Herbs that can boost your mood and memory

The herbs peppermint, chamomile, rosemary and lavender have been proven to have an impact on mood and memory, with significant benefits displayed for older people, according to new research from Northumbria University.

Researchers from the University’s Department of Psychology have found that drinking peppermint tea improves alertness, while chamomile tea has a calming effect. They also found that smelling the aromas of rosemary and lavender impacted on memory in people over 65, with the scent of rosemary enhancing their memory, while lavender impaired it.

The findings have been presented at the annual British Psychological Society Conference in Nottingham this week (26-28 April 2016).

In one study, the researchers asked 180 volunteers to consume either a chamomile or peppermint tea drink and tested their cognition and mood before and after drinking. A control group drank hot water for comparison.

They found that peppermint enhanced and aroused both mood and cognition, helping to improve long term memory, working memory and alertness, while chamomile had a calming and sedative effect which significantly slowed memory and attention speed.

In a separate study, 150 healthy people aged 65 and over were placed in rooms which had been scented with rosemary and lavender essential oils, or a control room which had no scent. They were asked to undertake tests that assessed their prospective memory – the ability to remember to do something at a given time, such as taking medication, or after receiving a prompt, such as posting a letter after seeing a post box. They also completed a mood assessment test.

Those who had been in the rosemary scented room displayed significantly enhanced prospective memory, with test scores 15% higher than those who had been in the room with no aroma. They were also more alert.

In contrast, those who had spent time in the lavender scented room displayed significantly increased calmness and contentedness, with a decrease in their ability to remember to do something at a given time.

Dr Mark Moss, Head of the Department of Psychology, said: “Peppermint has a reputation for being psychologically or mentally alerting. It picks you up and makes you feel a little bit brighter, so we endeavoured to test this out by giving people peppermint tea, or chamomile tea, which is a more calming drink and then put them through some computerised tests. We found that those people who had drunk the peppermint tea had better long-term memory. They were able to remember more words and pictures that they had seen. In contrast, the people who had the chamomile were slower in responding to tasks.

“Rosemary meanwhile has a reputation about being associated with memory – even Shakespeare said ‘rosemary is for remembrance’ – and it’s also associated with being invigorating. We have found that people are more alert after being in a room that has rosemary aroma in it. We tested prospective memory – our ability to remember to remember to do something – on people over 65 years of age, to see if we could improve their ability and we found that rosemary could do that. This is potentially very important because prospective memory, for example, enables you to remember to take your medication at certain times of the day.

“It is interesting to see the contrasting effects that different herbs can have on both mood and memory, and our research suggests that that they could have beneficial effects, particularly in older age groups. If you were otherwise healthy then this research suggests that there is an opportunity to have an improved memory.”

Northumbria University’s Department of Psychology has undertaken a number of studies into the effects of herbs and substances on mood and memory. They have also found that sage, ginseng, lemon balm and gingko biloba can all have positive effects on improving mental performance.

Northumbria is ranked in the top 20 in the UK for its research in psychology, which was judged to have outstanding reach and significance for its impact, according to the 2014 Research Excellence Framework, which measures the quality of research undertaken at UK universities.

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Stem cells know how to open up and unwind

Research led by the Babraham Institute with collaborators in the UK, Canada and Japan has revealed a new understanding of how an open genome structure supports the long-term and unrestricted developmental potential in embryonic stem cells. This insight provides new avenues for improving the quality and stability of embryonic stem cells – an essential requirement to fulfil their promise in regenerative medicine.

How our DNA is stored and packaged in the nucleus can be viewed as two different states: regions of the genome that are ‘open for business’ and can be actively read, and regions that are locked away by being tightly packed and inaccessible to the factors that read DNA.

The researchers looked in detail at the mysterious tightly packed portions of the genome, called constitutive heterochromatin. Previous research has shown that heterochromatin is maintained in an unusually open and uncompacted organisation in embryonic stem cells, which is different to all other cell types. It is thought that this rare form of genome architecture may contribute to keeping stem cells in an unspecialised state, still full of the potential to become any cell type in the body. Why heterochromatin is organised in this way in embryonic stem cells has previously been unknown.  

As described in the journal Genes & Development, the researchers identified a new pathway controlling heterochromatin organisation in mouse embryonic stem cells. Unexpectedly, this pathway assigns new roles for several well-known stem cell factors. The research showed that the stem cell factors, Nanog and Sall1, bind to heterochromatin and help to maintain this portion of the genome in an open form. Embryonic stem cells lacking Nanog and Sall1 showed major defects in heterochromatin organisation, including the closure and compaction of the chromatin. These new findings uncover the first direct connection between stem cell factors and the control of genome architecture, and explains why stem cell heterochromatin is normally in an open and uncompacted form. Loss of heterochromatin regulation has potential consequences for the long-term genetic stability of stem cells, and the ability of stem cells to mature into specialised cell types.

Dr Peter Rugg-Gunn, senior author on the research paper and research group leader at the Babraham Institute explained: “This unanticipated connection between stem cell factors and heterochromatin organisation is important because it tells us about how stem cells work. By tapping into this newly identified connection, we open up new avenues for more successful reprogramming of adult cells to a stem cell state, which is a priority for future regenerative medicine approaches.”

This research was funded by the Biotechnology and Biological Sciences Research Council (BBSRC), who strategically support the Babraham Institute, and grants from the BBSRC, Wellcome Trust and European Commission Network of Excellence EpiGeneSys to Dr Peter Rugg-Gunn. As a collaborative project, the work was also supported by the Medical Research Council in the UK and the Canadian Institutes for Health.

ENDS

Notes for editors

Publication reference: Novo et al. (2016) The pluripotency factor Nanog regulates pericentromeric heterochromatin organization in mouse embryonic stem cells. Genes and Development 10.1101/gad.275685.115

About the Babraham Institute

The Babraham Institute, which receives strategic funding (a total of £27.3M in 2014-15) from the Biotechnology and Biological Sciences Research Council (BBSRC), undertakes international quality life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. The Institute’s research provides greater understanding of the biological events that underlie the normal functions of cells and the implication of failure or abnormalities in these processes. Research focuses on signalling and genome regulation, particularly the interplay between the two and how epigenetic signals can influence important physiological adaptations during the lifespan of an organism. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and healthier ageing. www.babraham.ac.uk

About BBSRC

BBSRC invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge, to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.

Funded by Government, BBSRC invested over £509M in world-class bioscience in 2014-15. We support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals.

For more information about BBSRC, our science and our impact see: www.bbsrc.ac.uk.
For more information about BBSRC strategically funded institutes see: http://ift.tt/1zoWnT2.

External contact

Media enquiries: Knowledge Exchange and Commercialisation Office, Babraham Institute

[email protected]
+44 1223 496260

Contact

BBSRC Media Office

[email protected]
+44 1793 414694

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Gene therapy shows long-term benefit for treating rare blindness

Pioneering gene therapy has restored some vision to patients with a rare form of genetic blindness for as long as four years, raising hopes it could be used to cure common causes of vision loss, new University of Oxford research shows.

A technique which involves injecting a virus into the eye to deliver billions of healthy genes to replace a key missing gene for choroideremia sufferers has provided sustained improvement in vision for up four years for some patients.

There have recently been questions about the long term efficacy of gene therapy, but now we have unequivocal proof that the effects following a single injection of viral vector are sustained.

Professor Robert MacLaren, Nuffield Department of Clinical Neurosciences

This provides the strongest evidence so far in humans that the effects of gene therapy are potentially permanent and could therefore provide a single treatment cure for many types of inherited blindness. These include retinitis pigmentosa, which affects young people, and age-related macular degeneration, which affects the older age group.

Reporting the results this week in the New England Journal of Medicine, doctors from the University of Oxford examined the vision of six patients up to four years after receiving gene therapy at Oxford's John Radcliffe Hospital. These six were the first in the world to have the procedure for choroideremia in a trial funded by the Department of Health and the Wellcome Trust.

The gene therapy treatment was designed to slow or stop sight loss, however, two of the patients experienced a significant improvement in vision that was sustained for at least four years, despite a decline in their untreated eyes over this period. A further three maintained their vision in their treated eyes throughout this period. The sixth patient who had a lower dose had a slow decline in vision in both eyes.

It is hoped that gene therapy would ideally be applied to patients early in the disease process to prevent sight loss because the treatment is expected to be long lasting. Patients with choroideremia are missing a key gene in their retina and the technique involves injecting a virus to deliver billions of healthy genes to replace the missing gene.

Professor Robert MacLaren, the lead investigator of the study, said: 'There have recently been questions about the long term efficacy of gene therapy, but now we have unequivocal proof that the effects following a single injection of viral vector are sustained. Even sharpening up the little bit of central vision that these patients have can give them considerable independence.

'Gene therapy is a new technique in medicine that has great potential. As we learn more about genetics we realise that correcting faulty genes even before a disease starts may be the most effective treatment. Gene therapy uses the infectious properties of a virus to insert DNA into a cell, but the virial DNA is removed and replaced with DNA that is reprogrammed in the lab to correct whichever gene is faulty in the patient.

'In this case, success in getting a treatment effect that lasts at least several years was achieved because the viral DNA had an optimal design and the viral vector was delivered into the correct place, using advanced surgical techniques. In brief, this is the breakthrough we have all been waiting for.'

Dr Stephen Caddick, Director of Innovation at the Wellcome Trust, added: 'To permanently restore sight to people with inherited blindness would be a remarkable medical achievement.

'This is the first time we’ve seen what appears to be a permanent change in vision after just one round of treatment. It’s a real step forwards towards an era where gene therapy is part of routine care for these patients.'

Jonathan Wyatt, the first patient in the world to be treated with this gene therapy is still sight impaired, but he was able to double the level of vision in his treated left eye, which has been maintained for four years so far. The retired barrister, 68, of Bristol, suffered vision problems since the age of 20. The right eye has continued to degenerate and the left eye is now dominant.

Mr Wyatt, married to Diana, for nearly 30 years, could read 23 letters in eye chart tests prior to the operation but by three-and-a-half years could read 44.

Mr Wyatt said: 'I feel very lucky, privileged and honoured to be part of the fantastic John Radcliffe research group. I feel that even though I am the meat in a sandwich, my life will be making a contribution to help others.

'The left eye is much improved to such an extent that I use it mostly to get about these days. It has substantially improved, it is fantastic.

'It has made me more independent, I think I would be more dependent. I think I would feel more cautious about train journeys on my own. Without it I think I would be tapping with a white stick, I think I would have remained cheerful but I would be at home more.'

Joe Pepper, a 24-year-old teacher from Croydon, who was the last patient to receive the gene therapy treatment, said: 'I sat down and began the reading chart test on my treated right eye and I read the first two lines and for the first time in my memory I read on and on.

'I will remember that day for the rest of my life. I could see more than before the operation. I could read four lines beyond where I was earlier. I laughed and shed a tear. It was special.

'Six months on from the surgery the results have been more than I ever imagined. My vision now has a new found clarity and I am no longer putting stress on my vision when reading or looking into the distance. Instead of looking into the distance and seeing outlines of people or trees I am seeing their defined features. At night I now have a new found confidence in dimly lit areas that means I can feel independent and safe after dark.

'Without Professor MacLaren and his team, and their pioneering work I could have lost my sight and for the last 14 years I have feared I could. The work they do is special and I have nothing but thanks to them.'

The project is a collaboration between the University of Oxford and Oxford Hospitals NHS Foundation Trust with funding from the NIHR Oxford Biomedical Research Centre and the Department of Health and Wellcome Trust’s Health Innovation Challenge Fund. A follow on trial of 30 further patients has been funded by the Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and NIHR partnership.

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Gene therapy shows long-term benefit for treating rare blindness

95 per cent of GPs say they worry that lack of resources is putting patient care at risk

95% of GPs say they worry that lack of resources is putting patient care at risk and 98% say that without more resources, waiting times for GP appointments will increase

Almost half (45%) of NI GPs say they are planning to either leave general practice or reduce their hours in the next five years, and family doctors warn of potential future problems with access to general practice, with 15% saying it is unlikely or very unlikely that their current practice will be open in ten years time. In addition, 98% of GPs believe that, without more resources, waiting times for appointments will increase

The new figures from this ComRes poll also reveal that 93% of GPs here agree that their workload affects their ability to deliver high quality patient care.

Reacting to the findings, Chair of the Royal College of General Practitioners NI, Dr John O’Kelly said: “General practice in Northern Ireland is in serious difficulty. We need to see immediate action taken to tackle the challenges that family doctors are currently facing.

“Looking at the survey findings, the feelings of family doctors in NI have been made very clear. GPs are overworked, overtired and worried about being able to deliver sustainable, high quality health services to local communities in the future.

“It is appalling that more than nine in ten (93%) of family doctors feel that their workload affects their ability to deliver high quality patient care. General practice is the cornerstone of our health system and family doctors must be given the adequate tools in order to do their job effectively.

“We need the next Assembly to listen to GPs and invest in primary healthcare. The next Health Minister must reverse the negative trends in general practice and fully implement the recommendations from the GP-led Working Group to ensure the people of Northern Ireland will have the sustainable community-based health care that they deserve.

“We simply do not have enough GPs to manage the increasing demands on the service. RCGP NI has been calling on the government to increase the number of GPs in Northern Ireland by 400 by 2020. Alongside the development of the entire general practice team, this will help ensure that the best quality health care service is available to everyone.

“Being a GP is a challenging, yet most rewarding job but we need sufficient investment in order to allow the service to thrive. The College has consistently laid out why the profession needs 11% of the total health and social care budget in Northern Ireland.

“Such is the scale of the crisis in the primary care sector that 85% of GPs in NI worry that general practice will be unrecognisable as we know it by the time of the 2021 NI Assembly election. NHS England have recently backed general practice by increasing funding to almost 11% of the NHS budget. We need our politicians to commit to allocating this level of resource before we start to see practice closures and diminishing services across the entire region.”

Further Information

RCGP Press office: 020 3188 7574/7575/7581
Out of hours: 0203 188 7659
[email protected]

Notes to editor

The Royal College of General Practitioners is a network of more than 50,000 family doctors working to improve care for patients. We work to encourage and maintain the highest standards of general medical practice and act as the voice of GPs on education, training, research and clinical standards.

1. The Royal College of General Practitioners is the largest membership organisation in the United Kingdom solely for GPs. It aims to encourage and maintain the highest standards of general medical practice and to act as the ‘voice’ of GPs on issues concerned with education; training; research; and clinical standards. Founded in 1952, the RCGP has just over 50,000 members who are committed to improving patient care, developing their own skills and promoting general practice as a discipline.
2. Polling was conducted by ComRes on behalf of RCGPNI. 100 GPs in NI were surveyed online between 30 March and 19 April 2016. Full data tables are available at www.comres.co.uk.
3. The RCGP NI election campaign video can be found at http://ift.tt/1QGNa0c
4. If you would like any further information, please contact Clare Higgins on T: 020 3188 7726  E: [email protected]

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95 per cent of GPs say they worry that lack of resources is putting patient care at risk

Health system fails to prepare patients for reality of psoriatic arthritis

One of the recommendations of the study is that more account is taken of the emotional damage caused by the condition, by improving resources such as websites and leaflets. More psychologists, particularly those with a specialist interest in rheumatism should also be involved during the course of treatment.

Dr Bundy added, “The problems that came to light in this study are all treatable. With the right help and information, people can gain more confidence and recover quality of life. The prevalence of suicidal thoughts among this group is not yet known, but where it exists, effective and timely help could make a difference.”

Paper, ‘Distress, misperceptions, poor coping and suicidal ideation in psoriatic arthritis: a qualitative study’, was published in Rheumatology’. doi:10.1093/rheumatology/kew009

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Inadequate financial savings tied to increased childhood health risks

Study links “asset poverty” to higher risk of childhood obesity and chronic illness, as well as overall health of children

Dr. Adam Schickedanz discusses why the connection between a family’s savings is a better predictor of childhood health than income.

The connection between a family’s income and childhood health has been well-established, with lower income linked to poorer health and a greater likelihood of more chronic conditions. Now a new study by UCLA researchers shows that the size of the paycheck is not all that matters when it comes to children’s health risks. So does the amount that a family has tucked away in savings.

The study is the first to look at child health in the context of what economists call “asset poverty,” or economic strain caused by a lack of ready financial resources such as savings, rather than income relative to the Federal Poverty Level. The study abstract will be presented at the Pediatric Academic Societies annual meeting on May 3.

UCLA researchers found that children in households with less than three months of savings had a substantially higher risk of obesity and chronic illnesses — and worse overall health — than children in households with more money set aside, even if the families were earning an adequate income. Having enough savings to cover basic expenses for three months is considered by many economists and financial planners to be the minimum target amount needed to avoid slipping into debt in the event of a financial shock, such as a car repair or short-term job loss.

Lead author Dr. Adam Schickedanz, a clinical instructor in pediatrics at the David Geffen School of Medicine at UCLA and a Robert Wood Johnson clinical scholar, said that savings is an aspect of socioeconomic status that is increasingly relevant. The proportion of American households living in asset poverty now exceeds 40 percent, he said, and the proportion of families with children living in asset poverty is more than 50 percent, or more than double the proportion living in income poverty.

“The findings showed that the longer families lived paycheck-to-paycheck, the worse their children's health risk. The strong associations between wealth and child health were independent of other key factors known to influence child health, such as parental income, education, race and age,” Schickedanz said. “In fact, the study showed the differences in children’s health tied to household wealth level were most often equal to or larger than differences associated with income or education level — the factors typically used to measure economic-related health risks facing children and families.”

To conduct the study, researchers examined a nationally representative group of 2,907 children and their families using data collected between 1997 and 2007 from the Panel Study on Income Dynamics. The “Panel Study on Income Dynamics” is the longest-running economic survey of families in the world, beginning in 1969 as part of the Johnson administration’s War on Poverty, and it has tracked the economic prosperity and health of four generations of American ever since.

Compared to children in wealthier families, those living in asset poverty had a 25 percent higher risk of worse overall health, and each additional year in asset poverty increased the risk by 20 percent, according to the study. In addition, children in families living in asset poverty were 70 percent more likely to be obese and 25 percent more likely to have a chronic illness.

“Wealth is a key dimension of socioeconomic status in children that can no longer be overlooked when it comes to child health,” Schickedanz said. “Policymakers should be aware that efforts to help families save more money and reduce asset poverty and wealth inequality are likely to benefit health across generations.”

The next phase of research will evaluate the health impact of financial coaching programs that have been proven to help families in poor communities stretch their incomes further and increase their net worth. If these interventions can improve families’ health and well-being, they might offer a new way for health care systems to help low-income patients improve both their financial and physical health at the same time.

Additional authors include Dr. José Escarce and Dr. Paul Chung, both of UCLA. The authors have no conflicts to disclose relevant to the study.

The research was supported by The Robert Wood Johnson Foundation, the National Institutes of Health (National Institute of Child Health and Human Development) and the UCLA Children’s Discovery and Innovation Institute.

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Inadequate financial savings tied to increased childhood health risks

New Analysis Shows Hexvix®/Cysview® Significantly Prolongs Time To Progression Of Bladder Cancer

Photocure ASA (OSE: PHO), is pleased to announce publication of a new analysis demonstrating that Blue Light Cystoscopy (BLC) with Hexvix/Cysview significantly prolonged time to disease progression and showed a trend in the reduction of the rate of progression in patients with non-muscle invasive bladder cancer (NMIBC). The data was published online in the April issue of the peer reviewed journal, Bladder Cancer.

The new analysis of a long term follow-up study classified patients according to the new International Bladder Cancer Group (IBCG) definition of disease progression, which was created to more accurately identify patients with high risk of developing invasive disease at an earlier stage, in order to optimize treatment decisions¹.

Using the new IBCG definition, overall time to disease progression was significantly longer in the BLC with Hexvix/Cysview group (p=0.05). Additionally, there was a clear trend towards a reduction in the rate of progression, with 31 (12.2%) BLC with Hexvix/Cysview and 46 (17.6%) white light only patients progressing after 4.5 years (p=0.085). This trend was particularly pronounced in patients from having smaller, papillary lesions (stage Ta) to high risk flat lesions (CIS): 4 (1.6%) in the Hexvix/Cysview group compared to 11 (4.2%) in the white light group.

Dr. Ashish M. Kamat MD, MBBS, FACS Professor Department of Urology, Division of Surgery, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas and lead author on the publication commented “The updated findings support the importance of improved tumor detection and resection of bladder tumors at an early stage and its impact on the long term prognosis for patients. These results confirm and extend the prior reported benefits of using BLC with Hexvix/Cysview over white light alone in the management of NMIBC, particularly at the first resection.”

Dr. Kjetil Hestdal, President & CEO of Photocure ASA added: “We are delighted to see the ever growing body of clinical evidence that supports the beneficial impact of BLC with Hexvix/Cysview for bladder cancer patients. Better detection and reduction in recurrence for patients undergoing BLC with Hexvix/Cysview has been extensively documented. This long term follow-up study analyzed with the new definition of progression further demonstrates that BLC with Hexvix/Cysview plays an important role in the management of bladder cancer and provides patients with sustained and long term benefits.”

In the original analysis, published in the Journal of Urology in 2012, the definition of progression was from non-muscle invasive to muscle invasive bladder cancer. That analysis demonstrated a prolonged time to recurrence with a trend towards less progression; after 4.5 years (median), 8 (3.1%) Hexvix/Cysview and 16 (6.1%) white light patients had progressed.

The new IBCG definition includes the following as indicators of disease progression: an increase in stage from Ta to CIS or T1, CIS to T1 (indicating invasion of the bladder lining or lamina propria), development of T2 or greater, lymph node disease (N+), distant metastasis (M1) or an increase in grade from low to high.

Hexvix/Cysview is a photosensitizing agent taken up selectively by the tumor cells in the bladder that when exposed to blue light during a cystoscopic procedure results in a bright pink fluorescence of the suspicious tissue. Using Hexvix as an adjunct to standard white light cystoscopy enables the urologist to better detect and remove lesions, leading to a reduced risk of recurrence and prolongation in time to disease progression.

###

Notes for Editors
“The Impact of Blue Light Cystoscopy with Hexaminolevulinate (HAL) on Progression of Bladder Cancer – A New Analysis,” by Kamat, Ashish M., Cookson, Michael, Witjes, J. Alfred, Stenzl, Arnulf, Grossman, H. Barton. It is published in Bladder Cancer, Volume 2, Number 2, 2016 by IOS Press. The article is freely available online: http://ift.tt/26A5h3v. 

For further information, please contact:

Kjetil Hestdal
President and CEO
Photocure ASA
Tel. +47 913 19 535
[email protected]

About Photocure ASA

Photocure ASA, headquartered in Oslo, Norway, is a specialty pharmaceutical company and world leader in photodynamic technology. Based on our unique propriety Photocure Technology® platform, Photocure develops and commercializes highly selective and effective solutions in disease areas with high unmet medical needs such as bladder cancer, HPV and precancerous cervical lesions and skin conditions. Our aim is to provide solutions that can improve health outcomes for patients worldwide.  Photocure is listed on the stock exchange (OSE: PHO).  Information about Photocure is available at www.photocure.com.

About Hexvix®/Cysview® is the trademark in the USA and Canada

Hexvix®/Cysview® (hexaminolevulinate hydrochloride) is an innovative breakthrough technology in the diagnosis and management of non-muscle-invasive bladder cancer. Hexvix®/Cysview® is approved in Europe, USA and Canada.

About bladder cancer

Bladder cancer is the fifth most common cancer in men with more than 380 000 new cases annually and more than 150 000² die of the disease. It has a high recurrence rate with an average of 61% in one year and 78% over five years, making the lifetime costs of managing bladder cancer one of the highest amongst all cancers. It is a costly, potentially progressive disease for which patients have to undergo multiple surveillance cystoscopies because of the high risk of recurrence. There is an urgent need to improve both the diagnosis and the management of bladder cancer for the benefit of patients and healthcare systems alike.

1. Lamm et al: Defining Progression in NMIBC. It is time for a new standard definition of Journal of Urology Vol 191, 20-27 January 2014
2. www.globocan.iarc.fr (05-11-2013)

The information is subject of the disclosure requirements acc. To 5-12 vphl (Norwegian Securities Trading Act)

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New Analysis Shows Hexvix®/Cysview® Significantly Prolongs Time To Progression Of Bladder Cancer

A New Discovery in the Fight against Cancer: Tumor Cells Switch to a Different Mode

When medication is used to shut off the oxygen supply to tumor cells, the cells adapt their metabolism in the medium term – by switching over to producing energy without oxygen.

This observation by biomedical scientists at the University of Basel and University Hospital Basel could be used for treatments that can inhibit tumor growth in the long term, as the researchers report in the latest issue of the journal Cell Reports.

One in three people still develop cancer at some point in their lives, and even now half of these cases result in death. There is therefore a demand for new approaches in the fight against cancer. Today, it is common knowledge that the disease develops in a series of stages. One of these stages, tumor angiogenesis, involves the formation of new blood vessels to supply oxygen and nutrients to the growing tumor.

Following anti-angiogenic therapy, tumors develop regions containing no blood vessels (green) and therefore no oxygen (red). The tumor cells are made visible by dyeing the nuclei blue. (Image: University of Basel, Department of Biomedicine)

Understanding the basics of how cancer forms has led to the development of increasingly targeted techniques for combating tumors: today, medications can simultaneously inhibit several signaling pathways that regulate tumor angiogenesis. Understanding of the molecular basis for this process has paved the way for the routine application of specific therapies in the clinical setting: for example, so-called anti-angiogenic therapy can be used to prevent the formation of the blood vessels that supply tumors. But this usually achieves only temporary success. Tumor growth is initially slowed or even stopped for a time; however, as the treatment goes on, the tumors begins to develop resistance to these therapies – and they start to grow again.

“An unexpected observation”

Now, the research group lead by Prof. Gerhard Christofori of the Department of Biomedicine at the University of Basel and University Hospital Basel has shown that, although the latest medications are effective at preventing blood vessel formation, the tumors can continue growing even without a supply of new blood vessels – an unexpected observation, as the researchers report in the publication.

Analysis of this finding from a biochemical and molecular genetic perspective revealed that the tumor cells convert to a different type of metabolism: they no longer produce energy using oxygen delivered via the blood vessels – but instead switch over to glycolysis, a form of anaerobic energy production. The lactic acid formed as a result is delivered to cells that are still receiving sufficient oxygen and that can use the lactic acid, together with the oxygen, to produce energy.

New therapies possible

The research group also showed that this specific mode of metabolism – and therefore the tumor’s growth – can be interrupted, namely by inhibiting anaerobic energy production or transport of the lactic acid. “Our findings open up new approaches for the optimization of anti-angiogenic therapies and for inhibiting tumor growth effectively in the long term,” says co-author Christofori about the group’s results.

Original paper

Laura Pisarsky, Ruben Bill, Ernesta Fagiani, Sarah Dimeloe, Ryan William Goosen, Jörg Hagmann, Christoph Hess, and Gerhard Christofori
Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy
Cell Reports (2016), doi: 10.1016/j.celrep.2016.04.028

---

Further information

Prof. Dr. Gerhard Christofori, Department of Biomedicine at the University of Basel and University Hospital Basel, tel. +41 61 267 35 62, email: [email protected]

Illustration

An image suitable for printing with this press release can be found in the media database.

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A New Discovery in the Fight against Cancer: Tumor Cells Switch to a Different Mode

To save suicidal teens, listen to their voice

High-tech acoustic software can help clinicians identify young people at risk and step in before lives are lost

BY Andrew Good Researchers are working on voice analysis to identify at-risk individuals. (Photo/Pixabay)

Suicide rates among Americans are on the rise, underscoring the need for early intervention. USC researchers tested and found high-tech acoustic software can identify teens at risk to help clinicians intervene before it’s too late.

The difference between suicidal and non-suicidal patients can be as subtle as the breathiness of their speech and the tension or pitch of their voices.

Through speech analysis of teen patients, researchers at USC and Cincinnati Children’s Hospital Medical Center (CCHMC) have identified specific vocal cues as indicators of suicide risk. Researchers were surprised to realize that some of the cues they had identified were non-verbal.

“If you want to assess a person’s risk to attempt suicide, it’s important to look at what they say, as well as how they say it,” said lead author Stefan Scherer of the USC Institute for Creative Technologies.

The study was published in IEEE Transactions on Affective Computing in January.

The third-highest cause of death

Suicide is the third-highest cause of death for American teens; identifying risk is critical among this group in particular because it is often hesitant to let others know that help is needed. It’s also a key problem among military veterans who worry that seeking out therapy or admitting to mental health problems might stigmatize them.

“We want to develop software and algorithms to help clinicians objectively measure these changes or have a ‘warning light’ as to suicide risk,” Scherer said.

The researchers used software to analyze the voices of 60 patients at the Cincinnati hospital — 30 of whom were suicidal. The patients, ages 13 to 18, had been interviewed in 2011 for a study by John Pestian, a professor of pediatrics, psychiatry and biomedical informatics at the University of Cincinnati and CCHMC. A trained social worker interviewed them for their background and family history, asking the patients open-ended questions about their fears, secrets and emotional struggles.

Scherer’s team analyzed the interviews using computer software that identified both verbal and non-verbal cues. Verbal content, such as mentioning death, repeated references to the past or heavy use of first-person pronouns (I, me, myself) were all common in the speech of suicidal patients. But what was surprising to researchers were the non-verbal cues.

Especially significant were the differences between suicidal and non-suicidal subjects. Suicidal subjects had breathier speech, differences in pitch and other subtle changes in the tenseness or harshness of their voices.

All of these cues are significant precisely because they are non-verbal, Scherer said.

“If you want to assess a person’s risk to attempt suicide, it’s important to look at what they say, as well as how they say it,” he said.

Open-ended questions

Non-verbal cues are much easier to identify because you can ask the patient anything. In the case of the clinical interviews, some of the open-ended questions weren’t even specifically about emotion. Patients were asked about their sleep habits and Internet usage, as well as more direct questions about past traumas.

Scherer characterized the study as part of a wave of innovative mental health research that uses technology in new ways.

“Technology brings a different set of eyes and ears to the field so doctors can focus on their actual work with an individual,” Scherer said. “Doctors don’t have a lot of time, and they’re trying to assess an individual’s risk. It enables them to go back into the nitty-gritty details of what the behavior was really like with an individual and maybe make better assessments.”

Scherer characterized the study as part of a wave of innovative mental health research that uses technology in new ways. It also marks the latest study by USC researchers to use voice analysis for signs of psychological trouble.

Last year, researchers at the USC Viterbi School of Engineering developed algorithms analyzing speech between couples — even predicting whether couples will stay together more accurately than relationship experts.

The study was sponsored by the U.S. Army Research Laboratory and the CCHMC’s Innovation Fund.

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To save suicidal teens, listen to their voice

Exposure to Particulate Air Pollutants Associated With Numerous Types of Cancer

Particulate matter is the term for particles found in the air, including hydrocarbons and heavy metals produced by transportation and power generation, among other sources, Thach explained. This study focused on ambient fine particulate matter, or matter with an aerodynamic diameter of less than 2.5 micrometers (PM_2.5).

For this study, Thach, Thomas, and colleagues enrolled 66,280 people who were age 65 or older when initially recruited between 1998 and 2001. The researchers did not have data on whether they had cancer before they were enrolled. Researchers followed the study subjects until 2011, ascertaining causes of death from Hong Kong registrations. Annual concentrations of PM_2.5 at their homes were estimated using data from satellite data and fixed-site monitors.

After adjusting for smoking status and excluding deaths that had occurred within three years of the baseline to control for competing diseases, the study showed that for every 10 microgram per cubic meter (µg/m3) of increased exposure to PM_2.5, the risk of dying from any cancer rose by 22 percent. Increases of 10 µg/m3 of PM_2.5 were associated with a 42 percent increased risk of mortality from cancer in the upper digestive tract and a 35 percent increased risk of mortality from accessory digestive organs, which include the liver, bile ducts, gall bladder, and pancreas.

For women, every 10 µg/m3 increase in exposure to PM_2.5 was associated with an 80 percent increased risk of mortality from breast cancer, and men experienced a 36 percent increased risk of dying of lung cancer for every 10 µg/m3 increased exposure to PM_2.5.

Thach and Thomas indicated possible explanations for the association between PM_2.5 and cancer could include defects in DNA repair function, alterations in the body’s immune response, or inflammation that triggers angiogenesis, the growth of new blood vessels that allows tumors to spread. In the case of the digestive organs, heavy metal pollution could affect gut microbiota and influence the development of cancer, the authors added.

In 2015, the International Agency for Research on Cancer (IARC) published a series of monographs on the evaluation of various carcinogenic risks. In a monograph on air pollution, the organization pointed out the difficulty of assessing the effects of pollution on multiple types of cancers, given their different etiologies, risk factors, and variability in the composition of air pollutants in space and time. The IARC also identified certain key components of air pollution, including particulates. The large scale of Thach and Thomas’s study, as well as its documentation of cancer-specific mortality, enables the detailed investigation of the contribution of particulate matter to these cancers, the authors said.

Thomas added that further research would be required to determine whether other countries experience similar associations between PM_2.5 and cancer deaths, but this study combined with existing research suggests that other urban populations may carry the same risks.

“The implications for other similar cities around the world are that PM_2.5 must be reduced as much and as fast as possible,” he said. “Air pollution remains a clear, modifiable public health concern.”

Thach said a limitation of the study is that it focused solely on PM_2.5. He said emerging research is beginning to study the effects of exposure to multiple pollutants on human health. He also cautioned that pollution is just one risk factor for cancer, and others, such as diet and exercise, may be more significant and more modifiable risk factors.

This study was funded by the Wellcome Trust. Thach and Thomas declare no conflicts of interest.

AACR

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Exposure to Particulate Air Pollutants Associated With Numerous Types of Cancer

Magnetic nanoparticles may reveal early traces of cancer

Rice University students’ computer program aids MD Anderson diagnostic initiative

HOUSTON  ) – Nanoscale magnets offer a new way to find faint, early traces of cancer in patients, according to Rice University students working on a method to capitalize on the magnets’ properties. Three Rice computational and applied mathematics students are refining a program to analyze magnetic relaxometry signals from iron-oxide nanoparticles that find and attach themselves to cancerous cells.

Rice seniors Brian Ho, Rachel Hoffman and Eric Sung have developed a novel way to analyze data for cancer researchers who hope to use magnetic nanoparticles to locate signs of cancer that X-rays would never spot.

All magnets (or materials prone to magnetism) have magnetic “moments,” like invisible needles that can move and react to magnetic fields, even if their physical hosts can’t.

These ghostly needles align when exposed to an external magnetic field; when the field is removed, they “relax” once again. Relaxometry measures this latter characteristic. It turns out the moments relax at a very different rate when they belong to nanoparticles that are bound to cancer cells.

The students are working with Rice adviser Béatrice Rivière, the Noah G. Harding Chair and a professor of computational and applied mathematics, and doctors at the University of Texas MD Anderson Cancer Center in Houston to develop computer programs that analyze “traces” of these moments as they relax. Albuquerque, N.M.,-based Senior Scientific, in collaboration with MD Anderson, is developing a commercial relaxometry platform for the early detection of cancer.

The 25-nanometer superparamagnetic iron-oxide nanoparticles are enhanced with antibody proteins that target biomarker proteins produced by cancer cells, Sung said. “Once they bind to the cells, their range of motion is severely restricted, and this restricted movement is pretty important,” he said. “Once you apply an external magnetic field, the particles’ dipoles will align to counteract the field. Once the dipoles face each other, then you have a magnetic field of essentially zero. But the interesting part to us is what comes after.”

The students and the MD Anderson team are working to quantify this relaxation phase because it marks the location of cancer cells in lab samples and in mice.

Unbound nanoparticles will randomly reorient themselves in less than a millisecond, but because antibody-associated nanoparticle complexes that are bound to cancer cells are restricted in their movement, their magnetic relaxation is a lot slower – up to a second, Sung said. “We’re figuring out exactly what that means.” he said.

The team noted today’s best cancer detection methods only catch tumors with more than 10 million cancer cells. The new approach has the potential to detect tumors with as few as 20,000 cells. The students expect methods that rely on relaxometry will also be safer than current methods that expose patients to ionizing radiation.

The students’ software addresses two problems that can corrupt relaxometry data. One is that physical motion – like a patient’s breathing – can displace the target signal and skew the results.  The other is what the students call “flux jumps,” a recording artifact that causes a wholesale shift in the data. “The flux jump has to do with the way it’s measured,” Sung said. “But we’ve figured out an algorithm to take care of both these things. And it looks pretty nice.”

Hoffman said the Rice team brought new perspective to the problem recognized by MD Anderson’s David Fuentes, an assistant professor in the Department of Imaging Physics, and his colleagues. “They were looking at it very theoretically, whereas we look at it more pragmatically,” she said. “We researched what we can do with this particular data, as opposed to trying to develop an algorithm that could be applied to any data set.”

“Indeed, the senior design team’s contribution to motion correction and flux-jump detection will have a lasting impact and will be incorporated into future analysis pipelines,” Fuentes said.

Ho said the Rice team’s next step is to create a way to generate synthetic data traces to test the program. “Once we’re able to put in some flux jumps and breathing spikes, we can quantify how good our algorithm is,” he said.

-30-

Follow Rice News and Media Relations via Twitter @RiceUNews

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Rice Department of Computational and Applied Mathematics: www.caam.rice.edu

MD Anderson Department of Imaging Physics: http://ift.tt/1VYOYtw

George R. Brown School of Engineering: http://ift.tt/1O5CCcW

Image for download:

0425_NANOPARTICLE 1 SMALL
 

http://ift.tt/1VYOWBI

Rice University engineering students are helping to maximize the promise of magnetic nanoparticles to find faint traces of cancer in patients. From left: Brian Ho, Eric Sung and Rachel Hoffman. (Credit: Jeff Fitlow/Rice University)

Located on a 300-acre forested campus in Houston, Rice University is consistently ranked among the nation’s top 20 universities by U.S. News & World Report. Rice has highly respected schools of Architecture, Business, Continuing Studies, Engineering, Humanities, Music, Natural Sciences and Social Sciences and is home to the Baker Institute for Public Policy. With 3,910 undergraduates and 2,809 graduate students, Rice’s undergraduate student-to-faculty ratio is 6-to-1. Its residential college system builds close-knit communities and lifelong friendships, just one reason why Rice is ranked No. 1 for best quality of life and for lots of race/class interaction by the Princeton Review. Rice is also rated as a best value among private universities by Kiplinger’s Personal Finance. To read “What they’re saying about Rice,” go to http://ift.tt/1YXtco0.
Editor’s note: A link to an image for download appears at the end of this release.

David Ruth
713-348-6327
[email protected]

Mike Williams
713-348-6728
[email protected]

Editor’s note: A link to an image for download appears at the end of this release.

David Ruth
713-348-6327
[email protected]

Mike Williams
713-348-6728
[email protected]

Rice University students’ computer program aids MD Anderson diagnostic initiative  

HOUSTON – (April 28, 2016) – Nanoscale magnets offer a new way to find faint, early traces of cancer in patients, according to Rice University students working on a method to capitalize on the magnets’ properties. Three Rice computational and applied mathematics students are refining a program to analyze magnetic relaxometry signals from iron-oxide nanoparticles that find and attach themselves to cancerous cells.

Rice seniors Brian Ho, Rachel Hoffman and Eric Sung have developed a novel way to analyze data for cancer researchers who hope to use magnetic nanoparticles to locate signs of cancer that X-rays would never spot.

All magnets (or materials prone to magnetism) have magnetic “moments,” like invisible needles that can move and react to magnetic fields, even if their physical hosts can’t.

These ghostly needles align when exposed to an external magnetic field; when the field is removed, they “relax” once again. Relaxometry measures this latter characteristic. It turns out the moments relax at a very different rate when they belong to nanoparticles that are bound to cancer cells.

The students are working with Rice adviser Béatrice Rivière, the Noah G. Harding Chair and a professor of computational and applied mathematics, and doctors at the University of Texas MD Anderson Cancer Center in Houston to develop computer programs that analyze “traces” of these moments as they relax. Albuquerque, N.M.,-based Senior Scientific, in collaboration with MD Anderson, is developing a commercial relaxometry platform for the early detection of cancer.

The 25-nanometer superparamagnetic iron-oxide nanoparticles are enhanced with antibody proteins that target biomarker proteins produced by cancer cells, Sung said. “Once they bind to the cells, their range of motion is severely restricted, and this restricted movement is pretty important,” he said. “Once you apply an external magnetic field, the particles’ dipoles will align to counteract the field. Once the dipoles face each other, then you have a magnetic field of essentially zero. But the interesting part to us is what comes after.”

The students and the MD Anderson team are working to quantify this relaxation phase because it marks the location of cancer cells in lab samples and in mice.

Unbound nanoparticles will randomly reorient themselves in less than a millisecond, but because antibody-associated nanoparticle complexes that are bound to cancer cells are restricted in their movement, their magnetic relaxation is a lot slower – up to a second, Sung said. “We’re figuring out exactly what that means.” he said.

The team noted today’s best cancer detection methods only catch tumors with more than 10 million cancer cells. The new approach has the potential to detect tumors with as few as 20,000 cells. The students expect methods that rely on relaxometry will also be safer than current methods that expose patients to ionizing radiation.

The students’ software addresses two problems that can corrupt relaxometry data. One is that physical motion – like a patient’s breathing – can displace the target signal and skew the results.  The other is what the students call “flux jumps,” a recording artifact that causes a wholesale shift in the data. “The flux jump has to do with the way it’s measured,” Sung said. “But we’ve figured out an algorithm to take care of both these things. And it looks pretty nice.”

Hoffman said the Rice team brought new perspective to the problem recognized by MD Anderson’s David Fuentes, an assistant professor in the Department of Imaging Physics, and his colleagues. “They were looking at it very theoretically, whereas we look at it more pragmatically,” she said. “We researched what we can do with this particular data, as opposed to trying to develop an algorithm that could be applied to any data set.”

“Indeed, the senior design team’s contribution to motion correction and flux-jump detection will have a lasting impact and will be incorporated into future analysis pipelines,” Fuentes said.

Ho said the Rice team’s next step is to create a way to generate synthetic data traces to test the program. “Once we’re able to put in some flux jumps and breathing spikes, we can quantify how good our algorithm is,” he said.

-30-

Follow Rice News and Media Relations via Twitter @RiceUNews

Related Materials:

Rice Department of Computational and Applied Mathematics: www.caam.rice.edu

MD Anderson Department of Imaging Physics: http://ift.tt/1VYOYtw

George R. Brown School of Engineering: http://ift.tt/1O5CCcW

Image for download:

http://ift.tt/1VYOWBI

Rice University engineering students are helping to maximize the promise of magnetic nanoparticles to find faint traces of cancer in patients. From left: Brian Ho, Eric Sung and Rachel Hoffman. (Credit: Jeff Fitlow/Rice University)

Located on a 300-acre forested campus in Houston, Rice University is consistently ranked among the nation’s top 20 universities by U.S. News & World Report. Rice has highly respected schools of Architecture, Business, Continuing Studies, Engineering, Humanities, Music, Natural Sciences and Social Sciences and is home to the Baker Institute for Public Policy. With 3,910 undergraduates and 2,809 graduate students, Rice’s undergraduate student-to-faculty ratio is 6-to-1. Its residential college system builds close-knit communities and lifelong friendships, just one reason why Rice is ranked No. 1 for best quality of life and for lots of race/class interaction by the Princeton Review. Rice is also rated as a best value among private universities by Kiplinger’s Personal Finance. To read “What they’re saying about Rice,” go to http://ift.tt/1YXtco0.

- See more at: http://ift.tt/1YXtcEg

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Magnetic nanoparticles may reveal early traces of cancer

The good life: Good sleepers have better quality of life and less depression

DARIEN, IL – Getting six to nine hours of sleep per night is associated with higher ratings for quality of life and lower ratings for depression, suggests a research abstract that will be presented Tuesday, June 14, in Minneapolis, Minn., at SLEEP 2011, the 25th Anniversary Meeting of the Associated Professional Sleep Societies LLC (APSS).

Results show that people with a “normal” sleep duration of six to nine hours per night had higher self-reported scores for quality of life and lower scores for depression severity compared to short and long sleepers.  These differences were statistically significant in all comparisons.  Among patients who reported having perfect health, there were a higher percentage of normal sleepers, who also had significantly lower scores for depression severity compared to short and long sleepers with perfect health.

“These results are important because they provide more information about the importance of getting enough sleep, which is usually six to nine hours per night,” said principal investigator Dr. Charles Bae, neurologist at the Cleveland Clinic Sleep Disorders Center in Ohio.  “People may already expect that their quality of life could be decreased when they do not get enough sleep, but they may not realize that sleeping too much can also have a negative impact.”

Bae and colleagues analyzed data from 10,654 patient records, which were collected from January 2008 to May 2010.  Study subjects had a mean age of about 52 years.  Quality of life was assessed using the EQ-5D questionnaire, a standardized measure of health outcome.  The nine-item Patient Health Questionnaire was used as a screening tool for depression.  Generalized estimating equations were used to account for multiple visits per patient, and a multi-variable logistic regression model adjusted for demographic differences such as age, gender, race and marital status.  Short sleep was defined as less than six hours per night, and long sleep was classified as more than nine hours per night. 

“It was surprising to see that sleeping less than six hours and more than nine hours is associated with a similar decrease in quality of life and increase in depressive symptoms,” said Bae.  “I thought that there would be changes in quality of life and degree of depressive symptoms for short and long sleepers, but did not expect that those changes would be similar in both groups.”

The American Academy of Sleep Medicine reports that individual sleep needs vary.  However, most adults need about seven to eight hours of nightly sleep to feel alert and well rested during the day. 

The SLEEP 2011 abstract supplement is available for download on the website of the journal SLEEP at http://ift.tt/1nRdY6x. 

A joint venture of the American Academy of Sleep Medicine and the Sleep Research Society, the annual SLEEP meeting brings together an international body of more than 5,000 leading clinicians and scientists in the fields of sleep medicine and sleep research.  At SLEEP 2011 (www.sleepmeeting.org), more than 1,000 research abstract presentations will showcase new findings that contribute to the understanding of sleep and the effective diagnosis and treatment of sleep disorders such as insomnia, narcolepsy and sleep apnea.

Abstract Title: Effect of total sleep time on quality of life and depression
Abstract ID: 0771
Presentation Date: Tuesday, June 14, 2011
Presentation Type: Poster - #211
Presentation Time: 10:30 a.m. – 11:30 a.m.

###

CONTACT: Doug Dusik, 630-737-9700 ext. 9345, [email protected]

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Focus on Transitional Care Reduces Hospital Readmissions in Stroke Patients

WINSTON-SALEM, N.C. – A transitional stroke clinic developed by doctors and nurse practitioners at Wake Forest Baptist Medical Center reduced 30-day readmission rates by 48 percent, according to a study published in the April 28 online issue of the journal Stroke.

The study’s goal was to determine if a structured transitional stroke clinic led by nurse practioners could reduce 30-day and 90-day hospital readmission rates.

“The needs of patients discharged directly home after suffering a stroke are often complex,” said Cheryl Bushnell, M.D., director of the Stroke Center at Wake Forest Baptist and lead author of the study.

“Patients are faced with physical and cognitive limitations, complex medication regimens, new diagnoses of chronic conditions and lack of social support. These barriers challenge independence and stroke recovery and leave patients at high risk for readmissions.”

The study evaluated 510 stroke or transient ischemic attack patients who had been discharged to their homes over a three-year period. The Wake Forest Baptist transitional care model included follow-up phone calls within a week of discharge and follow-up clinic visits within two to four weeks of discharge.

The researchers found that a visit to the stroke clinic was associated with a 48 percent lower risk of 30-day readmissions compared to patients who did not attend the follow-up clinic visit. A clinic visit did not affect 90-day readmission rates. A limitation of the study was that only readmissions at Wake Forest Baptist were included.

“A lot of stroke programs are doing follow-up phone calls to patients, but our data shows that phone calls alone are not good enough to reduce readmissions,” Bushnell said. “It is really important for patients to be engaged in their own stroke recovery, and part of that involves coming to clinic and making sure they get all the services they need.”

Bushnell also said that primary care doctors caring for stroke patients should be alert to changes that are hallmarks of stroke: patients not thinking as clearly as they used to, memory problems, limited ability to use their hands or overall mobility issues, as well as depression and social isolation.

“We are at the forefront of a trend that really emphasizes the initial transition phase in post-stroke care,” Bushnell said. “The next steps include expanding our model to include community services and individualized electronic-care plans.”

A clinical trial is now being implemented across the state of North Carolina to determine if this model of care will improve stroke patients’ functional status and reduce caregiver burden 90 days post-stroke, Bushnell said. The trial is funded by the Patient-Centered Outcomes Research Institute.

Co-authors are: Christina Condon, M.S.N., N.P., Sarah Lycan, M.S.N., N.P., and Pamela Duncan, Ph.D., of Wake Forest Baptist. 

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USC Stem Cell study examines bone formation and vertebrate evolution

Colleagues explain how a shared gene directs the development of bone-forming cells

BY Cristy Lytal

Rendition of developing vertebrate bones. (Illustration/Kristen Chen/Courtesy of Developmental Cell)

With the emergence of bone, the diversity of life expanded to encompass the bone-forming vertebrates, a group of species ranging from the tiny frog Paedophryne amauensis to the mighty blue whale. Bone formation in vertebrates is linked to a shared gene, called Sp7 or Osterix, that acts early in establishing the bone-forming cells or osteoblasts.

In a new study in Developmental Cell, Hironori Hojo from the USC Stem Cell laboratory of Andrew McMahon and colleagues reveal how Sp7 directs the development of bone-secreting osteoblasts to fashion the skeleton.

“This is a wonderful example of how a narrow focus on the workings of a single gene illuminates bigger questions on the evolution of a skeletal scaffold we mammals share with fish, frogs, lizard and birds,” said McMahon, senior author, W.M. Keck Provost Professor and chair of the Department of Stem Cell Research and Regenerative Medicine at the Keck School of Medicine of USC.

The Sp7 gene encodes a protein known as a transcriptional regulator, which controls the activity of a large number of other osteoblast-specific genes. As other members of the Sp family regulate gene activity directly by binding to specific sequences encoded in the DNA, Sp7 was also thought to act this way. However, studies by Hojo and his colleagues demonstrate a very different mechanism: Sp7 partners with another group of transcriptional regulators, called the Dlx family, and relies on their DNA-binding action to control osteoblast genes.

Remarkably, there is a tight correlation between bone-forming ability and an Sp7-like gene. All major groups that comprise the diversity of vertebrates — such as zebrafish, frogs, geckos, alligators, birds, mice and humans — have an Sp7 gene.

Sea squirts and lampreys

In contrast, the closest living relatives to vertebrates, including sea squirts and lampreys, lack bone and an Sp7 gene. This correlation sheds light into a far-away, long-ago recess of the history of life on Earth: The emergence of Sp7 was likely connected to the evolution of bone formation in a common ancestor that gave rise to all modern vertebrates.

“This study provides a fascinating and compelling example of how the emergence of novel gene regulatory networks connects to new cellular capabilities in the evolutionary process — specifically here in the program of bone formation,” said Hojo, first author and postdoctoral research associate.

Additional co-authors include Shinsuke Ohba from the University of Tokyo, as well as Xinjun He and Lick Pui Lai from USC.

Support came from a National Institutes of Health grant (DK056246), the Japan Society for the Promotion of Science (23689079 and fellowships), a Uehara Memorial Foundation grant and a Takeda Science Foundation grant.

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Confused cells lead to genetic disorders such as heart problems, premature aging

By Inside Staff - It has been disorienting to the scientific and medical community why different, subtle changes in a protein-coding gene causes many different genetic disorders in different patients — including premature aging, nerve problems, heart problems and muscle problems. No other gene works like this.

According to a new study co-authored by Eric Hoffman, associate dean for research at the School of Pharmacy and Pharmaceutical Sciences, it has to do with cell “commitment.”

From initial conception of an egg and sperm, the cells that start dividing need to start making decisions as to what type of tissue or organ they are supposed to become (often called ‘cell lineages’).  This is part and parcel of ‘stem cells’ - e.g., how to get cells to make certain decisions to become nerve, heart, muscle or something else.

The study, “Laminopathies disrupt epigenomic developmental programs and cell fate,” published on April 20 in Science Translational Medicine, provides a unifying model for this process, and how it is disrupted by subtle mutations of the LMNA gene.

“A one-letter change, a one amino acid change, in this big protein, we see in patients that have severe muscle problems. Just a couple letters away, the same amino acid change instead causes loss of fat in other patients,” Hoffman said. “What we show is that’s because of subtle changes in the context of a cell trying to make a decision whether it’s going to be muscle or fat. It really needs to make sure the right areas are taken out of circulation. If you start taking the wrong areas or not enough areas or too many areas out of circulation, the cell starts getting confused; it’s not being given the right instructions.”

Different parts of the genome need to become attached to the outside of the nucleus (nuclear envelope — the key structure that separates animals with organs from bacteria), where these attached regions are taken out of genetic circulation (called heterochromatin — never to be used again). In a way, this attachment process defines what part of the genome is no longer useful to that particular cell/organ type, and this type of discarding of the DNA keeps a cell focused on what it is supposed to be (e.g., a heart cell not suddenly confused that it should be nerve instead).

“We provide a model for how these very subtle changes in a single protein cause such dramatically different clinical problems because of this process of taking parts of the genome out of circulation during cell commitment, when a cell’s trying to make these decisions,” Hoffman added.

Binghamton University, State University of New York

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What our gut tells us about the ‘hygiene hypothesis’

New research supports the ‘hygiene hypothesis,’ showing how differences in the bacterial communities found in the infant microbiome in westernized versus developing countries can affect the human immune response.

Over the past few decades, the healthcare community has observed an intriguing phenomenon: diseases related to the immune system—type 1 diabetes (T1D) and other autoimmune diseases, allergies, and the like—have taken hold in countries that have thriving, modern economies, while barely making a mark in the developing world. One of the best-supported theories to explain this peculiar public health pattern has been dubbed the “hygiene hypothesis.” The theory is based on the premise that exposure to pathogens early in life is actually beneficial to the education and development of the human immune system and that the sanitary conditions in “westernized” countries ironically hamper our natural immunity.

“If you look across the world geographically where incidence of autoimmune disease and allergies are high (and it’s mostly in the western world—America and Europe, etc.) and then superimpose a map that shows where diarrheal diseases and bacterial infections occur, you’ll see very little overlap. That suggests that exposure to bacteria and other ‘bugs’ may play a pivotal role in the immune system, and that we might be able to understand what that role is by studying the human microbiome,” says Aleksandar Kostic, a postdoctoral fellow in the lab of Ramnik Xavier at the Broad Institute of MIT and Harvard and co-first author of a new paper that appears this week in Cell.

The work, which was funded by JDRF, is the product of an extensive collaboration involving researchers at Broad, University of Helsinki and Aalto University in Finland, the Novartis Institute of Biomedical Research, and other organizations across the globe working together as part of the DIABIMMUNE Study Group. By looking at the gut microbiomes of infants from three different countries, the team uncovered evidence that not only supports the hygiene hypothesis, but also points to interactions among bacterial species that may account, at least in part, for the spike in immune disorders seen in western societies.

A “living laboratory”

The border of Finland and Russian Karelia separates two starkly contrasting economies, with a sevenfold difference in gross national product existing between “westernized” Finland and the more traditional, agrarian Russian Karelia. Nearby, just across the Gulf of Finland, sits Estonia, a country that has seen rapid economic growth and increased standard of living since the dissolution of the Soviet Union over twenty years ago.

Consistent with the hygiene hypothesis, the prevalence of T1D is six times lower in Russian Karelia than in Finland, even though there is little difference between the two populations in the frequency of the genetic risk factors that predispose individuals to, or protect them from, the disease. Estonia, meanwhile, has seen incidences of autoimmune disease increase in a linear fashion as its economy has improved over the past two decades.

The DIABIMMUNE Study Group saw in these three countries the perfect “living laboratory,” where genetics, climate, and the make-up of the community were relatively consistent, but the economic structure and standard of living were key variables. Over several years, the group recruited and began collecting monthly stool samples from infants in each of the three countries. Along with the samples, from which they would identify and quantify the bacteria that made up the infants’ gut microbiomes, they also collected lab tests and questionnaires about such topics as breastfeeding, diet, allergies, infections, and family history. They evaluated all of this data, which was collected from over 200 infants from one month after birth to age three, to see whether connections might exist between disease incidence and what they found in the microbiome.

By characterizing the microbial content of the stool samples, the team found a sharp distinction between the microbiomes of Finnish and Estonian infants and their Russian Karelian counterparts: the gut microbiomes of the Finnish and Estonian infants were dominated by Bacteroides species, while Russian Karelian infants had an overrepresentation of Bifidobacterium early in life and an overall greater variability in their microbiomes over the course of the three years that samples were collected.

“We can only speculate why this difference in bacterial populations exists; what we could show was what implications that difference in populations might have,” says Tommi Vatanen, a graduate student at the Broad and University of Aalto and co-first author of the Cell study. To do that, the Broad research team worked with researchers from Novartis, including co-first author Eva d’Hennezel and co-senior author Thomas Cullen, to compare and contrast the genes of the bacterial species they’d found.

“That led us to the lipopolysaccharides,” Vatanen says.

Not your father’s LPS

Lipopolysaccharides (LPS) are large molecules embedded in the outer membrane of certain types of bacteria, and are known to elicit an immune response in animals. In fact, LPS is so well-known for its ability to trigger the immune system that LPS from the bacteria E. coli is commonly used to stimulate immune cells in laboratory experiments. But, it turns out, not all LPS are created equal.

When the researchers looked at LPS signaling in the Russian Karelian microbiome, they saw a familiar pattern: E. coli LPS led the charge, likely performing its usual role triggering the immune response. However, when the researchers looked at LPS signaling in the Finnish and Estonian microbiomes, they found that the LPS from the Bacteroides species ruled the roost. What’s more, they discovered that the particular form of LPS found in Bacteroides fails to activate the immune system and even stifles the immune-activating LPS from the E. coli and other bacteria living in those communities.

“We believe that E. coli, which lives in the infant gut in all three countries, might be one of the immune educating bacteria responsible for training the immune system early in life. But, we found that if you mix Bacteroides with E. coli it can actually inhibit the immune-activating properties of E. Coli, and we suspect this might have consequences on the development of the immune system,” Vatanen explains.

“In the Finnish and Estonian infants, where Bacteroides dominates, the gut microbiome is immunologically very silent,” Kostic adds. “We believe that, later on, this makes them more prone to strong inflammatory stimuli.”

The researchers suspect that the LPS immune activation by E. coli (a common bacteria found in the human gut, not to be confused with the more serious strain known to cause food poisoning) seen in the Russian Karelian infants is reflective of the relationship humans developed with microbiota over the course of human evolution. The prevalence and dominance of Bacteroides, in contrast, is a more recent phenomenon related in some way to improved sanitation and standard of living.

Xavier, who is the corresponding author of the study, says that the LPS finding begins to explain mechanistically how differences in lifestyle brought on by economic disparities may be contributing to the rise of immune-related disease, as the hygiene hypothesis suggests.

“Our study underscores that the microbiome plays an important role in immune education, and when immune education goes wrong, individuals are set up for autoimmune disease,” says Xavier, who in addition to being an institute member of the Broad is also chief of gastroenterology at Massachusetts General Hospital, Kurt Isselbacher Professor of Medicine at Harvard Medical School, and co-director of MIT’s Center for Microbiome Informatics and Therapeutics. He notes that, by highlighting important principles about the relationship between healthy immune system development and exposure to pathogens – whether through skin-contact with unsanitized surfaces or through the air due to proximity to pets or farm animals – the findings may spur reflection about how humans interact with their environment.

The researchers say that they would next like to investigate how and why Bacteroides has come to dominate in the infant gut in these westernized countries. They also plan to expand their studies to include other geographic regions and hope to uncover additional mechanisms that help explain the connection between the microbiome and immune-related disease.

Michael Knip of the University of Helsinki also served as a co-senior author of the study. Other researchers who contributed to the work include: Heli Siljander, Eric Franzosa, Moran Yassour, Raivo Kolde, Hera Vlamakis, Timothy Arthur, Anu-Maaria Hämäläinen, Aleksandr Peet, Vallo Tillmann, Raivo Uibo, Sergei Mokurov, Natalya Dorshakova, Jorma Ilonen, Suvi Virtanen, Susanne Szabo, Jeff Porter, Harri Lähdesmäki, Curtis Huttenhower, and Dirk Gevers.

Paper cited:
Vatanen T, Kostic A, d’Hennezel E, et al. Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans. Cell. Online April 28, 2016. DOI: 10.1016/j.cell.2016.04.007

Broad Institute.

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What our gut tells us about the ‘hygiene hypothesis’

Hormone and neurotransmitter systems disturbed in alcoholics’ brains

The brain tissue of persons with alcohol dependence shows a variety of changes compared to non-alcoholic control persons. All alcoholics’ brains share some characteristics, but some are exclusive to the brain tissue of anxiety-prone type 1 alcoholics or impulsive type 2 alcoholics, according to a recent study from the University of Eastern Finland.

The researchers analysed post-mortem brain tissue from alcoholic persons and non-alcoholic controls. Alcoholics were divided into two groups on the basis of Cloninger’s typology: type 1 and type 2 alcoholics. Type 1 alcoholics develop alcohol dependence relatively late in life, and they are prone to anxiety. Type 2 alcoholics, on the other hand, develop alcohol dependence at a young age and they are characterised by antisocial behaviour and impulsiveness.

“From the viewpoint of the study setting, this division was made in order to highlight the wide spectrum of people suffering from alcohol dependence. The reality, of course, is far more diverse, and not every alcoholic fits into one of these categories,” says Olli Kärkkäinen, MSc (Pharm), who presented the results in his doctoral thesis.

One of the changes shared by all alcoholics were increased levels of dehydroepiandrosterone in the brain.  Dehydroepiandrosterone is a steroid hormone that affects the central nervous system. These increased levels can, for their part, explain alcohol tolerance, which develops as a result of long-term use and in which alcohol no longer causes a similar feeling of pleasure as before. Moreover, all alcoholics showed decreased levels of serotonin transporters in posterior insula and posterior cingulate cortex, brain regions associated with recognition of feelings and social cognitive processes. This finding could be related to social anxiety type behaviour seen in alcohol dependent individuals.

The study also found changes specific to the alcoholic type. For instance, the brain samples of impulsive, type 2 alcoholics had increased levels of AMPA receptors in the anterior cingulate cortex. By modifying the function of synapses between neurons, AMPA receptors play a role in the learning and regulation of, e.g., behavioural models. This can be associated with the impulsive nature of type 2 alcoholics. In type 1 alcoholics, however, changes were seen in the endocannabinoid system, which modulates stress responses, among other things. For example, docosahexaenoylethanolamide levels were increased in the amygdala, possibly associated with the anxiety prone nature of type 1 alcoholics.

“These findings enhance our understanding of changes in the brain that make people prone to alcoholism and that are caused by long-term use. Such information is useful for developing new drug therapies for alcoholism, and for targeting existing treatments at patients who will benefit the most,” Kärkkäinen says.

Globally, the disease burden caused by alcohol is estimated to be roughly as great as the burden caused by the use of all illegal substances together. In Western countries, approximately 10–15 per cent of the population are alcohol dependent.

The findings were originally published in Alcohol and Alcoholism, Psychiatry Research: Neuroimaging, and Alcohol.

The doctoral dissertation, entitled Post-mortem brains of alcoholics: changes in the glutamatergic, serotonergic, endocannabinoid and neuroactive steroid systems is available at http://ift.tt/24oxPuZ  

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Hormone and neurotransmitter systems disturbed in alcoholics’ brains

First Implantable Hemodynamic Monitoring Device in Single Ventricle Fontan Anatomy

The first IHM in a patient with Fontan anatomy and physiology enables real-time monitoring of central venous and pulmonary artery pressures

Columbus, OH - 4/28/2016

While the Fontan procedure has improved the short- and mid-term outcomes for patients born with single ventricle anatomy, long-term complications of Fontan circulation include heart failure. These complications are thought to be secondary to elevated central venous pressure, chronic venous congestion and low cardiac output.

In the recent case series published in the journal Catheterization and Cardiovascular Interventions, clinicians from The Heart Center at Nationwide Children’s Hospital and The Ohio State University Wexner Medical Center describe the first implantable hemodynamic monitor (IHM) placement in single ventricle Fontan anatomy. To date, Nationwide Children’s is the first pediatric hospital to perform the procedure, while Ohio State’s Wexner Medical Center is the first hospital to perform the procedure in a Fontan patient.

“This pressure gradient between central venous pressure and a combination of ventricular end diastolic pressure and resistance of flow across the pulmonary vascular bed is critical to cardiac output,” explains Darren Berman, MD, co-director of Cardiac Catheterization and Interventional Therapy in The Heart Center at Nationwide Children’s. “Recently, implantable hemodynamic monitors have been used to monitor pressures in patients with left heart disease.”

Noninvasive studies are unable to determine these pressures in the Fontan anatomy, thus limiting physicians’ understanding of the changes in pressure for a Fontan patient in heart failure, according to Curt Daniels, MD, director of Adolescent and Adult Congenital Heart Disease in The Heart Center at Nationwide Children’s and professor of Clinical Cardiology at The Ohio State University College of Medicine.

“Our ultimate goal is to improve care for patients with congenital heart disease,” says Dr. Daniels. “We are excited to be leading the charge to incorporate the use of this tool to learn more about the hemodynamic changes in real life ambulatory situations in Fontan patients.”

Two patients with single ventricle anatomy and Fontan physiology, both with New York Heart Association (NYHA) functional class III heart failure, were implanted with the CardioMEMS® HF System by Drs. Berman and Daniels. Real-time pulmonary artery catheter tracings were shown to correlate with IHM tracings in Fontan anatomy. Additionally, home transmission of IHM readings was successful.  

“We have shown early safety and feasibility of placement of the IHM in these two cases, and we will follow these patients to monitor the safety in the medium- and long-term, including assessment for pulmonary arterial thrombus,” says Dr. Berman, who is also an assistant professor at OSUCM.

Dr. Berman, Dr. Daniels and coauthor Elisa Bradley, MD, cardiologist at Nationwide Children's and assistant professor at OSUCM, hope that, as it does in patients with non-congenital heart disease, monitoring hemodynamic information from the transmissions will translate to improved fluid balance and heart failure symptoms, including reduced hospital admissions.

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Reference: Bradley EA, Berman D, Daniels CJ. First implantable hemodynamic monitoring device placement in single ventricle fontan anatomy. Catheterization and Cardiovascular Interventions.  2016 Mar 25. [Epub ahead of print]

Nationwide Children's Hospital
700 Children's Drive Columbus, Ohio 43205 614.722.2000

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First Implantable Hemodynamic Monitoring Device in Single Ventricle Fontan Anatomy

New mental health tool expedites patient evaluation

By Eric Sorensen, WSU science writer - SPOKANE, Wash. – Washington State University researchers have developed a new assessment tool to gauge the risk that someone with a mental illness will commit a crime. It could also speed up long-delayed competency evaluations for people awaiting trial.

The assessment provides a small but notable improvement over the current evaluation system, said Alex Kigerl, an assistant research professor in the WSU Department of Criminal Justice and Criminology.

Writing in a recent edition of the International Journal of Offender Therapy and Comparative Criminology, Kigerl and co-author Zachary Hamilton note a growing need to evaluate patients based on their risks to others and themselves before assigning them to inpatient hospital care or outpatient treatment.

“Often a balance must be struck between patient rights and freedoms and public safety and risk,” they write. Find the abstract for the article at http://ift.tt/1N5EK7Q.

State officials have struggled in recent years to ease overcrowding in mental-health facilities. They face legal action for delays in evaluating patients’ competency to stand trial. Last year, a U.S. district judge said Washington “is violating the constitutional rights of some of its most vulnerable citizens” by failing to undertake evaluations within the legal limit of seven days.

Kigerl’s new assessment aims to give mental health examiners a way to prioritize patients for quicker evaluation and help determine who should be involuntarily committed.

“If it’s looking like someone is at an exceptionally high risk of committing a violent crime, the process should be expedited for the patient to receive an evaluation and even to be hospitalized,” he said. “Less risky patients who are not likely to be a danger to other people can be put on a less restrictive alternative where they are in an outpatient setting and can receive treatment and visitations from mental health staff in a less oppressive environment.”

Kigerl and Hamilton prepared the assessment tool for the nonpartisan Washington State Institute for Public Policy, which the state legislature has asked to develop a risk-assessment instrument for patients with mental health issues. The researchers modified a tool used for offenders under state department of corrections supervision, called the Static Risk Assessment or SRA.

“Static” characteristics refer to characteristics that can’t be changed, like sex, age and prior offenses. The SRA only uses those items because they lend themselves to easy computation, saving the staff and evaluator time needed to manually assess dynamic factors like mental health and substance abuse, said Kigerl.

The researchers adapted the SRA to create the SRA for Mental Health Patients, or SRA-MHP, using a sample of 16,289 involuntarily committed patients and 8,713 patients undergoing evaluation after being charged with a crime. The researchers developed their assessment using data from half the pool of patients, then tested its predictive power by comparing it against the other half.

“The next step on this project would be to add dynamic characteristics – ones that can be changed – such as clinical variables about the patient, their mental health status, maybe chemical dependency, their employment and educational attainment and history,” said Kigerl. “If you look at a lot of literature on risk assessments, dynamic factors add slow but incremental improvement.”

The strength of the tool is measured by a figure called the “area under the curve,” or AUC. An AUC of .5 would mean a tool is about as good a predictor as a coin flip. An AUC of 1.0 is perfect.

The old evaluation method has an AUC of .79; the new SRA-MHP gave an AUC of .81.

“When we’re talking about violent offenses, a little bit can go a long way,” Kigerl said.

The research is in keeping with WSU’s Grand Challenges, research initiatives aimed at large societal problems. It is particularly relevant to the Sustaining Health challenge and its theme of promoting healthy communities, as well as the challenge Advancing Opportunity and Equity.

Contact:
Alex Kigerl, WSU assistant research professor, 503-936-3667, [email protected]

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New mental health tool expedites patient evaluation