The Gary Null Show - 04.22.21

Vitamin A derivative selectively kills liver cancer stem cells

 RIKEN Center for Integrative Medical Science (Japan), April 23, 2021

Acyclic retinoid, an artificial compound derived from vitamin A, has been found to prevent the recurrence of hepatocellular carcinoma (HCC), the most common form of liver cancer. Now, in research published in Proceedings of the National Academy of Sciences, scientists have discovered that the compound targets one class of cancer stem cells, preventing them from giving rise to new tumors.

HCC is a highly lethal cancer, which causes approximately 600,000 deaths each year around the world, making it the second deadliest cancer after non-small cell lung cancer. One of the reasons for the high lethality is that it has a high rate of recurrence—surgery and other treatments are initially effective, but the cancer often relapses. As a result, researchers have looked for ways to prevent recurrence, and acyclic retinoid was recently found to be effective in stopping recurrence of tumors. However, scientists were not sure exactly why it worked.

To find clues, a research group led by Soichi Kojima of the RIKEN Center for Integrative Medical Science looked at the transcriptome of cells that had been exposed to acyclic retinoid, and found that compared to control untreated cells, they had low expression of MYCN, a gene that is often expressed in tumors and is correlated with poor prognosis. Further experiments, which involved deliberately repressing the expression of the gene in cancer cells, showed that the reduction in MYCN expression led functionally to slower cell-cycle progression, proliferation, and colony formation, and to greater cell death, implying that the action of the acyclic retinoid on MYCN was slowing the cancer growth.

The group then focused on the role of "cancer stem cells"—special cells that are able to survive the onslaught of chemotherapy or other treatments and to then differentiate into new cancer cells, leading to recurrence. They found, indeed, that high expression of MYCN was correlated with the expression of a number of markers that are associated with cancer stem cells.

"The most interesting part of our finding," says Kojima, "is when we then looked at different subpopulations of heterogeneous cancer cells. We found one specific group of EpCAM-positive cancer stem cells, where MYCN was elevated. We wondered if perhaps the key to acyclic retinoid's effect was its ability to target these hepatic cancer stem cells."

Indeed, experiments revealed that when exposed to acyclic retinoid, in a dose dependent manner, the EpCAM-positive cells were selectively depleted. To test whether this had clinical significance, they took liver biopsies of patients who had been given acyclic retinoid following liver cancer surgery, and found that in four of the six who had received a higher dosage of 600 mg/d but rather than 300 mg/d, there were decreased levels of MYCN expression, suggesting that MYCN expression in response to acyclic retinoid could be an important part of the difference in recurrence seen in trials. Finally, they looked at data from the Cancer Genome Atlas, and found that elevated expressionof MYCN correlated with dramatically poorer prognosis.

According to Kojima, "It is remarkable that the acyclic retinoid clearly targets a certain category of cancer stem cells, and this provides us with important hints for decreasing cancer recurrence and truly curing patients. We are waiting to see what clinical data will show us."

A phase 3 clinical trial of acyclic retinoid (also called Peretinoin), is currently underway in Korea, Taiwan and Singapore to test the drug's ability to prevent HCC recurrence.

 

 

Light up your mind: A novel light-based treatment for neurodegenerative diseases

Researchers review growing knowledge on the methods and applications of light therapy in treating neurodegenerative diseases

Soochow University (China), April 2021

A lot about the human brain and its intricacies continues to remain a mystery. With the advancement of neurobiology, the pathogenesis of several neurodegenerative diseases (ND) has been uncovered to a certain extent, along with molecular targets around which current therapies revolve. However, while the current treatments offer temporary symptomatic relief and slow down the course of the disease, they do not completely cure the condition and are often accompanied by a myriad of side effects that can impair normal daily functions of the patient.

Light stimulation has been proposed as a promising therapeutic alternative for treating various ND like Alzheimer's disease (AD), Parkinson's disease (PD), cognitive and sleep disorders. Light therapy consists of controlled exposure to natural daylight or artificial light of specific wavelengths. While neurologists worldwide have begun testing its use in clinical practice, less remains understood about the mechanisms behind how light affects neurological function.

Thus, in a review article now published in Chinese Medical Journal, researchers from China comprehensively summarize the growing knowledge on the mechanism of action, effectiveness, and clinical applications of LT in the treatment of ND. Neurologist and author Dr. Chun-Feng Liu explains how their work can advance our understanding of novel emerging therapies for ND. "While light therapy has been investigated in mental and sleep disorders, comprehensive knowledge on its use in neurodegenerative diseases in lacking. We therefore sought to shed light on the potential therapeutic methods and implications of light therapy," he states.

Our body function is tuned to a circadian or day and night rhythm. The clock that controls this rhythm is housed in the hypothalamus region of the brain. The genes expressed in this region are crucial in maintaining the circadian rhythm. Thus, a malfunction of these genes can disrupt the rhythmic cycle. These defects have been associated with neurodegenerative, metabolic and sleep disorders. External stimuli such as light, physical activity and food intake can help reset the clock and restore normal circadian rhythms, thus alleviating symptoms.

Another mechanism by which the clock controls circadian rhythms is through the secretion of the melatonin (MT) hormone. MT secreted by the pineal gland in the brain is known to control sleep patterns as it is secreted in higher amounts in the night than the day. Light stimulation in this case suppresses the secretion of MT during the day time and thus reduces drowsiness.

Interestingly, different tissue and organs in the body may respond differentially to light stimulation. Furthermore, different biomolecules expressed in circulating immune cells and stem cells are sensitive to specific wavelengths of light and thus elicit different responses by promoting the secretion of neurotrophic factors that can rescue neuronal functions.

Next, the researchers go on to discuss the application of light stimulation in specific neurodegenerative disorders. In case of AD, a progressive dementia, sleep disturbance has been associated with an increased expression of biomarkers that promote disease progression. Patients with AD often experience confusion, emotional distress and hyperactivity after dusk and through the night. Preliminary clinical studies on AD mouse models as well as patients with AD suggest that light stimulation helps restore memory and cognition and decreases the burden of the pathogenic amyloid-β protein in the brain. Furthermore, LT has been shown to improve sleep quality and duration in patients with sleep disorders while bright environments help reduce anxiety and aggressive behaviors in patients with dementia.

In case of PD, patients suffer from motor impairment, tremors and posture imbalance and also display non-motor symptoms such as insomnia, depression and fatigue that can collectively impair their quality of life. While LT has been shown to decrease non-motor symptoms to some extent, evidences on its direct benefits towards motor-function however are limited.

The use of LT in other neurodegenerative disorders is currently at preclinical stages and needs to be pursued further. Overall, LT offers a safe and cost-effective alternative for treatment of ND. Additional studies and large scale clinical trials in this direction can help establish its effectiveness as a potential therapeutic strategy.

Explaining the long term clinical applications of LT, Dr. Liu says, "The light box or light therapy lamp will help improve the sleep quality of patients with sleep disorders. Light stimulation will also likely have therapeutic effects on neurodegenerative diseases and seasonal depression. Further studies are needed to elucidate its effectiveness."

This review not only advances our understanding on how LT functions in resetting the circadian rhythm and associated neurological symptoms but also highlights its applications in routine clinical practice.

 

Bad to the bone: Hebrew University reveals impact of junk food on kids' skeletal development

Study provides first comprehensive analysis for how junk foods impact skeletal development.

Hebrew University of Jerusalem, April 19, 2021

A team of researchers from the Hebrew University of Jerusalem has proven the linkages between ultra-processed foods and reduced bone quality, unveiling the damage of these foods particularly for younger children in their developing years. The study, led by Professor Efrat Monsonego-Ornan and Dr. Janna Zaretsky from the Department of Biochemistry, Food Science and Nutrition at the University's Faculty of Agriculture, was published in the journal Bone Research and serves as the first comprehensive study of the effect of widely-available food products on skeleton development.

Ultra-processed foods--aka, junk food--are food items products that undergo several stages of processing and contain non-dietary ingredients. They're popular with consumers because they are easily accessible, relatively inexpensive and ready to eat straight out of the package. The increasing prevalence of these products around the world has directly contributed to increased obesity and other mental and metabolic impacts on consumers of all ages. 

Children tend to like junk food. As much as 70% percent of their caloric consumption are estimated to come from ultra-processed foods. While numerous studies have reflected on the overall negative impact of junk food, few have focused on its direct developmental effects on children, particularly young children.

The Hebrew University study provides the first comprehensive analysis for how these foods impact skeletal development. The study surveyed lab rodents whose skeletons were in the post embryonic stages of growth. The rodents that were subjected to ultra-processed foods suffered from growth retardation and their bone strength was adversely affected. Under histological examination, the researchers detected high levels of cartilage buildup in the rodents' growth plates, the "engine" of bone growth. When subjected to additional tests of the rodent cells, the researchers found that the RNA genetic profiles of cartilage cells that had been subjected to junk food were showing characteristics of impaired bone development. 

The team then sought to analyze how specific eating habits might impact bone development and replicated this kind of food intake for the rodents. "We divided the rodents' weekly nutritional intake--30% came from a 'controlled' diet, 70% from ultra-processed foods", shared Monsonego-Ornan. They found that the rodents experienced moderate damage to their bone density albeit there were fewer indications of cartilage buildup in their growth plates. "Our conclusion was that even in reduced amounts, the ultra-processed foods can have a definite negative impact on skeletal growth." 

These findings are critical because children and adolescents consume these foods on a regular basis to the extent that 50 percent of American kids eat junk food each and every day. Monsonego-Ornan added. "when Carlos Monteiro, one of the world's leading experts on nutrition, said that there is no such thing as a healthy ultra-processed food, he was clearly right. Even if we reduce fats, carbs nitrates and other known harmful substances, these foods still possess their damaging attributes. Every part of the body is prone to this damage and certainly those systems that remain in the critical stages of development."

 

Results From The World's Largest Wellbeing Study Are In: Here's What We Know

South Australian Health and Medical Research Institute, April 20, 2021

For decades, researchers have known that positive mental wellbeing seems to deliver significant improvements in physical health, development, and lifespan – which suggests looking after your mind and mental state is one of the most effective ways to care for the rest of your body as well.

But what's the best way to actually promote personal mental wellbeing? In a new study led by scientists in Australia, researchers cast a wide net, analyzing data from almost 420 randomized trials employing different kinds of psychological interventions to help improve mental states of wellbeing.

The results – a meta-analysis examining data from over 53,000 participants involved in hundreds of psychological experiments – is being billed as the world's largest study of its kind on wellbeing, giving perhaps the most comprehensive overview ever on how interventions can help towards a healthy mind and body.

In the wake of the COVID-19 pandemic and the myriad hardships it has brought all over the world, new insights on how to successfully bolster mental states are in high demand.

"During stressful and uncertain periods in our lives, pro-actively working on our mental health is crucial to help mitigate the risk of mental and physical illness," says mental health researcher Joep Van Agteren from the South Australian Health and Medical Research Institute (SAHMRI).

"Our research suggests there are numerous psychological approaches people should experiment with to determine what works for them."

In itself that might seem obvious, but as the researchers point out, up until now our awareness of psychological interventions' relative efficacy has been obstructed, given much research treats mental wellbeing and mental illness as different things, although they are overlapping concepts in some ways.

Here, the researchers tried to take a broader view, looking at how a wide range of different types of psychological intervention can benefit mental wellbeing, irrespective of any particular theoretical foundation in psychology.

Amongst the many forms of interventions included, two in particular stood out for their consistent associations with positive findings across trial cohorts: mindfulness-based interventions, and multi-component PPIs (positive psychological interventions), which package together a range of treatment methods and activities designed to cultivate positive feelings, behaviors, and thinking patterns.

To a lesser extent, other interventions also appeared to deliver benefits, including acceptance and commitment therapy-based interventions, cognitive therapy, singular PPIs, and interventions focusing on reminiscence.

While the effect sizes of these interventions are often moderate, the analysis here suggests they are linked with positive improvements in wellbeing in both clinical and non-clinical populations – but there's no quick fix, the researchers emphasize.

"Just trying something once or twice isn't enough to have a measurable impact," says co-author Matthew Iasiello, a project coordinator at SAHMRI's Mental Health and Wellbeing program.

"Regardless of what method people are trying out, they need to stick at it for weeks and months at a time for it to have a real effect."

In their paper, the researchers make the same point in a different way.

"Our moderator analysis indicated that improvement in mental wellbeing seems to be related to effort," the team writes.

"While the review did not find a clear linear dose-response effect, with more exposure leading simply to better treatment outcomes, the results do indicate that more intense interventions seem to lead to more pronounced changes."

Another insight by the researchers is that many kinds of psychological interventions can be done safely in volunteer groups or via online platforms, not requiring clinical appointments with professionals such as psychologists.

With mental illness projected to become the largest contributor to disease by 2030, electing to look after yourself with these sorts of activities might not only benefit your own mental wellbeing and health – but the health of the health system too.

"It is therefore potentially a cost-effective addition to current referral pathways and treatment methods," says clinical psychologist Michael Kyrios from Flinders University.

"We need to take everyone's wellbeing seriously and ensure we're taking the necessary steps to improve mental and physical health so we can prevent future complications for ourselves and keep healthcare costs down."

The findings are reported in Nature Human Behaviour.

 

 

The Stuff Beer Cans are Made from is Linked to Alzheimer's Disease

Keele University (UK), April 15, 2021

There appears to be a troubling link between aluminum in the brain and the early signs of Alzheimer’s Disease, according to a new study.

Researchers have known for years that aluminum has something to do with Alzheimer’s, but now Keele University scientists have discovered that the metal pops up at the same places in the brain as the tangles of tau protein that appear in the early stages of the disease, according to research published last month in the Journal of Alzheimer’s Disease Reports. The discovery suggests that it’s possible that aluminum could even play a role in forming those tangles and plaques — which precede the onset of Alzheimer’s — in the first place.

“The presence of these tangles is associated with neuronal cell death, and observations of aluminum in these tangles may highlight a role for aluminum in their formation,” lead study author Matthew Bold said in a press release.

That doesn’t mean that you need to ban aluminum cans from your home. Aluminum, perhaps introduced through food or other exposures, is commonly found in healthy brains, according to the Alzheimer’s Society, a dementia-focused charity based in London. But as people age, their kidneys may lose the ability to filter it out of the brain ­— potentially leading to the Alzheimer’s ties uncovered in the new study.

“Aluminum accumulation has been associated with Alzheimer’s disease for nearly half a century,” Journal of Alzheimer’s Disease editor-in-chief George Perry said in the release, “but it is the meticulously specific studies of Drs. Mold and Exley that are defining the exact molecular interaction of aluminum and other multivalent metals that may be critical to formation of the pathology of Alzheimer’s disease.”

 

 

Drought-resistant cactus pear could become a sustainable food and fuel source, new research shows

University of Nevada, April 16, 2021

Cactus pears could become a sustainable source of food and fuel in places in need of these two resources. Those are the findings of a recent study by researchers from the University of Nevada, Reno.

Published in the journal GCB Bioenergy, the study covered five years of research. The group had set out to look at how successful different varieties of cactus pear would fare in warm, dry climates.

They found that the prickly pear variety (Opuntia ficus-indica) produced the most fruit and used up 80 percent less water than other varieties to do so.

With drought and heatwave events becoming more common worldwide, crops like corn and soybean may likely be heavily affected because they require more water than what might be available in the future. People will need to look for alternative crops that require less water, can tolerate droughts and still bear fruits.

Cactus pears as sustainable food and fuel source

Given current climate trends, the world is poised to get hotter and drier in the future. Therefore, plants that are drought-resistant and able to produce food with little water might soon become major sources of food.

According to study co-author John Cushman, about 42 percent of all land on Earth is classified as arid or semi-arid. Therefore, there is enormous potential for planting cactuspears. Doing so has two main benefits. For starters, scientists can grow cactus pears in fields that are far too arid to be suitable for other crops.

This increased production would put cactus pears on the map as food. Many cultures worldwide already eat the fruits from cactus pears and even the cactus pads themselves. However, cactus pears and other edible cactus varieties are far from being a major food and forage crop in the United States, let alone around the world.

But that is a missed opportunity because cactus pear fruits can be used just like other fruits. They are especially great for making jams because they contain natural sugars. They can also be consumed fresh or pickled once the spines have been removed. They are also great for feeding livestock due to their high water content.

The other benefit of utilizing arid fields for the cultivation of cactus pears is carbon sequestration. They capture and store carbon dioxide from the atmosphere, serving as a land-based carbon “sink.” They can also be harvested and used as raw materials for biofuels to replace fossil fuels.

“That’s the benefit of this perennial crop,” explained Cushman. After you have harvested the fruits and pads for food, you will be left with a large amount of biomass that can be used for biofuel production, he said. (Related: Hemp: the versatile biofuel that could save America’s energy independence.)

Cushman and his colleagues plan to continue researching cactus pears and their potential as sustainable fuel or foods. They plan to understand what it is about the genetic makeup of cactus pears that makes them so drought-resistant and use that information to make other crops more drought-resistant as well.

Scientists have long been interested in the potential of cactus pears to serve as food and fuel. In 2015, a team of researchers from the United Kingdom suggested that water-efficient plants like cacti could be the key to providing sustainable bioenergy for the future.

Plants like cacti carry out photosynthesis through a crassulacean acid metabolism (CAM) system. They grow on arid and semi-arid land with low or unpredictable rainfall, which can make conventional farming difficult.

Arid and semi-arid lands are unproductive. But they can be put to good use by filling them with cacti and many other CAM plants that can capture and store carbon efficiently. The researchers said CAM plants like prickly pear could make a huge contribution to sustainable biogas production this way.

 

Yeast in kefir drink combats disease-causing bacteria

Ben-Gurion University (Israel), April 17, 2021

People may have been producing and drinking kefir, a fermented milk drink that originated in Tibet and the North Caucasus, for thousands of years.

People can make the sour, slightly effervescent brew by infusing milk with kefir grains, which are a starchy matrix containing a symbiotic community of lactic acid bacteria, acetic bacteria, and yeasts. 

The drink has many reputed health benefits, which include lowering cholesterol, reducing inflammation, and exerting an antioxidant effect. 

In common with other probiotics, kefir also has antimicrobial properties. However, scientists were unsure exactly how it inhibits the growth of disease-causing bacteria.

Researchers at Ben-Gurion University of the Negev (BGU) in Be’er Sheva, Israel, have now discovered that a type of yeast in kefir called Kluyveromyces marxianus secretes a molecule that disrupts bacterial communication.

Scientists already knew that plants and algae produce this substance, called tryptophol acetate, but this is the first time that they have found a yeast that makes it.

They discovered that tryptophol acetate interferes with “quorum sensing” — a form of microbial communication — in several disease-causing bacteria. 

In quorum sensingTrusted Source, bacteria release signaling molecules into their surroundings. When the molecules reach a particular concentration, they trigger changes in the expression of genes in bacteria of the same species.

These changes allow disease-causing bacteria to coordinate their activity according to their numbers. This coordination is necessary for some bacteria to defend themselves or attack their hosts. 

In some cases, when they reach a certain density, the microbes may come together to form a slimy, protective coating, or “biofilm,” on a surface. 

Disease-causing bacteria

In lab cultures, the researchers found that tryptophol acetate had an inhibitory effect over quorum sensing in several disease-causing bacteria, including some Gram-negativeTrusted Source bacteria.

Some of the tested species were:

• Pseudomonas aeruginosa, which causes pneumonia when it infects the lungs. 
• S. enterica, which is responsible for food poisoning. 
• Staphylococcus aureus, which can trigger sepsis, among other life threatening infections.
• V. cholerae, which causes cholera.

The research, which Ph.D. student Orit Malka led, appears in the journal BMC Microbiome.

“These results are notable, since this is the first demonstration that virulence of human pathogenic bacteria can be mitigated by molecules secreted in probiotic milk products, such as yogurt or kefir,” says senior author Prof. Raz Jelinek.

The scientists focused in particular on the effect of tryptophol acetate on V. cholerae.

They found that the substance blocked quorum sensing in this bacteria and reduced its virulence.

It did this by changing the expression of bacterial genes that control quorum sensing.

The researchers write that this kind of interference in bacterial communication may be commonplace in complex environments where many different microorganisms live together, such as in probiotic food or the human gut.

 

Living near pesticide-treated farms raises risk of childhood brain tumors

Cedars-Sinai Medical Center, April 15, 2021

Pregnant women living within 2.5 miles of agricultural lands treated with pesticides have a greater risk of their children developing central nervous system (CNS) tumors, according to a recent study.

Published on Wednesday, March 31, in the Environmental Research journal, the study also revealed that the pregnant women did not have to be working in agriculture or in close contact with pesticides for health-harming exposures to occur.

Study co-author Christina Lombardi, a public health researcher at Cedars-Sinai Medical Center in Los Angeles, said there are large numbers of pregnant women and children living close to pesticide-treated farmlands. Both mothers and children could experience adverse health effects from their proximity to those farmlands.

The study is not the first to show that pesticide use poses a threat to pregnant women and their children. But it is unique in that it showed the specific pesticides linked to the development of different kinds of CNS tumors.

Maternal exposure to pesticides linked to childhood tumors

Experts have examined pesticide exposures as risk factors for the development of childhood brain cancers. But they have yet to assess the risk of developing childhood brain cancers from exposure to specific pesticides. (Related: California is going after another dangerous pesticide: Chlorpyrifos has been linked to brain damage.)

To that end, Lombardi and her colleagues from the University of California, Los Angeles made use of the California Cancer Registry to identify cases of childhood CNS tumors in children below six years old.

Overall, the researchers found 667 cases of CNS tumors in children below six. They matched each one with 20 controls to increase the statistical power of their findings.

They then checked pesticide application records from the California Department of Pesticide Regulation‘s (CDPR) Pesticide Use Reporting (PUR) system to determine whether chemicals classified as possible carcinogens were used within 2.5 miles of the mothers’ homes at the time of the children’s births.

Results showed that maternal exposure to certain pesticides heightened the risk of certain childhood CNS tumors by 2.5 times, even if the mother was not a farmworker.

Pesticides found to increase the risk of childhood CNS tumors include thiophanate- and kresoxim-methyl, chlorothalonil, bromacil, triforine, propiconazole, dimethoate and linuron.

Co-author Julia Heck said their findings are more precise than those of previous studies on pesticide exposure, which usually grouped pesticide use into broad categories based on type, such as herbicides or insecticides.

Heck added that their results suggest that exposure to specific pesticides may best explain the results of earlier studies that reported a link between broader pesticide types and CNS tumors.

Due to the risks that pesticide exposure poses on pregnant women and children, the researchers called for policy interventions to reduce pesticide exposure among people living near farms.

“The simplest way to mitigate these risks is by reductions in exposure to pesticides,” said co-author Myles Cockburn. This can be done by restricting harmful practices like aerial spraying and air blast. Exposure to pesticides may also be reduced by promoting farming methods that limit reliance on pesticides.