Connect with us

News

Scientists find key to potential breast cancer prevention and treatment

Published

on

New research from the US has revealed how a pathway inside cells essential for activating inflammatory immune response is unleashed to prevent cancer formation by detecting DNA damage within cells.

In doing so, the research team discovered the key that unlocks the cGAS/STING pathway, which is normally turned off to prevent excessive inflammation in healthy conditions.

Gaorav Gupta, MD, PhD is associate professor in the Department of Radiation Oncology at the the University of North Carolina (UNC) School of Medicine.

He said: “Our findings suggest that loss of this pathway may be what’s allowing breast cancer cells to withstand high levels of DNA damage without being recognised by the immune system.

“We’re very interested in identifying ways to reactivate this pathway to treat and potentially even prevent cancer development.”

The enzyme cyclic GMP-AMP synthase (cGAS) is well known for its role as a messenger for the immune system.

Double-stranded DNA viruses, such as chickenpox and herpes simplex and DNA-damaged cells are perceived as threats and waste to the body.

In response, cGAS calls on the immune system to seek out the threat and eliminate it from the body.

Robert McGinty, MD, PhD at the UNC Eshelman School of Pharmacy, Pengda Liu, PhD, and Qi Zhang, PhD, of the UNC Department of Biochemistry and Biophysics, were amongsthe first research teams to make a landmark discovery about cGAS.

Their research revealed that cGAS is “locked up” in an effort to prevent the body from unleashing the inflammatory immune response unless it is absolutely necessary.

Gupta said: “It’s in a ‘turned off’ state because it has a much stronger affinity for histones molecules, which are proteins around which our DNA is packaged, than to DNA itself.

“You can think of cGAS as being locked up through its binding to histones, not able to perform its duty to recognise DNA unless it is freed by some key.”

In light of his colleagues’ research, Gupta reached out to them to test a new hypothesis, using the assays they had previously developed and used in those studies.

Gupta’s lab was curious to know whether a protein being investigated in his lab, MRE11, which is known to recognise broken fragments of DNA, may also be the key that releases cGAS from its histone prison.

Indeed, the researchers found that MRE11, in the process of recognising and binding to broken DNA, simultaneously releases cGAS from the histones (proteins that provides structural support for a chromosome).

Min-Guk Cho, PhD is a postdoctoral fellow in Gupta’s lab and co-first author on the paper.

The researcher said: “This was fascinating because MRE11 was known for detecting and repairing DNA damage, but the evidence I uncovered indicated that MRE11 plays a different role, namely in activating the innate immune system.”

Researchers also found that when MRE11 and cGAS interact with one another, they initiate a specialised form of cell death called necroptosis.

As opposed to other forms of cell death, necroptosis causes cells to die in a way that triggers immune activation, making it easier for the body to trigger an all-hands-on-deck effort.

Gupta said: “Linking Mre11 and cGAS to necroptosis activation is a very effective way for suppressing tumour formation.

“When MRE11 and cGAS are activated by a damaged precancerous cell, they cooperate to activate an immune-boosting form of cell death, to help our bodies eliminate the cells before they develop into a cancer.”

Gupta and colleagues in the UNC Lineberger Comprehensive Cancer Center are now enrolling patients for a clinical trial at UNC to examine the combination of radiation and immunotherapy as a means of treating certain types of breast cancer.

With this new information in hand, scientists will see if the pathway is more or less responsive to these therapies, or if specific types of therapies may more effectively engage this pathway and result in improved clinical outcomes.

News

Europe: Improving access to early-stage lung cancer care

Published

on

Europe: Improving access to early-stage lung cancer care

Researchers from Amsterdam UMC Cancer Center Amsterdam have looked at inequalities in access to early-stage lung cancer care in Europe.

Early-stage lung cancer has stark differences between European countries regarding access and reimbursement.

There are also differences in reimbursement times and indications between the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA).

Researchers from Amsterdam UMC Cancer Center Amsterdam analysed the landscape, publishing their results in The Lancet Regional Health Europe as part of a series on the latest developments in the treatment of this lung cancer.

“Tackling inequalities in access to care must be a common European priority,” says Amsterdam UMC pulmonologist Idris Bahce. In collaboration with colleagues from seven European countries, Bahce used a literature review to map out the latest developments and analyse access to these new treatments from a European perspective.

“The existing differences in healthcare systems and reimbursement structures between European countries threaten to exacerbate healthcare inequalities at both European and national level. We therefore call for a collective European approach to reduce these inequalities,” says Bahce.

He suggests measures such as more international cooperation between the EMA and other registration authorities, harmonising cost-effectiveness procedures in European countries, a more critical evaluation of reimbursement criteria and improving multidisciplinary collaborations around the patient.

The standard treatment for fit patients with early-stage lung cancer has always been surgery, sometimes combined with pre- or post-operative chemotherapy. Recently, the EMA has approved new treatments such as immunotherapy, which appear to significantly improve survival rates after surgery. More approvals of innovative treatments are expected, potentially further exacerbating existing inequalities within Europe.

In addition to the Dutch hospitals Amsterdam UMC and Erasmus MC, colleagues from Spain, France, Germany, England, Italy and Poland also contributed to this international study as well as a Review and a Viewpoint in The Lancet Regional Health Europe.

Continue Reading

News

Study looks at link between adversity and cognitive decline

Published

on

A new paper has examined the relationship between childhood adversity and psychiatric decline, as well as adult adversity and psychiatric and cognitive decline. 

The findings revealed just one instance of adversity in childhood can increase cases of mental illness later in life. It also revealed that adverse events in adults can lead to a greater chance of both mental illness and cognitive decline later in life. 

The paper has been published by Saint Louis University associate professor of health management and policy in the College for Public Health and Social Justice, SangNam Ahn, Ph.D., in Journal of Clinical Psychology.

Ahn stated: “Life is very complicated, very dynamic. I really wanted to highlight the importance of looking into the lasting health effect of adversity, not only childhood but also adulthood adversity on health outcomes, especially physical health and psychiatric and cognitive health. 

“There have been other studies before, but this is one of the first that looks into these issues comprehensively.” 

Ahn, along with his team of researchers, examined data from nearly 3500 individuals over the course of 24 years. The group took the longitudinal data and evaluated it using a list of lifetime potential traumatic events.

The research team included childhood adversity events such as moving due to financial difficulties, family requiring financial help, a parent experiencing unemployment, trouble with law enforcement before the age of 18, repeating school, physical abuse and parental abuse of drugs or alcohol. 

Adulthood adversity events included the death of a child, the death of a spouse, experiencing a natural disaster after age 17, firing a weapon in combat, a partner abusing drugs or alcohol, being a victim of a physical attack after age 17, a spouse or child battling a serious illness, receiving Medicaid or food stamps and experiencing unemployment. 

The study determined that nearly 40% of all individuals experienced a form of childhood adversity, while that number climbed to nearly 80% for adulthood adversity. Those who experienced childhood adversity were also 17% more likely to experience adulthood adversity. Only 13% of individuals sampled reported two or more forms of childhood adversity, while 52% of adults experienced two or more forms of adult adversity. 

In cases of either childhood adversity or adulthood adversity, researchers found individuals who experienced adversity were also more likely to experience anxiety and depression later in life, and in the case of adulthood adversity, were also more likely to experience cognitive decline later in life. 

Individuals with one childhood adversity experience saw a 5% higher chance of suffering from anxiety, and those with two or more childhood adversity experiences had 26% and 10% higher chances of depression and anxiety, respectively. Individuals who experienced two adulthood adversities had a 24% higher chance of depression, while also experiencing a 3% cognitive decline later in life. 

While most of the results were expected or unsurprising, one area that stood out to Ahn was education. Those individuals studied who reported higher levels of education saw a reduction in the number of adversity experiences. Ahn hopes to study this avenue more to learn how education may be able to mitigate or prevent these declines. 

“Before including education, there was a significant association between childhood adversity and cognitive impairment,” Ahn said. 

“But when including education as a covariate, that significant association disappeared. Interesting. So there were important implications here. Education and attending school, people could be better off even if they were exposed to childhood adversity. They’re likely to learn positive coping mechanisms, which may help avoid  relying on unhealthy coping mechanisms, such as smoking or excessive drinking or drug use.

“Education is quite important in terms of health outcomes. If I am educated, I’m likely to get a better job, have a higher income, and live in areas with less crime. I’m likely to buy gym membership or regularly exercise. I’m likely to shop at Whole Foods and get proper nutrition. All of which help combat these adversities we hinted at in the study. So the education and health outcomes are already closely related, and that is what we saw in our study.”

Ahn also encourages clinicians and everyday people alike to discuss their stress. Clinicians can learn more about their patients and have a better approach when it comes to their physical and mental health, while others could potentially relate to shared experiences. But through awareness and recognition, these adverse experiences could potentially have less serious, lasting effects. 

“Public health is very interested in stress,” Ahn said. “But we’re still examining how daily stress impacts our long term health outcomes. So to see the effects here in the study, I want people to pay attention to their stress and proactively address it. Clinicians should have deep discussions with their patients about their stress and mental state. And those topics can be approached in other areas too, like the classroom or the dining room table. The more we are aware of stress and discuss our stress, the better we can handle any adversities we find in life.”

Continue Reading

News

New tool to explore mechanisms of age-related diseases

Published

on

New tool to explore mechanisms of age-related diseases

A new screening tool has been developed that will investigate the mechanisms behind conditions such as cancer, arthritis, neurodegeneration and cardiovascular disease.

Wellcome Sanger Institute researchers and their collaborators at Open Targets and EMBL’s European Bioinformatics Institute (EMBL-EBI) have developed the screening tool called scSNV-seq.

The tool has been designed to uncover how genetic changes affect gene activity that can lead to diseases such as cancer, autoimmunity, cardiovascular disease and neurodegenerative diseases such as Alzheimer’s and Parkinson’s. 

The tool enables the investigation of thousands of DNA mutations identified by genetic studies in one experiment, and will help to guide the development of advanced diagnostics and treatments.

scSNV-seq allows the rapid assessment of the impact of thousands of genetic changes in cells that have never been screened before, directly connecting these changes to how those same cells operate. 

This technique helps researchers to pinpoint mutations that contribute to disease, which will offer crucial insights for developing targeted therapies.

In a new study, published in Genome Biology, the team applied scSNV-seq to the blood cancer gene, JAK1, accurately assessing the impact of JAK1 mutations.

The assessment revealed for the first time that certain mutations caused a “halfway house” phenotype cycling between different states which was not possible under previous approaches.

The technique is designed to demonstrate versatility across cell types, including hard-to-culture primary cells like T cells and stem-cell derived neurons, as well as various editing methods such as base editing and prime editing. 

Applied on a large scale, scSNV-seq could transform understanding of the genetic changes driving cancer and decoding genetic risk for Alzheimer’s, arthritis, diabetes and other complex diseases.

Dr Sarah Cooper, first author of the study at the Wellcome Sanger Institute, stated: “In an era where the rate of genetic variant discovery outpaces our ability to interpret their effects, scSNV-seq fills a major gap for studying challenging cells like T cells and neurons. 

“We are already using it to shed light on the impact of Alzheimer’s and Parkinson’s risk variants on brain cells.”

Dr Andrew Bassett, senior author of the study at the Wellcome Sanger Institute, said: “Our technique is able to directly connect effects of mutations to how a cell behaves, revealing downstream impacts that previous technologies alone cannot deliver. 

“The technique speeds up the identification of causal genetic mutations, which will allow better diagnosis and deepens our molecular understanding of diseases, paving the way for more targeted and effective treatments.”

Continue Reading

Trending