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New Therapy Shrinks Five Types of Pediatric Cancers in Mice

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Cancerous pediatric brain tumors are some of the most aggressive cancers to affect children, and are frequently fatal. They’re difficult to treat due to their proximity to sensitive brain tissue in tiny brains, and children’s bodies can rarely tolerate the side effects of the levels of chemotherapy and radiation necessary to shrink tumors.

But recently, researchers at Stanford Medicine, the Lucile Packard Children’s Hospital, and several other institutions successfully tested a promising immunotherapy treatment that shrank multiple tumor types in mouse models. Immunotherapy treatments harness the body’s own immune system to fight the cancer, and usually come with few to no side effects compared to chemotherapy drugs and radiation.

The collaborative study, published in Science Translational Medicine, showed results on the five most common types of pediatric tumors: Group 3 medulloblastomas (MB), atypical teratoid rhabdoid tumors (ATRT), primitive neuroectodermal tumors (PNET), pediatric glioblastoma (PG), and diffuse intrinsic pontine glioma (DIPG).

The Stanford researchers designed their study after the recent discovery of a molecule known as CD47, a protein expressed on the surface of all cells. CD47 sends a “don’t eat me” signal to the immune system’s macrophages—white blood cells whose job it is to destroy abnormal cells. “Think of the macrophages as the Pac-Man of the immune system,” Samuel Cheshier, lead study author and assistant professor of neurosurgery at Stanford Medicine, tells mental_floss.

Cancer cells have adapted to express high amounts of CD47, essentially fooling the immune system into not destroying their cells, which allows tumors to flourish. Cheshier and his team theorized that if they could block the CD47 signals on cancer cells, the macrophages would identify the cells on the cancerous tumors and eat them—without any toxicity to healthy cells. To do so, they used an antibody known as anti-CD47, which, as its name implies, blocks CD47 on the cancer from binding to a receptor on the macrophage called SIRP-alpha.

“It is this binding that tells the macrophage, 'Don't eat the tumor,'” he says. The anti-CD47 fits perfectly into the binding pocket where CD47 and SIRP-alpha interact, “like a jigsaw puzzle,” helping the macrophage correctly identify the tumor as something to be removed. “Anti-CD47 is the big power pill in Pac-Man that makes him able to eat the ghosts,” says Cheshier.

Even better, not only does anti-CD47 block the “don’t eat me” signal, it has the rare ability to pass the blood brain barrier, making it “very effective against all brain tumor types,” Cheshier says.

His team tested anti-CD47 on each of the five tumor types both in vitro (in live tissue cultured in a dish) and in vivo (human cancer cells implanted inside living mice). For the initial in vitro studies, Cheshier explains, they developed the cancer cells “in a way that preserves the cancer stem cells and allows them to grow.” Then the researchers introduced macrophages and added anti-CD47. Excitingly, the scientists “watched the macrophages eat the tumors,” he says.

Next, for each of the five tumor types, they isolated two separate lines of cancer cells taken from separate patients and cultured all 10 in the lab. Then they injected each of these different lines of tumor cells directly into the brains of 10 to 20 mice, so that a minimum of 20 animals per tumor type were tested. The tumor cells had been modified with firefly luciferase genes, making the tumors light up under scans so the scientists could track the cells’ progress. “Once we confirmed the tumor was growing, we gave some mice anti-CD47,” Cheshier says, while the control mice received none. “Only the mice that received anti-CD47 lived,” he explains.

Additionally, the scientists created an experiment where they also injected healthy human brain stem cells into mouse brains, in addition to tumor cells, and then treated some of the mice with anti-CD47. “In the mice that received anti-CD47, the normal brain cells grew normally. So there was no effect on [the healthy cells] even in the context of very active tumor killing.” Cheshier finds this result exciting because “this is the first time in any study where anyone put normal human cells with the cancer and then showed that anti-CD47 wasn’t toxic in an animal.”

Depending on the tumor type, and the amount of anti-CD47 injected, the tumors visibly shrank over the course of one week to six months—even disappearing altogether in some cases. While not every tumor was completely eliminated, Cheshier says this is most likely a matter of the length of the experiment and the amount of anti-CD47 given. “We could achieve [elimination] in every tumor type,” he says.

Of course, Cheshier warns that humans might react differently than mice, but these initial results are promising: He is most excited that a single therapy worked in all five tumor types. “You can imagine a situation where instead of giving different types of drugs for different tumors, we can just say, ‘Here is the treatment. It’s universal.’”

The pre-clinical study took four years to complete, and now the therapy has moved to phase one of a human clinical trial process, in order to test for toxicity. He has plans for phase two, which will ask the question, “Does it actually work in treating the tumor [in humans]?” Cheshier says. And phase three will be the randomized, double-blind clinical trial that hopefully proves anti-CD47 will be superior to current treatments. Meanwhile, other studies will look at its combined effects with other cancer treatments.

While there’s much further work to be done, Cheshier is very optimistic that this therapy will be both “more effective and less toxic than current standards of care. I think anti-CD47 will be part of an armamentarium where we’re using the immune system to treat cancer instead of toxic chemicals and radiation beams.”

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Medicine
New Technique Can Spot a Heart Attack in the Making Long Before It Happens
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Cardiology experts have developed a noninvasive way of measuring the fat around a person's blood vessels, which could help determine their risk for dangerous cardiac events. The researchers described their technique today in the journal Science Translational Medicine.

Heart attacks are incredibly common, affecting around 750,000 Americans every year. Heart disease is the number one cause of mortality in the U.S., responsible for one out of every four deaths. There are many reasons for this. Among them is the difficulty of identifying at-risk patients before it's too late.

Cardiologists' current method of choice uses a metric called coronary calcification score (CCS) to measure the hardening of a patient's arteries. CCS is a reliable way to predict future heart problems, paper co-author Charalambos Antoniades said in a statement, but it has its limitations.

"When coronary calcification is detected," he said, "it is already too late, as the calcification is not reversible."

And so, rather than measuring calcification, many researchers have begun looking for a way to measure blood vessel inflammation, which is usually a pretty good—and early—predictor of heart disease.

The inflammation itself can be hard to see without entering a patient's body. But recent studies have shown that it rarely travels alone: Blood vessels that are inflamed are also often wrapped in larger fat cells than healthy vessels. 

With this link in mind, Antoniades and his colleagues decided to try measuring the fat cells instead. They reviewed computed tomography scans from 453 patients about to undergo heart surgery, and used these data to create what they call the fat attenuation index (FAI). The higher a patient's FAI, the more inflammation they had, and the more advanced or severe their heart disease. 

The researchers then compared the FAI of 40 additional patients with the results of invasive scans of the inflammation in their hearts. Sure enough, each patient's FAI matched the swelling onscreen.

There are many benefits to using FAI, the authors say. Not only is it noninvasive and accurate, but it can be used in tandem with CCS and other methods for an even more complete picture. The next step will be validating the test's safety and accuracy in clinical trials.

FAI scans "could help direct these new types of treatments to the appropriate subgroups of patients at greatest risk," Antoniades says, "reducing costs and targeting more powerful drugs to the patients who will benefit most."

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Health
Don't Panic About the Plague
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If reports of measles and whooping cough making a reappearance aren't alarming enough, the news that three people in New Mexico have contracted plague this year might have you on edge. But these aren't the only recent cases of plague in the state—the disease appeared in both 2016 and 2015, causing one death—or even in the U.S.

In 2015, a child contracted the plague in Yosemite National Park, and so did a tourist from Georgia; park officials closed a campground where they discovered two dead squirrels infected with the disease. That same year in Colorado, a pitbull infected four humans with pneumonic plague before being put down, and two other Colorado residents died from plague, including a 16-year-old boy.

It all seems very scary, but don't go sealing yourself in protective gear yet. There's less to fear about plague than you may think. While the public is prone to panic that a medieval illness, which wiped out a quarter of Europe in the Middle Ages during the Black Death, has suddenly arisen from obscurity, the truth is: Plague never left.

Though we haven't seen a widespread epidemic of plague since the early 20th century, thanks to advances in sanitation and medicine, and there hasn't been a human-to-human case of transmission in America since 1924, an average of seven new cases are reported every year in the U.S. From 2010 to 2015, there were 3248 cases, including 584 deaths, reported worldwide, according to the World Health Organization.

Yersinia pestis, the flea-borne bacteria that's most often responsible for plague, infects rodents; humans are “incidental hosts,” who can acquire the infection if bitten by an infected flea or rodent. Compared to the 14th century, when the Black Death spread wildly, or the late 19th century, when 10 million people died of the disease after it traveled from Hong Kong to port cities worldwide, most people today live in more sanitary conditions and have less frequent contact with the rodents most likely to carry the infected fleas. Today, 95 percent of plague cases originate in parts of sub-Saharan Africa and Madagascar.

The most common of the three strains of plague is the notorious bubonic plague, which causes painful swollen lymph nodes (also called buboes) and was responsible for Europe's Black Death—so named because internal hemorrhages caused by the infection make the skin appear black. But the pitbull that infected four Colorado residents carried the rarer respiratory strain of pneumonic plague, which is contagious when the infected person coughs up infected particulates. There is also septicemic plague, the most lethal form, which infects the blood, and most often occurs when plague virus has gone undetected and is allowed to spread.

In the U.S., you're generally only at risk of contracting plague in late spring to early fall if you've been in a rural or semi-rural area of the West, especially New Mexico, Arizona, or Colorado, and have had contact with fleas or rodents including ground squirrels, chipmunks, prairie dogs, or rats. And even then, the risk is low.

Only the pneumatic version of plague is contagious from human to human (though untreated bubonic plague can become pneumonic), but you have to be coughed upon, or receive fluid from an infected person upon an open wound or directly into your mouth or nose.

Plague symptoms mimic any flu—fever, chills, headache, difficulty breathing or coughing—but people have been known to cough up blood with the pneumonic variety. If you've been in a rural area, or camping, and come down with these symptoms two to three days later, it's best to go to a hospital.

Now for some good news: While untreated plague is quite deadly, people with plague who are treated with antibiotics within 24 hours of infection have strong recovery rates.

So while it's good to be aware and take precautions, the chances of another plague pandemic remain slim.

This story was originally published in 2015 and has been updated. 

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