Do You Know About The “Little Green Men” Encounter? (Astronomy / Aliens)

The 11 witnesses who arrived at the Hopkinsville police station were genuinely terror-struck.

Why are aliens so often depicted as “little green men” with bulbous heads and oversized eyes?

An illustration depicting the “little green men” described by Billy Ray Taylor, recorded in Close Encounter at Kelly and Others of 1955.
Image from J. Allen Hynek Center for UFO Studies

The mythology began, in part, on the night of August 21, 1955, when a large extended farm family called the Suttons arrived breathlessly at the Hopkinsville police station in southwestern Kentucky. Their story of a terrifying siege by otherworldly beings would become one of the most detailed and baffling accounts of an alien close encounter on record—notable for the large number of witnesses (nearly a dozen), the duration of the encounter (several hours) and the close proximity between the witnesses and creatures (sometimes just a few feet away). The incident quickly became regional and even national news.

The alleged encounter occurred on the Suttons’ farm in the tiny rural hamlet of Kelly, Kentucky, where the family lived in an unpainted three-room house without running water, telephone, radio, TV or books. Of all the details of their story—the UFO landing and the appearance of small alien creatures—one fact is indisputable: When the eight adults and three children arrived at the nearby Hopkinsville police station at about 11 p.m., they were genuinely terror-struck.

“These aren’t the kind of people who normally run to the police for help,” police chief Russell Greenwell later told investigators. “What they do is reach for their guns.” Yet here they were, women and children hysterical and one man with a pulse of 140 beats per minute, measured by an investigator.

Small metallic humanoids, impervious to bullets

According to accounts given to the police, at about 7 p.m. on the hot Sunday evening, Sutton family friend Billy Ray Taylor was fetching water from the backyard well when he saw a silvery object, “real bright, with an exhaust all the colors of the rainbow.” As he later recounted, it came silently toward the house, passed over it, stopped in the air—and then dropped straight to the ground.

Image from J. Allen Hynek Center for UFO Studies

Taylor, 21, and his 18-year-old wife had come from Pennsylvania to visit Lucky Sutton, with whom he had worked on a traveling carnival. The Suttons—50-year-old widow and matriarch Glennie Lankford, her two older sons and their wives, a brother-in-law and the widow’s three younger children (12, 10, and 7)—didn’t take Billy Ray seriously, laughing off his UFO account.

An hour later, alerted by the dog’s incessant barking. Lucky and Billy Ray went to the back door and made out a strange glow, in the midst of which they spied a small humanoid creature. About three-and-a-half feet tall, it had an “oversized head…almost perfectly round, [its] arms extended almost to the ground, [its] hands had talons…and [its oversized] eyes glowed with a yellowish light.” The body gave off an eerie shimmer in the light of the night’s new moon, they said—as if made of “silver metal.”

Terrified, the two men grabbed a 20-gauge shotgun and a .22 rifle and fired at the “little man”—its “hands” now raised as if held up at gunpoint as it came toward the back door. They reported that it then did a “flip,” scrambled upright and fled into the darkness.

Shortly after, the men saw a similar creature appear in a side window—and fired through the window screen. Still impervious to bullets, the “little man” again flipped, then disappeared. “I went out in the hallway and crouched down next to Billy, when I saw one approaching the door,” Mrs. Lankford told Isabel Davis, author of an extensive report called Close Encounter at Kelly and Others of 1955. “It looked like a five-gallon gasoline can with a head on top and small legs. It was a shimmering bright metal like on my refrigerator.”

Touched by an alien?

The drama escalated when Taylor stepped outside under the small overhanging roof, and those behind him saw a claw-like hand reach down and touch his hair. The group screamed and pulled Taylor back while Lucky shot above the overhang and then at another similar creature in a nearby tree. It floated to the ground and then scurried into the woods.

Image from J. Allen Hynek Center for UFO Studies

The Suttons moved inside and spent several hours listening for movements, hearing mostly occasional scratches on the roof. At 11 p.m., the whole group ran for the cars and high-tailed it to the Hopkinsville police station at top speed.

After the local police chief called for backup, his team was joined at the Sutton farm by state police, military police from nearby Fort Campbell and a photographer from the Kentucky New Era. There, investigators found shell casings from the gun shots, but no other evidence. Neither could they find proof of heavy drinking. According to the Sutton matriarch, “liquor was not allowed in the farmhouse.”

Once the police and others left, though, the creatures returned between 2:30 a.m. and daybreak. Mrs. Lankford said she saw one glowing repeatedly by her bedside window, its claw-like hand on the screen.

Curiosity seekers descend

In the following days, after radio stations and newspapers (including The New York Times) reported the incident, hundreds of curiosity seekers descended on the farm, often ridiculing the Suttons as ignorant or fraudulent. When “No Trespassing” signs proved useless at discouraging them, the family tried charging admission: 50 cents for entering the grounds, $1 for information, $10 for taking pictures. After that, skeptics blasted them as fortune-seeking fabulists.

Image from J. Allen Hynek Center for UFO Studies

As the Kelly story spread into the world, it took on a life of its own. The number of “little men” grew to a dozen or more. A few years later, the little metallic men were conflated with an Eastern Kentucky woman’s report of a flying saucer and a six-foot tall man in green, helping launch the myth of little green men.

What investigators say

The day after the incident, police investigators returned to the farmhouse, searching for evidence of a saucer landing, footprints, blood trails or scratch marks on the roof. They found nothing. Bud Ledwith, a local radio station employee, interviewed the adult eyewitnesses and made drawings based on their accounts. According to Davis, he was impressed by their remarkable specificity and consistency, even though the men were away from the farmhouse all day, unable to coordinate with the others.

Glennie Lankford’s firsthand account of the encounter reported in the Project Blue Book case file. ©USAF

While the incident eventually attracted the attention of the Air Force UFO-investigation program Project Blue Book, documents suggest that its team never officially pursued the matter—beyond checking in with their Fort Campbell counterparts who had been briefly at the scene the first night.

One of the most thorough investigations of the Kelly incident was undertaken in 1956 by ufologist Isabel Davis—and published several decades later by the Center for UFO Studies, a group founded by astronomer Dr. J. Allen Hynek, Project Blue Book’s civilian investigator. Her nearly 200-page report, co-written with Ted Bloecher, includes detailed maps, drawings, documentary records, summaries of similar accounts around the world and interviews with several Sutton family members and police investigators.

Davis summarized the latter’s concern about the lack of physical evidence. But to her reckoning, none of the possible explanations—a deliberate hoax, a publicity play, group hallucinations—made sense. While questions arose about whether the young men were exaggerating (possibly fueled by hidden stores of liquor), Davis’s strong impression after meeting Mrs. Lankford was one of a somber, no-nonsense matriarch who abhorred the limelight and had no reason to lie. None of the witnesses, Davis noted, had any history of making “preposterous allegations.”

In 2006, Joe Nickell, senior research fellow of the international Committee for Skeptical Inquiry and a self-styled paranormal investigator, reviewed the accumulated evidence in an article entitled “Siege of the ‘Little Green Men’: The 1955 Kelly, Kentucky Incident.” In it, he raised suspicion about what he called Billy Taylor’s “embroidered testimony.” He matched Taylor’s UFO sighting with similar reports from that day, which suggested a small meteor in the vicinity.

As for the “little men,” Nickell floated an explanation used for other alien encounter stories: owls. In particular, the Great Horned Owl (a.k.a. the “hoot” owl) has long wings that could be mistaken for arms—along with talons, yellow eyes, long ears and round head that might also match the “little men” description. As for their metallic shine, Nickell suggests, they could have easily been reflecting moonlight.

But while hoot owls are known to be active at dusk and extremely aggressive when defending their nest, some investigators question characterizations of the creatures as hostile. To some, their behavior that night in Kelly appeared to simply be…curious.

This article is originally written by Volker Janssen and is republished here from history under common creative licenses. To read original click here.

New Cancer Immunotherapy Shows Great Promise in Early Research (Medicine)

A new approach to cancer immunotherapy has the potential to be a universal treatment for solid tumors, according to researchers at Purdue University.

Timothy L. Ratliff, the Robert Wallace Miller Director of the Purdue University Center for Cancer Research, is part of a team of scientists who have developed the first universal cancer treatment that targets non-malignant cells in tumors. Credit: Purdue University

Two Purdue scientists worked together to develop and test the new treatment that works not by attacking the cancer cells themselves, but by focusing on immune system cells that, ironically, feed the tumor and block other immune system cells from destroying it.

The work was led by Philip Low, Purdue’s Presidential Scholar for Drug Discovery and Ralph C. Corley Distinguished Professor of Chemistry, and Timothy Ratliff, the Robert Wallace Miller Director of the Purdue Center for Cancer Research and Distinguished Professor of Comparative Pathobiology. The first details of the approach were published recently in the journal Cancer Research.

Low said the treatment is “totally unique” and has been shown to work in six different tumor types. So far, the treatment has been tested in human tumor cells in the laboratory and in human tumors in animal models.

This approach targets immune cells that the body uses to put the brakes on an immune response. In other situations, after an illness or injury, the body employs these immune suppressor cells to stop the normal healing response in order to prevent the response from careening out of control, just as you would use brakes in a car.

But in cancerous tumors, these cells have an unwelcome and disastrous effect: They hit the brakes at the wrong time and stop the body’s own defenses from killing the tumor.

“We can reprogram the immune cells within the tumor to help kill the tumor instead of allowing these cells to help the tumor grow,” Low said. “It’s just been realized recently that as a global approach to eradicating a solid tumor, we need to also treat the healthy, non-malignant cells in the tumor.”

Low explained that, depending on the type of cancer, 30%-80% of the cells in a solid tumor are not cancer cells and are used in normal functions in other tissues.

“The difference—and this is a very important difference—is that after these cells infiltrate a solid tumor mass, they are retrained by the cancer cells to facilitate tumor growth,” he said. “But even though the cancer cells are very specific to the type of cancer, so that the treatment for breast cancer is different from the treatment for brain cancer, which is different from the treatment for lung cancer, etc., these nonmalignant cells within the tumor microenvironment are often very similar from one tumor to the next; so a drug that corrects the misbehavior of these nonmalignant cells could be used to treat most solid tumors.”

In this technique, an anti-cancer drug that would normally be too toxic for human use is linked to folate, which is a type of vitamin B. Almost no normal cells have a receptor for the folate, so it passes on through the body, but certain cancer-associated immune cells do.

“We use the vitamin folate to target attached drugs specifically to these nonmalignant cells within a tumor mass that, unfortunately, promote tumor growth. These tumor-associated macrophages love folate,” Low said. “They have an enormous appetite for it. They take it up right away, and if they don’t, the compound passes in the urine within about 30 minutes. So, we ‘re using folate as a kind of Trojan horse to trick the tumor-promoting immune cells into eating a drug that will reprogram them into tumor-fighting immune cells.”

Low said part of the drug development effort will be to ensure that the drug payload, which would be lethal to a patient by itself, is released solely within the tumor-promoting macrophage cells.

“There’s a lot of molecular design and chemistry to optimize this combination,” he said. “We are designing them so that if they are not taken up by the cancer-promoting cells right away, then they are out of there. If the drug isn’t used right away, we want it gone.”

Ratliff said this treatment may prove to be more universally effective than current cancer immunotherapies.

“There are therapeutic antibodies that are used on some types of cancer. And many people have heard of checkpoint immunotherapies, which blocks certain parts of the immune response,” Ratliff said. “When I talk to groups, I always point out that former President Jimmy Carter had metastatic brain cancer, and he went through immunotherapy, and it eliminated the cancer for him.

“But the problem is that only about 20 percent of the patients actually respond. So, we need to take a different approach to modulating the immune response.”

Ratliff said the folate-targeted approach is exciting because it is the first research project that has found a way to target the cells that boost tumor growth in the tumor environment.

“These are cells that are important to the tumors, but they aren’t the tumor cells themselves,” he said. “By targeting these myeloid cells within the tumor, we have a universal process because these cells are present in all of the solid tumors.”

As director of the Purdue University Center for Cancer Research, Ratliff co-founded Boilermaker Health Innovations, a certified nonprofit that helps fund Purdue-discovered drugs through human clinical trials. Often, compounds that make it through a Phase I trial can be sold to an established pharmaceutical manufacturer or spun off into a for-profit company.

One of the center’s most recognized success stories is Endocyte Inc., a startup originating from the work of Low, co-founder of the Boilermaker Health Innovations. Low’s research, which focuses on providing direct-targeted treatment to diseased cells through the creation of small molecules, helped the biopharmaceutical company reach its $2.2 billion value.

Low said the new immunotherapy treatment could be available to patients within a decade.

“On average, this usually takes 10 years, but we have a small team and we’re aggressive. So, I think there’s a reasonable chance this could make it to the public within seven years or something like that,” he said. “It would probably cost a couple hundred million dollars, at the very least, to develop and test this drug.

“So it’s not going to be cheap, and it’s not going to be easy. But this drug has enormous potential to save many lives. So, we will do our best.”

Reference: Gregory M. Cresswell et al. Folate Receptor Beta Designates Immunosuppressive Tumor-Associated Myeloid Cells that Can Be Reprogrammed with Folate-Targeted Drugs., Cancer Research (2020). DOI: 10.1158/0008-5472.CAN-20-1414

Provided by Purdue University

New Algorithm Will Prevent Misidentification of Cancer Cells (Medicine)

Researchers from the University of Kent have developed a computer algorithm that can identify differences in cancer cell lines based on microscopic images, a unique development towards ending misidentification of cells in laboratories.

Cancer cell lines are cells isolated and grown as cell cultures in laboratories for study and developing anti-cancer drugs. However, many cell lines are misidentified after being swapped or contaminated with others, meaning many researchers may work with incorrect cells.

This has been a persistent problem since work with cancer cell lines began. Short tandem repeat (STR) analysis is commonly used to identify cancer cell lines, but is expensive and time-consuming. Moreover, STR cannot discriminate between cells from the same person or animal.

Based on microscopic images from a pilot set of cell lines and utilising computer models capable of ‘deep learning’, researchers from Kent’s School of Engineering and Digital Arts (EDA) and School of Computing (SoC) trained the computers through a period of mass comparison of cancer cell data. From this, they developed an algorithm allowing the computers to examine separate microscopic digital images of cell lines and accurately identify and label them.

This breakthrough has the potential to provide an easy-to-use tool that enables the rapid identification of all cell lines in a laboratory without expert equipment and knowledge.

This research was led by Dr Chee (Jim) Ang (SoC) and Dr Gianluca Marcelli (EDA) with leading cancer cell lines experts Professor Martin Michaelis and Dr Mark Wass (School of Biosciences).

Dr Ang, Senior Lecturer in Multimedia/Digital Systems, said: ‘Our collaboration has demonstrated tremendous results for potential future implementation in laboratories and within cancer research. Utilising this new algorithm will yield further results that can transform the format of cell identification in science, giving researchers a better chance of correctly identifying cells, leading to reduced error in cancer research and potentially saving lives.

‘The results also show that the computer models can allocate exact criteria used to identify cell lines correctly, meaning that the potential for future researchers to be trained in identifying cells accurately may be greatly enhanced too.’

Reference: Mzurikwao, D., Khan, M.U., Samuel, O.W. et al. Towards image-based cancer cell lines authentication using deep neural networks. Sci Rep 10, 19857 (2020). https://www.nature.com/articles/s41598-020-76670-6 https://doi.org/10.1038/s41598-020-76670-6

Provided by University of Kent

“Electronic Amoeba” Finds Approximate Solution to Traveling Salesman Problem in Linear Time (Engineering)

Researchers at Hokkaido University and Amoeba Energy in Japan have, inspired by the efficient foraging behavior of a single-celled amoeba, developed an analog computer for finding a reliable and swift solution to the traveling salesman problem — a representative combinatorial optimization problem.

A single-celled amoeboid organism, a plasmodium of true slime mold Physarum polycephalum (Photo: Masashi Aono)

Many real-world application tasks such as planning and scheduling in logistics and automation are mathematically formulated as combinatorial optimization problems. Conventional digital computers, including supercomputers, are inadequate to solve these complex problems in practically permissible time as the number of candidate solutions they need to evaluate increases exponentially with the problem size — also known as combinatorial explosion. Thus new computers called “Ising machines,” including “quantum annealers,” have been actively developed in recent years. These machines, however, require complicated pre-processing to convert each task to the form they can handle and have a risk of presenting illegal solutions that do not meet some constraints and requests, resulting in major obstacles to the practical applications.

These obstacles can be avoided using the newly developed “electronic amoeba,” an analog computer inspired by a single-celled amoeboid organism. The amoeba is known to maximize nutrient acquisition efficiently by deforming its body. It has shown to find an approximate solution to the traveling salesman problem (TSP), i.e., given a map of a certain number of cities, the problem is to find the shortest route for visiting each city exactly once and returning to the starting city. This finding inspired Professor Seiya Kasai at Hokkaido University to mimic the dynamics of the amoeba electronically using an analog circuit, as described in the journal Scientific Reports. “The amoeba core searches for a solution under the electronic environment where resistance values at intersections of crossbars represent constraints and requests of the TSP,” says Kasai. Using the crossbars, the city layout can be easily altered by updating the resistance values without complicated pre-processing.

Circuit diagram of the electronic amoeba (left: amoeba core, right: resistance crossbar); (Amoeba Energy).

Kenta Saito, a PhD student in Kasai’s lab, fabricated the circuit on a breadboard and succeeded in finding the shortest route for the 4-city TSP. He evaluated the performance for larger-sized problems using a circuit simulator. Then the circuit reliably found a high-quality legal solution with a significantly shorter route length than the average length obtained by the random sampling. Moreover, the time required to find a high-quality legal solution grew only linearly to the numbers of cities. Comparing the search time with a representative TSP algorithm “2-opt,” the electronic amoeba becomes more advantageous as the number of cities increases. “The analog circuit reproduces well the unique and efficient optimization capability of the amoeba, which the organism has acquired through natural selection,” says Kasai.

“As the analog computer consists of a simple and compact circuit, it can tackle many real-world problems in which inputs, constraints, and requests dynamically change and can be embedded into IoT devices as a power-saving microchip,” says Masashi Aono who leads Amoeba Energy to promote the practical use of the amoeba-inspired computers.

TSP solution-searching performance of the electronic amoeba as a function of the number of cities, N. (Left) Route length obtained by the electronic amoeba (red dots) was normalized by the average length calculated by random sampling. (Right) Solution search time of the electronic amoeba (red dots) and that of 2-opt run on a conventional computer (white circle), where the vertical axis represents the increment from the results for the 10-city TSP (Masashi Aono).

Supplementary video:
A movie introducing the operation of the electronic amoeba is available on YouTube

Funding:
This study was partially supported by JSPS KAKENHI (H8H01487).

Reference: Kenta Saito, Masashi Aono, Seiya Kasai. Amoeba‑inspired analog electronic computing system integrating resistance crossbar for solving the travelling salesman problem. Scientific Reports, November 27, 2020. https://www.nature.com/articles/s41598-020-77617-7
DOI: 10.1038/s41598-020-77617-7

Provided by Hokkaido University

Melatonin: Finally, A Supplement That Actually Boosts Memory (Neuroscience)

Researchers at Tokyo Medical and Dental University (TMDU) in Japan show that melatonin and its metabolites promote the formation of long-term memories in mice and protect against cognitive decline.

Three 1-minute training trials (A) revealed age-associated object memory decline in middle-aged and old mice at 1 day post-training (B). Systemic AMK (1 mg/kg) administered after a single 1-minute training trial enhanced object memory at 1 and 4 days post-training in all age groups (D-F). Data are presented as mean ± standard error. *P < .05 and **P < .01 indicate significantly different than chance performance (50%). Discrimination index (%) = time exploring novel object/ total object exploration time during test X 100 ©Department of Biology,TMDU

Walk down the supplement aisle in your local drugstore and you’ll find fish oil, ginkgo, vitamin E, and ginseng, all touted as memory boosters that can help you avoid cognitive decline. You’ll also find melatonin, which is sold primarily in the United States as a sleep supplement. It now looks like melatonin marketers might have to do a rethink. In a new study, researchers led by Atsuhiko Hattori at Tokyo Medical and Dental University (TMDU) in Japan have shown that melatonin and two of its metabolites help memories stick around in the brain and can shield mice, and potentially people, from cognitive decline.

One of the easiest ways to test memory in mice is to rely on their natural tendency to examine unfamiliar objects. Given a choice, they’ll spend more time checking out unfamiliar objects than familiar ones. The trick is that for something to be familiar, it has to be remembered. Like in people, cognitive decline in mice manifests as poor memory, and when tested on this novel object recognition task, they behave as if both objects are new.

The group of researchers at TMDU were curious about melatonin’s metabolites, the molecules that melatonin is broken down into after entering the body. “We know that melatonin is converted into N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK) in the brain,” explains Hattori, “and we suspected that they might promote cognition.” To test their hypothesis, the researchers familiarized mice to objects and gave them doses of melatonin and the two metabolites 1 hour later. Then, they tested their memory the next day. They found that memory improved after treatment, and that AMK was the most effective. All three accumulated in the hippocampal region of the brain, a region important for turning experiences into memories.

For young mice, exposure to an object three times in a day is enough for it to be remembered the next day on the novel object recognition task. In contrast, older mice behave as if both objects are new and unfamiliar, a sign of cognitive decline. However, one dose of AMK 15 min after a single exposure to an object, and older mice were able to remember the objects up to 4 days later.

Lastly, the researchers found that long-term memory formation could not be enhanced after blocking melatonin from being converted into AMK in the brain. “We have shown that melatonin’s metabolite AMK can facilitate memory formation in all ages of mice,” says Hattori. “Its effect on older mice is particularly encouraging and we are hopeful that future studies will show similar effects in older people. If this happens, AMK therapy could eventually be used to reduce the severity of Mild Cognitive Impairment and its potential conversion to Alzheimer’s disease.”

Reference: Iwashita, H, Matsumoto, Y, Maruyama, Y, Watanabe, K, Chiba, A, Hattori, A. The melatonin metabolite N1‐acetyl‐5‐methoxykynuramine facilitates long‐term object memory in young and aging mice. J Pineal Res. 2020; 00:e12703. https://onlinelibrary.wiley.com/doi/10.1111/jpi.12703 https://doi.org/10.1111/jpi.12703

Provided by Tokyo Medical and Dental University

UVA IDs Genes That Influence Our Risk for Deadly Coronary Artery Disease (Cardiology / Medicine)

Researchers at the University of Virginia have shed light on how our genes affect our risk for coronary artery disease, the most common form of heart disease. In addition to identifying gene variants that influence risk, they found that one gene in particular appears to have a protective effect.

Researcher Mete Civelek, PhD, of the University of Virginia School of Medicine’s Department of Biomedical Engineering and UVA’s Center for Public Health Genomics. Courtesy Civelek lab

Doctors may be able to use the findings to identify people at high risk and to develop better treatments and preventative interventions.

“Current drugs for coronary artery disease treat the risk factors, such as cholesterol or hypertension,” said researcher Mete Civelek, PhD, of UVA’s Department of Biomedical Engineering and UVA’s Center for Public Health Genomics. “Our studies used a genetic approach to identify the mechanisms in the wall of the blood vessels where the disease actually develops.”

About Coronary Artery Disease

Heart disease is the most common cause of death in the United States, killing one person every 36 seconds. About 18.2 million Americans have the form known as coronary artery disease, or CAD. The federal Centers for Disease Control and Prevention estimates that more than 350,000 Americans died from CAD in 2017.

Scientists have known that our risk for coronary artery disease is affected by diet, smoking, exercise and other factors, including family history, but the role of our genes remains poorly understood. To better understand that, Civelek and his colleagues began by examining cells from 151 ethnically diverse heart donors. These cells, called vascular smooth muscle cells, can prove either beneficial or harmful in the buildup of fatty plaques inside our blood vessels. That buildup, known as atherosclerosis, causes coronary artery disease.

The researchers examined the smooth muscle cells for 12 different characteristics that influence the stability of the plaque patches. Stability is important – plaques that break loose can cause strokes or heart attacks.

The researchers then compared their findings with vast amounts of genetic data to determine how genes were affecting the smooth muscle cells. They found that naturally occurring gene variations have “significant influence” on the functions of these cells that lead to atherosclerosis and CAD.

These variants, they found, affect how smooth muscle cells behave – how they proliferate, migrate and calcify. These factors determine the stability of the protective caps atop the plaque lesions.

“We found that nearly half of the gene variants that increase the risk for coronary artery disease also affect how the smooth muscle cells behave,” said Rédouane Aherrahrou, a postdoctoral fellow in Civelek’s team. “This implies that we should study these cells in more detail when it comes to understanding the inherited risk for coronary artery disease.”

Protective Effect

Civelek’s team also identified a gene, MIA3, that appears very important in ensuring thick, stable protective caps – the desirable kind.

The gene produces a protein that seems to have beneficial effects for cap formation, possibly by promoting smooth muscle cell proliferation. In lab models, reducing the activity of the gene suggested thinner, less stable caps, the researchers found.

“If we can increase the abundance of MIA3 protein in smooth muscle cells,” Civelek said, “we may be able to stabilize the plaque lesions and prevent heart attacks.”

The researchers have published, “Genetic Regulation of Atherosclerosis-Relevant Phenotypes in Human Vascular Smooth Muscle Cells” in the scientific journal Circulation Research. The study’s authors were Aherrahrou, Liang Guo, V.P. Nagraj, Aaron Aguhob, Jameson Hinkle, Lisa Chen, Joon Yuhl Soh, Dillon Lue, Gabriel F. Alencar, Arjan Boltjes, Sander W. van der Laan, Emily Farber, Daniela Fuller, Rita Anane-Wae, Ngozi Akingbesote, Ani W. Manichaikul, Lijiang Ma, Minna U. Kaikkonen, Johan L.M. Bjorkegren, Suna Onengut-Gumuscu, Gerard Pasterkamp, Clint L. Miller, Gary K. Owens, Aloke Finn, Mohamad Navab, Alan M. Fogelman, Judith A. Berliner and Civelek. Navab and Fogelman are principals in Bruin Pharma, and Fogelman is an officer in Bruin Pharma.

The research was supported by American Heart Association Postdoctoral Fellowship 18POST33990046; Transformational Project Award 19TPA34910021; National Institutes of Health grants R21HL135230, P01HL030568 and R01HL136314; Academy of Finland grants 287478 and 319324; European Research Council Horizon 2020 Research and Innovation Programme grant 802825; the Finnish Foundation for Cardiovascular Research; Netherlands CardioVascular Research Initiative of the Netherlands Heart Foundation grants CVON 2011/B019 and CVON 2017-20; Interuniversity Cardiology Institute of the Netherlands, grant ICIN, 09.001; ERA-CVD program grant 01KL1802; and Transatlantic Network of Excellence awards 12CVD02 and 18CVD02 from Foundation Leducq.

Provided by University of Virginia Health System

Biomarker of Aggressive Childhood Cancer Discovered (Medicine)

Johns Hopkins researchers have discovered a new diagnostic marker that distinguishes a fast-growing type of the pediatric brain cancer medulloblastoma from a less aggressive type. The researchers hope that this biomarker may lead to the development of more effective therapies.

The new study, led by Ranjan J. Perera, Ph.D., director of the Center for RNA Biology at Johns Hopkins All Children’s Hospital, uncovered that this biomarker differentiates aggressive group 3 medulloblastoma from the more treatment-responsive group 4 medulloblastoma. The two types look identical under the microscope and are currently classified as group 3/4 and treated the same, explains Perera, the study’s senior author, who is also a senior scientist at the Johns Hopkins All Children’s Cancer & Blood Disorders Institute and the Johns Hopkins All Children’s Institute for Fundamental Biomedical Research, an associate professor of oncology at the Johns Hopkins University School of Medicine and a Johns Hopkins Kimmel Cancer Center member.

“There is currently no radiographic or microscopic way to distinguish group 3 from group 4,” says George Jallo, M.D., pediatric neurosurgeon at Johns Hopkins All Children’s Hospital, medical director of its Institute for Brain Protection Sciences, professor of neurosurgery, pediatrics and oncology at the Johns Hopkins University School of Medicine, and a collaborator on the study. “Children with group 3 medulloblastoma do not respond well to treatment and almost always relapse and die. We currently have no treatment options for this treatment-resistant group other than experimental therapies.”

In an effort to identify features that differentiate group 3 from group 4 and shed light on the cause of its aggressive nature, Perera’s group and collaborators reviewed a public database of 175 medulloblastoma patients’ RNA sequencing data. They found that non-coding RNA—an RNA molecule that is not expressed as a protein but can nonetheless regulate gene expression through other biochemical processes—varied among the four subgroups of medulloblastoma.

When they took a closer look, exploring non-coding RNA in human cell lines of medulloblastoma, they found that the non-coding RNA Inc-HLX-2-7 was highly upregulated in group 3 medulloblastoma compared with the other three subgroups. In mouse tumor models, called xenografts, implanted into the brain with Inc-HLX-2-7-depleted medulloblastoma cells, tumors were smaller, grew more slowly, and cancer cell death increased compared with xenografts with functioning Inc-HLX-2-7.

The findings were published Dec. 1 in the Journal of Neuro-Oncology.”This study tells us that Inc-HLX-2-7 drives the growth of medulloblastoma and is a promising molecular marker and potential therapeutic target for group 3 medulloblastoma,” says Charles G. Eberhart, M.D., Ph.D., Charlotte Wilson and Margaret Whitener Professor of Ophthalmology, professor of pathology, oncology and ophthalmology at the Johns Hopkins University School of Medicine, a Johns Hopkins Kimmel Cancer Center member and collaborator on the study.

Medulloblastoma is a type of brain cancer that predominantly affects children. It is separated into four major molecular subgroups. About 10% of cases are classified as WNT-activated, and are associated with a very good prognosis. SHH-activated accounts for 30% of medulloblastomas and has a fair to good prognosis. They are so named for genetic characteristics that distinguish them from the other types and can serve as treatment targets. Group 4 medulloblastoma is associated with about 35% of cases and also has a fair to good prognosis. About 25% of patients have group 3, which has a poor prognosis.

Reference: Karisa C. Schreck et al. Incidence and clinicopathologic features of H3 K27M mutations in adults with radiographically-determined midline gliomas, Journal of Neuro-Oncology (2019). DOI: 10.1007/s11060-019-03134-x

Provided by Johns Hopkins University

Map Shows How Cancer Cells Spread Through The Body (Medicine)

The vast majority of cancer deaths are attributed to metastasis, or the spread of tumors from one organ to another. Determining if a cancer will metastasize has been all but impossible, but if it does, it becomes more difficult to treat because of its multiple locations in the body and resistance to cancer treatments.

Credit: Susanna Hamilton, Broad Communications

New work from a team led by researchers at the Broad Institute of MIT and Harvard shows that it is possible to predict metastasis of human cancer cells in animal models. In a study published in Nature, scientists from the Broad’s Cancer Program found that whether a cancer spreads, how well it spreads, and to which organ depends on a number of genetic and clinical factors. The team pulled together the features associated with metastasis for 500 human cancer cell lines to create the Metastasis Map, or MetMap, the first ever map of how different cancers spread.

The resource could help scientists discover new details about what drives metastasis, why some cancers spread more aggressively than others, and how to potentially slow or stop this deadly process with new cancer drugs.

“Unfortunately for too many cancer patients, their tumors continue to grow despite therapy,” said Todd Golub, Chief Scientific Officer of the Broad and the Charles A. Dana Investigator at the Dana-Farber Cancer Institute. “That would lead you to think that some tumors can survive anywhere, but it turns out that’s not the case.”

Tracking the spread

The MetMap grew out of research by Xin Jin, a Susan G. Komen Postdoctoral Fellow and now a research scientist in the Cancer Program. He and his collaborators labeled each of the 500 cancer cell lines, representing 21 different cancers, with unique DNA barcode molecules that allowed them to identify and track the cancer cells. The researchers then injected the cell lines in various combinations into the circulation of mice.

Jin and his team monitored the spread of the cells and after five weeks, collected samples from the brain, lung, liver, kidney and bone to determine which cell lines took up residence in which organ. The team found that over 200 of the cell lines survived and metastasized in the mice. They identified key features linked to tumor spread, including tumor type, the site of origin, and the age of the patient the cells were derived from. The researchers used this information to generate MetMap, along with an interactive graph showing the metastatic potential for each cancer cell line.

“Nobody believed this approach would work in the beginning, including myself,” said Jin. “It turns out that it worked pretty robustly and the results yielded unexpected information about what enables different cancers to adapt to the different environments of the organs.”

To show the value of their data, the researchers further studied a type of breast cancer that MetMap revealed tended to spread to the brain. They compared the genomes of these cell lines to those of non-metastatic breast cancers and pinpointed a number of differences that promoted spread to the brain. In particular, they noted that key changes in lipid metabolism in the breast cancer cells allowed them to survive in the brain’s microenvironment, suggesting that future treatments could interrupt lipid metabolism to potentially slow this metastasis.

“We hope to contribute to the metastasis field by creating high-quality, large-scale foundational data sets and making them freely available to the world,” said Golub.

Reference: Xin Jin et al. A metastasis map of human cancer cell lines, Nature (2020). DOI: 10.1038/s41586-020-2969-2

Provided by Broad Institute of MIT and Harvard

Why Failing Hearts Love Hard Workouts? (Cardiology / Medicine)

“Our research on rats with heart failure shows that exercise reduces the severity of the disease, improves heart function and increases work capacity. And the intensity of the training is really importance to achieve this effect,” says Tomas Stølen, a researcher at NTNU.

Research on rats with heart failure shows that exercise reduces the severity of the disease, improves heart function and increases work capacity. Credit: NTNU

Stølen and his colleague Morten Høydal are the main authors of a comprehensive study published in the Journal of Molecular and Cellular Cardiology. The researchers went to great lengths to investigate what happens inside tiny heart muscle cells after regular exercise.

“We found that exercise improves important properties both in the way heart muscle cells handle calcium and in conducting electrical signals in the heart. These improvements enable the heart to beat more vigorously and can counteract life-threatening heart rhythm disorders,” says Stølen.

Fine-tuned machinery

For a heart to be able to beat powerfully, regularly and synchronously, a lot of functions have to work together. Each time the heart beats, the sinus node—the heart’s own pacemaker—sends out electrical impulses to the rest of the heart. These electrical impulses are called action potentials.

All the heart muscle cells are enclosed by a membrane. At rest, the electrical voltage on the inside of the cell membrane is negative compared to the voltage on the outside. The difference between the voltage on the outside and the inside of the cell membrane is called the resting membrane potential.

When the action potentials reach the heart muscle cells, they need to overcome the resting membrane potential of each cell to depolarize the cell wall. When this happens, calcium can flow into the cell through channels in the cell membrane.

Calcium initiates the actual contraction of the heart muscle cells. When this process is complete, calcium is transported out of the cell or back to its storage site inside each heart muscle cell. From there, the calcium is ready to contribute to a new contraction the next time an action potential comes rushing by.

If the heart’s electrical conduction or calcium management system fails, the risk is that fewer heart muscle cells will contract, the contraction in each cell will be weak, and the electrical signals will become chaotic so that the heart chambers begin to flutter.

“All these processes are dysfunctional when someone has heart failure. The action potentials last too long, the resting potential of the cells is too high, and the transport function of the calcium channels in the cell wall is disturbed. Calcium then constantly leaks from its storage places inside every heart muscle cell,” Stølen says.

Before Stølen gives us the rest of the good news, he notes, “Our results show that intensive training can completely or partially reverse all these dysfunctions.”

100,000 weak hearts

Normally, the sinus node causes a human heart to beat between 50 and 80 beats every minute when at rest. This is enough to supply all the organ systems and cells in the body with as much oxygen-rich blood as they need to function properly.

When we get up to take a walk, our heart automatically starts beating a little faster and pumping a little harder so that the blood supply is adapted to the increased level of activity. The higher the intensity of the activity, the harder the heart has to work.

Exercise strengthens the heart so it can pump more blood out to the rest of the body with each beat. Thus, the sinus node can take it a little easier, and well-trained people have a lower resting heart rate than people who have not done regular endurance training.

At the other end of the continuum are people with heart failure. Here the pumping capacity of the heart is so weak that the organs no longer receive enough blood to maintain good functioning. People with heart failure have a low tolerance for exercise and often get out of breath with minimal effort.

In other words, increasing the pumping power to the heart is absolutely crucial for the quality of life and health of people with heart failure.

The photo shows researcher Tomas Stølen during a training session. Credit: Geir Mogen/NTNU

High-intensity intervals

Many of the more than 100,000 Norwegians who live with heart failure have developed the condition after suffering a major heart attack—just like the rats in Stølen and Høydal’s study.

In the healthy rats, the heart pumped 75 percent of the blood with each contraction. In rats with heart failure, this measure of pump capacity, called ejection fraction, was reduced to 20 percent, Stølen says.

The ejection fraction increased to 35 percent after six to eight weeks with almost daily interval training sessions on a treadmill. The rats did four-minute intervals at about 90 percent of their maximum capacity, quite similar to the 4 × 4 method that has been advocated by several research groups at NTNU for many years.

“The interval training also significantly improved the rats’ conditioning. After the training period, their fitness level was actually better than that of the untrained rats that hadn’t had a heart attack,” says Stølen.

Prevents life-threatening arrhythmia

Impaired calcium handling in a heart muscle cell not only causes the cell to contract with reduced force every time there is an action potential. It also causes the calcium to accumulate inside the fluid-filled area of the cell—the cytosol—where each contraction begins.

The calcium stores inside the cells are only supposed to release calcium when the heart is preparing to beat. Heart failure, however, causes a constant leakage of calcium out of these stores. After each contraction, calcium needs to be efficiently transported back into the calcium stores—or out of the heart muscle cell—via specialized pumps. In heart failure patients, these pumps work poorly.

When a lot of calcium builds up inside the cytosol, the heart muscle cells can initiate new contractions when they’re actually supposed to be at rest. An electrical gradient develops which causes the heart to send electrical signals when it shouldn’t. This can cause fibrillation in the heart chambers. This ventricular fibrillation is fatal and a common cause of cardiac arrest.

“We found that interval training improves a number of mechanisms that allow calcium to be pumped out of the cells and stored more efficiently inside the cells. The leakage from the calcium stores inside the cells also stopped in the interval-trained rats,” says Stølen.

The effect was clear when the researchers tried to induce ventricular fibrillation in the diseased rat hearts: they only succeeded at this in one of nine animals that had completed interval training. By comparison, they had no problems inducing fibrillation in all the rats with heart failure who had not exercised.

Micromolecules to the rescue

So far, the research group had shown that exercise improves calcium management in diseased heart muscle cells in several ways. The training also makes the electrical wiring system of the heart more functional.

In addition, they showed that exercise counteracted processes that cause the heart to become big and stiff.

Taken together, these improvements make each heartbeat more powerful and reduce the severity of heart failure. The risk of dangerous ventricular fibrillation was also reduced.

But Stølen and team still lacked an answer to why exercise corrects slow action potentials and ensures that the heart muscle cells are able to take care of calcium in the right way.

Therefore, they investigated whether the training had altered the genetic activity inside the rat cells. Thousands of different types of micromolecules called micro-RNA probably control most of this activity through direct interaction with genes.

“It turned out that 55 of the micro-RNA variants we examined were altered in rats with heart failure compared to the healthy rats. Interval training changed 18 of these back towards healthy levels. Several of the relevant micromolecules are known to play a role in both calcium management and the electrical conduction system of the heart, but the most interesting thing is that we discovered new micro-RNAs that can play an important role in heart failure,” says Stølen.

Moderate training also of some benefit

This article has mostly considered the effects of high-intensity interval training. But the study also includes a group of rats that trained more sedately.

The rats in this group ran the same distance and thus did as much total training work as the rats in the interval training group. However, they had to exercise longer each time since they trained at a lower intensity. Stølen notes that this form of training also resulted in several health improvements.

But, he emphasizes, the vast majority of improvements were greater with interval training. “For example, we were able to induce cardiac fibrillation in five of eight rats after a period of moderate exercise, and their pumping capacity had only improved half as much as in the interval training group.”

Reference: Tomas O. Stølen et al. Exercise training reveals micro-RNAs associated with improved cardiac function and electrophysiology in rats with heart failure after myocardial infarction, Journal of Molecular and Cellular Cardiology (2020). DOI: 10.1016/j.yjmcc.2020.08.015

Provided by Norwegian University of Science and Technology