̽��ֱ�� of Cambridge - medical

Identification of ‘violent’ processes that cause wheezing could lead to better diagnosis and treatment for lung disease

sc604 — Wed, 24 Feb 2021 00:01:31 +0000

̽��ֱ��researchers, from the ̽��ֱ�� of Cambridge, used modelling and high-speed video techniques to show what causes wheezing and how to predict it. Their results could be used as the basis of a cheaper and faster diagnostic for lung disease that requires just a stethoscope and a microphone.

Improved understanding of the physical mechanism responsible for generating wheezing sounds could provide a better causal link between symptoms and disease, and help improve diagnosis and treatment. ̽��ֱ��results are reported in the journal Royal Society Open Science.

At some point, most of us have experienced wheezing, a high-pitched whistling sound made while breathing. For most people, the phenomenon is temporary and usually the result a cold or mild allergic reaction. However, regular or chronic wheezing is often a symptom of more serious conditions, such as asthma, emphysema, chronic obstructive pulmonary disease (COPD) or certain cancers.

“Because wheezing makes it harder to breathe, it puts an enormous amount of pressure on the lungs,” said first author Dr Alastair Gregory from Cambridge’s Department of Engineering. “ ̽��ֱ��sounds associated with wheezing have been used to make diagnoses for centuries, but the physical mechanisms responsible for the onset of wheezing are poorly understood, and there is no model for predicting when wheezing will occur.”

Co-author Dr Anurag Agarwal, Head of the Acoustics lab in the Department of Engineering, said he first got the idea to study wheezing after a family vacation several years ago. “I started wheezing the first night we were there, which had never happened to me before,” he said. “And as an engineer who studies acoustics, my first thought was how cool it was that my body was making these noises. After a few days however, I was having real trouble breathing, which made the novelty wear off pretty quickly.”

Agarwal’s wheezing was likely caused by a dust mite allergy, which was easily treated with over-the-counter antihistamines. However, after speaking with a neighbour who is also a specialist in respiratory medicine, he learned that even though it is a common occurrence, the physical mechanisms that cause wheezing are somewhat mysterious.

“Since wheezing is associated with so many conditions, it is difficult to be sure of what is wrong with a patient just based on the wheeze, so we’re working on understanding how wheezing sounds are produced so that diagnoses can be more specific,” said Agarwal.

̽��ֱ��airways of the lung are a branching network of flexible tubes, called bronchioles, that gradually get shorter and narrower as they get deeper into the lung.

In order to mimic this setup in the lab, the researchers modified a piece of equipment called a Starling resistor, in which airflow is driven through thin elastic tubes of various lengths and thicknesses.

Co-author and computer vision specialist Professor Joan Lasenby developed a multi-camera stereoscopy technique to film the air being forced through the tubes at different degrees of tension, in order to observe the physical mechanisms that cause wheezing.

“It surprised us just how violent the mechanism of wheezing is,” said Gregory, who is also a Junior Research Fellow at Magdalene College. “We found that there are two conditions for wheezing to occur: the first is that the pressure on the tubes is such that one or more of the bronchioles nearly collapses, and the second is that air is forced though the collapsed airway with enough force to drive oscillations.”

Once these conditions are met, the oscillations grow and are sustained by a flutter mechanism in which waves travelling from front to back have the same frequency as the opening and closing of the tube. “A similar phenomenon has been seen in aircraft wings when they fail, or in bridges when they collapse,” said Agarwal. “When up and down vibrations are at the same frequency as clockwise and anticlockwise twisting vibrations, we get flutter that causes the structure to collapse. ̽��ֱ��same process is at work inside the respiratory system.”

Using these observations, the researchers developed a ‘tube law’ in order to predict when this potentially damaging oscillation might occur, depending on the tube’s material properties, geometry and the amount of tension.

“We then use this law to build a model that can predict the onset of wheezing and could even be the basis of a cheaper and faster diagnostic for lung disease,” said Gregory. “Instead of expensive and time-consuming methods such as x-rays or MRI, we wouldn’t need anything more than a microphone and a stethoscope.”

A diagnostic based on this method would work by using a microphone – early tests were done using the in-built microphone on a normal smartphone – to record the frequency of the wheezing sound and use this to identify which bronchiole is near collapse, and whether the airways are unusually stiff or flexible in order to target treatment. ̽��ֱ��researchers hope that by finding changes in material properties from wheezing, and locations that wheezes come from, the additional information will make it easier to distinguish between different conditions, although further work in this area is still needed.

Reference:.
A. L. Gregory, A. Agarwal and J. Lasenby. ‘An Experimental Investigation to Model Wheezing in Lungs.’ Royal Society Open Science (2021). DOI: 10.1098/rsos.201951

A team of engineers has identified the ‘violent’ physical processes at work inside the lungs which cause wheezing, a condition that affects up to a quarter of the world’s population.

Since wheezing is associated with so many conditions, it is difficult to be sure of what is wrong with a patient just based on the wheeze

Anurag Agarwal

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Dimensional Lungs

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 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.

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Cause of hardening of the arteries – and potential treatment – identified

sc604 — Tue, 11 Jun 2019 15:00:00 +0000

̽��ֱ��team, led by the ̽��ֱ�� of Cambridge and King’s College London, found that a molecule once thought only to exist inside cells for the purpose of repairing DNA is also responsible for hardening of the arteries, which is associated with dementia, heart disease, high blood pressure and stroke.

There is no current treatment for hardening of the arteries, which is caused by build-up of bone-like calcium deposits, stiffening the arteries and restricting blood flow to organs and tissues.

Supported by funding from the British Heart Foundation, the researchers found that poly(ADP ribose), or PAR, a molecule normally associated with DNA repair, also drives the bone-like calcification of arteries.

Additionally, using rats with chronic kidney disease, the researchers found that minocycline – a widely-prescribed antibiotic often used to treat acne – could treat hardening of the arteries by preventing the build-up of calcium in the circulatory system. ̽��ֱ��study, the result of more than a decade of fundamental research, is published in the journal Cell Reports.

“Artery hardening happens to everyone as they age, and is accelerated in patients on dialysis, where even children develop calcified arteries. But up until now we haven’t known what controls this process and therefore how to treat it,” said Professor Melinda Duer from Cambridge’s Department of Chemistry, who co-led the research as part of a long-term collaboration with Professor Cathy Shanahan from King’s College London.

“This hardening, or biomineralisation, is essential for the production of bone, but in arteries it underlies a lot of cardiovascular disease and other diseases associated with ageing like dementia,” said Shanahan. “We wanted to find out what triggers the formation of calcium phosphate crystals, and why it seems to be concentrated around the collagen and elastin which makes up much of the artery wall.”

In earlier research, Duer and Shanahan had shown that PAR – normally associated with the repair of DNA inside the cell – can in fact exist outside the cell and is the engine of bone production. This led the researchers to hypothesise that PAR may also play a role in biomineralisation. In addition, PARP1 and PARP2, the dominant PAR-producing enzymes, are expressed in response to DNA damage and oxidative stress, processes which are associated with both bone and vascular calcification.

“We could see signals from bone that we couldn’t explain, so we looked for molecules from first principles to figure it out,” said Duer.

“I’d been thinking for years that hardening of the arteries was linked to DNA damage, and that DNA damage is a pathway switched on by many agents including smoking and lipids,” said Shanahan. “When this pathway is switched on, it drives the pathologies associated with ageing. If enough damage is present, the arteries will eventually reflect it.”

Using NMR spectroscopy, the researchers found that when the cells become stressed and die, they release PAR, which binds very strongly to calcium ions. Once released, the PAR starts mopping up calcium into larger droplets which stick onto the components in artery walls that give the artery its elasticity, where they form ordered crystals and solidify, hardening the arteries.

“We never would have predicted that it was caused by PAR,” said Duer. “It was initially an accidental discovery, but we followed it up - and it’s led to a potential therapy.”

Having discovered the links between DNA damage, PAR, bone and artery calcification, the researchers then looked into a way of blocking this pathway through the use of a PARP inhibitor.

“We had to find an existing molecule that is cheap and safe, otherwise, it would be decades before we would get a treatment,” said Shanahan. “If something has already been shown to be safe in humans, the journey to the clinic can be much faster.”

Working together with Cycle Pharmaceuticals, a Cambridge-based company, the researchers identified six known molecules that they thought might inhibit the PARP enzymes. Detailed experiments with these showed that the antibiotic minocycline was highly effective in preventing hardening of the arteries.

“It’s been 12 years of basic research to get to this point,” said Duer. “We set out with absolutely no expectation of finding a potential treatment – there is no treatment currently and nobody would have believed us if we had said at that point we were going to cure hardening of the arteries.”

̽��ֱ��technology has been patented and has been licensed to Cycle Pharmaceuticals by Cambridge Enterprise, the ̽��ֱ��’s commercialisation arm. ̽��ֱ��researchers are hoping to carry out a proof of principle trial in patients in the next 12 to 18 months.

“Blood vessel calcification is a well-known risk factor for several heart and circulatory diseases, and can lead to high blood pressure and ultimately, a life-threatening heart attack,” said Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation. “Now, researchers have shown how calcification of the walls of blood vessels takes place, and how the process differs from normal bone formation. By doing so, they have been able to identify a potential treatment to reduce blood vessel calcification without any adverse effects on bone. This type of treatment would benefit many people, and we eagerly await the results of the anticipated clinical trials looking at whether this drug lives up to its early promise.”

Reference:
Karin H. Müller et al. ‘Poly(ADP ribose) links the DNA damage response and biomineralization.’ Cell Reports (2019). DOI: 10.1016/j.celrep.2019.05.038

A team of UK scientists have identified the mechanism behind hardening of the arteries, and shown in animal studies that a generic medication normally used to treat acne could be an effective treatment for the condition.

Artery hardening happens to everyone as they age...but up until now we haven’t known what controls this process and therefore how to treat it

Melinda Duer

False colour image of calcium phosphate deposits on bone

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Financial cycles of acquisitions and ‘buybacks’ threaten public access to breakthrough drugs

fpjl2 — Thu, 28 Jul 2016 10:10:12 +0000

New research on the financial practices surrounding a ‘wonder drug’ with a more than 90% cure rate for hepatitis C – a blood-borne infection that damages the liver over many years – shows how this medical breakthrough, developed with the help of public funding, was acquired by a major pharmaceutical company following a late-stage bidding war.

̽��ֱ��research shows how that company more than doubled the drug’s price over original pricing estimates, calculating “how much health systems could bear” according to researchers, and channelled billions of dollars in profits into buying its own shares rather than funding further research.

In this way, the company, Gilead Sciences, passed significant rewards on to shareholders while charging public health services in the US up to $86k per patient, and NHS England almost £35k per patient, for a three month course of the drug.

̽��ֱ��high prices have contributed to a rationing effect: many public systems across the US and Europe treat only the sickest patients with the new drug, despite its extraordinary cure rate, and the fact that earlier treatment of an infectious disease gives it less opportunity to spread.

Gilead’s strategy of acquisitions and buybacks is an example of an industry-wide pattern, say the researchers. Many big pharmaceutical companies now rely on innovation emerging from public institutes, universities, and venture-capital supported start-ups – acquiring the most promising drug compounds once there is a level of “certainty”, rather than investing in their own internal research and development.

̽��ֱ��researchers, from Cambridge ̽��ֱ��’s Department of Sociology, say this effectively leaves the public “paying twice”: firstly for the initial research, and then for patent-protected high priced medications. A summary of their research has been commissioned by the British Medical Journal (BMJ) and is published today.

“Large pharmaceutical companies rarely take a drug from early stage research all the way to patients. They often operate as regulatory and acquisition specialists, returning most of the subsequent profits to shareholders and keeping some to make further acquisitions,” said lead researcher Victor Roy, a Cambridge Gates Scholar.

̽��ֱ��study’s senior author, Prof Lawrence King, said: “Drug research involves trial and error, and can take years to bear fruit – too long for companies that need to show the promise of annual growth to investors, so acquisitions are often the best way to generate this growth.”

There are an estimated 150 million people worldwide chronically infected with hepatitis C. It disproportionately affects vulnerable groups such as drug users and HIV sufferers, and can ultimately lead to liver failure through cirrhosis if left untreated.

Roy and King’s article tells the story of the curative drug Sofosbuvir. ̽��ֱ��compound was developed by a start-up that emerged from an Emory-based laboratory that received funding from the US National Institutes of Health and the US Veterans Administration.

̽��ֱ��start-up, Pharmasset, eventually raised private funding to develop sofosbuvir. When Phase II trials proved more promising than Gilead’s in-house hepatitis C prospects, it acquired Pharmasset for $11bn following a bidding war – the final weeks of which saw Pharmasset’s valuation rocket by nearly 40%.

“ ̽��ֱ��cost of this late stage arms race for revenues has become part of the industry justification for high drug prices,” write Roy and King.

Once Sofosbuvir was market-ready in 2013, Gilead set a price of $84k. A US Senate investigation later revealed that Pharmasset had initially considered a price of $36k.

By the first quarter of 2016, Gilead had accumulated over $35bn in revenue from hepatitis C medicines in a little over two years – nearly 40 times Gilead and Pharmasset’s combined reported costs for developing the medicines.

Last year, Gilead announced that a lion’s share of those profits – some $27bn – will go towards ‘share buybacks’: purchasing its own shares to increase the value of the remaining ones for shareholders. By contrast, between 2013 and 2015 Gilead increased research investment by $0.9bn to $3bn total.

“Share buybacks are a financial manoeuvre that emerged during the early 1980s due to a change in rules for corporations by the Reagan administration. ̽��ֱ��financial community now expects companies to reward shareholders with buybacks, but directing profit into buybacks can mean cannibalising innovation,” said Roy.

A further example they cite is that of Merck, who spent $8.4bn in 2014 to acquire a drug developer specialising in staph infections. ̽��ֱ��next year they closed the developer’s early stage research unit, laying off 120 staff. Three weeks after that, Merck announced an extra $10bn in share buybacks.

In the BMJ article, the researchers set out a number of suggestions to counter the consequences of the current financial model. These include giving health systems greater bargaining power to negotiate deals for breakthrough treatments, and limiting share buybacks.

Roy and King also highlight a possible future model that uses a mix of grants and major milestone prizes to “push” and “pull” promising therapies into wider application, and, crucially, uncouples drug prices from supposed development costs, including those added by shareholder expectations. They write that this approach may be attempted for areas of major public health concern.

“ ̽��ֱ��treatments for Hepatitis C may portend a future of expensive therapies for Alzheimer’s to many cancers to HIV/AIDS. Health systems and patients could face growing financial challenges,” said King.

“We need to recognise what current business models around drug development might mean for this future.”

An analysis of a new drug’s journey to market, published today in the BMJ, shines a light on financial practices that see some major pharmaceutical companies relying on a cycle of acquisitions, profits from high prices, and shareholder-driven manoeuvres that threatens access to medicines for current and future patients.

̽��ֱ��treatments for Hepatitis C may portend a future of expensive therapies for Alzheimer’s to many cancers to HIV/AIDS. Health systems and patients could face growing financial challenges

Lawrence King

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New era in publishing for women’s health

amb94 — Tue, 23 Jul 2013 11:03:28 +0000

In a move that will benefit women’s lives in the UK and around the world, Cambridge will take over publication of the RCOG’s current medical book titles. Cambridge and the RCOG will also begin working in partnership to expand the list to offer a wider range of learning to all healthcare professionals in women’s health.

̽��ֱ��list, which will be published under joint RCOG–Cambridge branding, will build on Cambridge’s existing strength in reproductive medicine and maternal-fetal medicine and expand their offering to trainees in obstetrics and gynaecology.

̽��ֱ��venture will also help the RCOG to pursue its mission to improve the lives of women in developing countries. ̽��ֱ��RCOG has long provided expertise to medical professionals in the UK and Commonwealth countries and is keen to extend its reach to help doctors, midwives and nurses around the world. Cambridge offers RCOG the perfect launch-pad for making medical publishing available to students and professionals globally.

RCOG President, Dr Tony Falconer, said: “We look forward to working in partnership with Cambridge ̽��ֱ�� Press as they expand their obstetrics and gynaecology list to cater to everyone caring for women and to achieve cross-over into other specialties, such as general practice and mental health.

“This also ties in with the RCOG’s international objectives. Cambridge’s reach is truly global, making them the ideal partner to support our ambition to bring excellent learning and support to our international community, some of them working in difficult conditions.

“ ̽��ֱ��end goal for us both is very simple – to combine the RCOG’s expertise in medicine and Cambridge’s expertise in publishing to raise the standard of care for women all over the world.”

For Cambridge the long-term aim is to become the publisher of choice in the arena of women’s health generally, offering top-quality learning materials that become fundamental to practitioners at all levels.
Cambridge ̽��ֱ�� Press Chief Executive, Peter Phillips, commented: “We are excited about the huge opportunities that our partnership with the RCOG makes possible through our joint commitment to excellence in medical publishing.”

̽��ֱ��RCOG is the UK’s main training and professional body for obstetrics and gynaecology with over 12,000 members and fellows. ̽��ֱ��RCOG’s Global Health Unit works to help lower mother and child death rates in under-resourced countries.

Cambridge ̽��ֱ�� Press is the publishing business of the ̽��ֱ�� of Cambridge, its purpose is to further the ̽��ֱ��'s objective of advancing knowledge, education, learning, and research.

A step-change in publishing in women’s health is under way with the announcement that the Royal College of Obstetricians and Gynaecologists (RCOG) is to sell its prestigious publishing list to Cambridge ̽��ֱ�� Press.

Alvaro Canivell on Flickr

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Cambridge and Brazil discuss possibilities for further scientific collaboration

amb94 — Wed, 19 Jun 2013 10:05:53 +0000

̽��ֱ��group was led by Prof Jorge Guimarães, President of Brazil’s federal agency for the support of post-graduate education and research (CAPES), a division of the Ministry of Education; and by Prof Paulo Beirão, Director of Agricultural, Biological and Medical Sciences of Brazil’s national research council (CNPq), part of the Ministry for Science, Technology and Innovation.

Supported by CAPES, by the Brazilian embassy in London, and by the UK embassy in Brazil, the event sought to identify opportunities for Cambridge-Brazil research collaboration in biological sciences, medical sciences, and physical sciences and technology.

Welcoming the Brazilian delegates and over sixty Cambridge attendees at Clare College’s Gillespie Centre, Prof Lynn Gladden, Pro-Vice-Chancellor for Research, emphasised the ̽��ֱ��’s interest in pursuing collaborative opportunities with the world’s best researchers in strategic fields of knowledge. She welcomed the chance to explore ways of supporting the growing number of links established by Cambridge academics with their Brazilian counterparts.

Prof Guimarães told the audience that CAPES takes very seriously the opportunity of fostering collaboration with Cambridge–as shown by the fact that most of the Brazilian academics invited to join the delegation were full members of the Brazilian Academy of Science, one of the highest forms of scientific distinction.

Representing the Ministry of Science, Technology and Innovation (MCTI), Prof Beirão reminded the audience that, although science is relatively young in the country, Brazil has been catching up fast by investing significantly in its science base, and has already attained world excellence in certain fields of knowledge –represented by the National Institutes for Science and Technology (INCTs), which CNPq supports. A closer research relationship with a world-leading university like Cambridge would, he hoped, bring benefits to all.

Following the opening remarks, simultaneous breakout sessions were held during which panellists from Cambridge and Brazil offered overviews of their research interests and suggested possible areas for further collaboration.

̽��ֱ��session on Biological Sciences included presentations by Prof Geoffrey Smith, Head of Department of Pathology; Dr John Carr, Senior Lecturer in Plant Sciences; Prof Steve Oliver, Director of the Systems Biology Centre; and Dr David Sargan, from the Department of Veterinary Medicine. Their Brazilian counterparts were Prof Ricardo Gazinnelli, of the Federal ̽��ֱ�� of Minas Gerais (UFMG), and coordinator of the INCT for Vaccines; Prof Mauro Martins Teixeira, also of UFMG, and coordinator of the INCT for Dengue; and Prof Maria de Fatima Grossi de Sá, plant biotechnology researcher at Brazil’s national agricultural agency, EMBRAPA.

Physical Sciences and Technology were represented by Prof Lindsay Greer, Head of Department of Materials Science and Metallurgy; Prof Jeremy Baumberg, Director of the Nanophotonics Centre; Prof Simone Hochgreb, Professor of Experimental combustion at the Department of Engineering; Prof Richard McMahon, of the Institute of Astronomy; and Dr Sophie Jackson, Reader in Biophysical Chemistry. They shared the panel with Prof Carlos Aragão, Director of the Brazilian Center for Research in Energy and Materials (CNPEM); Prof Luiz Davidovich, quantum physicist at the Federal ̽��ֱ�� of Rio de Janeiro; Prof Alvaro T. Prata, mechanical engineer at the Federal ̽��ֱ�� of Santa Catarina and currently Secretary for Technological Development and Innovation at the MCTI; and Prof Virgilio Almeida, computer scientist at UFMG and Secretary for Information Technology Policy at the MCTI.

̽��ֱ��session on medical sciences involved Prof Christopher Rudd, from the Division of Immunology, Department of Pathology; Dr Kenneth Seamon, Development Director for Science at the Cambridge Cancer Centre; and Dr Thais Minnet, Senior Research Associate, Institute of Public Health. They discussed potential areas for collaborative work with Prof Jorge Kalil, Director of the Immunology laboratory at São Paulo’s InCor hospital; Prof Guilherme Kurtz, Head of Pharmacology at Brazil’s National Cancer Institute; and Prof Kleber Gomes Franchini, Director of the National Laboratory for Biosciences (LNBio), in Campinas.

̽��ֱ��breakout sessions and closing remarks were followed by a buffet lunch, during which attendees were able to discuss their research interests with the Brazilian delegates.

As immediate follow-up to the event, the International Strategy Office and Research Strategy Office are collecting and collating feedback from panellists and attendees. ̽��ֱ��purpose is to create a list of research themes and modes of engagement that Cambridge researchers would find most useful as they seek to establish or deepen research links to Brazilian scientists.

After comparing priorities and interests, CAPES and Cambridge will identify areas of research that CAPES is likely to support through the provision of funding for researcher mobility and for the organisation of thematic workshops. This initial form of support, it is hoped, will allow collaborators in Cambridge and Brazil to tap other sources of funding for joint research projects.

For enquiries, please contact Dr Ángel Gurría-Quintana, International Strategy Office (angel.gurria@admin.cam.ac.uk).

A delegation comprising some of Brazil’s most senior researchers and science administrators was in Cambridge on June 7 to take part in a half-day seminar, “Cambridge-Brazil: Opportunities for a strategic partnership.”

Phil Mynott

Prof Jorge Guimarães, President of CAPES; Prof Lynn Gladden, Pro-Vice-Chancellor for Research; Prof Paulo Beirão, of CNPq

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