune responses, but tumors can also stimulate PD-1 to protect themselves. Lifting this molecular “brake” allows the T cells to attack the cancer cells. PD-1 inhibitors have caused untreatable tumors to vanish for years in people with melanoma, lung cancer, and some other cancer types.

But only a minority of patients respond to the drugs, and a study early this year in The Lancet Oncology showed that the responders disproportionately include people who are overweight. In 330 advanced melanoma patients given a PD-1 inhibitor, researchers at MD Anderson Cancer Center in Houston, Texas, found that those who were male and overweight lived much longer on average: nearly 27 months compared with 14 months for patients with a normal body mass index (BMI).

Now, Murphy’s team has firmed up this clinical observation in the lab and identified a possible basis. After confirming that tumors grow faster in obese mice, his team studied the T cells of obese mice, monkeys, and people. They found that the cells were what immunologists call “exhausted.” They were slow to proliferate and had stopped making secreted proteins that stimulate other immune system helpers. They also displayed more PD-1 than average, meaning cancer cells could more easily suppress them and grow unhindered.

Leptin, a hormone made by fat cells, is one factor in the PD-1 excess, Murphy’s group found. Overweight animals and people produce high levels of the hormone, which normally signals the brain that the animal has had enough to eat. But leptin also affects the immune system, and the UC Davis team suspects it triggers a signaling pathway that increases PD-1 on T cells.

The PD-1 excess also has a paradoxical benefit: In obese mice, it makes T cells unusually responsive to PD-1 inhibitors, Murphy’s team reports today in Nature Medicine. Once the drugs released this brake, the T cells sprang back into action. Nourished by glucose and other nutrients abundant in an overweight animal’s tissues, they worked better at curbing tumors than in normal weight animals.

The finding suggests an “unexpected” benefit of obesity for cancer patients, says Harvard University immunologist Lydia Lynch. Her group reports in Nature Immunology today on a different way obesity impairs the immune system’s ability to attack tumors: by hampering a type of immune cell called natural killer cells that seek out and destroy abnormal cells.

Murphy plans to explore whether briefly giving normal weight mice with cancer a high-fat diet in order to mimic some effects of obesity could boost their response to PD-1 inhibitors. But such treatments for cancer patients could also have harmful effects, cautions tumor immunologist Suzanne Ostrand-Rosenberg of The University of Utah in Salt Lake City, who also studies how obesity spurs tumor growth. “It’s a balance here, a very careful balance,” Ostrand-Rosenberg says.

Whereas the UC Davis team’s findings suggest obese patients may respond better to PD-1 drugs, normal weight patients can also benefit and it’s too early to make treatment decisions based on BMI, says MD Anderson melanoma researcher Jennifer McQuade, lead author on The Lancet Oncology study. “Ultimately, we need an integrative analysis to understand the contributions of BMI, sex, age, and how these interact with each other,” McQuade says.

Journal article:

Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade

Ziming Wang, Ethan G. Aguilar, et al.

Nature Medicine (Published: 12 November 2018)

Supplements made with compound found in fish, seafood, and veggies reduces heart thickening (cardiac fibrosis) and markers of heart failure in animals with high blood pressure (and maybe humans also?)

http://www.sci-news.com/medicine/trimethylamine-n-oxide-hypertensive-rats-heart-disease-06599.html

Natural Compound Protects Hypertensive Rats against Heart Disease

Nov 13, 2018 by News Staff / Source

Low-dose treatment with trimethylamine N-oxide — a compound linked with the consumption of fish, seafood and a primarily vegetarian diet — reduced heart thickening (cardiac fibrosis) and markers of heart failure in an animal model of hypertension, according to a new study published in the American Journal of Physiology – Heart and Circulatory Physiology.

Trimethylamine N-oxide is found at high concentrations in the tissues of some fish and shellfish.

Trimethylamine N-oxide is found at high concentrations in the tissues of some fish and shellfish.

“Trimethylamine N-oxide (TMAO) levels in the blood significantly increase after eating TMAO-rich food such as fish and vegetables,” explained study senior author Dr. Marcin Ufnal from the Medical University of Warsaw in Poland and colleagues.

“In addition, the liver produces TMAO from trimethylamine, a substance made by gut bacteria.”

“The cause of high TMAO levels in the blood and the compound’s effects on the heart and circulatory system are unclear.”

It was previously thought that TMAO blood plasma levels — and heart disease risk — rise after the consumption of red meat and eggs.

“However, it seems that a fish-rich and vegetarian diet, which is beneficial or at least neutral for cardiovascular risk, is associated with a significantly higher plasma TMAO than red meat- and egg-rich diets, which are considered to increase the cardiovascular risk,” the scientists said.

The team examined the effect of TMAO in a rat model of hypertension.

One group of hypertensive rats was given low-dose TMAO supplements in their drinking water, and another group received plain water.

They were compared to a control group of rats that does not have the same genetic predisposition and received plain water.

The dosage of TMAO was designed to increase blood TMAO levels approximately four times higher than what the body normally produces.

The rats were given TMAO therapy for either 12 weeks or 56 weeks and were assessed for heart and kidney damage and high blood pressure.

TMAO treatment did not affect the development of high blood pressure in any of the hypertensive rats. However, condition of the animals given the compound was better than expected, even after more than a year of low-dose TMAO treatment.

“The new finding is that 4-5-fold increase in plasma TMAO does not exert negative effects on the circulatory system,” the study authors said.

“In contrast, a low-dose TMAO treatment is associated with reduced cardiac fibrosis and markers of failing heart in spontaneously hypertensive rats.”

“Our study provides new evidence for a potential beneficial effect of a moderate increase in plasma TMAO on pressure-overloaded heart,” they said.

Journal article:

Tomasz Huc et al. Chronic, Low-Dose Tmao Treatment Reduces Diastolic Dysfunction and Heart Fibrosis in Hypertensive Rats. American Journal of Physiology – Heart and Circulatory Physiology, published online September 28, 2018

https://www.physiology.org/doi/abs/10.1152/ajpheart.00536.2018