Month: March 2023

How Cancer DNA Recovers after Heavy Ion Radiation Treatment

Photo by Jo McNamara

A team of scientists has discovered a new type of DNA repair mechanism that cancer cells use to recover from next-generation heavy ion cancer radiation therapy. Their results are published in the journal Nucleic Acids Research.

Ionising radiation (IR) therapy is frequently used in the treatment of cancer and is believed to destroy cancer cells by inducing DNA breaks. The newest type of radiation therapy harnesses radiation produced by a particle accelerator, which consists of charged heavy particles such as carbon ions. The particle accelerator accelerates the carbon ions to about 70% of the speed of light, which collides with and destroys the DNA of cancer cells.

These ions have a high linear energy transfer (LET) and release most of their energy within a short range, called the Bragg peak. The next-generation cancer radiotherapy works by focusing the Bragg peak on the tumour, which has the added benefit of minimising damage to surrounding normal tissues compared to the commonly used low LET radiation such as gamma or x-rays.

DNA lesions generated by heavy ion bombardment (high LET radiation) are more “complex” than those induced by traditional radiation therapy (low LET radiation). The former carries additional DNA damage such as apurinic/apyrimidinic (AP) site and thymine glycol (Tg) in close proximity to the double-strand breaks (DSB) sites, which is far more difficult to repair than ordinary DNA damage. As a result, the advanced therapy is more cytotoxic per unit dose than low LET radiation.

This makes next-generation radiation therapy a potent weapon against cancer cells. However, it has not been fully investigated how these high LET-induced lesions are processed in mammalian cells, as DNA damage from heavy ion bombardment is a process that seldom occurs on Earth (though astronauts are subject to this in space). Figuring out the complex DSB repair mechanism is an attractive research interest since blocking the cancer cells’ repair mechanism can allow the new radiation therapy to become even more effective.

The researchers visited the QST hospital in Japan to use the synchrotron named HIMAC (Heavy Ion Medical Accelerator in Chiba), which has the ability to produce high LET radiation.

The research team discovered that DNA polymerase θ (POLQ) is an important factor when repairing complex DSBs such as those caused by heavy-ion bombardment. POLQ is a unique DNA polymerase that is able to perform microhomology-mediated end-joining as well as translesion synthesis (TLS) across an abasic (AP) site and thymine glycol (Tg). This TLS activity was found to be the biologically significant factor that allows for complex DSB repair.

Ms SUNG Yubin, one of the joint first authors, explains, “We provided evidence that the TLS activity of POLQ plays a critical role in repairing hiLET-DSBs. We found that POLQ efficiently anneals and extends substrates mimicking complex DSBs” .

The researchers also discovered that preventing the expression of POLQ in cancer cells greatly increased their vulnerability to the new radiation treatment.

“We demonstrated that genetic disruption of POLQ results in an increase of chromatid breaks and enhanced cellular sensitivity following treatment with high LET radiation,” explains Mr. YI Geunil, another joint first author .

The research team used biochemical techniques and Fluorescence Resonance Energy Transfer (FRET) to find out that POLQ protein can effectively repair synthetic DNA molecules that mimic complex DSB. This means that POLQ can be a possible new drug target to increase the cancer cells’ vulnerability against complex radiation damage.

Source: Institute for Basic Science

BP and Temperature Drop in Anaphylaxis Could be due to Nervous System

Photo by RODNAE Productions

Anaphylactic shock can occur in response to food allergies or bites from insects or venomous animals. A key feature of this severe allergic reaction is an abrupt drop in blood pressure and body temperature, causing fainting and, if left untreated, potentially death.

That response has long been attributed to a sudden dilation and leakage of blood vessels. Duke Health researchers have found that this response, especially body temperature drop, requires an additional mechanism: the nervous system.

Published in the journal Science Immunology, the mouse-based study could point to new targets for therapies to prevent or treat anaphylactic shock. “This finding for the first time identifies the nervous system as a key player in the anaphylactic response,” said senior author Soman Abraham, PhD, professor at Duke University School of Medicine.

“The sensory nerves involved in thermal regulation – especially the nerves that sense high environmental temperatures – send the brain a false signal during anaphylaxis that the body is exposed to high temperatures even though it is not the case,” Abraham said. “This causes a rapid drop in body temperature as well as blood pressure.”

Abraham and colleagues, including first author Chunjing “Evangeline” Bao, a Ph.D. candidate in Abraham’s lab at Duke, tracked the sequence of events when allergens activate mast cells — the immune cells that trigger the chemical reactions leading to swelling, difficulty breathing, itchiness, low blood pressure and hypothermia.

The researchers found that one of the chemicals mast cells unleash when they are activated is an enzyme that interacts with sensory neurons, notably those involved in the body’s thermoregulatory neural network.

When stimulated as part of an allergic reaction, this neural network gets the signal to immediately shut down the body’s heat generators in the brown fat tissue, causing hypothermia. The activation of this network also causes a sudden drop in blood pressure.

The researchers validated their findings by showing that depriving mice of the specific mast cell enzyme protected them against hypothermia, whereas directly activating the heat sensing neurons in mice induced anaphylactic reactions such as hypothermia and hypotension.

“By demonstrating that the nervous system is a key player – not just the immune cells – we now have potential targets for prevention or therapy,” Bao said. “This finding could also be important for other conditions, including septic shock, and we are undertaking those studies.”

Source: Duke University Medical Center

Monocytes are Still Capable of Proliferation, Study Shows

Scanning electron micrograph of a macrophage. Credit: NIAID

Cell proliferation from stem cells is vital for organisms to grow and form vital organs. In cancer, however, cell proliferation is no longer controlled and becomes chaotic. Research published in Nature Immunology revealed that monocytes, which are blood immune cells previously thought to be already differentiated, can in fact still proliferate. The study’s researchers at the University of Liège have discovered that, in a healthy individual, monocytes also have this ability to proliferate, in order to replace tissue macrophages.

Monocytes are white blood cells that derive from the bone marrow. A monocyte is part of the innate immune response and functions to regulate cellular homeostasis, especially in the setting of infection and inflammation. They account for approximately 5% of circulating nucleated cells in normal adult blood.

The formation of complex multicellular organisms necessitates billions of cells to be produced from progenitor cells, proliferating and taking on particular morphologies and functions while assembling into tissues and organs. Most of the cells that constitute a living organism are understood to arise from stem cells. When they stop proliferating, they specialise, differentiate and form muscles, brain, bones, immune cells, etc. When proliferation is no longer properly regulated, this can lead to the development of various diseases, chief if which is cancer.

Professor Thomas Marichal (Professor at ULiège, Welbio investigator at the WEL Research Institute) and his team from the GIGA Institute at ULiège discovered that this ability to proliferate is not merely restricted to stem cells, but is also an as-yet-unknown function of blood immune cells, the monocytes.

Indeed, blood monocytes, previously considered as differentiated cells, are capable of proliferating and generating a pool of monocytes in the tissues in order to give rise to macrophages, which are important immune cells that protect us against microbes and support the proper functioning of our organs.

“This is a major fundamental discovery, which changes our conception of the involvement of cell proliferation in the constitution and maintenance of our immune system,” explains Thomas Marichal, director of the study. “Our finding also suggests that the information that can be drawn from an enumeration of blood monocytes, classically carried out during a blood test, would reflect only little of what is happening at the level of the tissues, during ‘infection or inflammation, for example, since monocytes can proliferate when they enter tissues.”

He also adds, “Fortunately, this proliferation is extremely well controlled and does not lead to a humoral process. It has only one goal: to allow, as effectively as possible, the replacement of immune cells that populate our tissues: the macrophages.”

This discovery was possible thanks to the development of new tools and the use of innovative technologies. “This study is a great example of how technological advances can drive breakthrough scientific discoveries. It would have been extremely difficult, if not impossible, to study with such a resolution this population of proliferating monocytes only 10 years ago. This required the use of state-of-the-art equipment recently acquired at the GIGA Institute, the generation of complex genomic data and very sophisticated bioinformatics analyses,” explains Domien Vanneste, first author of the study.

This study paves the way for future investigations that will evaluate the possibility of manipulating or controlling monocyte proliferation for therapeutic purposes, at the benefit of an enhanced health.

Source: University de Liege

Could a Latté a Day Keep Inflammation Away?

Photo by Porapak Apichodilok on Pexels

A simple latté may have an anti-inflammatory effect in humans, according to a new study published in the Journal of Agricultural and Food Chemistry. The researchers found that a combination of proteins and antioxidants, such as in coffee with milk, doubles the anti-inflammatory properties in immune cells. The researchers hope to be able to study the health effects on humans.

Antioxidants known as polyphenols are found in humans, plants, fruits and vegetables. This group of antioxidants is also used by the food industry to slow the oxidation and deterioration of food quality and thereby avoid off flavours and rancidity. Polyphenols are also known to be healthy for humans, as they help reduce oxidative stress in the body that gives rise to inflammation, which can results from infection but also other causes such as muscle overuse or arthritis.

Despite this, understanding of polyphenols is lacking, and few studies have investigated what happens when polyphenols react with other molecules, such as proteins mixed into foods.

In a new study, researchers at the Department of Food Science, in collaboration with researchers from the Department of Veterinary and Animal Sciences, at University of Copenhagen investigated how polyphenols behave when combined with amino acids, the building blocks of proteins. The results have been promising.

“In the study, we show that as a polyphenol reacts with an amino acid, its inhibitory effect on inflammation in immune cells is enhanced. As such, it is clearly imaginable that this cocktail could also have a beneficial effect on inflammation in humans. We will now investigate further, initially in animals. After that, we hope to receive research funding which will allow us to study the effect in humans,” says Professor Marianne Nissen Lund from the Department of Food Science, who headed the study.

The study has just been published in the Journal of Agricultural and Food Chemistry. 

Twice as good at fighting inflammation

To investigate the anti-inflammatory effect of combining polyphenols with proteins, the researchers applied artificial inflammation to immune cells. Some of the cells received various doses of polyphenols that had reacted with an amino acid, while others only received polyphenols in the same doses. A control group received nothing.

The researchers observed that immune cells treated with the combination of polyphenols and amino acids were twice as effective at fighting inflammation as the cells to which only polyphenols were added.

“It is interesting to have now observed the anti-inflammatory effect in cell experiments. And obviously, this has only made us more interested in understanding these health effects in greater detail. So, the next step will be to study the effects in animals,” says Associate Professor Andrew Williams of the Department of Veterinary and Animal Sciences at the Faculty of Health and Medical Sciences, who is also senior author of the study.

Found in coffee with milk

Previous studies by the researchers demonstrated that polyphenols bind to proteins in meat products, milk and beer. In another new study, they tested whether the molecules also bind to each other in a coffee drink with milk. Indeed, coffee beans are filled with polyphenols, while milk is rich in proteins.

“Our result demonstrates that the reaction between polyphenols and proteins also happens in some of the coffee drinks with milk that we studied. In fact, the reaction happens so quickly that it has been difficult to avoid in any of the foods that we’ve studied so far,” says Marianne Nissen Lund.

Therefore, the researcher does not find it difficult to imagine that the reaction and potentially beneficial anti-inflammatory effect also occur when other foods consisting of proteins and fruits or vegetables are combined.

“I can imagine that something similar happens in, for example, a meat dish with vegetables or a smoothie, if you make sure to add some protein like milk or yoghurt,” says Marianne Nissen Lund.   

Spurred by polyphenols’ benefits, researchers and industry are working on how to add the right quantities of polyphenols in foods to achieve the best quality. The new research results are promising in this context as well:

“Because humans do not absorb that much polyphenol, many researchers are studying how to encapsulate polyphenols in protein structures which improve their absorption in the body. This strategy has the added advantage of enhancing the anti-inflammatory effects of polyphenols,” explains Marianne Nissen Lund.

Source: University of Copenhagen

Researchers Identify a Protein to Treat Intracerebral Haemorrhage

Photo by cottonbro studio from Pexels

University of Helsinki and Taiwanese researchers have found a new way to remove waste from the brain after haemorrhage, using a protein called cerebral dopamine neurotrophic factor (CDNF).

Intracerebral haemorrhage, and bleeding into the brain tissue, is a devastating neurological condition affecting millions of people annually. It has a high mortality rate, with long-term neurological deficits experienced by many survivors. To date, no medication has been identified that supports brain recovery following haemorrhage.

In an international collaboration, researchers from the Brain Repair laboratory, University of Helsinki, together with their Taiwanese colleagues investigated whether CDNF, a protein being currently tested for Parkinson’s disease treatment, could be a potential treatment for brain haemorrhage.

Research suggests that CDBF also has therapeutic effects and enhances immune cell’s response after brain haemorrhage. The authors found that the administration of cerebral dopamine neurotrophic factor accelerates haemorrhagic lesion resolution, reduces brain swelling, and improves functional outcomes in an animal model of brain haemorrhage.

“Surprisingly, we found that cerebral dopamine neurotrophic factor acts on immune cells in the bleeding brain, by increasing anti-inflammatory mediators and suppressing the production of the pro-inflammatory cytokines that are responsible for cell signalling. This is a significant step towards the treatment of injuries caused by brain haemorrhage, for which we currently have no cure,” says Professor Mikko Airavaara, from University of Helsinki.

Dr.Vassileios Stratoulias from the Brain Repair laboratory comments, “It’s interesting to note that after a bleeding episode, the brain contains a lot of waste and debris. Cerebral dopamine neurotrophic factor encourages immune cells in the brain to consume and remove the waste and debris, which is essential for the brain’s recovery!.”

The administration of cerebral dopamine neurotrophic factor also resulted in the alleviation of cell stress in the area that surrounds the haematoma.

Finally, the researchers demonstrated that systemic administration of cerebral dopamine neurotrophic factor promotes scavenging by the brain’s immune cells after brain haemorrhage and has beneficial effects in an animal model of brain haemorrhage.

Source: University of Helsinki

A Genetic Treatment for ALS That Restores Key Protein May Be Possible

DNA repair
Source: Pixabay/CC0

In virtually all persons with amyotrophic lateral sclerosis (ALS) and in up to half of all cases of Alzheimer’s disease (AD) and frontotemporal dementia, a protein called TDP-43 is lost from its normal location in the nucleus of the cell. In turn, this triggers the loss of stathmin-2, a protein crucial to regeneration of neurons and the maintenance of their connections to muscle fibres.

Writing in Science, a team of scientists demonstrate that stathmin-2 loss can be rescued using designer DNA drugs that restore normal processing of protein-encoding RNA.

“With mouse models we engineered to misprocess their stathmin-2 encoding RNAs, like in these human diseases, we show that administration of one of these designer DNA drugs into the fluid that surrounds the brain and spinal cord restores normal stathmin-2 levels throughout the nervous system,” said senior study author Don Cleveland, PhD, Distinguished Professor of Medicine, Neurosciences and Cellular and Molecular Medicine at University of California San Diego School of Medicine.

Cleveland is broadly credited with developing the concept of designer DNA drugs, which act to either turn on or turn off genes associated with many degenerative diseases of the aging human nervous system, including ALS, AD, Huntington’s disease and cancer.

Several designer DNA drugs are currently in clinical trials for multiple diseases. One such drug has been approved to treat a childhood neurodegenerative disease called spinal muscular atrophy.

The new study builds upon ongoing research by Cleveland and others regarding the role and loss of TDP-43, a protein associated with ALS, AD and other neurodegenerative disorders. In ALS, TDP-43 loss impacts the motor neurons that innervate and trigger contraction of skeletal muscles, causing them to degenerate, eventually resulting in paralysis.

“In almost all of instances of ALS, there is aggregation of TDP-43, a protein that functions in maturation of the RNA intermediates that encode many proteins. Reduced TDP-43 activity causes misassembly of the RNA-encoding stathmin-2, a protein required for maintenance of the connection of motor neurons to muscle,” said Cleveland.

“Without stathmin-2, motor neurons disconnect from muscle, driving paralysis that is characteristic of ALS. What we have now found is that we can mimic TDP-43 function with a designer DNA drug, thereby restoring correct stathmin-2 RNA and protein level in the mammalian nervous system.”

Specifically, the researchers edited genes in mice to contain human STMN2 gene sequences and then injected antisense oligonucleotides – small DNA or RNA pieces that can bind to specific RNA molecules, blocking their ability to make a protein or changing how their final RNAs are assembled – into cerebral spinal fluid. The injections corrected STMN2 pre-mRNA misprocessing and restored stathmin-2 protein expression fully independent of TDP-43 function.

“Our findings lay the foundation for a clinical trial to delay paralysis in ALS by maintaining stathmin-2 protein levels in patients using our designer DNA drug,” Cleveland said.

Source: University of California – San Diego

WHO Updates SARS-CoV-2 Definitions to Reflect Omicron Dominance

Source: Pixabay CC0

The World Health Organization (WHO) announced that it has updated its tracking system and working definitions for variants of SARS-CoV-2, to better reflect the current global variant landscape, to independently evaluate Omicron sublineages in circulation, and classify new variants more clearly when required.

Omicron variants now accounts for 98% of circulating SARS-CoV-2, and new variants will likely emerge from this genetic background. Based on its latest risk assessment [PDF], South Africa has reported a strong increase in XBB.1.5 from 1% in December 2022, to 10% in January 2023, and 76% as of the latest report from February 2023.

Based on comparisons of antigenic cross reactivity using animal sera, replication studies in experimental models of the human respiratory tract, and evidence from clinical and epidemiological studies in humans, WHO experts conclude that, compared to previous variants, Omicron represents the most divergent variant of concern (VOC) seen so far. Since its emergence, Omicron viruses have continued to evolve genetically and antigenically with an expanding range of sublineages, which so far have had all been characterised by evasion of existing population immunity and a preference to infect the upper respiratory tract (versus lower respiratory tract), as compared to pre-Omicron VOCs.

The previous system classified all Omicron sublineages as part of the Omicron VOC and was not detailed enough to compare new descendent lineages with altered phenotypes to the Omicron parent lineages (BA.1, BA.2, BA.4/BA.5). So, WHO variant tracking system will consider the classification of Omicron sublineages independently as variants under monitoring (VUMs), variants of interest (VOIs), or VOCs.

WHO is also updating the working definitions for VOCs and VOIs. The main update consists in making the VOC definition more specific, to include major SARS-CoV-2 evolutionary steps that require major public health interventions.

In addition, going forward, WHO will assign Greek labels for VOCs, and will no longer do so for VOIs.

With these changes factored in, Alpha, Beta, Gamma, Delta as well as the Omicron parent lineage (B.1.1.529) are considered previously circulating VOCs. WHO has now classified XBB.1.5 as a VOI. 

WHO emphasizes that these changes do not imply that the circulation of Omicron viruses no longer pose a threat to public health. Rather, the changes have been made in order to better identify additional or new threats over and above those posed by the current Omicron viruses in circulation.

Study Reveals How Androgen Receptor Functions are Affected by Mutations

Testosterone molecule
Model of a testosterone molecule. Source: Wikimedia CC0

The androgen receptor is a key transcriptional factor for proper sex development, especially in males and the physiological balance of all the tissues that express this receptor. The androgen receptor is involved in several pathologies and syndromes, such as spinal and bulbar muscular atrophy or androgen insensitivity syndrome, for which there is no specific treatment. Regarded as the main initial and progression factor in prostate cancer, this receptor has been the main therapeutic target for the treatment against this disease for decades.

Now, a study published in Science Advances describes the structural and functional effects of mutations on the androgen receptor, as well as how these changes lead to the development of prostate cancer.

Point mutations in the androgen receptor

The human androgen receptor is a key protein in the development and functioning of the prostate in response to male hormones, such as testosterone. Point mutations in the androgen receptor – specifically, one amino acid swapped for another – are one of the main mechanisms than can lead to structural and functional alterations in the receptor, which result in the development of diseases.

The results of the University of Barcelona-led study show that the analysed mutations affect several functional regions of the union domain of the androgen receptor to testosterone. In particular, these are mutations that alter a region of the receptor which is the target for posttranscriptional modifications (that is, modifications in the protein once this is produced).

This type of chemical alterations affect specific amino acids of the androgen receptor and are executed by regulating proteins which are critical for the proper functioning of the receptor. If this receptor’s regulation pathway is altered, such as the case of the presence of mutations described by the team, its function is deregulated and it can be dysfunctional and cause pathologies.

“In our study, we experimentally checked that these mutations deregulate a specific mutation, known as arginine methylation, which is one of the posttranscriptional modifications, due to the structural changes these alterations produce in a functional area of the receptor. Also, we could observe that the deregulation of the androgen receptor methylation involves relevant changes in its function within the cell,” the team concludes.

Source: University of Barcelona

Strenuous Jobs Increase Men’s Cardiovascular Risk, but Reduce Women’s

Photo by K. Mitch Hodge on Unsplash

A long-term Danish study found that high physical activity at work was associated with higher risk of ischaemic heart disease (IHD) in men, but in women, this was associated with lower risk. The findings, published in the European Journal of Preventive Cardiology, highlight the importance of taking gender into account when considering the impact of high levels of occupational physical activity (OPA).

While previous studies have shown that physical activities in leisure time are protective against cardiovascular disease, high levels of OPA were shown to have no benefit – or even a detrimental effect.

The study followed up participants aged 30–61 years old after 34 years who took part in the Danish Monica 1 study in 1982–84. Participants, 1399 women and 1706 men, were actively employed, without prior IHD and who answered a question on OPA. The participants’ medical records were located in the Danish National Patient Registry and the researchers analysed the data, controlling for increasing numbers of factors such as age, then age and sex, and then age and sex plus factors such as smoking.

Compared to women doing sedentary work, women in all other OPA categories had a lower hazard ratio (HR) for IHD. Among men, the risk of IHD was 22% higher among those with light OPA, and 42% and 46% higher among those with moderate OPA with some lifting or strenuous work with heavy lifting, respectively, compared to men with sedentary OPA. Compared to women with sedentary work, HR for IHD was higher among men in all OPA categories, and a statistically significant interaction between OPA and sex was found.

Demanding or strenuous OPA seems to be a risk factor for IHD among men, whereas a higher level of OPA seems to protect from IHD among women. The researchers wrote that this underlines the importance of taking into account sex differences in studies of health effects of OPA. Future studies should investigate the underlying mechanisms for this difference, such as differences in exposure and physiology.

New Oral Psoriasis Drug a Step Closer After Successful Clinical Trials

Source: Danilo Alvesd on Unsplash

In a Phase 2b clinical trial, patients who took the peptide-based drug candidate JNJ-2113 had a 75% improvement in their plaque psoriasis compared to placebo, passing an important milestone in developing an oral treatment for the common skin disease. The drug is being developed by a company launched from The University of Queensland’s Institute for Molecular Bioscience (IMB) in collaboration with Janssen.

Protagonist Therapeutics was spun out of work by Associate Professor Mark Smythe to develop new drugs for conditions previously only treated with injectables. Dr Smythe said the trial result was a significant achievement for patients and the scientists involved.

“The trial has shown it’s possible to treat systemic diseases like psoriasis with peptide-based drugs that are orally delivered,” Dr Smythe said.

“Diseases such as psoriasis and inflammatory bowel disease have targets that previously could only be blocked by large molecules called macromolecular antibodies, which had to be injected because they’re too big to be taken in pills.

“The key to finding a molecule that worked but was small enough to be taken orally was seeing the animal venom research of my IMB colleagues.

“I realised that the constrained peptide molecules in venoms could both block the right targets and were small.”

Dr Smythe and his team developed techniques to stabilise the peptides enough so that they could be developed into an oral drug.

Protagonist was founded in 2001 with commercial support from UniQuest Pty Ltd, UQ’s commercialisation company.

Protagonist is based in the USA with an office in Brisbane and is one of 15 spin-out companies from IMB and one of 125 start-ups based on UQ intellectual property.

Source: The University of Queensland