Connect with us

News

Personalisation may improve prostate cancer screening accuracy

Published

on

Scientists have moved a step closer to genetically personalised prostate cancer screening.

The most common assessment test for the cancer, which mainly affects men over the age of 50, is prostate-specific antigen (PSA) screening which often erroneously indicates signs of the disease.

But a joint team at UC San Francisco and Stanford University, both in the US, have come up with a method they believe will make screening more accurate by calibrating PSA levels to each man’s genetics.

They say applying this type of personalisation could significantly reduce overdiagnosis and better predict aggressive disease. In addition to the regular blood-based PSA test, such customised screening would need a germline genetic test, usually conducted on blood, saliva, or cheek swab samples, to look for inherited genetic variants that affect PSA levels.

Whilst raised PSA levels can be a sign of a cancerous prostate tumour, they can also be caused by other circumstances, like infection, an enlarged prostate, inflammation or simply old age.

In a study published in Nature Medicine, UCSF researchers and their collaborators conducted a large genome-wide association study of PSA in more than 95,000 men without diagnosed prostate cancer. This identified more than 80 novel PSA- associated variants.

They set out to discover whether accounting for genetic factors that cause variations in the levels of PSA that are not attributable to cancer could help improve PSA screening.

Senior author of the study, John Witte, a professor of epidemiology and population health and of biomedical data sciences at Stanford, said: “Some men have higher PSA levels due to their genetics. They don’t have cancer, but the higher PSA level leads to a cascade of unnecessary medical interventions like biopsy.”

Linda Kachuri, a former postdoctoral scholar in the Department of Epidemiology and Biostatistics at UCSF and lead author of the study, added: “PSA levels represent the main diagnostic biomarker for prostate cancer. This test is widely used but not currently implemented as part of a formal screening programme.

“Because of its poor sensitivity and specificity, PSA testing can often lead to detecting latent disease or, in some cases, missing aggressive tumours.”

The researchers identified 128 sites in the genome that can affect a person’s inherent PSA level. They developed a way to calculate PSA that accounts for an individual’s normal genetic variations at these sites – known as a PSA polygenic score, which is a quantitative way of measuring someone’s genetic predisposition for a trait in a single value. In this case, the trait is a higher baseline PSA level.

The researchers leveraged the new data to build a genome-wide polygenic score for PSA.

The polygenic score captured each individual’s genetic predisposition to high PSA levels. The team found the polygenic score was strongly associated with PSA levels in validation cohorts and was not associated with prostate cancer. This confirmed that it reflects benign PSA variation.

To examine whether the polygenic score could improve the detection of clinically significant disease and reduce overdiagnosis, each person’s PSA values were adjusted based on their unique genetic profile.

Dr Kachuri said: “PSA values personalised in this way are more likely to reveal changes in PSA due to prostate cancer because they are corrected for the influence of inherited genetics.”

Applying a correction to PSA levels improved the accuracy of biopsy referral decisions. Roughly 30% of men could have avoided biopsy, though adjusted PSA levels would have missed approximately 9% of positive cell samples.

Most of the latter cancers were low-grade disease that did not require treatment, but the researchers admit the misclassifications point to room for improving the polygenic score.

Dr Kachuri said: “We showed that genetic correction of PSA levels has the potential to both reduce unnecessary biopsies and improve our ability to detect tumours with a more aggressive profile. We hope that our findings represent a step forward in developing informative screening guidelines and reducing the diagnostic grey area in PSA screening.”

While the study was very large, almost 90% of the participants were of predominantly European ancestry.

According to Dr Kachuri, this represents a key limitation because the composition of the study doesn’t fully reflect the patient population impacted by prostate cancer.

The team is now working on a larger study in association with the Million Veteran Program, a US-based national research project launched in 2011 looking at how genes, lifestyle, military experience, and exposures affect health and wellness in former members of the armed forces. More than 950,000 veterans have now joined the MVP.

Nearly 1.5 million new prostate cancer cases are diagnosed each year globally and it is the fifth leading cause of cancer death among men. In the US, one in nine men will be diagnosed with prostate cancer, and one in 40 will die from it.

With a disease as prevalent as prostate cancer the researchers believe even a small improvement in screening could save lives.

Dr Kachuri concluded: “We hope to be able to share findings soon from our efforts to conduct larger and more diverse studies of PSA genetics.”

 

News

Gut microbes from aged mice induce inflammation in young mice

Published

on

Findings from a new study suggest that changes to the gut microbiome play a role in the systemwide inflammation that often occurs with ageing.

When scientists transplanted the gut microbes of aged mice into young “germ-free” mice — raised to have no gut microbes of their own — the recipient mice experienced an increase in inflammation that parallels inflammatory processes associated with ageing in humans. Young germ-free mice transplanted with microbes from other young mice had no such increase.

Published in Aging Cell, the study also found that antibiotics caused longer-lasting disruptions in the gut microbiomes of aged mice than in young mice.

“There’s been a growing consensus that ageing is associated with a progressive increase in chronic low-grade inflammation,” said Jacob Allen, a professor of kinesiology and community health at the University of Illinois Urbana-Champaign who led the new research with Thomas Buford, a professor of medicine at the University of Alabama at Birmingham.

“And there’s a kind of debate as to what drives this, what is the major cause of the ageing-induced inflammatory state. We wanted to understand if the functional capacity of the microbiome was changing in a way that might contribute to some of the inflammation that we see with ageing.”

Previous studies have found associations between age-related changes in the microbial composition of the gut and chronic inflammatory diseases such as Parkinson’s disease and Alzheimer’s disease. Some studies have linked microbial metabolism to an individual’s susceptibility to other health conditions, including obesity, irritable bowel syndrome and heart disease. Age-related changes in the gut microbiome also may contribute to the so-called leaky gut problem, the researchers said.

“Microbiome patterns in aged mice are strongly associated with signs of bacterial-induced barrier disruption and immune infiltration,” they wrote.

“The things that are in our gut are supposed to be kept separate from the rest of our system,” Buford said. “If they leak out, our immune system is going to recognize them. And so then the question was: ‘Is that a source of inflammation?’”

Many studies have compared the relative abundance and diversity of species of microbes in the gut, offering insight into some of the major groups that contribute to health or disease. But sequencing even a portion of the microbes in the gut is expensive and the results can be difficult to interpret, Allen said. That is why he and his colleagues focused on microbial function — specifically, how the gut microbiomes of ageing mice might spur an immune response.

The team focused on toll-like receptors, molecules that mediate inflammatory processes throughout the body. TLRs sit in cellular membranes and sample the extracellular environment for signs of tissue damage or infection. If a TLR encounters a molecule associated with a potential pathogen — for example, a lipopolysaccharide component of a gram-negative bacterium — it activates an innate immune response, calling in pro-inflammatory agents and other molecules to fight the infection.

The researchers first evaluated whether the colonic contents of young and aged mice were likely to promote TLR signalling. They found that microbes from aged mice were more likely than those from young mice to activate TLR4, which can sense lipopolysaccharide components of bacterial cell walls. A different receptor, TLR5, was not affected differently in aged or young mice. TLR5 senses a different bacterial component, known as flagellin.

Young germ-free mice transplanted with the microbes of aged mice also experienced higher inflammatory signalling and increased levels of lipopolysaccharides in the blood after the transplants, the team found.

This finding provides “a direct link between ageing-induced shifts in microbiota immunogenicity and host inflammation,” the researchers wrote.

In other experiments, the team treated mice with broad-spectrum antibiotics and tracked changes in the microbiomes during treatment and for seven days afterward.

“One of the most interesting questions for me was what microbes come back immediately after the treatment with antibiotics ends,” Buford said. And in the mice with aged microbiota in their guts, “these opportunistic pathogens were the most quick to come back.”

“It appears that as we age our microbiome might be less resilient to antibiotic challenges,” Allen said. “This is important because we know that in the U.S. and other Western societies, we’re increasingly exposed to more antibiotics as we age.”

The study is an important step toward understanding how age-related microbial changes in the gut may affect long-term health and inflammation, the researchers said.

Co-authors of the study also included Illinois postdoctoral researcher Elisa Caetano-Silva; U. of I. Ph.D. student Akriti Shrestha; National Children’s Hospital research scientist Michael Bailey; and Jeffrey Woods, the director of the Center on Health, Aging and Disability at Illinois.

Allen also is a professor of nutritional sciences at Illinois and an affiliate of the Carl R. Woese Institute for Genomic Biology at the U. of I.

Continue Reading

News

Evening exercise benefits elderly hypertensives

Published

on

Evening exercise benefits elderly hypertensives

A study conducted at the University of São Paulo with 23 volunteers found that aerobic exercise performed in the evening benefits elderly hypertensives more than morning exercise.

Aerobic training is known to regulate blood pressure more effectively when practiced in the evening than in the morning.

Researchers who conducted a study of elderly patients at the University of São Paulo’s School of Physical Education and Sports (EEFE-USP) in Brazil concluded that evening exercise is better for blood pressure regulation thanks to improved cardiovascular control by the autonomic nervous system via a mechanism known as baroreflex sensitivity.

Leandro Campos de Brito, first author of the article, commented: “There are multiple mechanisms to regulate blood pressure, and although morning training was beneficial, only evening training improved short-term control of blood pressure by enhancing baroreflex sensitivity.

“This is important because baroreflex control has a positive effect on blood pressure regulation, and there aren’t any medications to modulate the mechanism.”

In the study, 23 elderly patients diagnosed and treated for hypertension were randomly allocated into two groups: morning training and evening training. Both groups trained for ten weeks on a stationary bicycle at moderate intensity, with three 45-minute sessions per week.

Key cardiovascular parameters were analysed, such as systolic and diastolic blood pressure, and heart rate after ten minutes’ rest. The data was collected before and at least three days after the volunteers completed the ten weeks of training.

The researchers also monitored mechanisms pertaining to the autonomic nervous system, which controls breathing, heart rate, blood pressure, digestion, and other involuntary bodily functions, such as muscle sympathetic nerve activity, which regulates peripheral blood flow via contraction and relaxation of blood vessels in muscle tissue, and sympathetic baroreflex sensitivity, assessing control of blood pressure via alterations to muscle sympathetic nerve activity.

In the evening training group, all four parameters analysed were found to improve: systolic and diastolic blood pressure, sympathetic baroreflex sensitivity, and muscle sympathetic nerve activity. In the morning training group, no improvements were detected in muscle sympathetic nerve activity, systolic blood pressure or sympathetic baroreflex sensitivity.

“Evening training was more effective in terms of improving cardiovascular autonomic regulation and lowering blood pressure. This can be partly explained as due to an improvement in baroreflex sensitivity and a reduction of muscle sympathetic nerve activity, which increased in the evening. For now, all we know is that baroreflex control is the decisive factor, from the cardiovascular standpoint at least, to make evening training more beneficial than morning training, since it induces the other benefits analysed. However, much remains to be done in this regard in order to obtain a better understanding of the mechanisms involved,” said Brito, who is currently a professor at Oregon Health & Science University’s Oregon Institute of Occupational Health Sciences in the United States, and continues to investigate the topic via circadian rhythm studies.

Baroreflex sensitivity regulates each heartbeat interval and controls autonomic activity throughout the organism.

“It’s a mechanism that involves sensitive fibres and deformations in the walls of arteries in specific places, such as the aortic arch and carotid body. When blood pressure falls, this region warns the brain region that controls the autonomic nervous system, which in turn signals the heart to beat faster and tells the arteries to contract more strongly. If blood pressure rises, it warns the heart to beat more slowly and tells the arteries to contract less. In other words, it modulates arterial pressure beat by beat,” Brito explained.

In previous studies, the EEFE-USP research group showed that evening aerobic training reduced blood pressure more effectively than morning training in hypertensive men (read more at: agencia.fapesp.br/34194), and that the more effective response to evening training in terms of blood pressure control was accompanied by a greater reduction in systemic vascular resistance and systolic pressure variability (read more at: agencia.fapesp.br/37432).

“Replication of the results obtained in previous studies and in different groups of hypertensive patients, associated with the use of more precise techniques to evaluate the main outcomes, has strengthened our conclusion that aerobic exercise performed in the evening is more beneficial to the autonomic nervous system in patients with hypertension. This can be especially important for those with resistance to treatment with medication,” Brito said.

Continue Reading

News

Revolutionising cancer treatment: intracellular protein delivery using hybrid nanotubes

Published

on

Revolutionising cancer treatment: intracellular protein delivery using hybrid nanotubes

A new hybrid nanotube stamp system has been developed which revolutionises precision medicine with high efficiency and cell viability rates for cancer treatment.

Precision medicine and targeted therapies are gaining traction for their ability to tailor treatments to individual patients while minimising adverse effects. Conventional methods, such as gene transfer techniques, show promise in delivering therapeutic genes directly to cells to address various diseases.

However, these methods face significant drawbacks, hindering their efficacy and safety. Intracellular protein delivery offers a promising approach for developing safer, more targeted, and effective therapies. By directly transferring proteins into target cells, this method circumvents issues such as silencing during transcription and translation and the risk of undesirable mutations from DNA insertion. Additionally, intracellular protein delivery allows for precise distribution of therapeutic proteins within target cells without causing toxicity.

A group of researchers led by Professor Takeo Miyake at Waseda University, Japan in collaboration with the Mikawa Group at the RIKEN Institute have now developed a hybrid nanotube stamp system for intracellular delivery of proteins. This innovative technique enables the simultaneous delivery of diverse cargoes, including calcein dye, lactate oxidase (LOx) enzyme, and ubiquitin (UQ) protein, directly into adhesive cells for cancer treatment.

The researchers explored the therapeutic potential of delivering LOx enzyme for cancer treatment. “Through our innovative stamp system, we successfully delivered LOx into both healthy mesenchymal stem cells (MSC) and cancerous HeLa cells. While MSC cells remained unaffected, we observed significant cell death in HeLa cancer cells following LOx treatment with viabilities decreasing over time. Our findings highlight the promising efficacy of intracellularly delivered LOx in selectively targeting and killing cancer cells, while sparing healthy cells, offering a targeted therapeutic strategy for cancer treatment,” explains Miyake.

Finally, the team successfully delivered 15N isotope-labeled UQ proteins into HeLa cells using the HyNT stamp system. This delivery allowed for the analysis of complex protein structures and interactions within the cells. In addition, optical and fluorescence imaging confirmed the presence of delivered UQ in HeLa cells, and nuclear magnetic resonance spectroscopy matched the intracellular UQ protein concentration with that of a solution containing 15N-labeled UQ. These results demonstrate the effectiveness of the stamp system in delivering target proteins for subsequent analysis.

The results demonstrate the remarkable capability of the HyNT stamp system in delivering LOx and UQ into a substantial number of adhesive cells, as required for regenerative medicine applications. The system achieved a notably high delivery efficiency of 89.9%, indicating its effectiveness in transporting therapeutic proteins into the target cells with precision. Moreover, the cell viability rate of 97.1% highlights the system’s ability to maintain the health and integrity of the treated cells throughout the delivery process.

The HyNT stamp system offers transformative potential in intracellular protein delivery, with applications spanning from cancer treatment to molecular analysis. Beyond medicine, its versatility extends to agriculture and food industries, promising advancements in crop production and food product development. With precise cell manipulation and efficient delivery, the HyNT stamp system is poised to revolutionize biomedical research, clinical practice, and diverse industries, paving the way for personalized interventions and shaping the future of modern medicine.

Continue Reading

Trending