Day: July 21, 2022

Categories : New Compounds and TreatmentsTags :

A Novel Anticoagulant That can be ‘Deactivated’

On By ModernMedia
Source: NCI

A new biomolecular anticoagulant platform reported in Nano Letters holds promise as a revolutionary advancement over the anticoagulants currently used during surgeries and other procedures. The technology is based around injectable fibre structures which can be quickly dissolved and excreted by the kidneys.

“We envision the uses of our new anticoagulant platform would be during coronary artery bypass surgeries, kidney dialysis, and a variety of vascular, surgical and coronary interventions,” said Kirill Afonin, leader of the team which invented the technology. “We are now investigating if there are potential future applications with cancer treatments to prevent metastasis and also in addressing the needs of malaria, which can cause coagulation issues.”

The team’s technology turns to programmable RNA-DNA anticoagulant fibres that, when injected into the bloodstream, form into modular structures that communicate with thrombin. The technology allows the structures to prevent blood clotting as it is needed and then be quickly eliminated via the renal system once their job is done.

The fibre structures use aptamers, short sequences of DNA or RNA designed to specifically bind and inactivate thrombin.

“Instead of having a single small molecule that deactivates thrombin,” Afonin said, “we now have a relatively large structure that has hundreds of the aptamers on its surface that can bind to thrombin and deactivate them. And because the structure becomes larger, it will circulate in the bloodstream for a significantly longer time than traditional options.”

The extended circulation in the bloodstream allows for a single injection, instead of multiple doses. The design also decreases the concentration of anticoagulants in the blood, resulting in less stress on the body’s renal and other systems, Afonin said.

This technology also introduces a novel “kill-switch” mechanism, which reverses the fibre structure’s anticoagulant function with a second injection. This lets makes the fibres able to be metabolised into materials that are tiny, harmless, inactive and easily excreted by the renal system.

The entire process takes place outside the cell, through extracellular communication with the thrombin. The researchers note that this is important as immunological reactions do not appear to occur, based on their extensive studies.

The team has tested and validated the platform in computer models, human blood and various animal models. “We conducted proof-of-concept studies using freshly collected human blood from donors in the US and in Brazil to address a potential inter donor variability,” Afonin said.

The technology may provide a foundation for other biomedical applications that require communication via the extracellular environment in patients, he said. “Thrombin is just one potential application,” he said. “Whatever you want to deactivate extracellularly, without entering the cells, we believe you can. That potentially means that any blood protein, any cell surface receptors, maybe antibodies and toxins, are possible.”

The technique permits the design of structures of any shape desired, with the kill switch mechanism intact. “By changing the shape, we can have them go into different parts of the body, so we can change the distribution,” Afonin said. “It gets an extra layer of sophistication of what it can do.”

While the application is sophisticated, production of the structures is relatively easy. “The shelf life is amazingly good for these formulations,” Afonin said. “They’re very stable, so you can dry them, and we anticipate they will stay for years at ambient temperatures, which makes them very accessible to economically challenged areas of the world.”

Source: University of North Carolina

Categories : Cardiovascular DiseaseTags :

Blood Vascular Network Retains the ‘Memory’ of a Stroke

On By ModernMedia
Credit: American Heart Association

A study into the structure of blood vascular network structure found that it is dynamic and can adapt to external factors, resulting in a kind of memory of certain events such as an ischaemic stroke. In particular, the study researchers found that rarely used connections incrementally weaken until they disappear eventually.

Researchers from the Max Planck Institute for Dynamics and Self-Organization in Göttingen and the Technical University of Munich used computer simulations to model vascular networks and identified adaptation rules for their connections.

“We found that the strength of a connection within a network depends on the local flow,” explained Karen Alim, corresponding author of the study. “This means that links with a low flow below a certain threshold will decay more and more until they eventually vanish,” she continued. Since the limited amount of material available to build the vascular system needs to be efficiently used, this mechanism offers an elegant way to streamline the vascular system.

Persistent changes in the network

Once a connection has become very weak due to a low flow rate, recovering that connection is very difficult. For example, a blood vessel blockage of the type that could lead to an ischaemic stroke. During an ischaemic stroke, some blood vessels in the affected region are weakened by the blockage.

“We found that in such a case, adaptations in the network are permanent and are maintained after the obstacle is removed. One can say that the network prefers to reroute the flow through existing stronger connections instead of re-growing weaker connections – even if the flow would require the opposite,” explained Komal Bhattacharyya, principal author of the study.

The researchers have thus shown that blood flow permanently changes even after successful removal of the clot. This memory capability of networks can also be found in other living systems: for example, the slime mould Physarum polycephalum uses its adaptive network to navigate its environment based on imprints by food stimuli, as demonstrated previously.

The study was published in Physical Review Letters.

Source: Max Planck Institute for Dynamics and Self-Organization

Categories : New Compounds and Treatments Pain ManagementTags :

A Potent New Non-opioid Analgesic

On By ModernMedia
Woman using lab equipment
Source: NCI on Unsplash

Researchers co-led by University of Warwick have discovered a potent new non-opioid analgesic with potentially fewer side effects compared to other potent painkillers.

Their study found that a compound called BnOCPA (benzyloxy-cyclopentyladenosine), is a potent and selective analgesic which is non-addictive. BnOCPA also has a unique mode of action and potentially opens a new pipeline for the development of new analgesic drugs.

The research is published in Nature Communications.

Chronic pain has a negative impact on quality of life and many commonly prescribed analgesics come with side effects. Opioid drugs, such as morphine and oxycodone, can lead to addiction and are dangerous in overdose.

Drugs that act on G protein-coupled receptors (GPCRs) are one possibility, but their development is hampered by the propensity of GPCRs to couple to multiple intracellular signalling pathways. A unique feature of BnOCPA is that it only activates one type of GPCR, leading to very selective effects and thus reducing potential side effects.

University of Warwick’s Dr Mark Wall, who led the research said: “The selectivity and potency of BnOCPA make it truly unique and we hope that with further research it will be possible to generate potent painkillers to help patients cope with chronic pain.”

Source: University of Warwick

Categories : HospitalsTags :

Study Shows that Not Everyone can Adjust to Shift Work

On By ModernMedia
Photo by SJ Objio on Unsplash

A new study of French hospital workers have challenged the widely held belief that shift workers adjust to the night shift over time, using data drawn from wearable sensors.

By monitoring groups of the hospital workers working day or night shifts during their working and free time, the researchers have shown that not only does night work significantly disrupt both sleep quality and circadian rhythms, also that workers can experience such disruption even after years of night shift work.

Their findings, reported in eBioMedicine, are the most detailed analysis of the sleep and circadian rhythm profiles of shift workers yet attempted, and the first to also monitor body temperature. This key circadian rhythm is driven by the brain pacemaker clock, and coordinates the peripheral clocks in all organs.

In addition, the research demonstrates the value of telemonitoring technology for identifying early warning signs of disease risks associated with night-shift work opening up intervention opportunities to improve the health of workers.

The study compared 63 night-shift workers, working three or more nights of 10 hours each per week, and 77 day-shifters alternating morning and afternoon shifts at a single university hospital near Paris. Both groups wore accelerometers with chest surface temperature sensors throughout the day and night for a full week.

The accelerometer measured movement intensity and served as an estimate for participants’ sleep duration, how regular were their circadian rhythms, and whether that sleep was disrupted by movement. Patterns in the chest surface temperature gave a further indication of the participants’ circadian rhythm, which coordinates rest-activity phases, varying core body temperature, and an array of other bodily rhythms.

Analysis of interruptions to sleep and rhythmic variations in core body temperature showed that night-shift workers had less than half the median regularity and quality of sleep of their day-shift colleagues. 48% of the night-shift workers had a disrupted circadian temperature rhythm.

Using information from questionnaires on the participants’ chronotypes, they also found that the centre of sleep for those working the night shift didn’t correlate with their respective chronotype, ie their morningness or eveningness orientation. This meant they were not sleeping in synch with their internal clocks.

Even workers with years of being on night shifts still showed these negative effects on circadian and sleep health. The more years of night work they had, the more severe the circadian disruption – contradicting widely held assumptions about night work adaptation.

This helps explain why previous studies have shown an association between disrupted circadian rhythms with long term health risks, such as cancer and cardiovascular disease.

Professor Bärbel Finkenstädt from the University of Warwick Department of Statistics said: “There’s still an assumption that if you do night work, you adjust at some stage. But you don’t. We saw that most workers compensate in terms of quantity of sleep, but not in terms of quality during the work time.”

Dr Julia Brettschneider of the University of Warwick Department of Statistics said: “I think there’s a misunderstanding that night shift work is just an inconvenience, whereas it can be linked to serious health risks. We can’t avoid shift work for many professions, like healthcare workers, so we should be thinking about what can be done in terms of real-world adjustments to improve working conditions and schedules of shift workers. A better understanding of the biological mechanisms helps to find answers to this question.

“Together with our PhD student Yiyuan Zhang, we have developed a statistical analysis framework that enables the discovery of patterns and predictive factors in the complex data sets created by wearable tech.”

Professor Francis Lévi from Université Paris-Saclay further added: “Nearly 20% of the night workers could not even adjust their circadian rhythms during their free time, with the severity of impairment tending to increase with the number of years of night work. The telemonitoring technology, and analysis methods we have set up make it now possible to objectively evaluate circadian and sleep health in night workers in near real time, and design prevention measures for individual workers whenever necessary.”

In future research, the team may look at more long-term outcomes, such as diseases such as cancer that have been linked to circadian disruption.

Source: University of Warwick

Categories : Diseases, Syndromes and Conditions GeneticsTags :

Once-off Gene Therapy Reduces Haemophilia B Bleeding in Patients

On By ModernMedia
https://www.pexels.com/photo/a-close-up-shot-of-bags-of-blood-4531306/
Photo by Charlie-Helen Robinson on Pexels

A single gene therapy injection could dramatically reduce the bleeding risk faced by people with haemophilia B, according to the results of a Phase I/II clinical trial published in the New England Journal of Medicine.

Low levels of the factor IX (FIX) protein, needed for clot formation, are behind haemophilia B. The FIX protein gene is on the X chromosome, so the severe form of haemophilia B is much more common in men, though it can occur in women due to X chromosome inactivation.

To prevent excessive bleeding, patients with haemophilia B typically need regular replacement therapy consisting of weekly injections of recombinant FIX. Despite advances in treatment, patients may continue to see debilitating joint damage.

The new treatment, from University College London, Royal Free Hospital and biotechnology company Freeline Therapeutics, is a type of adeno-associated virus (AAV) gene therapy candidate, called FLT180a, is being developed to treat severe and moderately severe cases of haemophilia B.

The Phase I/II multi-centre clinical trial, called B-AMAZE, and the related long-term follow up study found that a single treatment with FLT180a led to sustained production of FIX protein from the liver in 9 of 10 patients, across four different dose levels, removing the need for regular replacement therapy.

Out of 17 male patients aged 18 or over who underwent screening, 10 with severe or moderately severe haemophilia B took part in the 26-week trial of FLT180a, will be followed-up to assess safety and durability of FIX expression for 15 years.

Lead author Professor Pratima Chowdary of the Royal Free Hospital said: “Removing the need for haemophilia patients to regularly inject themselves with the missing protein is an important step in improving their quality of life. The long term follow up study will monitor the patients for durability of expression and surveillance for late effects.”

One patient, Elliott Mason, told the BBC: “I’ve not had any treatment since I had my therapy, it’s all a miracle really, well it’s science, but it feels quite miraculous to me.

“My life is completely normal, there’s nothing that I have to stop and think ‘how might my haemophilia affect this?’.”

AAV gene therapy works uses a packaging from the proteins found in the outer coat of the virus to deliver a functional copy of a gene directly to patient tissues. Newly synthesised proteins are released into the blood and a one-time infusion can have long-term effects.

Over several weeks to several months, patients took immunosuppressive drugs to prevent their immune systems from rejecting the therapy, and all reported known side effects.

Though the therapy was well tolerated, patients all experienced adverse events, with an abnormal blood clot in one who received the highest FLT180a dose and had the highest levels of FIX protein.

Professor Amit Nathwani, who co-authored the study, said: “Gene therapy is still a young field that pushes the boundaries of science for people with severe genetic diseases.

“The B-AMAZE long-term data add to the growing body of evidence that gene therapy has the potential to free patients from the challenges of having to adhere to lifelong therapy or could provide treatment where none exists today.”

In nine out of the ten patients, the treatment led to a sustained increase in FIX protein production, which led to a decrease in excessive bleeding. They also no longer required weekly injections of FIX protein.

After 26 weeks, five patients had normal levels of FIX protein, three had low but increased levels, and one patient treated at the highest dose had an abnormally high level.

Pamela Foulds, MD, Chief Medical Officer of Freeline, said: “The B-AMAZE long-term data continue to support our confidence that a single dose of FLT180a could protect people with haemophilia B from bleeding and the need for lifelong FIX replacement through durable expression of FIX at protective levels.”

Source: EurekAlert!