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Letters to the Editor Issue 286

by Letters(more info)

listed in letters to the editor, originally published in issue 286 - May 2023

Daily Blueberries for Cognitive and Vascular Health in Older People, Study Suggests

Researchers have found that the equivalent of a handful of wild blueberries in the morning helped people improve their memory and lower their blood pressure, in a new study.

The study, published this week in the American Journal of Clinical Nutrition,[1] involved a 12-week clinical trial of wild blueberry powder, led by researchers from King’s College London and the University of Reading.

Professor Claire Williams, University of Reading said:

“It’s clear from this study that consuming wild blueberries is beneficial to cognitive function, as well as vascular health. We saw improvements in healthy older adults who consumed a freeze-dried wild blueberry powder, daily, for 12 weeks.

“The group who had the wild blueberry powder showed signs of better memory and greater mental flexibility when completing cognitive tasks.

“This is consistent with what we already know about the health benefits of dark purple fruits, which contain pigments called polyphenols. It points to an important role of polyphenols in healthy ageing.”

Dr Ana Rodriguez-Mateos, King’s College London, said:

“We think the blue pigments in blueberries, the anthocyanins, which are a type of polyphenols also present in other foods such as strawberries, raspberries, red grapes and purple vegetables, are behind these effects as increases in their metabolites were seen in the urine of the volunteers after 12 weeks consumption.

“This study is the first of its kind and the results suggest that a daily intake of wild blueberries could help lower people’s risk of cardiovascular disease by lowering their blood pressure and improving blood vessel function.”

The study involved a randomised, double blind, placebo-controlled trial of 61 healthy men and women aged ages 65 to 80, who drank a beverage made with 26 grams of freeze-dried wild blueberry powder (equivalent to about 178 grams of whole berries), whilst the other group drank a placebo matched for macro and micronutrients, as well as fibre, colour and taste.

The researchers found that over the course of twelve weeks, volunteers who consumed the berry powder in drinks experienced better memory and an 8.5% improved performance on an attention task, as well as lower blood pressure.

The blood pressure of the test group was significantly lower (3.59 mmHg) after consuming berries over 12 weeks when compared to the placebo group, in addition to experiencing an increased flow mediated dilation (FMD) of 0.86%, which is a biomarker of cardiovascular disease risk and good function of the blood vessels.

Dr Ana Rodriguez-Mateos, Reader in Nutrition at the Department of Nutritional Sciences of King’s College London, said:

“We know from previous research that there are potential advantages from consuming blueberries, but this study went further by exploring how a daily and dietary achievable measure of blueberries could benefit our cognitive and cardiovascular health simultaneously in a healthy older population.”

Reference

  1. Wood E, Hein S, Mesnage R, Fernandes F, Abhayaratne N, Xu Y, Zhang Z, Bell L, Williams C, Rodriguez-Mateos A. Wild Blueberry (Poly)phenols can Improve Vascular Function And Cognitive Performance In Healthy Older Males And Females: A Double-Blind Randomized Controlled Trial. Am J Clin Nutr. Mar 25 2023: S0002-9165(23)46300-9. https://doi.org/10.1016/j.ajcnut.2023.03.017 https://ajcn.nutrition.org/article/S0002-9165(23)46300-9/fulltext  

 Media Contact and Further Information

Nancy Mendoza n.w.mendoza@reading.ac.uk

University of Reading Press Office pressoffice@reading.ac.uk

Tel: +44(0)118 378 5757

Notes

Funding for two PhD students working on the project came from the Wild Blueberry Association of North America. The funder had no input into the design or reporting of the trial.

The study, called BluFlow, involved a randomized, double blind, placebo-controlled trial focused on healthy older men and women, ages 65 to 80. Participants were divided into two groups with one receiving a beverage made with 178 grams of freeze dried whole wild blueberry powder (equivalent to about ¾ cup whole berries) and the other, a placebo matched for macro and micronutrients, as well as fibre, colour and taste. Both groups consumed their beverages daily at the same time over the course of 12 weeks.

The results are reported in a paper in the American Journal of Clinical Nutrition: https://doi.org/10.1016/j.ajcnut.2023.03.017

 

 

High Spring Pollen Count will Increase Allergies and Covid Cases, Warns Medical Testing Expert

A wet March and global warming mean Brits are facing a severe allergy season and a heightened risk of Covid this spring, warns expert.

 The ‘double-whammy’ of global warming and a wet March means there is an increased chance of high pollen levels this April. That means a potential surge in Covid cases and allergy sufferers should prepare for an early start to the hay fever season, warns a leading testing expert.

Dr Avinash Hari Narayanan (MBChB), Clinical Lead at London Medical Laboratory, says: “This spring could see higher pollen counts than normal, because of an unfortunate combination of weather conditions. Not only is this likely to lead to an early start to hay fever and other spring allergies, but there’s convincing evidence that it could create the perfect storm, resulting in increased Covid infections.

“Global warming is leading to an earlier, longer, spring pollen season here in the UK. The Met Office has warned changes in temperature and rainfall may lengthen the UK pollen season and potentially make atmospheric pollen concentrations higher.

“You might think that the drier the early spring the higher the pollen count but the opposite is true. A dry season reduces the amount of pollen production, whereas spring rainfall increases it. The early signs are ominous, with March having been so wet.

“Low temperatures during the winter keep plants and trees dormant for longer into the new year. The lower the temperature, the less pollen is produced. However, December and January’s temperatures were close to the average this winter and February was notably warmer than normal. That means we’re on course for a high spring pollen count.

“Not only does that mean increased cases of spring allergies such as hay fever, but it could also mean higher Covid levels. A 2021 paper by an international team of scientists, published in the “Proceedings of the National Academy of Sciences” (PNAS), found that higher airborne pollen concentrations correlated with increased Covid infection rates. The research spanned 31 countries and presents the most comprehensive dataset in this research area.[1]

“It has been recognised for some time that exposure to airborne pollen enhances susceptibility to viral respiratory infections. This research specifically examined the link between Covid infection rates and pollen concentrations. It revealed what the scientists termed a “robust and significant positive correlation between SARS-CoV-2 infection rates and airborne pollen concentrations”.

“Whether this is a result of complex immune system interactions, or increased transmission due to hay fever symptoms compounded by diminishing face mask use, or both, remains to be determined, but its impact is palpable.

“The team concluded that it was impossible to completely avoid exposure to pollen, recommending and encouraging particle filter mask use among high-risk individuals during high springtime pollen concentrations.

“As well as potentially increasing the number of Covid cases, pollen is also responsible for many, sometimes severe, allergic reactions. Global warming is having an impact on the types of pollen and allergens we are facing in the UK.

“New University of Michigan research reveals that, by the end of this century, global pollen emissions could begin up to 40 days earlier in the spring, compared to 1995. Allergy sufferers could see that season last an additional 19 days before high pollen counts subside, resulting in prolonged allergen exposure.

“As the average UK temperature rises, new species of plants, grasses and trees are taking root here. These bring with them new pollens and a gradual shift in pollen seasonality and densities, potentially triggering allergies in people who have never suffered from problems such as hay fever.

“While wearing a particle filter mask is an understandable precaution for at-risk individuals worried about the impact of Covid, most people will consider it an overreaction to the risk presented by spring allergies. That said, there is growing interest in understanding allergic risk, suggesting a gradual holistic shift from treatment to prevention. That’s why increasing numbers of people are testing for typical allergies before they ever suffer a reaction.

“Allergy testing was once costly, difficult to access and yielded narrow testing windows, but the evolution of immunology and technology has vastly improved things. Today, allergy testing is a single finger-prick blood test that will identify a wide array of potential allergic triggers, including pollen, pet hair and both plant and animal-derived allergens. For example, London Medical Laboratory’s Allergy Complete is the UK’s most comprehensive allergy test, analysing 295 allergens.

“Tree pollens will be the first to hit Brits this year. As new tree species arrive in the UK, they can trigger early spring allergic reactions in people who have never had them. That’s why LML’s test covers not just many typical British trees, but many non-native varieties. These include: Acacia, Alder, Arizona cypress, Ash, Beech pollen, Cottonwood, Cypress, Date Palm, Elm, Hazel, London plane tree, Mountain cedar, Mulberry tree, Olive, Paper mulberry, Silver birch, Sugi pollen, Tree of heaven, Walnut and Weeping fig.

“The test includes grass, weed and flower pollens, as well as a wide variety of insect venoms, such as potentially fatal allergies to bee and wasp stings. Everything from dust mites and pet hair to fruit, eggs, nuts, fungi and moulds are also covered. It can be taken at home through the post, or at one of the many drop-in clinics that offer it across London and nationwide in over 95 selected pharmacies and health stores. For full details see: https://www.londonmedicallaboratory.com/product/allergy-complete

Contact and Further Information 

London Medical Laboratory’s Clinical Lead, Dr Avinash Hari Narayanan, is available to supply exclusive written comment or for interview. To contact Dr Hari Narayanan, or for more information, please email London Medical Laboratory’s Head of Public Relations, David Jinks M.I.L.T., at david.jinks@londonmedicallaboratory.co.uk

Reference

  1. Athanasios Damialis, Stefanie Gilles, Mikhail Sofiev and Claudia Traidl-Hoffmann. Higher airborne pollen concentrations correlated with increased SARS-CoV-2 infection rates, as evidenced from 31 countries across the globe. PNAS 118(12)e2019034118. 8 March 2021. https://doi.org/10.1073/pnas.2019034118

 

Resolving Persistent Spike Protein Syndrome

by Thomas E. Levy MD JD

Originally published at: orthomolecular.activehosted.com

https://orthomolecular.activehosted.com/index.php?action=social&chash=4734ba6f3de83d861c3176a6273cac6d.272&s=c7ae1002d2f579a22c16a1b89c854212

 

Editor's Note: Dr Levy's paper, to follow, is both interesting and important. One might think it is not orthomolecular as such and is not really appropriate for the Orthomolecular Medicine News Service. While I respect that viewpoint, I do not agree. My publication mentor, Dr Abram Hoffer, taught me by example that physician viewpoints need to be presented for consideration. "Where are the good old days," he wrote, "when honest physicians honestly reported what they saw in language that any doctor could understand?" The NY TIMES used to live by the motto, "All the news that's fit to print." During the heyday of COVID hysteria we saw otherwise. There was considerable bias, even censorship, by legacy media. I do not intend to make that mistake. With nearly 20 years of continuous publication, as long as I am editor, OMNS will stand for open discussion of plausible medical ideas that can save lives. In conjunction, readers should work with their own healthcare providers before making any heath decision. That is common sense. Recognizing the value of a second – or even a third – medical opinion is also common sense. Abram taught me to be inclusive, not exclusive. OMNS will present these ideas. Linus Pauling, who gave orthomolecular medicine its name, said "The best way to have a good idea is to have a lot of ideas." Dr Pauling, a chemist, was roundly criticized by the medical profession for speaking out on health and nutrition. I am glad he did. – Andrew W. Saul, OMNS Editor-in-Chief

 

As the acute cases of COVID have continued to decline, the prevalence of the Persistent Spike Protein (PSP) syndrome has continued to increase. The spike protein is that part of the COVID pathogen that attaches to ACE2 receptors throughout the body and permits the entry of the entire virus into the newly infected cell. There appear to be no cells, tissues, or organs in the body that are completely spared from this PSP attack once enough of it has been introduced into the body.

The persistent presence of the spike protein has been shown to be secondary to the inability to completely resolve a bout of COVID (chronic COVID or long-haul COVID) as well as the spike protein exposure from mRNA inoculation(s). And as more time has passed, the PSP syndrome following one or more mRNA shots has emerged as the most common reason for PSP, especially following a booster injection. Not surprisingly, the likelihood of developing a PSP syndrome relates directly to the total amount of spike protein exposure, and the amounts delivered by repeated inoculations substantially exceed the amounts that result from incompletely resolved cases of COVID.

The goal of any therapy designed to eliminate a chronic spike protein presence in the body needs to address its presence in the blood, its presence on the many ACE2 binding sites throughout the body, its presence inside the cells, and the mechanisms that allow it to replicate itself and keep it from being eliminated completely in the body. It has been shown that the sickest of PSP patients have intact spike protein circulating in the blood. [1]

However, eliminating it from the blood does not assure a cure. It is also vital to destroy the cells where the virus and/or spike protein replication is taking place, as well as to destroy any cells that are producing new spike protein because of the presence of the vaccine-supplied mRNA. It remains unclear at the time of this writing whether the cells of tissues or organs not known to regenerate on a regular basis will instead serve as virus/spike protein reservoirs that are not readily accessible to therapeutic agents. Multiple autopsy studies have revealed the presence of spike protein throughout the body, without any particular areas being spared. [2,3]

By itself, the spike protein is also toxic. As all toxins ultimately inflict damage by oxidizing biomolecules needed for normal metabolic function, any effective PSP protocol needs to include significant antioxidative capacity in order to repair damaged (oxidized) biomolecules. Spike protein has been shown to induce inflammation (acute oxidative stress) even without resulting in viral infection. [4]

Bio-Oxidative Therapies

While any therapy that can eradicate an infectious agent must involve its destruction via enhanced oxidation, the most prominent of these therapies involve the appropriate application of:

  • Vitamin C (multiple modalities);
  • Hydrogen peroxide (multiple modalities);
  • Ozone (multiple modalities);
  • Ultraviolet blood irradiation;
  • Hyperbaric oxygen.

While still not widely appreciated, these bio-oxidative therapies have been curing acute infectious diseases for very many years now. The resolution of acute viral infections has been especially well-established to result with any of these therapies administered individually or when combined together. All these therapies share the ability to rapidly increase the oxidative stress inside the pathogens themselves and/or the cells that have become infected with the pathogens. Nothing destroys a pathogen or pathogen-infected cell that cannot elevate such oxidative stress to lethal levels. And even though different treatments might have unshared mechanisms in fuelling this increased oxidative stress, it is this singular effect that ultimately resolves the infection.

Vitamin C and Hydrogen Peroxide

Vitamin C (VC), interacting directly with extracellular and intracellular hydrogen peroxide (HP) already in the body, works to eradicate pathogens, including the COVID pathogen, by a mechanism known as the Fenton reaction. This reaction produces hydroxyl radical formation in a pathogen or a pathogen-infected cell, which works to oxidize whatever it is next to when it is formed. This ultimately results in the destruction of the pathogen, inside or outside of the cell, when enough VC and HP are present.

Enough HP by itself will also quickly oxidize pathogens and their infected host cells. This can occur with HP nebulization, the direct ingestion of appropriately-dosed HP, and the appropriate infusion of hydrogen peroxide intravenously. Intravenous HP has long been established as a powerful anti-viral agent, curing many of the most critically ill patients in the 1918 influenza pandemic. [5] HP nebulization is especially effective in clearing out areas of chronic pathogen colonization in the nose and throat areas. Even though such areas are usually asymptomatic, they work to keep these "virus-manufacturing" areas of the body much more susceptible to the contraction of new infectious agents, viral or otherwise.

An agent naturally present in the body in large amounts, hydrogen peroxide plays an important role in the pathogen-killing effect of all the bio-oxidative. While the biochemical details of these bio-oxidative therapies remain to be clearly defined, the anti-pathogen effect of HP appears to be an essential part of the final common pro-oxidant pathway in these therapies that is needed to kill the pathogen and clinically resolve the infection.

The nature of the immune system gives further support to the role of both VC and HP in the control and resolution of infections. The monocytes and phagocytes in the immune response are the first cells to appear at new sites of inflammation or infection. Of note, these two types of immune cells have exceptionally high levels of both VC and HP inside them. This results in the immediate delivery of the most important elements of the pathogen-killing Fenton reaction to the new site of infection. [6-10]

Ozone

No agent exceeds the pro-oxidant, pathogen-killing ability of properly-administered ozone. Interestingly, the basic chemical structure of ozone is very close to HP. HP (H2O2) can be regarded as a dioxide of hydrogen, and ozone (O3) can be regarded as a dioxide of oxygen. This dioxide-like structure (two bound oxygens in the molecule) is also present in other molecules with powerful pro-oxidant, pathogen-killing capacity. Chlorine dioxide, nitrogen dioxide, sulphur dioxide, carbon dioxide, titanium dioxide, and silica dioxide have all been shown to have significant anti-pathogen properties. [11-17]

Like HP, ozone has been shown to increase blood oxygen levels and oxygen delivery to the tissues in addition to its anti-pathogen effects. Such an effect can only be expected to further enhance the healing of damaged tissues after the pathogen presence has been eradicated. Furthermore, tumor cells that have been incubated in an ozonated medium have been shown to accumulate HP, supporting the concept that ozone utilizes HP-related mechanisms in its pro-oxidant response involved in cancer cells as well as pathogens. [18] Anything that can increase HP levels in or around a target cell or pathogen greatly facilitates its susceptibility to destruction when the microenvironment triggers the conversion of HP to hydroxyl radical.

Although VC appears to have been much more studied during the pandemic as an anti-COVID agent, there is no evidence to suggest that ozone is not just as effective in destroying the COVID pathogen versus any other pathogen. [19] Furthermore, ozone has been shown to be clearly beneficial while maintaining a high safety profile when used as adjuvant therapy in the treatment of advanced COVID patients. [20-23] Applied early enough in the course of a COVID infection, ozone significantly reduces hospitalization time and improves blood oxygenation. Laboratory markers of coagulation and inflammation are significantly improved with such therapy as well. [24,25]

The PSP (persistent spike protein) syndrome is now affecting literally millions of patients around the world. Some are due to the PSP presence resulting from COVID infection that never really resolves completely. However, many more now appear to be resulting from the COVID shots. Not surprisingly, the likelihood of having PSP syndrome directly correlates to the total amount of spike protein in the body, and every shot supplies more of this toxic protein. Feeling well after the first one or two shots and then deteriorating rapidly following a booster shot is an increasingly common occurrence.

Chronic COVID symptomatology secondary to the PSP syndrome responds very well to oxygen-ozone autohemotherapy. Fatigue remains the singular most common symptom in such PSP patients, even though very many other symptoms can be present as well. In fact, over 50 long-term symptoms from COVID have been reported. [26] In a series of 100 chronic COVID patients suffering prominently with chronic fatigue, one to nine autohemotherapy ozone treatments were administered over a period of up to three weeks. All the patients reported less fatigue, and impaired functionality secondary to chronic fatigue was restored to a normal level in at least two thirds of the patients. [27]

Anecdotal evidence seen with before-and-after dark field examinations on patients with indirect evidence of ongoing spike protein evidence (increased rouleaux formation) show very clearly that ozone treatments quickly resolve this PSP-associated abnormality seen under the microscope. [28]

Since PSP appears to be the primary, or even sole, culprit in patients suffering from chronic COVID symptomatology, the ability of ozone to resolve such symptomatology indicates that any spike protein present in the body can be obliterated by properly-administered ozone. Since ozone is known to degrade and inactivate intact viruses, it is perfectly logical that it can degrade "pieces" of a virus, such as the spike protein part of the COVID pathogen.

Ultraviolet Blood Irradiation

Direct ultraviolet (UV) irradiation without involving blood irradiation has been well-established for a very long time to be an ideal way to kill pathogens outside of the body. [29-31] The COVID pathogen has also been shown to be easily inactivated by such irradiation. [32]

The awareness of the impact of direct UV irradiation on pathogens eventually lead to investigating the impact of ultraviolet blood irradiation (UBI) on patients with various infections. UBI proved to be as effective against pathogens inside the body as it was against pathogens outside the body. In a series of 47 early to moderate advanced cases of spinal type polio infection, UBI alone cured all of the cases. Dramatic responses have also been documented for the UBI treatment of acute viral hepatitis and advanced sepsis. Even conditions such as arthritis and asthma have responded well to UBI. [33,34]

UBI has also been shown to increase the content of HP inside the phagocytic white blood cells. This fits well with the concept that all the bio-oxidative therapies ultimately utilize the anti-pathogen properties of HP to resolve an infection. [35]

Hyperbaric Oxygen Therapy

An exceptionally powerful therapy for resolving deep-seated and otherwise non-healing infections, hyperbaric oxygen therapy (HBOT) involves the inhalation of oxygen inside a chamber that is pressurized to between 1.5 to 3.0 times normal atmospheric pressure. In addition to increasing blood and tissue oxygen levels, HBOT also appears to utilize the anti-pathogen properties of HP in killing pathogens and resolving infections. [36]

The expense and limited availability of HBOT around the country is the main limiting factor in its more routine usage. It is always worth remembering that this therapy exists when dealing with life- and limb-threatening infections. No patient should ever have an infected limb amputated before all the bio-oxidative therapies, including HBOT, have been administered.

Persistent Spike Protein Treatment

PSP syndrome following unresolved COVID infection and/or following one or more COVID inoculations is gradually becoming its own pandemic. The massive morbidity and mortality secondary to this syndrome must be vigorously treated whenever encountered, as it does not appear to be a condition that many people can resolve on their own, even over an extended period of time.

Except for the rarest of individuals, one or more bio-oxidative therapies must be included in an optimal treatment protocol. Vitamin C, hydrogen peroxide, ozone, and ultraviolet blood irradiation would be the best initial approaches. If a protocol utilizing the highest doses of vitamin C does not readily resolve the persistent symptoms seen in the PSP syndrome, there should be no hesitation to seek out a qualified healthcare practitioner familiar with the proper administration of ozone. In addition to the resolution of all persistent and chronic symptoms associated with the PSP syndrome, troponin and D-dimer should end up normal, and the most common of inflammation-related blood tests, like CRP, should be at minimal levels inside the laboratory reference range.

A good protocol, only administered with the oversight of a qualified healthcare practitioner, for the PSP syndrome should include:

  • Ozone autohemotherapy, followed by
  • IV vitamin C (50 to 150 grams daily); or any oral form in the highest doses possible
  • IV or oral hydrocortisone (25 to 50 mg) in the IV or with the first oral dose of vitamin C
  • Ultraviolet blood irradiation if available
  • Hydrogen peroxide nebulization
  • Methylene blue, 25 to 50 mg two or three times daily

It is up to the treating practitioner to determine how long the protocol should be administered and/or modified as the patient responds positively.

Proteolytic enzymes that can break down the spike protein should also be added (bromelain, N-acetyl cysteine, nattokinase).

A protocol like this can be used for many conditions, but this one is designed in particular to resolve the PSP syndrome.

About Dr Levy

OMNS Contributing Editor Dr Thomas E. Levy televymd@yahoo.com  is board certified in internal medicine and cardiology. He is also an attorney, admitted to the bar in Colorado and in the District of Columbia. The views presented in this article are the author's and not necessarily those of all members of the Orthomolecular Medicine News Service Editorial Review Board.

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  33. Rowen R (1996) Ultraviolet blood irradiation therapy (photo-oxidation), the cure that time forgot. International Journal of Biosocial and Medical Research 14:115-132. https://www.drmichaelschoenwalder.com/wp-content/uploads/2020/12/Ultraviolet-Blood-Irradiation-Therapy-Photo-Oxidation-The-Cure-That-Time-Forgot.pdf
  34. Hamblin M (2017) Ultraviolet blood irradiation of blood: "The cure that time forgot"? Advances in Experimental Medicine and Biology 996:295-309. PMID: https://pubmed.ncbi.nlm.nih.gov/29124710
  35. Boretti A, Banik B, Castelletto S (2021) Use of ultraviolet blood irradiation against viral infections. Clinical Reviews in Allergy & Immunology 60:259-270. PMID: https://pubmed.ncbi.nlm.nih.gov/33026601
  36. Hink J, Jansen E (2001) Are superoxide and/or hydrogen peroxide responsible for some of the beneficial effects of hyperbaric oxygen therapy? Medical Hypotheses 57:764-769. PMID: https://pubmed.ncbi.nlm.nih.gov/11918444

Nutritional Medicine is Orthomolecular Medicine

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New Research into Modified RNA Messages Could Help Treat Lewy Body Dementia and Parkinson’s Disease

New research suggests how toxic proteins in the brain that cause Lewy body dementia and Parkinson’s disease to develop, could be used to help develop new targeted treatments.

Experts from the University of Nottingham have discovered that modification of Ribonucleic acid (RNA) in human brain tissue is disrupted in neurodegenerative diseases including dementia with Lewy bodies and Parkinson’s disease.

Published in Neuropathology and Applied Neurobiology, this is the first ever report to identify modified m6A RNAs as a novel molecular mechanism that is altered in Lewy body disease, which may drive the formation of neurotoxic protein aggregates called Lewy Bodies.[1] This RNA modified mechanism, which shows important differences between Lewy body disorders, could be targeted for developing better molecular therapeutics.

The research was led by Dr Helen Miranda Knight in the School of Life Sciences at the University of Nottingham, along with other researchers across the Schools of Life Science and Biosciences. It was conducted using the University of Nottingham’s state-of-the-art School of Life Sciences Imaging (SLIM) microscopy facility.

The function of nerve cells in the brain depends on proteins that are made using information encoded by bases within RNA. If a methyl group is added to an adenosine base (known as m6A modification), this can influence the fate of RNAs. It also suggests that proteins needed for normal neuronal function, may be displaced, or produced at the wrong time in the right subcellular structures within cells.

Researchers used microscopy and a machine learning approach to investigate the spatial location and abundance of modified RNA in human cells in brain regions important for memory and cognitive ability, such as the hippocampus, and frontal and cingulate cortices.

This showed that m6A modification is considerably increased in dementia with Lewy bodies but significantly decreased in Parkinson’s disease. In both diseases, researchers discovered that modified RNA are misplaced within cells, particularly in regions of the brain where synapses are located. Data also indicated that the proteins involved in the process of m6A modification are changed in individuals with Alzheimer’s disease or who show cognitive resilience.

Commenting on the research, Dr Helen Miranda Knight, said:

“Our findings support evidence that changes in m6A modification of RNA may be a mechanism influencing the formation of toxic protein aggregates such as Lewy bodies, amyloid plagues and neurofibrillary tangles, which cause neuronal dysfunction in Lewy body dementia, Parkinson’s disease and Alzheimer’s disease.

“With treatment studies of neurodegenerative diseases currently aiming to target the build-up of such abnormal toxic aggregates, this research provides new understanding of molecular processes going awry, and which are potentially driving, early-stage disease.

“The implications of these findings are important for the development of molecular interventions that target early stage disordered protein aggregation occurring within cellular nanodomains, and which could be protective against disease progression.”

The research paper, titled m6A mRNA methylation in human brain is disrupted in Lewy body disorders can be read in full here.[1]

 Reference

  1. Martinez De La Cruz, B, Gell, C, Markus, R, Macdonald, I, Fray, R, Knight, HM. m6A mRNA methylation in human brain is disrupted in Lewy body disorders. Neuropathol Appl Neurobiol; 49( 1):e12885. doi:10.1111/nan.12885 . 2023.

About the University of Nottingham 

The University of Nottingham is a research-intensive university with a proud heritage. Studying at the University of Nottingham is a life-changing experience, and we pride ourselves on unlocking the potential of our students. We have a pioneering spirit, expressed in the vision of our founder Sir Jesse Boot, which has seen us lead the way in establishing campuses in China and Malaysia - part of a globally connected network of education, research and industrial engagement. Ranked 18th in the UK by the QS World University Rankings 2023, the University’s state-of-the-art facilities and inclusive and disability sport provision is reflected in its crowning as The Times and Sunday Times Good University Guide Sports University of the Year twice in three years, most recently in 2021. We are ranked seventh for research power in the UK according to REF 2021. We have six beacons of research excellence helping to transform lives and change the world; we are also a major employer and industry partner - locally and globally. Alongside Nottingham Trent University, we lead the Universities for Nottingham initiative, a pioneering collaboration which brings together the combined strength and civic missions of Nottingham’s two world-class universities and is working with local communities and partners to aid recovery and renewal following the COVID-19 pandemic

Further Information

Please contact Dr Helen Miranda Knight in the School of Life Sciences at helen.knight@nottingham.ac.uk or contact Adam Mallaby, Media Relations Manager at the University of Nottingham, on +44 (0)115 748 5719 or  adam.mallaby@nottingham.ac.uk

 

Immune Checkpoint Inhibitor Antitumor Response: Decoding Molecular Mechanisms

Researchers reveal that the diverse subset of T-cell clones plays a role in the antitumor effects of immune checkpoint inhibitors

Although immune checkpoint inhibitors (ICIs) are widely used anti-cancer treatments, the mechanisms underlying their antitumour effects are not clear. Now, researchers from Tokyo University of Science, Japan have found that the T-cell repertoire of tumour infiltrating lymphocytes (TILs) holds the key. Using tumour-bearing mouse models, they demonstrated that ICI treatments induce expansion of diverse TIL clones, leading to a robust antitumour and therapeutic effect.

Immune checkpoint inhibitors (ICIs) are widely sought after for the treatment of different types of cancers. Unfortunately, only 20–30% patients with cancer respond to ICI treatment. Although the factors that influence the positive or negative response to ICI treatment are poorly understood, the strength of the ICIs’ antitumor response by TILs is thought to play a key role. Hence, investigating the antitumor response induced by ICIs might provide insights into their underlying mechanism.

It is known that CD8+ tumour-infiltrating T-lymphocytes (TILs) are the primary effector cells that lead to antitumour response. TILs are composed of various T-cell clones that are determined by their unique T-cell receptor (TCR) genes. A diverse TCR repertoire can indicate the existence of TIL population that can recognize multiple tumour-antigens. However, the way the diversity of tumour-reactive clones influences their antitumour effects remains unclear.To this end, a team of researchers led by Associate professor Satoshi Ueha, including Dr Shigeyuki Shichino and Professor Kouji Matsushima from the Tokyo University of Science, and Mr. Hiroyasu Aoki from The University of Tokyo, Japan, investigated the correlation between TIL clones and their antitumour effects. Their work was published in  Cancer Immunology Research [1]

Discussing the team’s motivation behind this study, Prof. Ueha explains,

“By clarifying the mechanism by which ICIs increase tumour reactive CD8+ T cells, we hoped to develop a diagnostic method to predict the efficacy of this therapy as well as a new combined cancer immunotherapy”.

First, the team analyzed the TCR repertoire of B16F10 and Lewis lung carcinoma (LLC) tumor bearing mice, treated with the ICIs – anti-PD-L1 anti-CD4, and a combination of both (CD4 + PDL1) antibodies. They observed that the antibodies increased the mobilization of overlapping (OL) T-cell clones in draining lymph nodes (dLNs) and tumours.

Next, they categorized the dLN-tumour OL clones into oligoclonal and polyclonal fractions. They found that ICI administration significantly increased the polyclonal fraction of OL repertoire but not the oligoclonal fraction in both tumour models. These findings confirmed that the increase in dLN-tumour repertoire was due to clonal spreading, i.e., the expansion of diverse polyclonal clones, and not clonal skewing, i.e., the expansion of oligoclonal clones.

The team further found that increase of the polyclonal fraction of OL repertoire due to ICI administration was correlated with the tumour volume after treatment, a parameter reflecting an antitumour effect. Moreover, single-cell RNA and TCR sequencing exhibited that the polyclonal dLN-tumour OL clones were rich in progenitor exhausted T cells (T cells having more proliferative potential and play an important role in the antitumor effects of ICI).

After establishing that clonal spreading was responsible for effective antitumour response to ICIs, Associate Prof. Ueha and his team investigated the mechanism of clonal spreading. They used tumour-bearing knock-in mice that were selectively depleted of dLN migratory dendritic cells (migDCs) and treated them with anti-PD-L1 and anti-CD4 antibodies. Upon examining the dLN-tumour OL clones, they noted that ICIs enhanced the priming of polyclonal tumour-reactive T-cells by migDCs in the dLN, resulting in clonal spreading.

So, what are the future implications of these findings?

“Our results can be used to predict and diagnose the efficacy of ICIs, thereby making it possible to deliver these rather expensive drugs to patients who can benefit from them. In the long term, the clonal spreading response found in our study may be used to develop therapeutic drugs that induce stronger anti-tumor T-cell responses when used in combination with ICIs,”

 muses a hopeful Prof. Ueha. He also believes that focusing on a greater variety of tumour reactive clones and their proliferation can have important implications in advancing this field of research.

We are confident that the applications of these ICIs will soon extend to clinical trials and bring much needed respite to patients grappling with cancer.

Reference

  1. Clonal spreading of tumor-infiltrating T cells underlies the robust antitumor immune responses Cancer Immunology Research CIR-22-0517. 29 March 2023. https://doi.org/10.1158/2326-6066.CIR-22-0517

About The Tokyo University of Science

Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan's development in science through inculcating the love for science in researchers, technicians, and educators.

 With a mission of “Creating science and technology for the harmonious development of nature, human beings, and society", TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today's most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.

Website: https://www.tus.ac.jp/en/mediarelations/

About Associate Professor Satoshi Ueha from Tokyo University of Science

Dr Satoshi Ueha is an Associate Professor at the Research Institute for Biomedical Sciences, Tokyo University of Science, Japan. Prof. Ueha specializes in tumor immunology and transplantation immunology. He has over 150 publications that have been extensively read and cited. He also holds 9 patents, of which the latest one has been granted for a method that can predict cancer treatment effects using immune checkpoint inhibitors.

Funding Information

This study was supported by the Japan Society for the Promotion of Science under Grant Number 20281832 and 17929397, and by the Japan Agency for Medical Research and Development (AMED) under Grant Number JP 21gm6210025, 22fk0310509s0101, and 22ama221306h0001.

Further Information and Media contact        

Hiroshi Matsuda, Public Relations Division, Tokyo University of Science

mediaoffice@admin.tus.ac.jp

Media Source

Rishita Sachan rishita.sachan1@cactusglobal.com

 

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