Researchers at Baylor College of Medicine have discovered a new mechanism that helps maintain and repair bones in adults. Ultimately, this could help develop new therapeutic strategies to improve bone healing.

Knee Bones

Osteoporosis is a skeletal disease characterized by reduced bone density and changes in the microarchitecture of bones. These changes weaken the bone and increase the risk of fracture. This disease develops particularly in older people. Today, a new study could eventually lead to the development of therapeutic strategies to improve bone healing in these patients. According to the results published in the journal Cell Stem Cell on the 5th December, 2019 researchers have discovered a new mechanism that contributes to the maintenance and repair of bones in adults.

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Adult bone repair relies on the activation of bone stem cells, which still remain poorly characterized. Bone stem cells have been found both in the bone marrow inside the bone and also in the periosteum the outer layer of tissue that envelopes the bone. Previous studies have shown that these two populations of stem cells, although they share many characteristics, also have unique functions and specific regulatory mechanisms. said Dr. Dongsu Park, assistant professor of molecular and human genetics, pathology and immunology at Baylor College of Medicine, where the study was conducted.

Of these two populations, periosteal stem cells are the least known. Although the scientists know that this is a heterogeneous population of cells that can contribute to the thickness, formation and repair of bone fractures, no one has yet been able to distinguish between the different subtypes of bone stem cells in order to study the regulation of their different functions.

Here, however, Dongsu Park and colleagues were able to develop a technique in mice to identify different subpopulations of periosteal stem cells, define their contribution to the repair of bone fractures and identify the specific factors that regulate their migration and proliferation under physiological conditions.

In rats, they discovered specific markers for this class of cells. They identified a specific subset of stem cells that contribute to lifelong bone regeneration in adults. They also observed that periosteal stem cells react to inflammatory molecules, chemokines, which are normally produced in bone injuries.

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In detail, periosteal stem cells have receptors that bind to the CCL5 chemokine. The CCL5 chemokine sends a signal to the cells to migrate to the injured bone and repair it. By suppressing the CCL5 gene in rats, the researchers found defects in bone repair that delayed healing. However, when they gave CCL5 to rats that had lost CCL5, the bones recovered faster.

Our findings contribute to a better understanding of the healing of adult bones. We believe this is one of the first studies to show that bone stem cells are heterogeneous and that different subtypes have unique properties that are regulated by specific mechanisms, said Dongsu Park. We have identified markers that allow us to distinguish between the subtypes of bone stem cells and have investigated what each subtype contributes to bone health. The understanding of how the functions of bone stem cells are regulated offers the possibility of developing new therapeutic strategies for the treatment of bone damage in adults.

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In the long term, these findings may therefore have potential therapeutic applications, particularly in people with osteoporosis or diabetes.Indeed, people with diabetes may be prone to falls and fractures due to possible neurological, visual or renal complications. In addition, bone fragility in diabetics is likely to be due to changes in bone remodeling and, in particular, an increase in bone resorption.

https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(19)30458-8?

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Researchers at Baylor College of Medicine Discover How to Improve Bone Repair - Gilmore Health News

John Thuku,30, known by his peers in the hospital corridors as El Medico, battled Acute Myeloid Leukemia (AML). He shared his story with Agnes Aineah. Sometime last month, I was diagnosed with a type of blood cancer that has made my past few days the most difficult days I have ever had. I remember waking up with abdominal pain in the area below my ribs. I tried painkillers but the pain persisted for two weeks. At the end of the two weeks, I decided to see a doctor at Moi Teaching and Referral Hospital (MTRH) where I visited the wards as part of my coursework at Moi University School of Medicine where I am a final year student. The pain had become too much it kept me sleepless, writhing in bed the whole night.The doctor at MTRH conducted some tests and gave me medication which he said would work within a week. And true to his word, the pain disappeared after I completed the dosage he prescribed. But the doctor suggested a haemogram (or blood count) just as a routine checkup. It was a test on my blood components including the Red Blood Cells, White Blood Cells and Platelets.The first test revealed that I had a low count of all my blood components. The doctor was worried by the results and said to wait for a week before I took another test. But there was no improvement when I took the second test. Doctors said my low blood cell count could be attributed to a viral infection, bone marrow cancer, or certain tumors. They took a sample of my bone marrow to test for any of these possibilities and what came out of it was the worst revelation in my life ever.They found abnormalities in the way my cells were developing. They found that 90 per cent of my cells were immature and they were stuck together so that they were not developing like normal cells do. Normal body cells have a cell membrane, the nucleus and other parts that all have their specific functions in the body. But mine didnt have these parts. This meant I had only 10 per cent of functioning blood cells. It explained the fatigue and dizziness I had felt before. I was used to jogging 5 kilometres everyday. Then suddenly, I couldnt complete even one. I also felt dizzy most times and I had battled tonsillitis for months. Then it occurred to me that my immunity had been low those days I battled tonsillitis.I was diagnosed with Acute Myeloid Leukemia (AML), a type of blood cancer that starts in the bone marrow and causes cells in the bone marrow not to develop properly. Doctors said it was a type of cancer with high mortality rate if not treated urgently. I havent been more scared in life. A medical student in my final year, I understood the magnitude of my diagnosis and I didnt need the doctor to explain to me what I faced. My girlfriend who is also a medical student was with me when the news was broken to me. I saw her agony.That day, I proceeded to my room and locked myself there, all alone, trying to wrap my mind to the sudden twist in my life. I saw my life crumble at my feet. I had such huge dreams of rising from my humble background to become a successful doctor. Now I knew that to survive, I needed a lot of money which my family couldnt afford. I knew my family couldnt afford the chemotherapies and the numerous blood transfusions which my life was now pegged on.I called my mother to tell her I had been diagnosed with leukemia. She hang up on me and then called back weeping. She said it was a lie. It has been a month and none of my family members has accepted that I have AML.

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Isolation that comes with chemo is maddening - Standard Digital

A multiple myeloma expert helps newly diagnosed patients understand the standard of care for their disease.

Richter, an assistant professor of medicine at the Tisch Cancer Institute at the Ichan School of Medicine in Mt. Sinai Hospital located in New York City, noted that there are always exceptions to this rule, but the standard of care is to keep patients with multiple myeloma to continue therapy long term.

This standard of care, however, presents unique challenges and questions for newly diagnosed patients about to undergo treatment. In an interview during the 2019 CURE Educated Patient Summit on Multiple Myeloma in Charlotte, North Carolina, Richter had the chance to address the key aspects of a multiple myeloma diagnosis and how he addresses common questions from patients.

CURE: What does transplant eligible and transplant ineligible mean for patients?

Richter: The notion of transparent eligibility in the U.S. is not clearly defined. One of the people who trained me used to say, Do the patients have the tiger? relating back to Rocky, and essentially what this means is people who are younger tend to be more eligible. So, are you able to undergo the intensive nature of that procedure and chemotherapy?

If you're younger and healthier, you're generally transplant eligible. As you get older, with more medical problems, it becomes more of a risk. Everything in medicine from a Tylenol to a transplant has a risk and benefit. If you are 105 years old and had a heart attack last week, you're not going to be eligible. If you're 40 and otherwise healthy, you're eligible and everywhere in between is an evaluation of risks and benefits.

How would you describe the standard of care for patients with multiple myeloma?

In general, the standard of care is to attempt to get people onto three drugs. The three drugs usually mean a steroid, and then either an immunomodulatory drug, a proteasome inhibitor or a monoclonal antibody, and using those different combinations to come up with two or three-drug combinations, and actually in some cases four-drug combinations.

The general discussion of which one makes sense is we generally try to put some on a three-drug combination and the two most common ones now VRd (Velcade, Revlimid, and dexamethasone) is really a very big standard approach. There's some really wonderful, emerging data from the MAIA study, looking at taking Revlimid and dexamethasone and adding Darzalex (daratumumab) as a three-drug regimen for people who are not going on to transplant and some of that data looks amazing.

But for the most part, the precision that we use has to do not so much with the tumor but with the patient. Meaning for some diseases, the precision in the upfront setting is we look at a genetic marker and we target that. But for myeloma our upfront choice of therapy is saying, what are your comorbidities? What are your risks? For someone who has neuropathy, we may avoid Velcade. Someone has heart issues, we may avoid carfilzomib (Kyprolis) and if someone has difficult coming back and forth for long infusions, we may avoid Darzalex. So, most of the precision that we use is custom tailoring it not necessarily to the disease upfront, although that's part of it, but also to the patient.

What is the role of stem cell transplantation in treating patients with multiple myeloma?

The role of transplant is constantly evolving in myeloma. A generation ago, when we didn't have very good drugs, transplant was clearly the best thing to do because we didn't have good medicines. Transplant was the only way to get deep and durable remissions. Nowadays that we have such better therapies and even better ones along the way, it's being called into question about how much do we still need transplant. And it's a case by case basis, some people still clearly benefit from transplant.

It's an important discussion to have with your provider. But the risks have been well established for many years and we know how to manage them very well. Although there are risks for it, they're generally consolidated into a couple weeks to a couple of months, as opposed to being on long term treatment that can have ongoing risk of side effects. So, yes, they may be higher, but it's usually for a self-contained amount of time.

It's still a very important tool in our armamentarium to treat patients. Now, that being said, the majority of patients in the United States do not receive autologous transplant, so only about 30% and part of the reason has to do with the age of patients. The average age of a myeloma patient in the U.S. is 69, and many people in their 70s and 80s have other medical problems that make them not eligible for transplant.

There are some socioeconomic reasons, as well as referral patterns and access to care. I live in New York City, you can throw a rock and hit a transplant center, but there are parts of the country where the closest transplant center is hours and hours and hours away. And if you are older, sick or don't have easy transportation, it may be more difficult. So, many people do not receive transplant. However, many people nowadays may not even need it because our drugs have gotten so much better.

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Understanding the Key Aspects of a Multiple Myeloma Diagnosis - Curetoday.com

P. Todd Stukenberg, PhD, of UVAs Department of Biochemistry and Molecular Genetics and the UVA Cancer Center, works in his lab. Credit: Dan Addison | UVA

Scientists at the University of Virginia School of Medicine have discovered a strange new organelle inside our cells that helps to prevent cancer by ensuring that genetic material is sorted correctly as cells divide.

The researchers have connected problems with the organelle to a subset of breast cancer tumors that make lots of mistakes when segregating chromosomes. Excitingly, they found their analysis offered a new way for doctors to sort patient tumors as they choose therapies. They hope these insights will allow doctors to better personalize treatments to best benefit patients sparing up to 40 percent of patients with breast cancer, for example, a taxing treatment that wont be effective.

Some percentage of women get chemotherapy drugs for breast cancer that are not very effective. They are poisoned, in pain and their hair falls out, so if it isnt curing their disease, then thats tragic, said researcher P. Todd Stukenberg, PhD, of UVAs Department of Biochemistry and Molecular Genetics and the UVA Cancer Center. One of our goals is to develop new tests to determine whether a patient will respond to a chemotherapeutic treatment, so they can find an effective treatment right away.

The organelle Stukenberg and his team have discovered is essential but ephemeral. It forms only when needed to ensure chromosomes are sorted correctly and disappears when its work is done. Thats one reason scientists havent discovered it before now. Another reason is its mind-bending nature: Stukenberg likens it to a droplet of liquid that condenses within other liquid. That was the big wow moment, when I saw that on the microscope, he said.

These droplets act as mixing bowls, concentrating certain cellular ingredients to allow biochemical reactions to occur in a specific location. Whats exciting is that cells have this new organelle and certain things will be recruited into it and other things will be excluded, Stukenberg said. The cells enrich things inside the droplet and, all of a sudden, new biochemical reactions appear only in that location. Its amazing.

P. Todd Stukenberg, PhD, of UVAs Department of Biochemistry and Molecular Genetics and the UVA Cancer Center, discovered an unknown organelle in our cells that helps ensure genetic material is sorted correctly when cells divide. Credit: Dan Addison | UVA

Its tempting to think of the droplet like oil in water, but its really the opposite of that. Oil is hydrophobic it repels water. This new organelle, however, is more sophisticated. Its more of a gel, where cellular components can still go in and out but it contains binding sites that concentrate a small set of the cells contents, Stukenberg explained. Our data suggests this concentration of proteins is really important. I can get complex biochemical reactions to occur inside a droplet that Ive been failing to reconstitute in a test tube for years. This is the secret sauce Ive been missing.

While its been known for about eight years that cells make such droplets for other processes, but it was unknown that they make them on chromosomes during cell division. Stukenberg believes these droplets are very common and more important than previously realized. I think this is a general paradigm, he said. Cells are using these non-membranous organelles to regulate much of their work.

In addition to helping us understand mitosis how cells divide Stukenbergs new discovery also sheds light on cancer and how it occurs. The organelles main function is to fix mistakes in tiny microtubules that pull apart chromosomes when cells are dividing. That ensures each cell winds up with the correct genetic material. In cancer, though, this repair process is defective, which can drive cancer cells to get more aggressive.

He has also developed tests to measure the amount of chromosome mis-segregation in tumors, and he hopes that this might allow doctors to pick the proper treatment to give cancer patients. We have a way to identify the tumors where the cells are mis-segregating chromosomes at a higher rate, he said. My hope is to identify the patients where treatments such as paclitaxel are going to the most effective.

Having looked at breast cancer already, he next plans to examine the strange organelles role in colorectal cancer.

###

Stukenberg and his colleagues have described their discovery in the scientific journal Nature Cell Biology. The research team consisted of Prasad Trivedi, Francesco Palomba, Ewa Niedzialkowska, Michelle A. Digman, Enrico Gratton and Stukenberg.

Reference: The inner centromere is a biomolecular condensate scaffolded by the chromosomal passenger complex by Prasad Trivedi, Francesco Palomba, Ewa Niedzialkowska, Michelle A. Digman, Enrico Gratton and P. Todd Stukenberg, 3 September 2019, Nature Cell Biology.DOI: 10.1038/s41556-019-0376-4

The research was supported by the National Institutes of Health, grants R01GM124042, R24OD023697 and P41-GM103540; and the National Science Foundation, grant MCB-1615701.

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Strange New Organelle That Helps Prevent Cancer Discovered in Our Cells - SciTechDaily

IN the summer of 2019, a mother in Nashville, Tennessee in the United States, with a seemingly incurable genetic disorder finally found an end to her suffering by editing her genome.

Victoria Grays recovery from sickle cell disease, which had caused her painful seizures, came in a year of breakthroughs in one of the hottest areas of medical research gene therapy.

I have hoped for a cure since I was about 11, the 34-year-old said.

Since I received the new cells, I have been able to enjoy more time with my family without worrying about pain or an out-of-the-blue emergency.

Over several weeks, Grays blood was drawn so that doctors could get to the cause of her illness stem cells from her bone marrow that were making deformed red blood cells.

The stem cells were sent to a Scottish laboratory, where their DNA was modified using Crispr/Cas9 pronounced Crisper a new tool informally known as a molecular scissors.

The genetically-edited cells were transfused back into Grays veins and bone marrow. A month later, she was producing normal blood cells.

Medics warn that caution is necessary, but theoretically, she has been cured.

This is one patient. This is early results. We need to see how it works out in other patients, said her doctor, Haydar Frangoul, at the Sarah Cannon Research Institute in Nashville.

But these results are really exciting.

In Germany, a 19-year-old woman was treated with a similar method for a different blood disease beta thalassemia.

She had previously needed 16 blood transfusions per year. Nine months later, she is completely free of that burden.

For decades, the DNA of living organisms such as corn and salmon has been modified. But Crispr, invented in 2012, made gene editing more widely accessible.

It is much simpler than preceding technology, cheaper and easy to use in small labs.

The technique has given new impetus to the perennial debate over the wisdom of humanity manipulating life itself.

Its all developing very quickly, said French geneticist Emmanuelle Charpentier, one of Crisprs inventors and the co-founder of Crispr Therapeutics, the biotech company conducting the clinical trials involving Gray and the German patient.

Gene cures

Crispr was the latest breakthrough in a year of great strides in gene therapy, a medical adventure that started three decades ago, when the first TV telethons were raising money for children with muscular dystrophy.

Scientists practising the technique insert a normal gene into cells containing a defective gene.

It does the work the original could not, such as making normal red blood cells in Grays case or making tumour-killing super white blood cells for a cancer patient.

Crispr goes even further: instead of adding a gene, the tool edits the genome itself.

After decades of research and clinical trials on a genetic fix to genetic disorders, 2019 saw a historic milestone: approval to bring to market the first gene therapies for a neuromuscular disease in the US and a blood disease in the European Union.

They join several other gene therapies bringing the total to eight approved in recent years to treat certain cancers and an inherited blindness.

Serge Braun, the scientific director of the French Muscular Dystrophy Association, sees 2019 as a turning point that will lead to a medical revolution.

Twenty-five, 30 years, thats the time it had to take, he said. It took a generation for gene therapy to become a reality. Now, its only going to go faster.

Just outside Washington, at the US National Institutes of Health (NIH), researchers are also celebrating a breakthrough period.

We have hit an inflection point, said US NIHs associate director for science policy Carrie Wolinetz.

These therapies are exorbitantly expensive, however, costing up to US$2 million (RM8.18 million) meaning patients face grueling negotiations with their insurance companies.

They also involve a complex regimen of procedures that are only available in wealthy countries.

Gray spent months in hospital getting blood drawn, undergoing chemotherapy, having edited stem cells reintroduced via transfusion and fighting a general infection.

You cannot do this in a community hospital close to home, said her doctor.

However, the number of approved gene therapies will increase to about 40 by 2022, according to Massachusetts Institute of Technology (MIT) researchers.

They will mostly target cancers and diseases that affect muscles, the eyes and the nervous system.

In this Oct 10, 2018, photo, He speaks during an interview at his laboratory in Shenzhen, China. The scientist was recently sentenced to three years in prison for practicing medicine illegally and fined 3 million yuan (RM1.76 million). AP

Bioterrorism potential

Another problem with Crispr is that its relative simplicity has triggered the imaginations of rogue practitioners who dont necessarily share the medical ethics of Western medicine.

In 2018 in China, scientist He Jiankui triggered an international scandal and his excommunication from the scientific community when he used Crispr to create what he called the first gene-edited humans.

The biophysicist said he had altered the DNA (deoxyribonucleic acid) of human embryos that became twin girls Lulu and Nana.

His goal was to create a mutation that would prevent the girls from contracting HIV (human immunodeficiency virus), even though there was no specific reason to put them through the process.

That technology is not safe, said Kiran Musunuru, a genetics professor at the University of Pennsylvania, explaining that the Crispr scissors often cut next to the targeted gene, causing unexpected mutations.

Its very easy to do if you dont care about the consequences, he added.

Despite the ethical pitfalls, restraint seems mainly to have prevailed so far.

The community is keeping a close eye on Russia, where biologist Denis Rebrikov has said he wants to use Crispr to help deaf parents have children without the disability.

There is also the temptation to genetically edit entire animal species, e.g. malaria-causing mosquitoes in Burkina Faso or mice hosting ticks that carry Lyme disease in the US.

The researchers in charge of those projects are advancing carefully however, fully aware of the unpredictability of chain reactions on the ecosystem.

Charpentier doesnt believe in the more dystopian scenarios predicted for gene therapy, including American biohackers injecting themselves with Crispr technology bought online.

Not everyone is a biologist or scientist, she said.

And the possibility of military hijacking to create soldier-killing viruses or bacteria that would ravage enemies crops?

Charpentier thinks that technology generally tends to be used for the better.

Im a bacteriologist -- weve been talking about bioterrorism for years, she said. Nothing has ever happened. AFP Relaxnews

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Gene editing breakthroughs that cured genetic diseases in 2019 - The Star Online