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Scientists taste sweet success with ageing bone regeneration



Scientists have unwrapped what could be a sweet fix for ageing bones.

A team from Dresden in Germany have designed novel bio-inspired molecules based on long-chained sugars to boost bone regeneration in mice.

Now the multi-disciplinary team is applying for funding for a pre-clinical study to further develop their work as they look to transfer the technology from the small rodents to humans.

By 2050 nearly one in five people in developing countries are expected to be aged over 60, as a result of  lower birth rates and increased life expectancy thanks to better healthcare and scientific advances in treating chronic illnesses.

But as people age their ability to regenerate bones decreases. Fractures take longer to heal and diseases like osteoporosis only add to the problem. This doesn’t just pose a serious health challenge to an ageing population, but also puts a massive economic strain on society.

To help tackle this issue, researchers are looking for new therapeutic approaches that can improve bone regeneration.

The new molecules unearthed by the Dresden team are based on glycosaminoglycans, which are long-chained sugars such as hyaluronic acid or heparin, and can be incorporated into biomaterials and applied locally to bone defects.

Bone expert Professor Lorenz Hofbauer at the Medical Faculty of TU Dresden, explained:  “Thanks to our group’s work and the work of other researchers, we know a distinct molecular pathway that regulates bone formation and repair. In fact, we can narrow it down to two proteins that work together to block bone regeneration – sclerostin and dickkopf-1.

“The big challenge for developing drugs that improve bone healing is to efficiently turn off both of these proteins, which act as brake signals, at the same time.”

(L-r) Prof Maria Teresa Pisabarro, Dr Gloria Ruiz Gómez, Dr Juliane Salbach-Hirsch and prof Lorenz Hofbauer

An interdisciplinary approach was a key to this challenge.

The Structural Bioinformatics group led by Professor Maria Teresa Pisabarro at the Biotechnology Center (BIOTEC) and the Functional Biomaterials group headed by Dr Vera Hintze at the Max Bergmann Center of Biomaterials (MBC), Institute of Materials Science, both of TU Dresden, combined their know-how with Professor Hofbauer.

“For several years, we have harnessed the power of computer simulations to investigate how proteins regulating bone formation interact with their receptors. All this to design new molecules that can efficiently interfere with these interactions,” Professor Pisabarro said.

“We worked in tandem between the computer and the bench, designing new molecules and testing them, feeding the results back to our molecular models and learning more about the molecular properties required for our goal.”

Finally, the team of Professor Hofbauer’s Bone Lab used a biomaterial loaded with the new molecules on bone defects in mice to test their effectiveness.

The results are reported in the international Biomaterials journal.

The group found that materials containing the novel molecules outperformed the standard biomaterial and enhanced bone healing by up to 50%, which indicates their potential for improving bone regeneration.

The multidisciplinary team used rational drug design to create novel molecules with tailored properties and minimal side effects.

By using computational methods to predict and refine the properties of the designed molecules, the team was able to develop a series of candidates with the greatest potential for turning off the proteins that block bone regeneration.

The expertise of Professor Pisabarro’s group allowed the thorough analysis of the three-dimensional structures of the two proteins that block bone regeneration.

With that, they were able to model their interaction with their receptors in 3D and identify so-called hot spots – specific physicochemical and dynamic properties that are essential for the biological interaction to occur.

Professor Pisabarro said: “We used molecular modelling to design new structures that mimic relevant receptor interactions with both proteins. We wanted this binding to be stronger than their natural interactions.

“In this way, our novel molecules would simultaneously hijack the proteins and effectively turn them off to turn the bone regeneration on.”

Dr Hintze added: “The molecules designed by Professor Pisabarro’s group were synthesized by our colleagues at the Free University of Berlin and then analyzed regarding their protein binding properties via biophysical interaction analysis.

“For each of the molecules we were able to measure the binding strength with the proteins and their interference with natural receptor binding of the proteins.

“Thus, we could reveal empirically how effective each of the small molecules could be at turning off the inhibitory proteins.”

Professor Hofbauer’s group then tested the biological relevance of these interaction studies in a cell culture model, and later in mice.

The results of repetitive testing are a valuable asset that enhances the current molecular models of the Pisabarro group and can be used to guide the development of novel and better molecules in the future.

Such an approach also ensures that animal research is minimized and enters the project only in its final phase.

The newly designed molecules could potentially be used to turn off the proteins that block bone regeneration and lead to the development of novel, more effective treatments for bone fractures and other bone-related conditions.


Europe: Improving access to early-stage lung cancer care



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.

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Study looks at link between adversity and cognitive decline



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.”

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New tool to explore mechanisms of age-related diseases



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.”

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