A blood test to detect and classify cancer at its earliest stages

via Medical Xpress

Cancer scientists led by principal investigator Dr. Daniel De Carvalho at Princess Margaret Cancer Centre have combined “liquid biopsy,” epigenetic alterations and machine learning to develop a blood test to detect and classify cancer at its earliest stages.

The findings, published online today in Nature, describe not only a way to detect cancer, but hold promise of being able to find it earlier when it is more easily treated and long before symptoms ever appear, says Dr. De Carvalho, Senior Scientist at the cancer centre, University Health Network.

“We are very excited at this stage,” says Dr. De Carvalho. “A major problem in cancer is how to detect it early. It has been a ‘needle in the haystack’ problem of how to find that one-in-a-billion cancer-specific mutation in the blood, especially at earlier stages, where the amount of tumour DNA in the blood is minimal.”

By profiling epigenetic alterations instead of mutations, the team was able to identify thousands of modifications unique to each cancer type. Then, using a big data approach, they applied machine learning to create classifiers able to identify the presence of cancer-derived DNA within blood samples and to determine what cancer type. This basically turns the “one needle in the haystack” problem into a more solvable “thousands of needles in the haystack,” where the computer just needs to find a few needles to define which haystack has needles.

The scientists tracked the cancer origin and type by comparing 300 patient tumour samples from seven disease sites (lung, pancreatic, colorectal, breast, leukemia, bladder and kidney) and samples from healthy donors with the analysis of cell-free DNA circulating in the blood plasma. In every sample, the “floating” plasma DNA matched the tumour DNA. The team has since expanded the research and has now profiled and successfully matched more than 700 tumour and blood samples from more cancer types.

Beyond the lab, next steps to further validate this approach include analysing data from large population health research studies already under way in several countries, where blood samples were collected months to years before cancer diagnosis. Then the approach will need to be ultimately validated in prospective studies for cancer screening.

Learn more: A NEW APPROACH TO DETECTING CANCER EARLIER FROM BLOOD TESTS: STUDY

 

 

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First functional pacemaker cells for biological pacemaker therapy holds the promise of a lifelong cure

Dr. Stephanie Protze, post-doc fellow, and Dr. Gordon Keller, Director of the McEwen Centre for Regenerative Medicine, examine a cell cuture plate with human pacemaker cells generated from pluripotent stem cells for the first time. This development paves the way for a biological pacemaker taking the place of an electronic one. (Photo: Courtesy of the McEwen Centre for Regenerative Medicine)

Scientists from the McEwen Centre for Regenerative Medicine, University Health Network, have developed the first functional pacemaker cells from human stem cells, paving the way for alternate, biological pacemaker therapy.

Their findings, “Sinoatrial node cardiomyocytes derived from human pluripotent cells function as a biological pacemaker,” published online in Nature Biotechnology on Dec. 12, detail how human pluripotent stem cells can be coaxed in 21 days to develop into pacemaker cells, which regulate heart beats with electrical impulses. These human pacemaker cells were tested in rat hearts and were shown to function as a biological pacemaker, by activating the electrical impulses that trigger the contraction of the heart.

Pluripotent stem cells have the potential to differentiate into more than 200 different cell types that make up every tissue and organ in the body.

Sinoatrial node pacemaker cells are the heart’s primary pacemaker, controlling the heartbeat throughout life. Defects in the pacemaker can lead to heart rhythm disorders that are commonly treated by implantation of electronic pacemaker devices. Learning how to generate pacemaker cells could help in understanding disorders in pacemaker cells, and provide a cell source for developing a biological pacemaker. Biological pacemakers represent a promising alternative to electronic pacemakers, overcoming such drawbacks as a lack of hormonal responsiveness and the inability to adapt to changes in heart size in pediatric patients.

The researchers used a developmental-biology approach to establish a specific protocol for generating the pacemaker cells.

“What we are doing is human biology in a petri dish,” says Dr. Gordon Keller, Director of the McEwen Centre, the senior author, and a trailblazer in generating a wide variety of specialized cells from human stem cells. “We are replicating nature’s way of making the pacemaker cell.”

Based on previous findings in animal models, the researchers at the McEwen Centre tested and mapped out the specific developmental pathway of how human pluripotent stem cells become pacemaker cells.  This was achieved by testing different signaling molecules at different times throughout the 21 days to guide the cells towards their goal.

“It’s tricky,” says Dr. Stephanie Protze, a post-doctoral fellow in the laboratory of Dr. Keller and the first author in the Nature paper. “You have to determine the right signaling molecules, at the right concentration, at the right time to stimulate the stem cells.”

Adds Dr. Keller, who is also a Professor in the Department of Medical Biophysics at the University of Toronto: “We understand the importance of precision in developmental biology in setting out the process by which organisms grow and develop. We use that same precision in the petri dish because we are replicating these same processes.”

This is an in-vitro (petri dish) demonstration of pacemaker heart cells generated from human stem cells from the McEwen Centre for Regenerative Medicine. Shown are a cluster of human pacemaker cells on top of a sheet of human heart muscle cells. The pacemaker cells initiate and regulate the heartbeat of the heart cells below. (Video: Courtesy of the McEwen Centre for Regenerative Medicine)

Once the team established which signaling pathways are activated at different stages to generate the pacemaker cells, they demonstrated that the new pacemaker cells could initiate and regulate the heartbeat in rats.

The researchers noted that human clinical trials to test such biological pacemakers are from five to 10 years away, and that the next step is to launch safety and reliability pre-clinical trials on the pacemaker cells.

Meanwhile, researchers can use their new technology to make pacemaker cells from patients suffering from pacemaker dysfunction. They can then use these patient-specific cells to study the “disease in a (petri) dish” and to identify new drugs that will improve their pacemaker function.

Long term, the team hopes to develop a biological pacemaker to transplant into patients who need an electronic one. More than 10,000 electric pacemakers are implanted annually in Canada, with more than 120,000 patients living with them. They can last anywhere from five to 10 years or more – on the average about seven years. If successful, the biological pacemaker holds the promise of a lifelong cure.

Learn more: MCEWEN CENTRE SCIENTISTS PRODUCE FUNCTIONAL HEART PACEMAKER CELLS

 

 

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The Latest on: Biological pacemaker
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Simple Drug Regimen Cures Hepatitis C Virus in Patients After 12 Weeks

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Researchers at the Toronto Western Hospital (TWH) Liver Clinic have found that a simple drug regimen delivered over 12 weeks achieved sustained eradication of several genotypes of the hepatitis C virus (HCV) in 99 per cent of the trial’s patients.

The study, released today in the New England Journal of Medicine, showed that receiving a once daily drug combination of sofosbuvir-velpatasvir for a 12 week period was effective in both treatment-naïve and previously treated patients with HCV genotype 1, 2, 4, 5, or 6, including those with compensated cirrhosis (where scarring of the liver has occurred but patients have yet to experience symptoms as a result of it).

“This drug regimen changes the standard of care in treating patients with HCV – we can now cure almost everyone with a very simple treatment,” said Dr. Jordan Feld, Hepatologist, Francis Family Liver Clinic, TWH and the first author of the study. “It’s incredibly gratifying to be part of research where we not only cure a disease but can also think about eliminating HCV in Canada.”

Current approved treatments for chronic HCV are not equally effective in combating the virus’ different genotypes. Testing to determine the genotype and subtype of the virus is required before treatment could be initiated. But the combination of sofosbuvir-velpatasvir has been shown to be applicable to all strains of HCV, effectively eliminating the need to test for the viral genotype – an obstacle that often delayed treatment.

The regimen was tested in an international, randomized, double-blind placebo-controlled phase three trial conducted at 81 sites in eight different countries. After 12 weeks, 99 per cent of the 624 patients who had been treated with a daily tablet of sofosbuvir-velpatasvir experienced a sustained virologic response – the medical term for eradication or cure of HCV – meaning that patients remained free of the virus three months after completing treatment. None of the 116 patients receiving a placebo experienced the same result.

“This is truly a one size fits all treatment that is very easy to administer and extremely well tolerated,” said Dr. Feld. “Our challenge now is getting treatment to those who need it.  Over half of people living with hepatitis C remain undiagnosed. Fortunately this regimen, along with other advances in therapy, will allow us to move treatment out of specialty clinics so that we can deliver care and ideally cure all infected Canadians.”

Chronic HCV is known as a “silent” killer because symptoms often don’t appear until the liver is severely damaged. Left undiagnosed, HCV can lead to cirrhosis which can progress to liver failure or liver cancer. HCV is primarily spread by blood-to-blood contact and is associated with intravenous drug use, contact with poorly sterilized medical equipment and blood transfusions before 1992.

Approximately 170 million people are infected with chronic HCV worldwide with an estimated 252,000 in Canada. HCV causes the greatest burden of disease, measured in years of life lost, than any infectious disease in Canada.?

Read more: SIMPLE DRUG REGIMEN CURES HEPATITIS C VIRUS IN PATIENTS AFTER 12 WEEKS

 

 

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New Treatment for “Arthritis of the Spine” Prevents Paralysis

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Decompression surgery has a significant improvement in both the symptoms and quality of life of CSM patients at all levels of severity

In a world-first, decompression surgery has been shown to be  an effective procedure to treat cervical spondylotic myelopathy (CSM) – a common progressive, degenerative disease of the spine that can lead to paralysis – according to the results of a multi-centre clinical trial published today.

The study, with its use of multiple outcome measures to determine patient improvement, is the first research of its kind to show that decompression surgery has a significant improvement in both the symptoms and quality of life of CSM patients at all levels of severity.

The study, “Efficacy and Safety of Surgical Decompression in Patients with Cervical Spondylotic Myelopathy: Results of the AOSpine North America Prospective Multi-Center Study,” published in the Journal of Bone and Joint Surgery, found that patients with mild, moderate and severe CSM show significant recovery after undergoing decompression surgery – a procedure that alleviates pressure on the nerves of the spinal cord.

“The results of this trial support the use of decompression surgery as a viable treatment for Cervical Spondylotic Myelopathy and could lead to a change in practice to treat this condition,” said Dr. Michael Fehlings, neurosurgeon and Medical Director of the Krembil Neuroscience Centre, Toronto Western Hospital and the study’s lead author. “With few existing interventions available for these patients, it is encouraging to have data showing improvements in quality of life as a result of surgery, in some cases, even reversing serious neurological damage that could have resulted in paralysis.”

To date, the limited research and mixed reports have concluded that there was no added benefit from surgical intervention for CSM patients, and that the best approach was to monitor the progression of their condition and, in some cases, treat conservatively with non-surgical approaches. However, in 30 to 50 per cent of CSM cases, it has been observed that the condition gets progressively worse, impairing patients’ ability to walk and perform daily tasks such as dressing themselves and performing their own personal hygiene. This study clearly shows that many more patients with CSM could benefit from surgery than previously thought.

CSM is the leading cause of spinal cord dysfunction in the world, mostly affects people over the age of 50 and is very common in people of Asian and South Asian descent. Over time, the normal process of aging can sometimes lead to the narrowing of the spinal canal creating pressure on the spinal cord. As CSM progresses, it can cause neck stiffness, arm pain, numbness in the hands and, in severe cases, inhibits movement in limbs, impairs walking and can eventually lead to paralysis.

An unrecognized condition that is often misdiagnosed, CSM incidence and prevalence remain undetermined in Canada but, based on clinical caseloads and statistics from the U.S., is estimated to occur among 20 per cent of Canadians with approximately 10 per cent of them requiring surgery to treat the spinal cord dysfunction.

Other than medication to alleviate pain caused by the condition, there are no treatments available for CSM patients and surgery was usually only considered for the most severe cases in an attempt to stop further neurological deterioration.

From 2005 to 2007, researchers at 12 trial centres across North America, including Toronto Western Hospital, recruited patients with symptoms of CSM whose x-rays showed evidence of spinal cord compression. Patients were then categorized as having mild, moderate or severe CSM. The aim of the study was to evaluate the impact of decompression surgery on functional, quality of life and disability outcomes one year after patients had undergone surgery. The study also set out to determine, if the degree of improvement depended on the severity of CSM in patients before surgery.

Using a variety of outcome indices that measure the severity of functional and neurological impairment, such as the Nurick Grade and Neck Disability Index (NDI), researchers evaluated patients before and after surgery to determine the effect of the surgical intervention on the patients’ CSM.

At the one year follow up after decompression surgery, researchers found that the majority of study participants experienced statistically significant improvements in their condition. They also noted that for functional, disability and quality of life measures, the degree of improvement did not depend on the severity of preoperative symptoms, indicating that even cases of mild and moderate CSM benefit from surgical intervention.

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New ‘Biowire’ Technology Matures Human Heart by Mimicking Fetal Heartrate

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A new method of maturing human heart cells that simulates the natural growth environment of heart cells while applying electrical pulses to mimic the heart rate of fetal humans has led researchers at the University of Toronto to an electrifying step forward for cardiac research.

The discovery, announced this week in the scientific journal Nature Methods, offers cardiac researchers a fast and reliable method of creating mature human cardiac patches in a range of sizes.

“You cannot obtain human cardiomyocytes (heart cells) from human patients,” explains Milica Radisic, Canada Research Chair in Functional Cardiovascular Tissue Engineering and Associate Professor at the Institute of Biomaterials & Biomedical Engineering (IBBME) and the Department of Chemical Engineering. Because human heart cells — integral for studying the efficacy of cardiac drugs, for instance — do not naturally proliferate in large numbers, to date researchers have been using heart cells derived from reprogrammed human induced pluripotent stem cells (hiPSC’s), which tend to be too immature to use effectively in research or transplantation.

“The question is: if you want to test drugs or treat adult patients, do you want to use cells and look like and function like fetal cardiomyocytes?” asks Radisic, who was named a “Top Innovator Under 35” by MIT Technology Review and more recently was awarded the Order of Ontario and the Young Engineers of Canada 2012 Achievement Award. “Can we mature these cells to become more like adult cells?”

In response to the challenge, Radisic and her team, which includes graduate student Jason Miklas and Dr. Sara Nunes, a scientist at the University Health Network (UHN) in Toronto, created a ‘biowire’. Stem-cells derived human cardiomyocytes are seeded along a silk suture typical to medical applications. The suture allows the cells to grow along its length, close to their natural growth pattern.

Like a scene lifted from Frankenstein, the cells are then treated to cycles of electric pulses, like a mild version of a pacemaker, which have been show to stimulate the cells to increase in size, connect and beat like a real heart tissue.

But the key to successfully and rapidly maturing the cells turns out to be the way the pulses are applied.

Mimicking the conditions that occur naturally in cardiac biological development — in essence, simulating the way fetal heart rates escalates prior to birth, the team ramped up the rate at which the cells were being stimulated, from zero to 180 and 360 beats per minute.

“We found that pushing the cells to their limits over the course of a week derived the best effect,” reports Radisic.

Grown on sutures that can be sewn directly into a patient, the biowires are designed to be fully transplantable. The use of biodegradable sutures, important in surgical patches that will remain in the body, is also a viable option.

Miklas argues that the research has practical implications for health care. “With this discovery we can reduce costs on the health care system by creating more accurate drug screening.”

Read more . . .

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