Monthly Archives: March 2017

Physicians, healthcare professionals and members of the MLB community will keep a close eye on Red Sox pitcher Andrew Pomeranz's recovery from a potentially career-saving stem cell procedure, according to The Boston Globe.

Here are five things to know:

1. Steve Yoon, MD, of the Los Angeles-based Kerlan-Jobe Orthopaedic Clinic extracted bone marrow from Mr. Pomeranz's hip bone and back and injected it into his flexor tendon.

2. Mr. Pomeranz was motivated to undergo the procedure after fellow pitchers Garrett Richards and Andrew Heaney opted for the treatment instead of undergoing Tommy John Surgery to treat the partial tears in their ulnar collateral ligaments.

3. Lyle Cain, MD, of Birmingham, Ala.-based Andrews Sports Medicine & Orthopedic Center said, "Stem cells are a way to try to deliver the chemicals to cells and the chemical attractive factors to that area to allow the body to heal that tissue. That's what PRP was used for as well. Stem cells have more promise because not only do they have the chemicals that platelet-rich plasma has, but you're also putting some of the healing cells themselves in that area."

4. Pitcher Bartolo Colon was the first baseball player known to receive stem cell treatment when he received injections in his injured rotator cuff and elbow in the Dominican Republic in 2010. The 43-year-old pitcher's career was resurrected following the operation, partially prompting the method's increased popularity.

5. If Mr. Pomeranz has a successful 2017 season, the number of players undergoing stem cell procedures may rise.

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The stem cell procedure that may change the sports medicine field in 2017 5 observations - Becker's Orthopedic & Spine

March 23, 2017 Two fast-aging mice. The mouse on the left was treated with a FOXO4 peptide, which targets senescent cells and leads to hair regrowth in ten days. The mouse on the right was not treated with the peptide. Credit: Peter L.J. de Keizer

Regular infusions of a peptide that can selectively seek out and destroy broken-down cells that hamper proper tissue renewal, called senescent cells, showed evidence of improving healthspan in naturally-aged mice and mice genetically engineered to rapidly age. The proof-of-concept study, published March 23 in Cell, found that an anti-senescent cell therapy could reverse age-related loss of fur, poor kidney function, and frailty. It is currently being tested whether the approach also extends lifespan, and human safety studies are being planned.

The peptide took over four years of trial and error to develop and builds on nearly a decade of research investigating vulnerabilities in senescent cells as a therapeutic option to combat some aspects of aging (Trends in Molecular Medicine, 10.1016/j.molmed.2016.11.006). It works by blocking the ability of a protein implicated in senescence, FOXO4, to tell another protein, p53, not to cause the cell to self-destruct. By interfering with the FOXO4-p53 crosstalk, the peptide causes senescent cells to go through apoptosis, or cell suicide.

"Only in senescent cells does this peptide cause cell death," says senior author Peter de Keizer, a researcher of aging at Erasmus University Medical Center in the Netherlands. "We treated mice for over 10 months, giving them infusions of the peptide three times a week, and we didn't see any obvious side effects. FOXO4 is barely expressed in non-senescent cells, so that makes the peptide interesting as the FOXO4-p53 interaction is especially relevant to senescent cells, but not normal cells."

Results appeared at different times over the course of treatment. Fast-aging mice with patches of missing fur began to recover their coats after 10 days. After about three weeks, fitness benefits began to show, with older mice running double the distance of their counterparts who did not receive the peptide. A month after treatment, aged mice showed an increase in markers indicating healthy kidney function.

Senescent cell therapy is one of several strategies being tested in mice aimed at reversing aging or lengthening healthspan. In 2015, the Valter Longo laboratory at the University of Southern California reported that mice on a calorie-restricted diet that mimics fasting benefited from a longer life, a reduction in inflammatory disease, and improved memory (Cell Metabolism, 10.1016/j.cmet.2015.05.012). And last December, Juan Carlos Izpisua Belmonte at the Salk Institute of Biological Science and colleagues made headlines with their discovery that cellular reprogramming of epigenetic marks could extend lifespan and improve health in fast-aging mice (Cell, 10.1016/j.cell.2016.11.052).

"This wave of research on how we can fight aging is complementary, and not in competition," says de Keizer. "The common thread I see for the future of anti-aging research is that there are three fronts in which we can improve: The prevention of cellular damage and senescence, safe therapeutic removal of senescent cells, to stimulate stem cellsno matter the strategyto improve tissue regeneration once senescence is removed."

de Keizer aims to start a company based on these findings, but in the short term, he and his group want to show that their peptide is non-toxic in humans with no unforeseen side effects. They plan to offer a safety clinical trial in people with Glioblastoma multiforme, an aggressive brain tumor, which also shows high levels of the biomarkers needed for this FOXO4 peptide to be effective.

Explore further: Anti-aging therapies targeting senescent cells: Facts and fiction

More information: Cell, Baar et al.: "Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging" http://www.cell.com/cell/fulltext/S0092-8674(17)30246-5 DOI: 10.1016/j.cell.2017.02.031

Sebastian Brandhorst et al. A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan, Cell Metabolism (2015). DOI: 10.1016/j.cmet.2015.05.012

Alejandro Ocampo et al. In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming, Cell (2016). DOI: 10.1016/j.cell.2016.11.052

Journal reference: Cell Cell Metabolism

Provided by: Cell Press

It's an exciting time to be an elderly mouse. Researchers believe that by removing senescent cells (cells with a persistent damage response), which naturally accumulate with age, senior rodents can regrow hair, run faster, ...

Most cells can divide only a limited number of times and eventually undergo permanent cell cycle arrest, a state known as cellular senescence. Cellular senescence is mediated by activation of specific cellular signaling pathways ...

An enzyme that blocks cellular senescence and its mechanisms has been discovered by a research team from Kumamoto University, Japan. They found that a reduction of the enzyme SETD8, which regulates cell proliferation and ...

Mayo Clinic researchers have uncovered three new agents to add to the emerging repertoire of drugs that aim to delay the onset of aging by targeting senescent cells - cells that contribute to frailty and other age-related ...

Researchers at Mayo Clinic have shown that senescent cells - cells that no longer divide and accumulate with age - negatively impact health and shorten lifespan by as much as 35 percent in normal mice. The results, which ...

A Mayo Clinic study has shown evidence linking the biology of aging with idiopathic pulmonary fibrosis, a disease that impairs lung function and causes shortness of breath, fatigue, declining quality of life, and, ultimately, ...

McMaster University researchers have discovered that while survivors of childhood brain tumours have a similar Body Mass Index (BMI) to healthy children with no cancer, they have more fat tissue overall, and especially around ...

Wellcome Trust Sanger Institute scientists and their collaborators at the University of Cambridge have created a new technique that simplifies the production of human brain and muscle cells - allowing millions of functional ...

Regular infusions of a peptide that can selectively seek out and destroy broken-down cells that hamper proper tissue renewal, called senescent cells, showed evidence of improving healthspan in naturally-aged mice and mice ...

Scientists at The Rockefeller University have mapped the three-dimensional structure for one of the more notorious disease-causing molecules in the human body: the protein responsible for the genetic disorder cystic fibrosis. ...

A new study from the University of South Carolina has found a gastrointestinal link that could help explain many of the health issues facing those with Gulf War Illness (GWI) as well as opening new pathways to treatment options ...

People with cystic fibrosis (CF) suffer repeated lung infections because their airway mucus is too thick and sticky to keep bacteria, viruses, and other pathogens from causing chronic infection. How mucus becomes abnormal ...

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A stem cell-derived heart muscle cell. Proteins that are important for muscle cell contraction are highlighted in red and green, and cell nuclei are blue. Credit: Joseph C. Wu, M.D., Ph.D., Stanford Cardiovascular Institute

Using human heart cells generated from adult stem cells, researchers have developed an index that may be used to determine how toxic a group of cancer drugs, called tyrosine kinase inhibitors (TKIs), are to human cells. While 26 TKIs are currently used to treat a variety of cancers, some can severely damage patients hearts, causing problems such as an irregular heartbeat or heart failure.

For the study, reported February 15 in Science Translational Medicine, the researchers used stem cell-derived heart cells from 13 volunteers to develop a cardiac safety index that measures the extent to which TKIs kill or alter the function of heart cells. They found that the TKIs' toxicity score on the index was generally consistent with what is known about each drug's heart-related side effects.

This work follows on the heels of an earlier study from the same research team, published in Nature Medicine, in which they assessed the heart cell toxicity of doxorubicin, a chemotherapy drug that also causes heart-related side effects, including heart failure. In that study, the researchers used stem cell-derived heart cells from women with breast cancer to correctly predict how sensitive each womans heart cells were to doxorubicin.

Such tests could ultimately help the pharmaceutical industry identify drugs that cause heart-related side effects earlier in the drug development process and help the Food and Drug Administration (FDA) during the drug review and approval process, said the study's senior author Joseph C. Wu, M.D., Ph.D., director of the Stanford Cardiovascular Institute.

I hope this research will be helpful for individual patients, once we further implement precision medicine approaches, he added.

Ranking Heart Toxicity

To assess the potential risk of heart toxicity for drugs in development, pharmaceutical companies use laboratory tests involving animals (usually rats or mice) or cells from animals or humans that are engineered to artificially express heart-related genes. Drug candidates that appear to have an acceptable balance of benefits and risks typically proceed to testing in human clinical trials.

But there can be biological differences between these existing models and humans, so non-clinical lab tests can have significant limitations, explained Dr. Wu.

Currently, the first time humans are exposed to a new drug is during clinical trials, he said. We think it would be great if you could actually expose patients heart, brain, liver, or kidney cells to a drug in the lab, prior to clinical treatment, allowing researchers to determine whether the drug has any toxic effects.

Dr. Wu, a cardiologist by training, studies toxicities cancer drugs cause in heart cells. Human heart muscle cells (called cardiomyocytes), however, are hard to obtainrequiring risky heart surgery that may be of no direct benefit to the patientand are notoriously difficult to grow in the lab.

As an alternative, researchers have developed a method to produce heart cells from human induced pluripotent stem cells (hiPSCs). hiPSCs are created by genetically engineering normal human skin or blood cells to express four specific genes that induce them to act like stem cells. Chemical treatments can prompt hiPSCs to develop into mature cell types, such as heart muscle cells.

A large body of research has established that human adult stem cell-derived heart cells, which function and grow in cell culture, can be used as an initial model to screen drug compounds for toxic effects on the heart, said Myrtle Davis, Ph.D., chief of the Toxicology and Pharmacology Branch of NCIs Division of Cancer Treatment and Diagnosis, who was not involved in the studies.

For the Science Translational Medicine study, Dr. Wu and his colleagues set out to determine if a panel of human stem cell-derived heart cells could be used to evaluate the heart toxicity of 21 different FDA-approved TKIs.

They generated hiPSC-derived heart endothelial, fibroblast, and muscle cells from 13 volunteers: 11 healthy individuals and 2 people with kidney cancer who were being treated with a TKI. Using drug concentrations equivalent to what patients receive, the investigators next determined how lethal each TKI was to the heart cells.

They found that several TKIs were very lethal to endothelial, fibroblast, and heart muscle cells from all 13 individuals, while others were more benign.

Stem cell-derived heart muscle cells grown in a dish spontaneously contract as a beating heart does, so the researchers also analyzed the effects of TKIs on the cells beat rate, or contractility. They found that several TKIs altered the cells beat rate before they were killed by the drug treatment. If severe enough, an irregular heartbeat (called an arrhythmia), can disrupt normal heart function.

From these lethality and contractility experiments, the team developed a cardiac safety index, a 0-to-1 scale that identifies how toxic a TKI is to heart cells (with 0 being the most toxic). They then used the index to rank the 21 TKIs. The control treatment scored a 1, while a few TKIs that are labeled by the FDA with boxed warnings for severe heart toxicity scored close to 0.

Safety indices like this one can be very useful during drug discovery, said Dr. Davis, and the applicability of the index developed by Dr. Wu and his colleagues will become clear when they evaluate its performance with more compounds.

And for the safety index to be applicable to more patients, the panel of cells used to develop it would need to be gathered from a sufficiently representative population of people reflecting different ages, races/ethnicities, health statuses, and other characteristics, said Lori Minasian, M.D., deputy director of NCIs Division of Cancer Prevention, who was not involved in either study.

For example, the study did not include cells derived from patients with [pre-existing] cardiac disease, said Dr. Davis.

A Personalized Approach

In addition to their potential application during drug development, Dr. Wu believes that stem cell-derived heart cells could potentially be used to predict toxicity risk for individual patients. He and his colleagues explored this possibility in their Nature Medicine study.

Doxorubicin, used on its own or in combination with other drugs, is an effective treatment for breast cancer and several other types of cancer. Like TKIs, however, it is known to cause heart toxicities, such as arrhythmias and heart failure, in a small proportion of patients. But there has been no way to predict which patients will experience these side effects.

The researchers developed stem cell-derived heart cells from eight women with breast cancer who had been treated with doxorubicinhalf of whom experienced cardiotoxicity from the treatment and half who did not.

In several different lab tests, the heart cells from women who had experienced cardiotoxicity were more sensitive to doxorubicin than those from women who had not. More specifically, in heart cells from women who had experienced cardiotoxicity, doxorubicin treatment caused more severe irregularities in cell contractility, and even low concentrations of the drug killed the cells.

An Improved Model

While the stem cell-derived heart cell model may be an improvement over the current [drug testing] system, its not perfect, said Dr. Minasian. For example, the model does not capture contributions of other organs and cells to the toxic effects of a drug, she explained. The drug may be broken down in the liver, for instance, and side products (called metabolites) may also cause toxic effects.

In addition, the lab-grown stem cell-derived version of someones heart cells are not going to be exactly the same as the cells found in that persons heart, Dr. Wu noted. Nevertheless, they reflect the same genetics and they are pretty good at predicting drug response, he said.

Looking forward, Dr. Minasian said, figuring out how to best use this approach is going to take more work, but being able to better predict human response [to cancer drugs] is important.

The research teams next steps include conducting prospective studies to determine whether they can use a patients stem cell-derived heart cells to potentially predict if that person will develop heart toxicity before they actually receive cancer treatment.

This article has been republished frommaterialsprovided byNCI. Note: material may have been edited for length and content. For further information, please contact the cited source.

Reference

Sharma, A., Burridge, P. W., McKeithan, W. L., Serrano, R., Shukla, P., Sayed, N., ... & Matsa, E. (2017). High-throughput screening of tyrosine kinase inhibitor cardiotoxicity with human induced pluripotent stem cells. Science translational medicine, 9(377), eaaf2584.

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Measuring Heart Toxicity of Cancer Drugs - Technology Networks