Tag: 27/7/21

Categories : Cancer Immune SystemTags :

Unleashing the Immune System to Attack Cancers

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Shown here is a pseudo-colored scanning electron micrograph of an oral squamous cancer cell (white) being attacked by two cytotoxic T cells (red), part of a natural immune response. Photo by National Cancer Institute on Unsplash

A potential treatment has been identified, that could boost the immune system’s ability to find and destroy cancer cells, by impeding certain cells which regulate the immune system, which in turn can unleash other immune cells to attack tumours in cancer patients.

“A patient’s immune system is more than able to detect and remove cancer cells and immunotherapy has recently emerged as a novel therapy for many different types of cancers,” explained study leader Nullin Divecha, Professor of Cell Signalling at the University of Southampton. “However, cancer cells can generate a microenvironment within the tumour that stops the immune system from working thereby limiting the general use and success of immunotherapy,” he continued.

One of a number of types of T cells, Teffector cells (Teffs) carry out the task of detection and removal of cancer cells . How well Teff cells work in detecting and removing cancer cells is partly governed by other T cells called T-regulatory cells, or Tregs for short. Tregs physically interact with the Teff cells, producing molecules which dampen the functioning of the Teff cells.

Prof Divecha added, “Tregs carry out an important function in the human body because without them, the immune system can run out of control and attack normal cells of the body. However, in cancer patients we need to give the Teff cells more freedom to carry out their job.”

Molecules released by tumour cells exacerbate the problem by attracting and gathering Tregs, reducing the activity and function of Teff cells even further. Though there are mechanisms to inhibit Treg cells, since Treg and Teff cells are very similar, Teff cells are also generally inhibited.

In this new study, published in PNAS, scientists from the University of Southampton and the National Institute of Molecular Genetics in Milan showed that inhibition of a family of enzymes in cells called PIP4K could be the answer to how to restrict Tregs without affecting Teffs.

The research team isolated Tregs from healthy donors and used genetic technology to suppress the production of the PIP4K proteins. They saw that loss of PIP4Ks from Treg cells stopped their growth and response to immune signals, in turn stopping them from impeding Teff cell growth and function.

Importantly, the loss of the same enzymes in Teff cells did not limit their activity.

“This was surprising because PIP4Ks are in both types of T cells in similar concentrations but our study shows that they seem to have a more important function for Tregs than Teffectors,” said Dr. Alessandro Poli who carried out the experimental research.

Scientists must next develop molecules in order to inhibition of PIP4K as a potential therapy for patients. “Towards this end we show that treatment with a drug like inhibitor of PIP4K could enable the immune system to function more strongly and be better equipped to destroy tumour cells.”

Source: EurekAlert!

Categories : Mental HealthTags :

Excess Body Fat Associated with Dementia Risk

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Photo by Siora Photography on Unsplash
Photo by Siora Photography on Unsplash

Researchers at the University of South Australia are warning that high levels of body fat can add to the risk of dementia and stroke.

Having examined grey brain matter from about 28 000 people, the reseachers’ study demonstrated that increased body fat incrementally leads to increased atrophy of grey matter in the brain, resulting in greater risk of declining brain health. Obesity is a major and growing issue worldwide; World Health Organization data shows that more than 1.9 billion adults are overweight, with 650 million being obese. 

The lead researcher, Dr Anwar Mulugeta of UniSA, said the findings add to the growing number of issues known to be associated with being overweight or obese.

“Obesity is a genetically complex condition characterised by the excessive body fat,” Dr Mulugeta said. “Commonly linked to cardiovascular disease, type 2 diabetes, and chronic inflammation (a marker of dementia), obesity currently costs Australia’s economy about $8.6 billion dollars each year.

“While the disease burden of obesity has increased over the past five decades, the complex nature of the disease means that not all obese individuals are metabolically unhealthy, which makes it difficult to pinpoint who is at risk of associated diseases, and who is not.

“Certainly, being overweight generally increases your risk for cardiovascular disease, type 2 diabetes, and low-grade inflammation, but understanding the level of risk is important to better direct supports.

“In this study, we investigated the causal relationships of individuals within three metabolically different obesity types* ­– unfavourable, neutral and favourable – to establish whether specific weight groups were more at risk than others.”

These three obesity subtypes are:

  • ‘unfavourable’ – people who tend to have fat around their lower torso and abdominal area. These people have a higher risk of type 2 diabetes and heart diseases.
  • ‘favourable’ – people who have have wider hips but a lower risk of type 2 diabetes and heart diseases.
  • ‘neutral’ – people who have relatively low or very low risk of the cardiometabolic diseases.

Dr Mulugeta continued, “Generally, the three obesity subtypes have a characteristic of higher body mass index, yet, each type varies in terms of body fat and visceral fat distribution, with a different risk of cardiometabolic diseases.

“We found that people with higher levels of obesity especially those with metabolically unfavourable and neutral adiposity subtypes had much lower levels of grey brain matter, indicating that these people may have compromised brain function which needed further investigation.

“However, we did not find conclusive evidence to link a specific obesity subtype with dementia or stroke. Instead, our study suggests the possible role of inflammation and metabolic abnormalities and how they can contribute to obesity and grey matter volume reduction.”

The study analysed the genetic data of up to 336 000 individual records in the UK Biobank, along with self-reported information and linked hospital and death register records to connect dementia and stroke.

It found that, in middle to elderly age groups (37-73), grey brain matter decreased by 0.3 percent for every extra 1 kg/m2, which is equivalent of an extra 3 kg of weight for persons of average height (173 cm).

Senior investigator Professor Elina Hyppönen, Director of UniSA’s Australian Centre for Precision Health based at SAHMRI, said keeping to a healthy weight is important for general public health.

“It is increasingly appreciated that obesity is a complex condition, and that especially excess fat which is located around the internal organs have particularly harmful effects on health,” Prof Hyppönen said.

“Here, we used the individuals’ genetic and metabolic profiles to confirm different types of obesity. In practice, our findings very much support the need to look at the type of obesity when assessing the type of likely health impact.

“Even in a relatively normal weight individual, excess weight around the abdominal area may be a cause of concern.”

Source: University of South Australia

Categories : AgeingTags :

AI Model Identifies Compounds That Could Extend Life

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Photo by Tara Winstead from Pexels
Photo by Tara Winstead from Pexels

The University of Surrey has developed an artificial intelligence (AI) model that identifies chemical compounds that promote healthy ageing, which could help the development of pharmaceuticals for human lifespan extension.

In a paper published in Scientific Reports, a team of chemists from Surrey built a machine learning model based on the information from the DrugAge database to predict whether a compound can extend the life of Caenorhabditis elegans, a translucent worm whose metabolism is similar to humans. Because the worm has such a short lifespan, the researchers were able to test the effectiveness of the compounds.

The AI model identified three compounds that have an 80 percent chance of increasing the lifespan of elegans:

  • flavonoids (anti-oxidant pigments found in plants that promote cardiovascular health, examples include certain spices and herbs),
  • fatty acids (such as omega 3), and
  • organooxygens (compounds that contain carbon to oxygen bonds, such as alcohol).

Co-author Sofia Kapsiani, final year undergraduate student at the University of Surrey, said: “Ageing is increasingly being recognized as a set of diseases in modern medicine, and we can apply the tools of the digital world, such as AI, to help slow down or protect against ageing and age-related diseases. Our study demonstrates the revolutionary ability of AI to aid the identification of compounds with anti-aging properties.”

Commenting on the research, lead author Dr Brendan Howlin, Senior Lecturer in Computational Chemistry at the University of Surrey, said: “This research shows the power and potential of AI, which is a specialty of the University of Surrey, to drive significant benefits in human health.”

Source: SciTech Daily

Journal information: “Random forest classification for predicting lifespan-extending chemical compounds” by Sofia Kapsiani and Brendan J. Howlin, 5 July 2021, Scientific Reports.
DOI: 10.1038/s41598-021-93070-6

Categories : Mental HealthTags :

Researchers Hit upon a Possible Biomarker for Schizophrenia

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Investigators at Sanford Burnham Prebys have discovered that a certain protein circulating in blood could be a potential biomarker for schizophrenia. The activity of this protein, present in both the brain and blood, affects neural connections in human brains and is uniquely imbalanced in people with schizophrenia. 

The study, an international collaboration among groups at Yokohama City University Graduate School of Medicine in Japan and the Department of Psychiatry at Harvard Medical School in Belmont, Massachusetts, was recently published in PNAS.

“This study examined the activity of CRMP2, a protein found in the brain (called a ‘cytoskeletal protein’) that regulates how neurons make connections with each other,” said co-senior author of the study Evan Y Snyder, MD, PhD, director of the Center for Stem Cells and Regenerative Medicine at Sanford Burnham Prebys. “CRMP2 also happens to be expressed in lymphocytes in the blood and can therefore be readily sampled in people by doing nothing more than a simple venipuncture.

“There was an abundance of CRMP2 levels in samples from people with schizophrenia compared to people without the disorder. We also saw structural abnormalities in the dendrites of neurons that could potentially be disabling because dendrites play an important role in receiving impulses from other nerve cells in the brain.”

In previous research, most people were found to maintain an even proportion of the two forms of CRMP2: its active, non-phosphorylated form and its inactive, phosphorylated form. Postmortem brain tissue and then blood samples from people with schizophrenia were examined and compared these levels to those in people without the disorder.

The findings indicated that the amount of active CRMP2 was too high in people with schizophrenia and, at least in young people with schizophrenia, was not balanced by an appropriate amount of increased inactive CRMP2. That imbalance between active and inactive CRMP2 could account for some dysfunctions in neural connections.

Testing blood for high levels of active CRMP2, along with low levels of inactive CRMP2, could support schizophrenia diagnosis.

“Schizophrenia can be challenging to diagnose early on or in young patients for a number of reasons,” explained Dr Snyder. “Pairing a blood test with psychiatric and neurobehavioral exams could help doctors distinguish schizophrenia from other conditions that have somewhat similar symptomologies, such as the manic phase of bipolar disorder or other behavioral, personality, or thought disorders.

“Our results were most striking in people under the age of 40, and even more so in people under the age of 30. An early diagnosis could improve the clinical management of affected individuals as well as accelerate the development of new therapeutic options,” Dr Snyder added.

As a next step, the researchers want to delve into the molecular biology of the disease to discover the ‘regulator’  that balances most people’s CRMP2 levels. They also want to conduct a larger, multi-centre clinical study that compares schizophrenia with other psychiatric disorders, which would include participants from more ethnicities and age groups.

Source: Sanford Burnham Prebys Medical Discovery Institute

Journal information: Munetaka Nomoto el al., “Clinical evidence that a dysregulated neural network modulator may aid in diagnosing schizophrenia,” PNAS (2021). www.pnas.org/cgi/doi/10.1073/pnas.2100032118

Categories : Metabolic DisordersTags :

Quality of Life Improvements with Continuous Glucose Monitoring

On By ModernMedia
Photo by Towfiqu barbhuiya on Unsplash

A study found that patients with poorly controlled type 2 diabetes benefitted more from continuous blood glucose monitoring than standard blood glucose monitoring using finger pricks.

While continuous glucose monitoring has well-demonstrated benefits for patients with diabetes, the benefits have only been well studied in patients with type 1 diabetes or patients with type 2 treated with  prandial insulin, consisting of multiple daily insulin injections, and not those treated with basal insulin, which is long-lasting and injected only once or twice daily.

Study author Rodica Busui, MD, PhD, at University of Michigan Health, said this of the first studies to assess the impact of continuous glucose monitor in adults with poorly controlled type 2 diabetes with basal insulin.

“Not only does this trial demonstrate the benefits of continuous glucose monitoring for these patients, a technology that hasn’t been covered by many insurers for those with type 2 diabetes, but these benefits were seen across a broad spectrum of socio-economic status and racial backgrounds,” said Dr Busui, adding that about half of the study’s participants were of a racial or ethnic minority.

The randomised clinic trial began enrolling patients in mid-2018 to late-2019, with follow up in mid-2020. The participants received basal insulin, with or without non-insulin medications to help lower blood sugar levels.

“This work wouldn’t have been possible without the partnership between endocrinologists and primary care physicians, as all the patients were recruited and treated by our primary care teams,” said Busui, who is also associate director for clinical research in the Elizabeth Weiser Caswell Diabetes Institute.

The investigators found that continuous glucose monitoring, compared to blood glucose meter monitoring using finger pricks, significantly decreased their haemoglobin A1C over eight months (-1.1% versus -0.16%, respectively).

In addition to testing the efficacy of continuous glucose monitoring paired with basal insulin, Dr Busui and her team sought approach affected patients’ adherence to managing their disease as well as their overall life satisfaction. The 175 study participants exhibited better adherence to managing their diabetes, and their life satisfaction was higher.

“For me, what’s most exciting is that this work demonstrates that using continuous glucose monitoring is effective in substantially improving blood sugars levels and decreasing the risks of hypoglycemia in those that were randomized to use a continuous glucose monitor compared with the usual finger-prick,” said Busui.

“This may open the door for broader coverage of this game-changing technology for all patients with diabetes. More patients can manage their diabetes if they have access to this resource and their primary care physicians are educated on the benefits of their patients utilising it.”

Source: Science Daily

Journal information: Thomas Martens et al, Effect of Continuous Glucose Monitoring on Glycemic Control in Patients With Type 2 Diabetes Treated With Basal Insulin, JAMA (2021). DOI: 10.1001/jama.2021.7444

Categories : COVID Immune SystemTags :

Initial Immune Reaction Determines Severity of COVID

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Image source: CDC on Unsplash

Researchers have found that the course of severe COVID could be determined very early on, depending on the body’s initial reaction to the disease in the upper airway as well as inflammatory reactions.

Scientists at the Ragon Institute of MGH, MIT, and Harvard; the Broad Institute of MIT and Harvard; Boston Children’s Hospital (BCH); MIT; and the University of Mississippi Medical Center (UMMC) wondered whether COVID’s path towards severe disease could start much earlier than expected — perhaps even within the initial response created when the virus enters the nose.

To test this, they studied cells taken from nasal swabs of patients at the time of their initial COVID diagnosis, comparing patients who went on to develop mild COVID to those who progressed into more severe disease and eventually required respiratory support. Their results showed that patients who went on to develop severe COVID exhibited a much more muted antiviral response in the cells collected from those early swabs, compared to patients who had a mild course of the disease. The paper appears in Cell.

“We wanted to understand if there were pronounced differences in samples taken early in the course of disease that were associated with different severities of COVID as the disease progressed,” said co-senior author José Ordovás-Montañés, an associate member in the Klarman Cell Observatory at Broad and assistant professor at BCH and Harvard Medical School. “Our findings suggest that the course of severe COVID may be determined by the body’s intrinsic antiviral response to initial infection, opening up new avenues for early interventions that could prevent severe disease.”

To understand the early response to infection, Sarah Glover of the Division of Digestive Diseases at UMMC and her laboratory collected nasal swabs from 58 people, 35 of whom were just recently diagnosed with COVID, representing a variety of disease states from mild to severe. Seventeen swabs came from healthy volunteers and six came from patients with other causes of respiratory failure. The team  sequenced RNA from these samples to find out what kind of proteins the cells were making — a snapshot of the cell’s activity when collected.

By studying a cell’s transcriptome, which is its collection of RNA, can researchers understand how a cell is responding to environmental changes such as a viral infection. It can even be used to see if individual cells are infected by an RNA virus-like SARS-CoV-2.

“Our single-cell sequencing approaches allow us to comprehensively study the body’s response to disease at a specific moment in time,” said co-senior author Alex Shalek, who is also an associate professor at MIT in the Institute for Medical Engineering & Science, the Department of Chemistry, and the Koch Institute for Integrative Cancer Research. “This gives us the ability to systematically explore features that differentiate one course of disease from another as well as cells that are infected from those that are not. We can then leverage this information to guide the development of more effective preventions and cures for COVID and other viral infections.”

Analysing the transcriptome, the team investigated how epithelial and immune cells were responding to early COVID infection from the single-cell transcriptome data. Firstly, in patients who progressed to severe COVID, the initial interferon-driven antiviral response was muted. Second, patients with severe COVID had higher amounts of highly inflammatory macrophages, and high inflammation levels are often seen in severe or fatal COVID.

Since these samples were taken well before COVID had peaked in the patients, both these findings indicate that COVID’s course may be determined by the initial response of the nasal epithelial and immune cells to the virus. The weak initial antiviral response may allow a rapid spread of the virus, making it more likely to move from upper to lower airways, while the recruitment of inflammatory immune cells could help drive the dangerous inflammation in severe disease.

Finally, the team also identified infected host cells and pathways associated with protection against infection — cells and responses unique to patients that went on to develop mild disease. These findings may allow researchers to discover new therapeutic strategies for COVID and other respiratory viral infections.

If the early stages of infection can determine disease, it could enable the development of early interventions that can help prevent the development of severe COVID. Potential markers of severe disease were also identified, genes that were expressed in mild, but not severe COVID.

“Nearly all our severe COVID samples lacked expression of several genes we would typically expect to see in an antiviral response,” said co-first author Carly Ziegler, a graduate student in the Health Science and Technology Program, MIT and Harvard.

“If further studies support our findings, we could use the same nasal swabs we use to diagnose COVID-19 to identity potentially severe cases before severe disease develops, creating an opportunity for effective early intervention,” said Ziegler.

Source: Broad Institute of MIT and Harvard

Journal information: Ziegler, C G K., et al (2021) Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19. Cell. doi.org/10.1016/j.cell.2021.07.023.