̽��ֱ�� of Cambridge - Victor Phillip Dahdaleh Heart and Lung Research Institute

Routine asthma test more reliable in the morning and has seasonal effects

cjb250 — Wed, 12 Mar 2025 00:01:06 +0000

Using real world data from 1,600 patients, available through a database created for speeding up research and innovation, the team also found that its reliability differs significantly in winter compared to autumn.

Asthma is a common lung condition that can cause wheezing and shortness of breath, occasionally severe. Around 6.5% of people over six years old in the UK are affected by the condition. Treatments include the use of inhalers or nebulisers to carry medication into the lungs.

̽��ֱ��majority of asthma attacks occur at nighttime or early in the morning. Although this may in part be due to cooler nighttime air and exposure to dust mites and allergens, it also suggests that circadian rhythms – our ‘body clocks’ – likely play a role.

Researchers at the Victor Phillip Dahdaleh Heart and Lung Research Institute, a collaboration between the ̽��ֱ�� of Cambridge and Royal Papworth Hospital NHS Foundation Trust (RPH), wanted to explore whether these circadian rhythms may also have an impact on our ability to diagnose asthma, using routinely performed clinical testing.

Typically, people with suspected asthma will be offered a spirometry test, which involves taking a deep breath in, then breathing out hard and fast for as long as possible into a tube to assess lung function. They will then be administered the drug salbutamol via an inhaler or nebuliser, and shortly afterwards retake the spirometry test.

Salbutamol works by opening up the airways, so a positive test result – that is, a difference in readings between the initial and follow-up spirometry tests – means that the airways must have been narrower or obstructed to begin with, suggesting that the patient could have asthma.

Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust (CUH) has recently set up the Electronic Patient Record Research and Innovation (ERIN) database so that researchers can access patient data in a secure environment to help in their research and speed up improvements in patient care.

Using this resource, the Cambridge team analysed data from 1,600 patients referred to CUH between 2016 and 2023, adjusted for factors such as age, sex, body mass index (BMI), smoking history, and the severity of the initial impairment in lung function.

In findings published today in Thorax, the researchers found that starting at 8.30am, with every hour that passed during the working day, the chances of a positive response to the test – in other words, the patient’s lungs responding to treatment, suggesting that they could have asthma – decreased by 8%.

Dr Ben Knox-Brown, Lead Research Respiratory Physiologist at RPH, said: “Given what we know about how the risk of an asthma attack changes between night and day, we expected to find a difference in how people responded to the lung function test, but even so, we were surprised by the size of the effect.

“This has potentially important implications. Doing the test in the morning would give a more reliable representation of a patient's response to the medication than doing it in the afternoon, which is important when confirming a diagnosis such as asthma.”

̽��ֱ��researchers also discovered that individuals were 33% less likely to have a positive result if tested during autumn when compared to those tested during winter.

Dr Akhilesh Jha, a Medical Research Council Clinician Scientist at the ̽��ֱ�� of Cambridge and Honorary Consultant in Respiratory Medicine at CUH, said that there may be a combination of factors behind this difference.

“Our bodies have natural rhythms – our body clocks,” Jha said. “Throughout the day, the levels of different hormones in our bodies go up and down and our immune systems perform differently, for example. Any of these factors might affect how people respond to the lung function test.

“ ̽��ֱ��idea that the time of day, or the season of the year, affects our health and how we respond to treatments is something we’re seeing increasing evidence of. We know, for example, that people respond differently to vaccinations depending on whether they’re administered in the morning or afternoon. ̽��ֱ��findings of our study further support this idea and may need to be taken into account when interpreting the results of these commonly performed tests.”

Reference
Knox-Brown, B et al. ̽��ֱ��effect of time of day and seasonal variation on bronchodilator responsiveness: ̽��ֱ��SPIRO-TIMETRY study. Thorax; 12 March 2025; DOI: 10.1136/thorax-2024-222773

A lung function test used to help diagnose asthma works better in the morning, becoming less reliable throughout the day, Cambridge researchers have found.

Throughout the day, the levels of different hormones in our bodies go up and down and our immune systems perform differently. Any of these factors might affect how people respond to the lung function test

Akhilesh Jha

Koldunov (Getty Images)

Man testing breathing function by spirometry - stock photo

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

̽��ֱ��medic making a difference to the care of trans patients

cjb250 — Mon, 03 Feb 2025 08:00:21 +0000

Medical students are taught about some of the rarest diseases, yet do not learn something as important as how to care for trans patients. This needs to change, says intensive care specialist Luke Flower.

High cholesterol levels at a young age significant risk factor for atherosclerosis

cjb250 — Wed, 04 Sep 2024 15:00:18 +0000

̽��ֱ��research also suggests that people who are taking lipid-lowering drugs such as statins to lower their cholesterol levels should remain on them, even if their cholesterol levels have fallen, as stopping treatment could increase their risk of atherosclerosis.

Atherosclerosis is one of the major causes of heart and circulatory disease. It involves the hardening and narrowing of the vessels that carry blood to and from the heart. It is caused by the build-up of abnormal material called plaques – collections of fat, cholesterol, calcium and other substances circulating in the blood.

Atherosclerosis is largely considered a disease of the elderly and so most screening, prevention and intervention programmes primarily target those with high cholesterol levels, generally after the age of 50.

But in a study published today in Nature, a team led by scientists at the ̽��ֱ�� of Cambridge shows that high cholesterol levels at a younger age – particularly if those levels fluctuate – can be even more damaging than high cholesterol levels that only begin in later life.

To study the mechanisms that underlie atherosclerosis, scientists often use animal modes, such as mice. ̽��ֱ��mice will typically be fed a high fat diet for several weeks as adults to see how this leads to the build up of the plaques characteristic of the condition.

Professor Ziad Mallat and colleagues at the Victor Phillip Dahdaleh Heart and Lung Research Institute at the ̽��ֱ�� of Cambridge decided to explore a different approach – to see whether giving mice the same amount of high fat food but spread over their lifetime changed their atherosclerosis risk.

“When I asked my group and a number of people who are experts in atherosclerosis, no one could tell me what the result would be,” said Professor Mallat, a British Heart Foundation (BHF) Professor of Cardiovascular Medicine.

“Some people thought it would make no difference, others thought it would change the risk. In fact, what we found was that an intermittent high fat diet starting while the mice were still young – one week on, a few weeks off, another week on, and so on – was the worst option in terms of atherosclerosis risk.”

Armed with this information, his team turned to the Cardiovascular Risk in Young Finns Study, one of the largest follow-up studies into cardiovascular risk from childhood to adulthood. Participants recruited in the 1980s returned for follow-up over the subsequent decades, and more than 2,000 of them had received ultrasound scans of their carotid arteries when they were aged around 30 years and again at around 50 years.

Analysing the data, the team found that those participants who had been exposed to high cholesterol levels as children tended to have the biggest build of plaques, confirming the findings in mice.

“What this means is that we shouldn’t leave it until later in life before we start to look at our cholesterol levels,” Professor Mallat said. “Atherosclerosis can potentially be prevented by lowering cholesterol levels, but we clearly need to start thinking about this much earlier on in life than we previously thought.”

̽��ֱ��mouse studies showed that fluctuating levels of cholesterol appeared to cause the most damage. Professor Mallat says this could explain why some people who are on statins but do not take them regularly remain at an increased risk of heart attack.

“If you stop and start your statin treatment, your body is being exposed to a yo-yo of cholesterol, which it doesn’t like, and it seems this interferes with your body’s ability to prevent the build-up of plaques,” he added.

̽��ֱ��reason why this is so damaging may come down to the effect that cholesterol has on specific types of immune cells known as ‘resident arterial macrophages’. These reside in your arteries, helping them to clear damaged cells and fatty molecules known as lipids, which include cholesterol, and stopping the build-up of plaques.

When the team examined these macrophages in their mouse models, they found that high cholesterol levels – and in particular, fluctuating cholesterol levels – changed them physically and altered the activity of their genes. This meant that the cells were no longer protective, but were instead detrimental, accelerating atherosclerosis.

̽��ֱ��research was funded by the British Heart Foundation.

Reference
Takaoka, M et al. Early intermittent hyperlipidaemia alters tissue macrophages to boost atherosclerosis. Nature; 4 Sept 2024; DOI: 10.1038/s41586-024-07993-x

Our risk of developing atherosclerosis – ‘furring’ of the arteries – can begin much earlier in life than was previously thought, highlighting the need to keep cholesterol levels low even when we are young, new research has discovered.

Atherosclerosis can potentially be prevented by lowering cholesterol levels, but we clearly need to start thinking about this much earlier on in life

Ziad Mallat

SolStock (Getty Images)

Teenagers eating pizza by the river

Yes

Anti-inflammatory drug could reduce future heart attack risk

Anonymous — Mon, 02 Sep 2024 10:52:31 +0000

A cancer drug that unlocks the anti-inflammatory power of the immune system could help to reduce the risk of future heart attacks, according to research part-funded by the British Heart Foundation. By repurposing an existing drug, researchers hope it could soon become part of routine treatment for patients after a heart attack.

̽��ֱ��findings will be presented at the European Society of Cardiology Congress in London by Dr Rouchelle Sriranjan, NIHR Clinical Lecturer in Cardiology at the ̽��ֱ�� of Cambridge.

High levels of inflammation in blood vessels are linked to an increased risk of heart disease and heart attacks. After a heart attack, the body’s immune response can aggravate existing inflammation, causing more harm and increasing risk even further. However, NICE guidelines don’t currently recommend the use of any anti-inflammatory drugs to reduce future risk.

Now, a team of researchers, led by Dr Joseph Cheriyan from Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust, have found that low doses of an anti-inflammatory drug called aldesleukin, injected under the skin of patients after a heart attack, significantly reduces inflammation in arteries.

̽��ֱ��researchers are currently following up patients to investigate the longer-term impact of this fall in inflammation. To date, in the two and a half years after their treatment, there have been no major adverse cardiac events in the group that received aldesleukin, compared to seven in the group that received the placebo.

Professor Ziad Mallat, BHF Professor of Cardiovascular Medicine at the ̽��ֱ�� of Cambridge who developed the trial, said: “We associate inflammation with healing – an inbuilt response that protects us from infection and injury. But it’s now clear that inflammation is a culprit in many cardiovascular conditions.

“Early signs from our ongoing trial suggest that people treated with aldesleukin may have better long-term outcomes, including fewer heart attacks. If these findings are repeated in a larger trial, we’re hopeful that aldesleukin could become part of routine care after a heart attack within five to 10 years.”

Aldesleukin is already used to treat kidney cancer, as high doses stimulate the immune system to attack cancer cells. ̽��ֱ��Cambridge team previously found that doses one thousand times lower than those used in cancer treatment increased the number of regulatory T cells – a type of anti-inflammatory white blood cell – in patients’ blood compared to a placebo.

In the current trial at Addenbrooke's and Royal Papworth hospitals in Cambridge, 60 patients admitted to hospital with a heart attack or unstable angina received either low dose aldesleukin or placebo. Patients received an injection once a day for the first five days, then once per week over the next seven weeks. Neither the participants nor their doctors knew whether they had received the drug or placebo.

At the end of treatment, Positron Emission Tomography (PET) scans showed that inflammation in the artery involved in patients’ heart attack or angina was significantly lower in the group treated with aldesleukin, compared to those who received the placebo.

̽��ֱ��anti-inflammatory effect of aldesleukin appeared even more striking in the most inflamed arteries, leading to a larger reduction in inflammation levels in these vessels and a bigger difference between the two groups by the end of the study.

Dr Sonya Babu-Narayan, Associate Medical Director at the British Heart Foundation and consultant cardiologist said: “Thanks to research, we have an array of effective treatments to help people avoid heart attacks and strokes and save lives. But, even after successful heart attack treatment, unwanted inflammation in the coronary arteries can remain, which can lead to life-threatening complications.

“A treatment to reduce inflammation after a heart attack could be a game-changer. It would help doctors to interrupt the dangerous feedback loop that exacerbates inflammation and drives up risk. This research is an important step towards that treatment becoming a reality.”

̽��ֱ��study was predominantly funded by the Medical Research Council, with significant support from the BHF and National Institute for Health and Care Research Cambridge Biomedical Research Centre (NIHR-BRC).

Originally published by the British Heart Foundation.

Repurposed cancer drug helps to calm inflammation in arteries.

Sebastian Kaulitzki/Science Photo Library via Getty Images

Illustration of human heart

Yes

Scientists map how deadly bacteria evolved to become epidemic

cjb250 — Thu, 04 Jul 2024 18:00:53 +0000

P. aeruginosa is responsible for over 500,000 deaths per year around the world, of which over 300,000 are associated with antimicrobial resistance (AMR). People with conditions such as COPD (smoking-related lung damage), cystic fibrosis (CF), and non-CF bronchiectasis, are particularly susceptible.

How P. aeruginosa evolved from an environmental organism into a specialised human pathogen was not previously known. To investigate this, an international team led by scientists at the ̽��ֱ�� of Cambridge examined DNA data from almost 10,000 samples taken from infected individuals, animals, and environments around the world. Their results are published today in Science

By mapping the data, the team was able to create phylogenetic trees – ‘family trees’ – that show how the bacteria from the samples are related to each other. Remarkably, they found that almost seven in ten infections are caused by just 21 genetic clones, or ‘branches’ of the family tree, that have rapidly evolved (by acquiring new genes from neighbouring bacteria) and then spread globally over the last 200 years. This spread occurred most likely as a result of people beginning to live in densely-populated areas, where air pollution made our lungs more susceptible to infection and where there were more opportunities for infections to spread.

These epidemic clones have an intrinsic preference for infecting particular types of patients, with some favouring CF patients and other non-CF individuals. It turns out that the bacteria can exploit a previously unknown immune defect in people with CF, allowing them to survive within macrophages. Macrophages are cells that ‘eat’ invading organisms, breaking them down and preventing the infection from spreading. But a previously-unknown flaw in the immune systems of CF patients means that once the macrophage ‘swallows’ P. aeruginosa, it is unable to get rid of it.

Having infected the lungs, these bacteria then evolve in different ways to become even more specialised for a particular lung environment. ̽��ֱ��result is that certain clones can be transmitted within CF patients and other clones within non-CF patients, but almost never between CF and non-CF patient groups.

Professor Andres Floto, Director of the UK Cystic Fibrosis Innovation Hub at the ̽��ֱ�� of Cambridge and Royal Papworth Hospital NHS Foundation Trust, and senior author of the study said: “Our research on Pseudomonas has taught us new things about the biology of cystic fibrosis and revealed important ways we might be able to improve immunity against invading bacteria in this and potentially other conditions.

“From a clinical perspective, this study has revealed important information about Pseudomonas. ̽��ֱ��focus has always been on how easily this infection can spread between CF patients, but we’ve shown that it can spread with worrying ease between other patients, too. This has very important consequences for infection control in hospitals, where it’s not uncommon for an infected individual to be on an open ward with someone potentially very vulnerable.

“We are incredibly lucky at Royal Papworth Hospital where we have single rooms and have developed and evaluated a new air-handling system to reduce the amount of airborne bacteria and protect all patients.”

Dr Aaron Weimann from the Victor Phillip Dahdaleh Heart & Lung Research Institute at the ̽��ֱ�� of Cambridge, and first author on the study, said: “It’s remarkable to see the speed with which these bacteria evolve and can become epidemic and how they can specialise for a particular lung environment. We really need systematic, pro-active screening of all at risk patient groups to detect and hopefully prevent the emergence of more epidemic clones.”

̽��ֱ��research was funded by Wellcome and the UK Cystic Fibrosis Trust.

Reference
Weimann, A et al. Evolution and host-specific adaptation of Pseudomonas aeruginosa. Science; 4 July 2024; DOI: 10.1126/science.adi0908

Pseudomonas aeruginosa – an environmental bacteria that can cause devastating multidrug-resistant infections, particularly in people with underlying lung conditions – evolved rapidly and then spread globally over the last 200 years, probably driven by changes in human behaviour, a new study has found.

It’s remarkable to see the speed with which these bacteria evolve and can become epidemic and how they can specialise for a particular lung environment

Aaron Weimann

engin akyurt

A man with a respirator on his face

Yes

Licence type:

Public Domain

Significant gaps in COVID-19 vaccine uptake may have led to over 7,000 hospitalisations and deaths

cjb250 — Mon, 15 Jan 2024 23:30:03 +0000

̽��ֱ��findings, published today in ̽��ֱ��Lancet, suggest that more than 7,000 hospitalisations and deaths might have been averted in summer 2022 if the UK had had better vaccine coverage.

With COVID-19 cases on the rise and a new variant strain recently identified, this research provides a timely insight into vaccine uptake and hesitancy and could inform policy-makers.

̽��ֱ��research relied on secure access to anonymised health data for everyone in all four nations of the UK, an advance which has only become possible during the pandemic.

Co-author Angela Wood, Professor of Health Data Science at the Victor Phillip Dahdaleh Heart & Lung Research Institute, ̽��ֱ�� of Cambridge and Associate Director of the British Heart Foundation Data Science Centre said: “This is the first epidemiological study to use individual-level anonymised health data covering the entire UK population. We have created a detailed, UK-wide picture of who is under-vaccinated against COVID-19 and the associated risks of under-vaccination.

“These results can be used to help create health policy and public health interventions to improve vaccine uptake. This approach could be extended to many other areas of medicine with great potential for new discoveries in the understanding and treatment of disease.”

Early COVID-19 vaccine rollout began strongly in the UK, with over 90% of the population over the age of 12 vaccinated with at least one dose by January 2022. However, rates of subsequent booster doses across the UK were not fully understood until now.

Scientists from England, Scotland, Northern Ireland and Wales – led by Health Data Research UK (HDR UK) and the ̽��ֱ�� of Edinburgh – studied securely-held, routinely collected NHS data from everyone over five years of age during 1 June to 30 September 2022. All data was de-identified and available only to approved researchers.

Data from across the four countries was then pooled and harmonised, a feat that was not possible until now. People were grouped by vaccine status, with under-vaccination defined as not having had all doses of a vaccine for which that a person was eligible.

̽��ֱ��findings reveal that the proportion of people who were under-vaccinated on 1 June 2022 ranged between one third and one half of the population – 45.7% for England, 49.8% for Northern Ireland, 34.2% for Scotland and 32.8% Wales.

Mathematical modelling indicated that 7,180 hospitalisations and deaths out of around 40,400 severe COVID-19 outcomes during four months in summer 2022 might have been averted, if the UK population was fully vaccinated.

Under-vaccination was related to significantly more hospitalisations and deaths across all age groups studied, with under-vaccinated people over 75 more than twice as likely to have a severe COVID-19 outcome than those who were fully protected.

̽��ֱ��highest rates of under-vaccination were found in younger people, men, people in areas of higher deprivation, and people of non-white ethnicity.

Researchers say the study – the largest ever study carried out in the UK – also ushers in a new era for UK science by overcoming challenges in uniting NHS data that is gathered and stored in different ways between devolved nations.

Professor Cathie Sudlow, Chief Scientist at Health Data Research UK and Director of the British Heart Foundation (BHF) Data Science Centre, said: “ ̽��ֱ��infrastructure now exists to make full use of the potential of routinely collected data in the NHS across the four nations of the UK. We believe that we could and should extend these approaches to many other areas of medicine, such as cancer, heart disease and diabetes to search for better understanding, prevention and treatment of disease."

Professor Sir Aziz Sheikh, Director of the Usher Institute at the ̽��ֱ�� of Edinburgh, HDR UK Research Director and study co-lead, said: “Large-scale data studies have been critical to pandemic management, allowing scientists to make policy-relevant findings at speed. COVID-19 vaccines save lives. As new variants emerge, this study will help to pinpoint groups of our society and areas of the country where public health campaigns should be focused and tailored for those communities.”

Reference
HDR UK COALESCE Consortium. Undervaccination and severe COVID-19 outcomes: meta-analysis of national cohort studies in England, Northern Ireland, Scotland, and Wales. Lancet; 16 Jan 2024; DOI: 10.1016/S0140-6736(23)02467-4

Adapted from a release from HDR-UK

Between a third and a half of the populations of the four UK nations had not had the recommended number of COVID vaccinations and boosters by summer 2022, according to the first research study to look at COVID-19 vaccine coverage of the entire UK population.

These results can be used to help create health policy and public health interventions to improve vaccine uptake

Angela Wood

KoldoyChris (Getty Images)

Girl being injected with COVID-19 vaccine

Yes

Lab-grown ‘small blood vessels’ point to potential treatment for major cause of stroke and vascular dementia

cjb250 — Thu, 16 Nov 2023 16:00:19 +0000

̽��ֱ��study, published today in Stem Cell Reports, also identifies a drug target to ‘plug’ these leaks and prevent so-called small vessel disease in the brain.

Cerebral small vessel disease (SVD) is a leading cause of age-related cognitive decline and contributes to almost half (45%) of dementia cases worldwide. It is also responsible for one in five (20%) ischemic strokes, the most common type of stroke, where a blood clot prevents the flow of blood and oxygen to the brain.

̽��ֱ��majority of cases of SVD are associated with conditions such as hypertension and type 2 diabetes, and tend to affect people in their middle age. However, there are some rare, inherited forms of the disease that can strike people at a younger age, often in their mid-thirties. Both the inherited and ‘spontaneous’ forms of the disease share similar characteristics.

Scientists at the Victor Phillip Dahdaleh Heart and Lung Research Institute, ̽��ֱ�� of Cambridge, used cells taken from skin biopsies of patients with one of these rare forms of SVD, which is caused by a mutation in a gene called COL4.

By reprogramming the skin cells, they were able to create induced pluripotent stem cells – cells that have the capacity to develop into almost any type of cell within the body. ̽��ֱ��team then used these stem cells to generate cells of the brain blood vessels and create a model of the disease that mimics the defects seen in patients’ brain vessels.

Dr Alessandra Granata from the Department of Clinical Neurosciences at Cambridge, who led the study, said: “Despite the number of people affected worldwide by small vessel disease, we have little in the way of treatments because we don’t fully understand what damages the blood vessels and causes the disease. Most of what we know about the underlying causes tends to come from animal studies, but they are limited in what they can tell us.

“That’s why we turned to stem cells to generate cells of the brain blood vessels and create a disease model ‘in a dish’ that mimics what we see in patients.”

Our blood vessels are built around a type of scaffolding known as an extracellular matrix, a net-like structure that lines and supports the small blood vessels in the brain. ̽��ֱ��COL4 gene is important for the health of this matrix.

In their disease model, the team found that the extracellular matrix is disrupted, particularly at its so-called ‘tight junctions’, which ‘zip’ cells together. This leads to the small blood vessels becoming leaky – a key characteristic seen in SVD, where blood leaks out of the vessels and into the brain.

̽��ֱ��researchers identified a class of molecules called metalloproteinases (MMPs) that play a key role in this damage. Ordinarily, MMPs are important for maintaining the extracellular matrix, but if too many of them are produced, they can damage the structure – similar to how in ̽��ֱ��Sorcerer’s Apprentice, a single broom can help mop the floor, but too many wreak havoc.

When the team treated the blood vessels with drugs that inhibit MMPs – an antibiotic and anti-cancer drug – they found that these reversed the damage and stopped the leakage.

Dr Granata added: “These particular drugs come with potentially significant side effects so wouldn’t in themselves be viable to treat small vessel disease. But they show that in theory, targeting MMPs could stop the disease. Our model could be scaled up relatively easily to test the viability of future potential drugs.”

̽��ֱ��study was funded by the Stroke Association, British Heart Foundation and Alzheimer’s Society, with support from the NIHR Cambridge Biomedical Research Centre and the European Union’s Horizon 2020 Programme.

Reference
Al-Thani, M, Goodwin-Trotman, M. A novel human 1 iPSC model of COL4A1/A2 small vessel disease unveils a key pathogenic role of matrix metalloproteinases. Stem Cell Reports; 16 Nov 2023; DOI: https://doi.org/10.1016/j.stemcr.2023.10.014

Cambridge scientists have grown small blood vessel-like models in the lab and used them to show how damage to the scaffolding that supports these vessels can cause them to leak, leading to conditions such as vascular dementia and stroke.

Despite the number of people affected worldwide by small vessel disease, we have little in the way of treatments because we don’t fully understand what damages the blood vessels and causes the disease

Alessandra Granata

Alessandra Granata/ ̽��ֱ�� of Cambridge

Disease mural cells stained for calponin (mural cells marker, green), collagen IV (magenta) and DAPI (nuclei, blue)

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

Licence type:

Attribution

Cancer drug could hold hope for treating inflammatory diseases including gout and heart diseases

cjb250 — Wed, 01 Nov 2023 08:00:30 +0000

In a study published on 1 November in the Journal of Clinical Investigation, the researchers have identified a molecule that plays a key role in triggering inflammation in response to materials in the body seen as potentially harmful.

We are born with a defence system known as innate immunity, which acts as the first line of defence against harmful materials in the body. Some of these materials will come from outside, such as bacterial or viral infections, while others can be produced within the body.

Innate immunity triggers an inflammatory response, which aims to attack and destroy the perceived threat. But sometimes, this response can become overactive and can itself cause harm to the body.

One such example of this is gout, which occurs when urate crystals build up in joints, causing excessive inflammation, leading to intense pain. Another example is heart attack, where dead cell build up in the damaged heart – the body sees itself as being under attack and an overly-aggressive immune system fights back, causing collateral damage to the heart.

Several of these conditions are characterised by overactivation of a component of the innate immune response known as an inflammasome – specifically, the inflammasome NLRP3. Scientists at the Victor Phillip Dahdaleh Heart and Lung Research Institute at Cambridge have found a molecule that helps NLRP3 respond.

This molecule is known as PLK1. It is involved in a number of processes within the body, including helping organise tiny components of our cells known as microtubules cytoskeletons. These behave like train tracks inside of the cell, allowing important materials to be transported from one part of the cell to another.

Dr Xuan Li from the Department of Medicine at the ̽��ֱ�� of Cambridge, the study’s senior author, said: “If we can get in the way of the microtubules as they try to organise themselves, then we can in effect slow down the inflammatory response, preventing it from causing collateral damage to the body. We believe this could be important in preventing a number of common diseases that can cause pain and disability and in some cases can lead to life-threatening complications.”

But PLK1 also plays another important role in the body – and this may hold the key to developing new treatments for inflammatory diseases.

For some time now, scientists have known that PLK1 is involved in cell division, or mitosis, a process which, when it goes awry, can lead to runaway cell division and the development of tumours. This has led pharmaceutical companies to test drugs that inhibit its activity as potential treatments for cancer. At least one of these drugs is in phase three clinical trials – the final stages of testing how effective a drug is before it can be granted approval.

When the Cambridge scientists treated mice that had developed inflammatory diseases with a PLK1 inhibitor, they showed that it prevented the runaway inflammatory response – and at a much lower dose than would be required for cancer treatment. In other words, inhibiting the molecule ‘calmed down’ NLRP3 in non-dividing cells, preventing the overly aggressive inflammatory response seen in these conditions.

̽��ֱ��researchers are currently planning to test its use against inflammatory diseases in clinical trials.

“These drugs have already been through safety trials for cancer – and at higher doses than we think we would need – so we’re optimistic that we can minimise delays in meeting clinical and regulatory milestones,” added Dr Li.

“If we find that the drug is effective for these conditions, we could potentially see new treatments for gout and inflammatory heart diseases – as well as a number of other inflammatory conditions – in the not-too-distant future.”

̽��ֱ��research was funded by the British Heart Foundation. Professor James Leiper, Associate Medical Director at the British Heart Foundation said: “This innovative research has uncovered a potential new treatment approach for inflammatory heart diseases such as heart failure and cardiomyopathy. It’s promising that drugs targeting PLK1 – that work by dampening down the inflammatory response – have already been proven safe and effective in cancer trials, potentially helping accelerate the drug discovery process.

“We hope that this research will open the door for new ways to treat people with heart diseases caused by overactive and aggressive immune responses, and look forward to more research to uncover how this drug could be could be repurposed.”

Reference
Baldrighi, M et al. PLK1 inhibition dampens NLRP3 inflammasome-elicited response in inflammatory disease models. JCI; 1 Nov 2023; DOI: 10.1172/JCI162129

A cancer drug currently in the final stages of clinical trials could offer hope for the treatment of a wide range of inflammatory diseases, including gout, heart failure, cardiomyopathy, and atrial fibrillation, say scientists at the ̽��ֱ�� of Cambridge.

We believe [our findings] could be important in preventing a number of common diseases that can cause pain and disability and in some cases can lead to life-threatening complications

Xuan Li

kazuma seki (Getty Images)

̽��ֱ��feet of a man suffering from gout - stock photo

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes