CHAPEL HILL When Sabrina Shelton received her college degree in 2007, her thoughts were focused on her future. She considered grad school and going straight into the workforce, looking for housing and starting salaries, but what she didnt expect was a cancer diagnosis.

In April of 2008, Shelton, now 34, of Bedford, Virginia, was diagnosed with acute lymphoblastic leukemia, derailing her plans for the next phase of her life and fast tracking her into a month of cancer treatment, followed by a year of after care.

At the time, youre asking yourself, What do I want to do? What do I want? she said. Its the kind of existential question that were all asking ourselves as we graduated college, and then you get your answer.

For Shelton, her cancer journey started off smoothly. She was in remission within a month of starting treatment and was cancer-free for almost five years a standard cancer survivorship benchmark. But her cancer returned in 2012 and again in 2014. And still again in 2018.

I just wanted to get to that five-year mark so bad, Shelton said. I was of course upset about it and disappointed that it didnt at least get me to the five-year mark, because thats the target number that I wanted. With every recurrence, I do have those moments where when I initially hear about it, Im shocked.

The bulk of Sheltons care had been at the University of Virginia Cancer Center, with the exception of a stem cell transplant with UNC LinebergersPaul Armistead, MD. With her recurrence in 2018, she had exhausted traditional treatment options, so Sheltons care team referred her to UNC LinebergersMatthew Foster, MD, for a chimeric antigen receptor T-cell (CAR-T) therapy clinical trial.

CAR-T immunotherapyuses a patients own immune system to fight their cancer. This involves extracting the patients T-cells, manipulating them to recognize the patients cancer, and then re-infusing them into the patient to attack their cancer cells.

One advantage of these altered T-cells is that they can survive and persist within the body and, not only be an army of cells for one time, but an occupying force, Foster said.

At the North Carolina Cancer Hospital clinic in Chapel Hill, Foster was both optimistic and realistic about Sheltons prognosis, taking time to answer her questions. CAR-T being a relatively new treatment, however, there were not a lot of outcomes and results he could share with Shelton, a self-proclaimed numbers person.

I want to know how many people have had it, how many have survived, how long has it lasted? she said. And they just cant tell me its going to last short term or long term. But the clinical trial itself went way better than I had imagined in my mind of how it would go.

Foster and the cellular immunotherapy team at UNC Lineberger look for new treatments for difficult-to-treat cancers, and Shelton was part of the corresponding study that aimed to make treatments safer.

Fortunately, she had an easier pathway with these CAR-T therapies than she did with her transplant, Foster said. Thats not necessarily true for all patients. There are patients who have had more profound toxicities.

For Shelton, the difference in treatment strategies was significant. With CAR-T, she didnt suffer the same types of side effects she had with chemotherapy and radiation or the lengthy hospital stay and recovery with the stem cell transplant. There was no hair loss; no mouth sores; no bone-deep fatigue. She said her real fear was neurological effects from the CAR-T treatment, but her cognition was unaffected.

The only major thing Ive had was a fever. I never had any of the hallucinations or the other major neurological symptoms, she said. For that to be the biggest side effect that I had, I was certainly blessed.

We see a number of young adults and adolescents with acute lymphoblastic leukemia. Unfortunately, this population is often in the midst of launching themselves from under their parents wings and launching their careers or education, Foster said. Sometimes the parents take an active role, and sometimes the parents dont. Sabrina is fortunate to have supportive parents and a great attitude herself in terms of taking care of herself and trying to blend her care for herself with her career aspirations and personal life.

These days, Sheltons focus is on her life outside of cancer. She enjoys volunteering at a bridal shop that receives donated dresses from high-end shops like Kleinfeld Bridal in New York and gives the proceeds to help women in need. She recently took trips to Colorado and California. Shes even planning to go to New York something she couldnt imagine doing during her initial diagnosis and recurrence.

I see everybody else around me living life. So, I feel like, why cant I? she said. Of course, life can happen in between all of these plans, but Im just not going to sit back and watch life pass me. Im going to get out there as much as I possibly can.

Learn more about theCAR-T Immunotherapy Programat UNC Lineberger.

(C) UNC

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Treatment in clinical trial offers options to woman fighting return of cancer (+ video) - WRAL Tech Wire

Recent developments in the field of stem cell research are paving a path towards a radical shift in the way we diagnose and treat dementia. Stem cells have excited scientists for years and research groups across the globe are using them to advance modern medicine. Using stem cells to aid the fight against dementia is perhaps one of the most critical applications of the technology. Dementia is the leading cause of death in the UK, sixth in US and fifth globally, with an estimated 50 million people currently affected.

The term dementia does not relate to a single disease, but more an array of symptoms that can arise from multiple conditions. The most common is Alzheimers disease (AD) which accounts for up to 80% of all cases. Dementia itself is caused by the death of cells that make up the complex circuitry of our brains and an eventual loss of large portions of the brain. Patients suffering with dementia often exhibit the same general symptoms such as confusion, memory loss and an inability to perform day to day functions. It is a debilitating condition that often strikes the most vulnerable members of society and, consequently, many research groups around the globe work to try to understand dementia-causing diseases to provide better diagnostic and treatment platforms.

In 2007, a research group at Kyoto University in Japan published a study with the potential to change the face of research into dementia along with many other fields. Professor Shinya Yamanaka and his research team developed a method whereby stem cells (cells that can be transformed/differentiated into cells from any tissue) could be generated from a sample of skin. The study, which resulted in a 2012 Nobel Prize for Prof. Yamanaka, demonstrated that skin cells could be isolated from a patient and genetically reprogrammed into induced pluripotent stem cells (iPSCs). In short, this technology made it possible to generate and study brain cells from a patient with dementia without having to remove any of their brain. All they would need to do is provide scientists with a sample of skin.

Since this development, research groups around the globe have started using iPSCs from many patients with dementia in order to understand the biological mechanisms that underlie disease. Dr Eric Hill runs a research group at Aston University in the UK that specializes in iPSCs for dementia research and he had the following to say about the technology:

Its really exciting because it allows us to study cells with genetic mutations that are patient specific. We can get a much better picture of what is actually happening in the brains of these patients. We can now generate all the different cell types found in the human brain and understand how they function together and map the changes that result in disease.

The latter was perhaps most powerfully demonstrated in a study published by a team at the University of North Carolina, led by Professor Hansang Cho. The team was able to generate three key cell subtypes that play important roles in brain function; study the impact of mutations associated with Alzheimers disease; and even replicate some of the core malfunctions found to trigger disease in the brains of patients.

Studies like this are of significance because a large part of the focus in dementia research is on trying to understand how such changes in function arise. When a patient is diagnosed with a disease such as Alzheimers it is often too late for effective treatment. Scientists, instead, seek to elucidate those early changes in brain cell function in order to diagnose patients earlier to give more time for treatment. It is very much a case of prevention being better than a cure. Dr Hill provided an encouraging statement regarding this:

When we generate brain cells from iPSCs the cells we get are developmentally very young. What is interesting is the fact we still see differences between cells from dementia patients versus healthy patients suggesting we could find markers to help us detect and prevent disease some years before it develops.

Despite such promise, however, iPSCs have yet to provide the field of dementia research with that big break. Multiple treatments have progressed into clinical trials since the technology first emerged but no therapies have been approved. Drugs that show promise in the lab fail to deliver on their potential in patient clinical trials, sending researchers back to square one.

We should not be disheartened by this, however, and should instead view it as space into which the technology of using iPSCs to study dementia can grow. A lot of drugs fail in clinical trials because the platforms used to run initial tests dont provide scientists with a wide enough perspective of how those drugs will influence human cells. Additionally, many preclinical studies use animals with dementia-causing disease artificially induced into them. Studies like this often fail to translate into humans because the initial data is not from a human perspective. This is where researchers like Dr. Hill think iPSCs can provide us with an advantage:

iPSCs could provide us with much better platforms for screening drugs to treat and prevent these diseases. They can really add to what we already have, and while we might not be able to grow a full human brain, we can generate the cells that provide the building blocks for one. They give us the chance to screen new therapies more efficiently, better test their effectiveness and reduce the amount of animal use in dementia research.

Dr Hill is not alone in seeing the promise of using iPSCs to find better treatments for preventing the progression of dementia. Multiple research groups around the world have shown the potential of iPSC-derived brain cells for studying the effectiveness of new therapies.

In the last 12 months we have observed a wave of new studies using iPSCs to try to develop better treatments for diseases like Alzheimers, Parkinsons, Huntingtons disease and ALS. From studies in the University of California identifying cholesterol metabolism as a potential target to treating Alzheimers to studies in Luxembourg helping us find better treatments for Parkinsons, it is easy to see why the global effort to get that big break from iPSCs continues to gain interest. We might still be waiting for that next Noble Prize-winning discovery that will improve the lives of millions of patients but the collective effort of iPSC research groups across the world brings us a step closer with every study they publish. Dementia may, one day, be a thing of the past and iPSC research will likely be a significant part in getting us there.

Sam Moxon has a PhD in regenerative medicine and is currently involved in dementia research. He is a freelance writer with an interest in the development of new technologies to diagnose and treat degenerative diseases. Follow him on Twitter @DrSamMoxon

Originally posted here:
Searching for the 'big break' that could turn stem cells into a weapon against dementia - Genetic Literacy Project

Like many other respiratory conditions, COVID-19the disease caused by SARS-CoV-2can vary widely among patients. The vast majority of confirmed cases are considered mild, involving mostly cold-like symptoms to mild pneumonia, according to the latest and largest set of data on the new coronavirus outbreak released February 17 by the Chinese Center for Disease Control and Prevention.

Fourteen percent of confirmed cases have been severe, involving serious pneumonia and shortness of breath. Another 5 percent of patients confirmed to have the disease developed respiratory failure, septic shock, and/or multi-organ failurewhat the agency calls critical cases potentially resulting in death. Roughly 2.3 percent of confirmed cases did result in death.

Scientists are working to understand why some people suffer more from the virus than others. It is also unclear why the new coronaviruslike its cousins SARS and MERSappears to be more deadly than other coronaviruses that regularly circulate among people each winter and typically cause cold symptoms. I think its going to take a really, really long time to understand the mechanistic, biological basis of why some people get sicker than others, says Angela Rasmussen, a virologist at Columbia Universitys Mailman School of Public Health.

In the meantime, the latest data from China and research on other coronaviruses provide some hints.

The latest data from China stem from an analysis of nearly 45,000 confirmed cases, and on the whole suggest that the people most likely to develop severe forms of COVID-19 are those with pre-existing illnesses and the elderly.

While less than 1 percent of people who were otherwise healthy died from the disease, the fatality rate for people with cardiovascular disease was 10.5 percent. That figure was 7.3 percent for diabetes patients and around 6 percent for those with chronic respiratory disease, hypertension, or cancer.

While overall, 2.3 percent of known cases proved fatalwhich many experts say is likely an overestimate of the mortality rate, given that many mild cases might go undiagnosedpatients 80 years or older were most at risk, with 14.8 percent of them dying. Deaths occurred in every age group except in children under the age of nine, and, generally speaking, we see relatively few cases among children, World Health Organization Director General Tedros Adhanom Ghebreyesus said last week.

This pattern of increasing severity with age differs from that of some other viral outbreaks, notably the 1918 flu pandemic, for which mortality was high in young children and in people between 20 and 40 years of age. However, its broadly consistent with records of the SARS and MERS coronavirus outbreaks, notes Lisa Gralinski, a virologist at the University of North Carolina at Chapel Hill. If youre over fifty or sixty and you have some other health issues and if youre unlucky enough to be exposed to this virus, it could be very bad, she says.

I think its going to take a really, really long time to understand the mechanistic, biological basis of why some people get sicker than others.

Angela Rasmussen, Columbia University

Scientists dont know what exactly happens in older age groups. But based on research on other respiratory viruses, experts theorize that whether a coronavirus infection takes a turn for the worse depends on a persons immune response. The virus matters, but the host response matters at least as much, and probably more, says Stanley Perlman, a virologist and pediatric infectious disease specialist at the University of Iowa.

Once SARS-CoV-2 gets inside the human respiratory tract, its thought to infect and multiply in cells lining the airway, causing damage that kicks the immune system into action. In most people, it should trigger a wave of local inflammation, recruiting immune cells in the vicinity to eradicate the pathogen. The immune response then recedes, and patients recover.

For reasons that arent entirely clear, some peopleespecially the elderly and sickmay have dysfunctional immune systems that fail to keep the response to particular pathogens in check. This could cause an uncontrolled immune response, triggering an overproduction of immune cells and their signaling molecules and leading to a cytokine storm often associated with a flood of immune cells into the lung. Thats when you end up with a lot of these really severe inflammatory disease conditions like pneumonia, shortness of breath, inflammation of the airway, and so forth, says Rasmussen.

Local inflammation can turn into widespread inflammation of the lungs, which then has ripple effects across all organs of the body. This could also happen if the virus replicates faster than the immune system can respond, so that it then has to play catch-up to contain the pathogena situation that could also cause the immune defense to spiral out of control. With mice, we know that in some cases, particularly for SARS and MERS coronaviruses, virus replication is very rapid and in some cases overwhelming to the immune system, says Perlman.

Its harder to explain why young, healthy people also sometimes die from the diseasefor instance, Li Wenliang, a 34-year-old doctor who first sounded the alarm about the virus. He died a few weeks after contracting the pathogen.

Genetic and environmental risk factors might help explain the severity of infections. Though its clear that genetic factors can strongly determine the outcome of viral infections in miceas some of Rasmussens work has shown for Ebola, for instanceresearchers havent yet been able to tease out specific genes or variants in mice, let alone in people, that are responsible for varying degrees of illness. Environmental factors, such as smoking or air quality, may also play a role in disease severity, Rasmussen adds.

A lot of research has gone into understanding what causes respiratory failure that results from systemic inflammation of the lungsalso called acute respiratory distress syndrome (ARDS)that can occur from coronaviruses and other infections. Yet researchers still dont know how it occurs exactly, let alone how to treat it, Gralinksi notes. Its still a really poorly understood issue.

An intriguing finding in the new data released last week is that although similar numbers of men and women have contracted SARS-CoV-2, more men are dying from the disease. The death rate for males was 2.8 percent and 1.7 percent for women. Rasmussen is quick to caution that although the data encompass nearly 45,000 patients, thats still not that many people to determine if theres really a gender biasyoud have to look at this in a much larger population of patients in a number of different countries, she says.

That said, if there is a bias, it would be consistent with what epidemiologists have observed during the SARS and MERS outbreaks. In the 2003 SARS outbreak in Hong Kong, for instance, nearly 22 percent of infected men died, compared to around 13 percent of women. In an analysis of MERS infections between 2017 and 2018, around 32 percent of men died, and nearly 26 percent of women. The difference could have something to do with the fact that the gene for the ACE-2 receptor, which is used by both SARS-CoV-2 and the SARS virus to enter host cells, is found on the X chromosome, she speculates. If its a particular variant of the protein that makes people more susceptible to the virus, then females could compensate for that one bad variant because theyd have two copies of the X chromosome, whereas men would be stuck with only one copy. Or, it could be that men are more likely to be smokers and so their lungs are already a bit compromised. Theres definitely more to be teased out there, Gralinski says.

Some of Perlmans research, which demonstrated that the sex disparity also holds true in SARS-infected mice, points to the hormone estrogen as possibly having protective effects: Removing the ovaries of infected female mice or blocking the estrogen receptor made the animals more likely to die compared to infected control mice. The effects are probably more pronounced in mice than in people, Perlman tells The New York Times.

Whether patients develop antibodies after SARS-CoV-2 infection that will protect them against future infections is still a mystery. Surveys of SARS patients around five or 10 years after their recovery suggest that the coronavirus antibodies dont persist for very long, Gralinski says. They found either very low levels or no antibodies that were able to recognize SARS proteins.

However, for the new coronavirus, we would expect some immunity, at least in the short term, she says.

There are seven coronaviruses known to infect people. Four of them229E, NL63, OC43, and HKU1typically cause a cold and only rarely result in death. The other threeMERS-CoV, SARS-CoV, and the new SARS-CoV-2have varying degrees of lethality. In the 2003 SARS outbreak, 10 percent of infected people died. Between 2012 and 2019, MERS killed 23 percent of infected people. Although the case fatality rate of COVID-19 is lower, the virus has already killed more people than the other two outbreaks combined, which some have attributed to the pathogens fast transmission.

The cold-causing coronaviruses, as well as many other viruses that cause common colds, are typically restricted to the upper respiratory tract, that is, the nose and sinuses. Both SARS-CoV and SARS-CoV-2, however, are capable of invading deep into the lungs, something that is associated with more severe disease.

One possible reason for this is that the virus binds to the ACE-2 receptor on human cells in order to gain entry. This receptor is present in ciliated epithelial cells in the upper and lower airway, as well as in type II pneumocytes, which reside in the alveoli in the lower airway and produce lung-lubricating proteins. The type II pneumocytes are . . . important for lung function, so this is part of why the lower respiratory disease can be so severe, notes Gralinksi.

The new coronavirus also appears to use the ACE-2 receptor, which may help partially explain why, like SARS, it is more deadly than the other four coronaviruses. Those pathogens use different receptors, except for NL63, which also uses the ACE-2 receptor but binds to it with less affinity, says Gralinski. (MERS is thought to use an entirely different receptor, which is also present in the lower airways.)

To understand these questions fully will take time, research, and consistent funding for long-term studies. Coronavirus funding has been criticized for following a boom-and-bust cycle; viral spillovers from animals to people cause an initial surge of interest that tends to wane until the next outbreak occurs, Rasmussen warns.

Im hopeful that in this case it will be really apparent to everybody in the world that we need to be funding this type of basic science, fundamental science, to understand these mechanisms of disease, she says. Otherwise, were going to be in the same situation when the next outbreak happenswhether its a coronavirus or something else.

Katarina Zimmer is a New Yorkbased freelance journalist. Find her on Twitter@katarinazimmer.

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Why Some COVID-19 Cases Are Worse than Others - The Scientist