What are the possible stem cell therapy side effects of going to an unproven clinic? This is a common question I get asked. Most often it is asked by patients who reach out.

Check out the YouTube video below on our stem cell channel. If you like such videos please subscribe to our channel.

Many clinics have said over the years to potential customers that the worst that can happen is that the stem cells wont work.

We know this isnt true and its irresponsible.

Anything that has the potential to help a medical condition also poses some risks of harm. For this reason, its important to discuss potential stem cell therapy side effects. In this case I am focusing on the risks primarily associated with unproven stem cell clinics. Not for established methods like bone marrow transplantation.

Recent publications in journals including one by my colleague Gerhard Bauer and a special report by The Pew Charitable Trust have helped clarify risks. Gerhards paper presents the types of side effects that appear more common after people go to stem cell clinics. After closely following this area for a decade I was familiar with many of the examples of problems. However, some were new to me.

One of the highest profiles examples of bad outcomes was the case where three people lost their vision due to stem cells injected by a clinic.See image below of one set of damaged eyes. More on that case at the end of the post.

Why do stem cells pose risks?

Stem cells are uniquely powerful cells.

By definition they can both make more of themselves and turn into at least one other kind of specialized cells. This latter process is called differentiation. That former ability to make more of themselves is called self-renewal.

The most powerful stem cells are totipotent stem cells that can literally make any kind of differentiated cell. The fertilized human egg is the best example of a cell having totipotency. Next in the power line are pluripotent stem cells including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Adult stem cells are multipotent. The best type of stem cell depends on the condition that is trying to be treated. The best type may not be the most powerful.

In any case, the power of stem cells is a main reason they also pose risks. These cells are not always easy to control and misdirected power can do harm.

Let me explain and start with the side effect that seems scariest to most.

If someone injects a patient with stem cells, its possible that the self-renewal power of stem cells just wont get shut off. In that scenario the stem cells could drive formation of a tumor or even cancer. Note that tumors are not always malignant whereas cancer is always malignant.

Why wouldnt a transplanted stem cell always eventually hit the brakes on self-renewal? It could be that the stem cell has one or more mutations. For any stem cells grown in a lab, within the population of millions of cells in a dish, there are going to be at least a few with mutations that crop up. Thats just the way it goes with growing cells in a lab.

Even stem cells not grown in the lab have the same spectrum of mutations as the person they were isolated from. It may seem weird to think about, but we all have some mutations.

When someone like a clinic person tells us that theres a risk to you thats a one in a million chance it doesnt sound that bad. However, with cells being injected into a person in theory all it takes is one cell out of a million cells in a syringe with a couple really bad mutations to potentially cause disaster. Research suggests it takes more than one cell with cancer-causing potential to make a tumor in experiments in the lab, but in actual people we just dont know. Many cancers may arise from one stem cell gone awry. If a clinic injects 50 or 100 million cells, a one-in-a-million rate of dangerous cells means that 50-100 such cells end up in the patient.

The odds are far lower for cells never grown in a lab to cause a tumor, but its still possible. Oddly, its possible that receiving someone elses stem cells (we call this allogeneic) might pose a lower cancer risk because your immune system is going to see those cells as foreign from the start.

But some stem cells, especially those with mutations, might be able to somewhat fly under the radar of the immune system to some extent even if they are from another person. This could allow them to grow into a tumor. The Pew report does a nice job of summarizing risks and there are several reports of tumors.

The possibility of infections after stem cell injections is another risk that is often discussed. Infections from injections of stem cells or other materials like PRP are probably the most common type of side effect. Bacteria can either sometimes already be in the product that is injected or can be introduced by poor injection or preparation methods by the one doing the procedure.

The distributor Liveyon had a product contaminated with bacteria that sickened at least a dozen people who were hospitalized. Some of them ended up in the ICU. A few may even have permanent issues.

Clinics using excellent procedures and products should have a low risk of infection more similar to getting any kind of invasive procedure even unrelated to stem cells.

Many preparations of stem cells sold at stem cell clinics these days are made from fat tissue or birth-related materials. I put stem cells in quotes because most fat and birth-related preparations only contain a small population of true stem cells.

In the case of adipose biologics, they mostly consist of a mixture of a dozen or so other kinds of cells found in fat.

The injections of fat cells are most often made IV right into the bloodstream. Fat cells just live in fat so they arent supposed to be floating around in your blood. As a result, after IV injection, many fat cells are thought to get killed right away.

Others end up landing in the lungs, where many are also probably meeting their doom. However, during this process of wiping out the fat cells it is possible that clots can start forming. Maybe the fat cells form small clots in the blood before they even get into the lungs. Either way, if the clots grow and are big enough, patients can get pulmonary emboli.

The same kind of risk may apply to IV injections or nebulizer inhalations of other kinds of stem cells.

There are other possible risks to stem cell injections too.

I wrote a post about possible graft versus host disease in stem cell recipients. This would only happen in people receiving someone elses stem cells. Its not clear if GvHD is something that happens to patients after going to clinics.

Beyond outright tumor formation it is also possible that stem cells will turn into an undesired or even dangerous tissue type. The example that comes to mind is the practice mentioned earlier of some clinics injecting fat cells into peoples eyeballs. What seems to have happened in some cases is that the mesenchymal cells (MSCs) that were injected turned into scar tissue, which caused retinal detachment. Unfortunately, what are called MSCs by some clinics can mostly consist of close relatives of fibroblasts or in some cases may even largely consist of fibroblasts. Fibroblasts are good at making scar tissue under some circumstances and that can create pull on surrounding tissues including the retina if inside the body.

Specific kinds of stem cells or routes of administration may pose unique risks as well. For instance, intranasal administration of stem cells is getting popular with unproven clinics and could lead to stem cells ending up in the brain.

Other products in the regenerative sphere that are not stem cells may be risky as well for various reasons. For instance, an exosome product harmed quite a few people in Nebraska.Some problems may relate to product contamination.

There have also been cases of unusual immune reactions to stem cell injections.

Finally, stem cells also pose unknown risks because of their power. We just dont have long-term follow up data to have a clear sense of risks.

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Stem cell therapy side effects & risks: infections, tumors & more

Recommendation and review posted by Bethany Smith

Stem cell therapy holds immense promise for the treatment of patients with diabetes mellitus. Research on the ability of human embryonic stem cells to differentiate into islet cells has defined the developmental stages and transcription factors involved in this process. However, the clinical applications of human embryonic stem cells are limited by ethical concerns, as well as the potential for teratoma formation. As a consequence, alternative forms of stem cell therapies, such as induced pluripotent stem cells, umbilical cord stem cells and bone marrow-derived mesenchymal stem cells, have become an area of intense study. Recent advances in stem cell therapy may turn this into a realistic treatment for diabetes in the near future.

Keywords: Embryonic stem cell, induced pluripotent stem cell, mesenchymal stem cell, diabetes

This lecture is based on a recent review.[1]

The increasing burden of diabetes worldwide is well-known, and the effects on health care costs and in human suffering, morbidity, and mortality will be primarily felt in the developing nations including India, China, and countries in Africa. New drugs are being developed at a rapid pace, and the last few years have seen several new classes of compounds for the treatment of diabetes e.g. glucagon-like peptide (GLP-1) mimetics, dipeptidyl-peptidase-4 (DPP-4) inhibitors, sodium glucose transporter-2 (SGLT2) inhibitors. New surgical treatments have also become increasingly available and advocated as effective therapies for diabetes. Gastric restriction surgery, gastric bypass surgery, simultaneous pancreas-kidney transplantation, pancreatic and islet transplantation have all been introduced in recent years. To avoid the trauma of a major operation, there have been many studies on the transplantation of isolated islets removed from a cadaveric pancreas. There was encouragement from the Edmonton protocol described by Shapiro and colleagues in the New England Journal in 2000. The islets were injected into the portal vein and patients, especially those suffering from dangerous, hypoglycemic unawareness, were treated before they had developed severe complications of diabetes, especially renal complications. While the early results were promising, with some 70% of the patients requiring no insulin injections after two years, at five years, most of these patients had deteriorated and required insulin supplements, despite some having received more than one transplant of islets. In the more recent series of patients, the Edmonton group has reported better long-term results with the use of the monoclonal anti-lymphocyte antibody, Campath 1H given as an induction agent, 45% of patients being insulin-independent at five years, and 75% had detectable C-peptide.

However, cadavaric pancreata and islets compete for the same source and are limited in number, and so, neither treatment could readily be offered to the vast majority of diabetic patients. Some have attempted to use an alternative source, for example, encapsulated islets from neonatal or adult pigs. This is still very experimental and will be a far away alternative with many technical and possibly ethical obstacles to overcome.

More recently, with the successes in the development of pluripotent adult stem cells (from Yamanaka, awarded the 2012 Nobel prize for medicine for developing induced pluripotent stem cells iPSCs), new approaches to seek a methods that may be more accessible and available have been attempted. Much hope was derived initially from embryonic stem cell (ESC) research, since these cells can be persuaded to multiply and develop into any tissue, but the process was expensive, and the problem of teratoma formation from these stem cells proved extremely difficult to overcome. Many of the important factors related to fetal development are not understood and cannot be reproduced. However, some progress has been made, and (occasionally) cells been persuaded to secrete insulin, but so far, there have been very minimal therapeutic application.

Scientists are now aware that to persuade a cell to produce insulin is only one step in what may be a long and difficult journey. Islets cells are highly specialized to have not only a basal release of insulin but also to respond rapidly to changes in blood glucose concentration. With insulin, the process and regulation of switching off secretion is as important as the switching on secretion.

A variety of approaches has been made with different starting points. The stem cell reproduces itself and can then also divide asymmetrically and form another cell type: This is known as differentiation. Although initially they were thought to be available only from embryos, non-embryonic stem cells can now be obtained without too much difficulty from neonatal tissue, umbilical cord, and also from a variety of adult tissues including bone marrow, skin, and fat. These stem cells can be expanded and made to differentiate, but their repertoire is restricted compared with embryonic stem cells: oligo- or pluri- as opposed to toti-potent embryonic stem cells. Even more, recently, there has been much interest in the process of direct cell trans-differentiation, in which a committed and fully differentiated cell, for example a liver cell, is changed directly to another cell type, for example an islet beta-cell, without induction of de-differentiation back to a stem cell stage.

Yamanaka, in 2006, was able to produce pluripotent stem cells from mouse neonatal and adult fibroblast cultures by adding a cocktail of four defined factors.[2] This led to a series of other studies developing the process, which was shown to be repeatable with human tissue as well as laboratory mice. The use of iPS cells avoided the ethical constraints of using human embryos, but there have been other problems and obstacles still. There have been emerging reports of iPS cells becoming antigenic to an autologous or isologous host, and the cells can accumulate DNA abnormalities and even retain epigenetic memory of the cell type of origin and thus have a tendency to revert back. Like embryonic stem cells, iPS cells can form teratoma, especially if differentiation is not complete.

Despite this, there has been very little success in directing differentiation of iPSCs to form islet beta-cells in sufficient quantity that will secrete and stop secretion in response to changes in blood glucose levels.

Another approach that has been tried is to combine gene therapy with stem cells. Some progress has been made in trying to express the desired insulin gene in more primitive undifferentiated cells by coaxing stem cells with differentiation factors in vitro and then by direct gene transfection using plasmids or a viral vector. We, and others, have used a human insulin gene construct and introduced ex vivo or in vivo into cells by direct electroporation (in ex vivo cells obviously) or by viral vectors. The adenovirus, adeno-associated virus, and various retro viruses have been most studied, especially the Lentivirus. However, any type of genetic engineering raises fears not only of infection from the virus but also of the unmasking of onco-genes, leading to malignancy, and there are strict regulations how to proceed to avoid these risks.

We have been interested in umbilical cord stem cells and in mesenchymal stem cells as targets for combined stem cell and gene therapy. These cells can be obtained in a reasonably easy and reproducible manner from otherwise discarded umbilical cord, or readily accessible bone marrow, selecting out the cells using various standard techniques. Fat, amnion, and umbilical cord blood are also sources, from which mesnechymal stem cells can be derived. After a proliferative phase, the cells take up an appearance similar to a carpet of fibroblasts, which can differentiate into bone, cartilage, or fat cells. Although mesenchymal stem cells from the various sources mentioned may look similar, their differentiation potentials are idiosyncratic and differ, which makes it inappropriate and difficult to think of them as a uniform source of target cells. Neonatal amnion cells and umbilical cord cells have low immunogenicity and do not express HLA class II antigens. They also secrete factors that inhibit immune reactions, for example, soluble HLA-G. Although immunogenicity is reduced significantly, they are still not autologous and, therefore, there remains a risk for allograft rejection. They have the advantage that they could be multiplied, frozen, and banked in large numbers and could be used in patients already needing immunosuppressive agents, for examples those having renal transplants.

In Singapore, our studies of umbilical cord-derived amnion cells have shown some success in having expression of insulin and glucagon genes, but little or no secretion of insulin in vitro. Together with insulin gene transfection in vitro, after peritoneal transplantation into sterptozotocin-induced diabetic mice, there was some improvement in glucose levels.[3] Our colleagues in Singapore[4,5] have used another model of autologous hepatocytes from streptozotocin-induced diabetic pigs. These separated hepatocytes were successfully transfected ex-vivo with a human insulin gene construct by electrophoration, and then the cells were injected directly back into the liver parenchyma using multiple separate injections. The pigs were cured of their diabetes for up to nine months - which is a remarkable achievement. As these were autotransplantations, no immunosuppressive drugs were necessary, but the liver cells were obtained from large open surgical biopsies. This necessity of surgical removal of liver tissue would limit its applicability, but nevertheless has been a good proof of concept study. In the context of autoimmune diabetes, the risk of recurrent disease may well persist unless the target of autoimmune attack could be defined and eliminated. In these porcine experiments, the human insulin gene with a glucose sensing promoter EGR-1 was used. There was no virus involved, and the plasmid does not integrate. Division of the transfected cell would dilute gene activity, but large numbers of plasmid can be produced cheaply. The same group of workers successfully transfected bone marrow mesenchymal stem cells with the human insulin gene plasmid using the same EGR-1 promoter and electrophoration. This cured diabetic mice after direct intra-hepatic and intra-peritoneal injection.

Finally, there should be caution in interpreting the results of these and other reports of cell and gene therapy for diabetes. In gene transfection and/or transplantation of insulin-producing cells or clusters in the diabetic rodent, there have been many reports in the literature, but only a few of these claims have been reproduced in independent laboratories. We have suggested the need to satisfy The Seven Pillars of Credibility as essential criteria in the evaluation of claims of success in the use of stem cell and/or gene therapy for diabetes.[1]

Cure of hyperglycemia

Response to glucose tolerance test

Evidence of appropriate C-peptide secretion

Weight gain

Prompt return of diabetes when the transfecting gene and/or insulin producing cells are removed

No islet regeneration of stereptozotocin-treated animals and no re-generation of pancreas in pancreatectomized animals

Presence of insulin storage granules in the treated cells

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Amniotics led consortium selected for EIC-Pathfinder grant of 3.8 million from the European Innovation Council  Marketscreener.com

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We created the world's first donkey embryo using IVF in a bid to save species from extinction  The Conversation

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CNN

The first time molecular biologist Doris Taylor saw heart stem cells beat in unison in a petri dish, she was spellbound.

It actually changed my life, said Taylor, who directed regenerative medicine research at Texas Heart Institute in Houston until 2020. I said to myself, Oh my gosh, thats life. I wanted to figure out the how and why, and re-create that to save lives.

That goal has become reality. On Wednesday at the Life Itself conference, a health and wellness event presented in partnership with CNN, Taylor showed the audience the scaffolding of a pigs heart infused with human stem cells creating a viable, beating human heart the body will not reject. Why? Because its made from that persons own tissues.

Now we can truly imagine building a personalized human heart, taking heart transplants from an emergency procedure where youre so sick, to a planned procedure, Taylor told the audience.

That reduces your risk by eliminating the need for (antirejection) drugs, by using your own cells to build that heart it reduces the cost and you arent in the hospital as often so it improves your quality of life, she said.

Debuting on stage with her was BAB, a robot Taylor painstakingly taught to inject stem cells into the chambers of ghost hearts inside a sterile environment. As the audience at Life Itself watched BAB functioning in a sterile environment, Taylor showed videos of the pearly white mass called a ghost heart begin to pinken.

Can we grow a personalized human heart?

Its the first shot at truly curing the number one killer of men, women and children worldwide heart disease. And then I want to make it available to everyone, said Taylor to audience applause.

She never gave up, said Michael Golway, lead inventor of BAB and president and CEO of Advanced Solutions, which designs and creates platforms for building human tissues.

At any point, Dr. Taylor could have easily said Im done, this just isnt going to work. But she persisted for years, fighting setbacks to find the right type of cells in the right quantities and right conditions to enable those cells to be happy and grow.

Taylors fascination with growing hearts began in 1998, when she was part of a team at Duke University that injected cells into a rabbits failed heart, creating new heart muscle. As trials began in humans, however, the process was hit or miss.

We were putting cells into damaged or scarred regions of the heart and hoping that would overcome the existing damage, she told CNN. I started thinking: What if we could get rid of that bad environment and rebuild the house?

Taylors first success came in 2008 when she and a team at the University of Minnesota washed the cells out of a rats heart and began to work with the translucent skeleton left behind.

Soon, she graduated to using pigs hearts, due to their anatomical similarity to human hearts.

We took a pigs heart, and we washed out all the cells with a gentle baby shampoo, she said. What was left was an extracellular matrix, a transparent framework we called the ghost heart.

Then we infused blood vessel cells and let them grow on the matrix for a couple of weeks, Taylor said. That built a way to feed the cells we were going to add because wed reestablished the blood vessels to the heart.

The next step was to begin injecting the immature stem cells into the different regions of the scaffold, and then we had to teach the cells how to grow up.

We must electrically stimulate them, like a pacemaker, but very gently at first, until they get stronger and stronger. First, cells in one spot will twitch, then cells in another spot twitch, but they arent together, Taylor said. Over time they start connecting to each other in the matrix and by about a month, they start beating together as a heart. And let me tell you, its a wow moment!

But thats not the end of the mothering Taylor and her team had to do. Now she must nurture the emerging heart by giving it a blood pressure and teaching it to pump.

We fill the heart chambers with artificial blood and let the heart cells squeeze against it. But we must help them with electrical pumps, or they will die, she explained.

The cells are also fed oxygen from artificial lungs. In the early days all of these steps had to be monitored and coordinated by hand 24 hours a day, 7 days a week, Taylor said.

The heart has to eat every day, and until we built the pieces that made it possible to electronically monitor the hearts someone had to do it person and it didnt matter if it was Christmas or New Years Day or your birthday, she said. Its taken extraordinary groups of people who have worked with me over the years to make this happen.

But once Taylor and her team saw the results of their parenting, any sacrifices they made became insignificant, because then the beauty happens, the magic, she said.

Weve injected the same type of cells everywhere in the heart, so they all started off alike, Taylor said. But now when we look in the left ventricle, we find left ventricle heart cells. If we look in the atrium, they look like atrial heart cells, and if we look in the right ventricle, they are right ventricle heart cells, she said.

So over time theyve developed based on where they find themselves and grown up to work together and become a heart. Nature is amazing, isnt she?

As her creation came to life, Taylor began to dream about a day when her prototypical hearts could be mass produced for the thousands of people on transplant lists, many of whom die while waiting. But how do you scale a heart?

I realized that for every gram of heart tissue we built, we needed a billion heart cells, Taylor said. That meant for an adult-sized human heart we would need up to 400 billion individual cells. Now, most labs work with a million or so cells, and heart cells dont divide, which left us with the dilemma: Where will these cells come from?

The answer arrived when Japanese biomedical researcher Dr. Shinya Yamanaka discovered human adult skin cells could be reprogrammed to behave like embryonic or pluripotent stem cells, capable of developing into any cell in the body. The 2007 discovery won the scientist a Nobel Prize, and his induced pluripotent stem cells (iPS), soon became known as Yamanaka factors.

Now for the first time we could take blood, bone marrow or skin from a person and grow cells from that individual that could turn into heart cells, Taylor said. But the scale was still huge: We needed tens of billions of cells. It took us another 10 years to develop the techniques to do that.

The solution? A bee-like honeycomb of fiber, with thousands of microscopic holes where the cells could attach and be nourished.

The fiber soaks up the nutrients just like a coffee filter, the cells have access to food all around them and that lets them grow in much larger numbers. We can go from about 50 million cells to a billion cells in a week, Taylor said. But we need 40 billion or 50 billion or 100 billion, so part of our science over the last few years has been scaling up the number of cells we can grow.

Another issue: Each heart needed a pristine environment free of contaminants for each step of the process. Every time an intervention had to be done, she and her team ran the risk of opening the heart up to infection and death.

Do you know how long it takes to inject 350 billion cells by hand? Taylor asked the Life Itself audience. What if you touch something? You just contaminated the whole heart.

Once her lab suffered an electrical malfunction and all of the hearts died. Taylor and her team were nearly inconsolable.

When something happens to one of these hearts, its devastating to all of us, Taylor said. And this is going to sound weird coming from a scientist, but I had to learn to bolster my own heart emotionally, mentally, spiritually and physically to get through this process.

Enter BAB, short for BioAssemblyBot, and an uber-sterile cradle created by Advance Solutions that could hold the heart and transport it between each step of the process while preserving a germ-free environment. Taylor has now taught BAB the specific process of injecting the cells she has painstakingly developed over the last decade.

When Dr. Taylor is injecting cells, it has taken her years to figure out where to inject, how much pressure to put on the syringe, and the best speed and pace to add the cells, said BABs creator Golway.

A robot can do that quickly and precisely. And as we know, no two hearts are the same, so BAB can use ultrasound to see inside the vascular pathway of that specific heart, where Dr. Taylor is working blind, so to speak, Golway added. Its exhilarating to watch there are times where the hair on the back of my neck literally stands up.

Taylor left academia in 2020 and is currently working with private investors to bring her creation to the masses. If transplants into humans in upcoming clinical trials are successful, Taylors personalized hybrid hearts could be used to save thousands of lives around the world.

In the US alone, some 3,500 people were on the heart transplant waiting list in 2021.

Thats not counting the people who never make it on the list, due to their age or heath, Taylor said. If youre a small woman, if youre an underrepresented minority, if youre a child, the chances of getting an organ that matches your body are low.

If you do get a heart, many people get sick or otherwise lose their new heart within a decade. We can reduce cost, we can increase access, and we can decrease side effects. Its a win-win-win.

Taylor can even envision a day when people bank their own stem cells at a young age, taking them out of storage when needed to grow a heart and one day even a lung, liver or kidney.

Say they have heart disease in their family, she said. We can plan ahead: Grow their cells to the numbers we need and freeze them, then when they are diagnosed with heart failure pull a scaffold off the shelf and build the heart within two months.

Im just humbled and privileged to do this work, and proud of where we are, she added. The technology is ready. I hope everyone is going to be along with us for the ride because this is game-changing.

See more here:
'Ghost heart': Built from the scaffolding of a pig and the ... - CNN

Recommendation and review posted by Bethany Smith

Research Article

09 Nov 2022

Aucubin Impeded Preosteoclast Fusion and Enhanced CD31hi EMCNhi Vessel Angiogenesis in Ovariectomized Mice

Ziyi Li|Chang Liu|...|Peng Xue

Osteogenesis is tightly correlated with angiogenesis during the process of bone development, regeneration, and remodeling. In addition to providing nutrients and oxygen for bone tissue, blood vessels around bone tissue also secrete some factors to regulate bone formation. Type H vessels which were regulated by platelet-derived growth factor-BB (PDGF-BB) were confirmed to couple angiogenesis and osteogenesis. Recently, preosteoclasts have been identified as the most important source of PDGF-BB. Therefore, inhibiting osteoclast maturation, improving PDGF-BB secretion, stimulating type H angiogenesis, and subsequently accelerating bone regeneration may be potent treatments for bone loss disease. In the present study, aucubin, an iridoid glycoside extracted from Aucuba japonica and Eucommia ulmoides, was found to inhibit bone loss in ovariectomized mice. We further confirmed that aucubin could inhibit the fusion of tartrate-resistant acid phosphatase (TRAP)+ preosteoclasts into mature osteoclasts and indirectly increasing angiogenesis of type H vessel. The underlying mechanism is the aucubin-induced inhibition of MAPK/NF-B signaling, which increases the preosteoclast number and subsequently promotes angiogenesis via PDGF-BB. These results prompted that aucubin could be an antiosteoporosis drug candidate, which needs further research.

Review Article

07 Nov 2022

The Influence of Intervertebral Disc Microenvironment on the Biological Behavior of Engrafted Mesenchymal Stem Cells

Jing Zhang|Wentao Zhang|...|Zhonghai Li

Intervertebral disc degeneration is the main cause of low back pain. Traditional treatment methods cannot repair degenerated intervertebral disc tissue. The emergence of stem cell therapy makes it possible to regenerate and repair degenerated intervertebral disc tissue. At present, mesenchymal stem cells are the most studied, and different types of mesenchymal stem cells have their own characteristics. However, due to the harsh and complex internal microenvironment of the intervertebral disc, it will affect the biological behaviors of the implanted mesenchymal stem cells, such as viability, proliferation, migration, and chondrogenic differentiation, thereby affecting the therapeutic effect. This review is aimed at summarizing the influence of each intervertebral disc microenvironmental factor on the biological behavior of mesenchymal stem cells, so as to provide new ideas for using tissue engineering technology to assist stem cells to overcome the influence of the microenvironment in the future.

Research Article

07 Nov 2022

CD44v6+ Hepatocellular Carcinoma Cells Maintain Stemness Properties through Met/cJun/Nanog Signaling

Wei Chen|Ronghua Wang|...|Bin Cheng

Cancer stem cells (CSCs) are characterized by their self-renewal and differentiation abilities. CD44v6 is a novel CSC marker that can activate various signaling pathways. Here, we hypothesized that the HGF/Met signaling pathway promotes stemness properties in CD44v6+ hepatocellular carcinoma (HCC) cells via overexpression of the transcription factor, cJun, thus representing a valuable target for HCC therapy. Magnetic activated cell sorting was used to separate the CD44v6+ from CD44v6- cells, and Met levels were regulated using lentiviral particles and the selective Met inhibitor, PHA665752. An orthotopic liver xenograft tumor model was used to assess the self-renewal ability of CD44v6+ cells in immunodeficient NOD/SCID mice. Luciferase reporter and chromatin immunoprecipitation assays were also conducted using cJun-overexpressing 293 T cells to identify the exact binding site of cJun in the Nanog promoter. Our data demonstrate that CD44v6 is an ideal surface marker of liver CSCs. CD44v6+ HCC cells express higher levels of Met and possess self-renewal and tumor growth abilities. Xenograft liver tumors were smaller in nude mice injected with shMet HCC cells. Immunohistochemical analysis of liver tissue specimens revealed that high Met levels in HCC cells were associated with poor patient prognosis. Further, a cJun binding site was identified 1700 bp upstream of the Nanog transcription start site and mutation of the cJun binding site reduced Nanog expression. In conclusion, the HGF/Met signaling pathway is important for maintenance of stemness in CD44v6+ HCC cells by enhancing expression of cJun, which binds 1700 bp upstream of the Nanog transcription start site.

Research Article

26 Oct 2022

Stage-Dependent Regulation of Dental Pulp Stem Cell Odontogenic Differentiation by Transforming Growth Factor-1

Yu Bai|Xin Liu|...|Wenxi He

Transforming growth factor-1 (TGF-1) is an important multifunctional cytokine with dual effects on stem cell differentiation. However, the role of TGF-1 on odontogenic differentiation of dental pulp stem cells (DPSCs) remains to be entirely elucidated. In the present study, we initially investigated the effect of TGF-1 at a range of concentrations (0.1-5ng/mL) on the proliferation, cell cycle, and apoptosis of DPSCs. Subsequently, to determine the effect of TGF-1 on odontogenic differentiation, alkaline phosphatase (ALP) activity and Alizarin Red S (ARS) staining assays at different concentrations and time points were performed. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis were used to determine the levels of odonto-/osteo-genic differentiation-related gene and protein expression, respectively. For in vivo studies, newly formed tissue was assessed by Massons trichrome and von Kossa staining. Data indicated that TGF-1 inhibited DPSCs proliferation in a concentration-and time-dependent manner () and induced cell cycle arrest but did not affect apoptosis. ALP activity was enhanced, while ARS reduced gradually with increasing TGF-1 concentrations, accompanied by increased expression of early marker genes of odonto-/osteo-genic differentiation and decreased expression of late-stage mineralization marker genes (). ALP expression was elevated in the TGF-1-treatment group until 14 days, and the intensity of ARS staining was attenuated at days 14 and 21 (). Compared with the control group, abundant collagen but no mineralized tissues were observed in the TGF-1-treatment group in vivo. Overall, these findings indicate that TGF-1 promotes odontogenic differentiation of DPSCs at early-stage while inhibiting later-stage mineralization processes.

Research Article

20 Oct 2022

miR-31 from Mesenchymal Stem Cell-Derived Extracellular Vesicles Alleviates Intervertebral Disc Degeneration by Inhibiting NFAT5 and Upregulating the Wnt/-Catenin Pathway

Baodong Wang|Na Xu|...|Yang Cao

In this study, we explored the regulatory mechanism of intervertebral disc degeneration (IDD) that involves miR-31 shuttled by bone marrow mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) and its downstream signaling molecules. Nucleus pulposus cells (NPCs) were isolated and treated with TNF- to simulate IDD in vitro. The TNF--exposed NPCs were then cocultured with hBMSCs or hBMSC-EVs in vitro to detect the effects of hBMSC-EVs on NPC viability, apoptosis, and ECM degradation. Binding between miR-31 and NFAT5 was determined. A mouse model of IDD was prepared by vertebral disc puncture and injected with EVs from hBMSCs with miR-31 knockdown to discern the function of miR-31 in vivo. The results demonstrated that hBMSC-EVs delivered miR-31 into NPCs. hBMSC-EVs enhanced NPC proliferation and suppressed cell apoptosis and ECM degradation, which was associated with the transfer of miR-31 into NPCs. In NPCs, miR-31 bound to the 3UTR of NFAT5 and inhibited NFAT5 expression, leading to activation of the Wnt/-catenin pathway and thus promoting NPC proliferation and reducing cell apoptosis and ECM degradation. In addition, miR-31 in hBMSC-EVs alleviated the IDD in mouse models. Taken together, miR-31 in hBMSC-EVs can alleviate IDD by targeting NFAT5 and activating the Wnt/-catenin pathway.

Review Article

20 Oct 2022

Variability in Platelet-Rich Plasma Preparations Used in Regenerative Medicine: A Comparative Analysis

Raghvendra Vikram Tey|Pallavi Haldankar|...|Ravindra Maradi

Background. Platelet-rich plasma (PRP) and its derivatives are used in several aesthetic, dental, and musculoskeletal procedures. Their efficacy is primarily due to the release of various growth factors (GF), interleukins, cytokines, and white blood cells. However, the PRP preparation methods are highly variable, and studies lack consistency in reporting complete procedures to prepare PRP and characterize PRP and its derivatives. Also, all the tissue-specific (in vivo and in vitro) interactions and functional properties of the various derivatives/factors of the PRP have not been taken into consideration by any study so far. This creates a potential space for further standardization of the PRP preparation methods and customization of PRP/PRP derivatives targeted at tissue-specific/pathology specific requirements that would enable efficacious and widely acceptable usage of PRP as main therapy, rather than being used as adjuvant therapy. The main objective of our study was to investigate the variability in PRP preparation methods and to analyze their efficacy and reliability. Method. This study considered articles published in the last 5 years, highlighting the variability in their PRP preparation methods and characterization of PRP. Following the PRISMA protocol, we selected 13 articles for the study. The selected articles were assessed using NHLBI quality assessment tool. Results. We noted differences in (1) approaches to producing PRP, (2) extent of characterization of PRP, (3) small scale and large-scale preparation methods, (4) in vitro and in vivo studies. Conclusion. We identified two studies describing the procedures which are simple, reproducible, economical, provide a good yield of platelets, and therefore can be considered methods for further tissue-specific and pathology-specific standardizations of PRP and its derivatives. We recommend further randomized studies to understand the full therapeutic potential of the constituents of PRP and its derivatives.

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Stem Cells International | Hindawi

Recommendation and review posted by Bethany Smith

Ono Exercises Option to HER2-targeted CAR T-Cell Product Candidate for Solid Tumors Generated from the Collaboration with Fate Therapeutics  Marketscreener.com

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Ono Exercises Option to HER2-targeted CAR T-Cell Product Candidate for Solid Tumors Generated from the Collaboration with Fate Therapeutics -...

Recommendation and review posted by Bethany Smith

Rev Urol. 2004; 6(Suppl 6): S3S8.

Auxilium Pharmaceuticals, Inc., Norristown, PA

Hypogonadism can be of hypothalamic-pituitary origin or of testicular origin, or a combination of both, which is increasingly common in the aging male population. In the postpubertal male, testosterone replacement therapy can be used to treat the signs and symptoms of low testosterone, which include loss of libido, erectile dysfunction, diminished intellectual capacity, depression, lethargy, osteoporosis, loss of muscle mass and strength, and some regression of secondary sexual characteristics. Before initiation of testosterone replacement therapy, an examination of the prostate and assessment of prostate symptoms should be performed, and both the hematocrit and lipid profile should be measured. Absolute contraindications to testosterone replacement therapy are prostate or breast cancer, a hematocrit of 55% or greater, or sensitivity to the testosterone formulation.

Key words: Hypogonadism, Testosterone replacement therapy, Serum hormone-binding globulin, Luteinizing hormone, Follicle-stimulating hormone

Hypogonadism is a lack of testosterone in male patients and can be of central (hypothalamic or pituitary) or testicular origin, or a combination of both. Hypogonadism in male patients with testicular failure due to genetic disorders (eg, Klinefelters syndrome), orchitis, trauma, radiation, chemotherapy, or undescended testes, is known as hypergonadotropic hypogonadism or primary hypogonadism. Hypogonadism in male patients with gonadotropin deficiency or dysfunction as a result of disease or damage to the hypothalamic-pituitary axis is known as hypogonadotropic hypogonadism, central hypogonadism, or secondary hypogonadism. This might be due to Kallmanns syndrome, tumor, trauma, radiation, sarcoidosis, or tuberculosis. In addition, men older than 50 years might have low testosterone levels with functional abnormalities at multiple levels of the hypothalamic-pituitary-testicular axis.1,2,3

The prevalence of hypogonadism has increased in recent years. It has been reported that 12%, 19%, 28%, and 49% of men greater than 50, 60, 70, or 80 years of age, respectively, fit the criteria of hypogonadism.4

During puberty, testosterone is required for the development of male secondary sexual characteristics, stimulation of sexual behavior and function, and initiation of sperm production.5,6 In adult males, testosterone is involved in maintaining muscle mass and strength, fat distribution, bone mass, red blood cell production, male hair pattern, libido and potency, and spermatogenesis.13,5,6

In men, the major gonadal steroid hormone is testosterone. Testosterone circulates in 3 major forms: unbound, or free, testosterone; tightly bound testosterone, which is bound to sex hormone-binding globulin (SHBG); and weakly bound testosterone, which is bound to albumin. Only free and weakly bound testosterone is bioavailable or able to bind to the androgen receptor.2,3

In males, serum testosterone levels show a circadian variation, with the highest levels in the morning and lowest levels in the late afternoon. In young men, the variation in testosterone levels is approximately 35%. Although the normal range for serum testosterone might vary between different laboratories, the normal range for early morning total testosterone in healthy adult males is approximately 300 ng/dL to 1000 ng/dL.7,8

To determine whether a patient is testosterone deficient, a clinician must consider clinical signs and symptoms in conjunction with laboratory values. The initial clinical picture will vary depending on the age of the patient at the onset of the disorder.

In the normal male, the start of puberty is apparent by enlargement of the testes and the appearance of pubic hair, followed by the appearance of auxiliary and facial hair. At puberty there is also increased penile length and the onset of spermatogenesis. If signs of puberty are not evident in boys by 14 years of age, a workup for delayed puberty is warranted.

In the prepubertal age group, hypogonadism might be either primary hypogonadism or secondary hypogonadism. To differentiate primary from secondary hypogonadism, early morning luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels must be obtained. Because LH and FSH are secreted during the early morning at the beginning of puberty, it is necessary to measure these hormones in the early morning (8:0010:00 AM). Primary hypogonadism is associated with low levels of testosterone and high-normal to high levels of LH and FSH. Secondary hypogonadism is associated with low levels of testosterone and normal to low levels of LH and FSH.5,6

The signs and symptoms of low testosterone in postpubertal adult males can be more difficult to diagnose and might include loss of libido, erectile dysfunction, diminished intellectual capacity, depression, lethargy, osteoporosis, loss of muscle mass and strength, and some regression of secondary sexual characteristics.13 At the initial visit, the first objective is to distinguish between primary gonadal failure, in which low testosterone is accompanied by increased FSH and increased LH, and hypothalamic-pituitary disorders (secondary hypogonadism), with low testosterone and low to normal FSH and LH levels.

Initial laboratory testing should include early morning (8:0010:00 AM) measurement of serum testosterone, prolactin, FSH, and LH levels. For the diagnosis of primary hypogonadism, FSH measurement is particularly important because FSH has a longer half life, is more sensitive, and demonstrates less variability than LH.2,3

The aging male patient can present with signs and symptoms of low testosterone, including loss of libido, erectile dysfunction, diminished intellectual capacity, depression, lethargy, osteoporosis, and loss of muscle mass and strength.13 At the initial visit, laboratory testing should include early morning (8:0010:00 AM) measurement of serum testosterone. In elderly men, testosterone levels decrease between 15% and 20% over the course of 24 hours.8

Total testosterone levels might be normal with hypogonadism if the SHBG levels are increased.79 Levels of SHBG increase with age, causing a decrease in bioavailable testosterone.9 If testosterone levels are low-normal but the clinical symptoms and signs indicate hypogonadism, measurement of serum total testosterone levels should be repeated and an SHBG level should be determined. With the total testosterone and SHBG levels, a bioavailable testosterone value can be calculated. A bioavailable testosterone calculator is available at http://www.issam.ch/freetesto.htm.

It is usually not necessary to determine FSH or LH levels in the aging male.

It is well accepted that testosterone levels should be measured in the early morning, when they are at their peak level. However, in community practice the choice of which testosterone parameter to measure is still debatable.

Total testosterone assay is widely available and inexpensive to perform. Although the ranges and methods vary, physicians can consult their local laboratories for the applicable values in their clinical practice. Total testosterone values, however, must be interpreted carefully in the aging male because SHBG levels might be elevated. If the total testosterone level is normal in the aging male presenting signs of hypogonadism, the clinician can measure free testosterone or measure SHBG and calculate bioavailable testosterone.9

Free testosterone can be measured by equilibrium dialysis or ultrafiltration, which are difficult to perform and largely unavailable but reliable. In contrast, the radioimmunoassay for free testosterone is widely available but unreliable. Because total testosterone and SHBG assays are readily available and cheap, calculating bioavailable testosterone might be a good compromise. Whichever method is chosen, if the early morning testosterone level is at or below the lower limit of normal for the individual laboratory, then a repeat measurement of the early morning testosterone level should be performed to confirm the result. Because testosterone is secreted in a pulsatile fashion, it is important to obtain 2 early morning testosterone levels.

In selected patients, FSH, LH, and prolactin can be measured. If the FSH and LH levels are raised, this suggests a primary testicular cause, and if levels are low or normal, a hypothalamic or pituitary cause should be considered. A raised prolactin level suggests that further investigation of the pituitary gland should be undertaken.1,2

The clinical signs and symptoms of hypogonadism will vary depending on whether the patient presents before or after puberty. Depending on the age of the patient, the degree of pubertal development is important for establishing the differential diagnosis.

Boys aged 14 years or older should be suspected of being hypogonadal if on examination they have underdeveloped testes, lack of penile enlargement, and absence of pubic, auxiliary, and facial hair.

In patients with primary hypogonadism, history might reveal the cause for primary testicular failure, such as familial autoimmune disease, physical trauma to the testes, or trauma to the testes caused by radiation, chemotherapy, or infection.

A karyotype should be obtained to diagnose chromosomal abnormalities, such as Klinefelters syndrome, and a physical examination will reveal small or absent testes resulting from anorchia, Noonans syndrome, or other testicular disorders.

Hypothalamic or pituitary deficiency might be transitory or permanent. Transient secondary hypogonadism might be related to malnutrition or stress states and can be diagnosed by physical examination and evaluation of the patients growth chart. If permanent hypothalamic or pituitary hormone deficiency is suspected, serum levels of pituitary hormones and magnetic resonance imaging of the brain and pituitary should be obtained to screen for hypothalamic or pituitary disease.

If both physical examination and serum chemistry tests are normal, then by exclusion a diagnosis of constitutional pubertal delay must be considered.

To establish a diagnosis of hypogonadism, it is important to take a careful history to determine whether there have been major medical problems, toxic exposure, concomitant drug therapy that might cause hypogonadism, or fertility problems.

Low libido, impotence, fatigue, impaired concentration, and sexual dysfunction are important clinical problems that might not be raised by the patient in the clinic. Therefore, these symptoms need to be asked about specifically if hypogonadism is suspected.13

Formal assessment of intellectual changes, mood, and cognitive changes can be performed. Changes in lean body mass will be apparent from the medical history and examination, as will changes in hair, skin, and fat distribution. Decreases in bone mineral density might be apparent from a history of recent fractures but can only be confirmed by dual energy x-ray absorptiometry (DEXA).1

Physical examination should include testicular examination, including size and consistency. The distribution and amount of body hair should also be noted. Penile size is not affected by postpubertal testosterone deficiency. An assessment of the prostate by digital rectal examination (DRE) should be performed and a prostate-specific antigen (PSA) value obtained.3

To establish a diagnosis of hypogonadism in the aging male, it is important to assess the patient carefully for signs and symptoms. Low libido, impotence, fatigue, impaired concentration, and sexual dysfunction are important clinical problems that might not be raised by the patient in the clinic, especially by an aging patient. Therefore, as with the younger postpubertal patient, these symptoms need to be asked about specifically if hypogonadism is suspected.1,2 As with the postpubertal patient (see previous section), changes in intellectual functioning; mood; lean body mass; and hair, skin, and fat distribution should all be assessed, and DEXA can be used to confirm decreases in bone mineral density.1

In older patients, an important part of the physical examination includes an assessment of the prostate by DRE and PSA assay. In addition, an assessment of prostate-related symptoms should be undertaken. The presence of gynecomastia or carcinoma of the breast are important physical findings.

In cases of primary and permanent secondary hypogonadism diagnosed in the prepubertal male, life long testosterone treatment is needed. The usual treatment is initiation of therapy with small doses of testosterone (50100 mg IM) every 3 to 4 weeks at the appropriate psychosocial stage in development. When a final adult height is thought to have been obtained, the adult dose of testosterone replacement is inaugurated.

In the postpubertal period, once the diagnosis of testosterone deficiency has been made, replacement therapy should be considered in light of the clinical signs and symptoms in conjunction with the laboratory values. The objective of testosterone replacement therapy is to normalize serum testosterone and maintain the level within the eugonadal state. In addition, treatment objectives might include improving sexual dysfunction, intellectual capacity, depression, and lethargy; maintaining bone mineral density and possibly reducing fracture risk; increasing muscle mass and strength; and enhancing the quality of life.13,9

Although the normal range for serum testosterone might vary between different laboratories, the normal range for early morning testosterone in male adults is approximately 300 ng/dL to 1000 ng/dL.7 An early morning total serum testosterone level of less than 300 ng/dL clearly indicates hypogonadism, and under most circumstances benefit will be derived from testosterone replacement therapy. A healthy male adult patient with a serum testosterone level greater than 400 ng/dL is unlikely to be testosterone deficient, and therefore clinical judgment should be exercised if he has symptoms suggestive of testosterone deficiency.

There are some absolute contraindications to testosterone replacement therapy. These include prostate cancer, which must be assessed by history and clinical examination. If on DRE the prostate is enlarged or if the PSA level is greater than 4.0 ng/mL, biopsy of the prostate should be undertaken to confirm a diagnosis of prostate cancer or benign prostatic hyperplasia (BPH).3

An existing or prior history of breast cancer is also an absolute contraindication to testosterone replacement therapy. Testosterone therapy is known to increase the hematocrit, and therefore a pre-existing hematocrit of 55% or greater is an absolute contraindication to replacement therapy.

Sensitivity to any of the ingredients in the testosterone formulation would also be an absolute contraindication. Relative contraindications include an increased hematocrit, untreated sleep apnea, severe obstructive symptoms of BPH, and advanced congestive cardiac failure.2,3

The goal of replacement therapy is to maintain testosterone in the normal physiological range; therefore, a combination of clinical and biochemical measures should be monitored 6 to 12 weeks after initiating therapy. In most cases, an early morning serum total testosterone level is adequate to determine whether dosage adjustment is necessary. However, patients receiving injections of testosterone enanthate or cypionate every 2 weeks will require an earlier measurement of serum testosterone at 1 to 2 weeks after commencement of therapy.3

Examination of the prostate should be performed routinely, although the exact frequency after initiation of testosterone replacement is still debatable. Digital rectal examination of the prostate and PSA assay should be performed before initiation of therapy, along with an assessment of prostate-related symptoms. In elderly men, a DRE and PSA assay should be performed at 3 and 6 months after commencing testosterone therapy and then annually thereafter.3 A high PSA level should be further evaluated with a highly specific PSA assay, if available. A patient should be referred to a urologist if his PSA level increases over time or if he has a PSA level greater than 4.0 ng/mL.3

It is known that testosterone stimulates bone marrow production of erythrocytes, which might result in an increased hematocrit in some men, and therefore this should be checked at the same time as the PSA level.2,3

Lipid disturbances in testosterone-treated male patients are generally not a problem because the ratio of high-density lipoprotein to total cholesterol usually remains constant. An initial lipid profile should be performed before therapy, and a follow-up profile should be obtained after 6 to 12 months of therapy and annually thereafter.3

Hypogonadism can be of hypothalamic-pituitary origin or of testicular origin, or a combination of both, which is increasingly common in the aging male population. It can be easily diagnosed with measurement of the early morning serum total testosterone level, which should be repeated if the value is low. Follicle-stimulating hormone, LH, and prolactin might also need to be measured. If the clinical signs and symptoms suggest hypogonadism but the serum testosterone level is near normal, then assay of serum testosterone should be repeated in conjunction with SHBG because serum testosterone might be normal in the presence of hypogonadism if the SHBG level is raised, which commonly occurs in elderly male patients.

Before initiation of testosterone replacement therapy, an examination of the prostate, including DRE, PSA assay, and assessment of prostate symptoms should be undertaken, and both the hematocrit and lipid profile should be measured. There are few absolute contraindications to testosterone replacement therapy other than prostate or breast cancer, a hematocrit of 55% or greater, or sensitivity to the testosterone formulation. Monitoring of the prostate (assessed with DRE and PSA assay) and hematocrit and lipid profile should be repeated during testosterone replacement therapy.

The benefits of testosterone replacement therapy may include restoring metabolic parameters to the eugonadal state; improving psychosexual function and intellectual capacity, including depression and lethargy; maintaining bone mineral density and reducing bone fractures; improving muscle mass and strength; and enhancing quality of life.

Hypogonadism is a lack of testosterone in male patients and can be of central (hypothalamic or pituitary) or testicular origin, or a combination of both.

Boys ages 14 years or older should be suspected of being hypogonadal if on examination they have underdeveloped testes, a lack of penile enlargement, and an absence of pubic, auxiliary, and facial hair.

In pre- and postpubertal male patients, primary hypogonadism is associated with low levels of testosterone and high-normal to high levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH); secondary hypogonadism is associated with low levels of testosterone and normal to low levels of LH and FSH.

In the aging male patient, signs and symptoms of hypogonadism can include loss of libido, erectile dysfunction, diminished intellectual capacity, depression, lethargy, osteoporosis, and loss of muscle mass and strength.

For aging men, laboratory testing should include early morning (8:0010:00 AM) measurement of serum testosterone; levels less than 300 ng/dL clearly indicate hypogonadism, and under most circumstances benefit will be derived from testosterone replacement therapy.

Before initiation of testosterone replacement therapy, an examination of the prostate and assessment of prostate symptoms should be performed, and both the hematocrit and lipid profile should be measured.

There are few absolute contraindications to testosterone replacement therapy other than prostate or breast cancer, a hematocrit of 55% or greater, or sensitivity to the testosterone formulation.

See the original post:
Diagnosis of Hypogonadism: Clinical Assessments and Laboratory Tests

Recommendation and review posted by Bethany Smith

Hypogonadotropic hypogonadism (HH) or secondary hypogonadism is defined as a clinical syndrome that results from gonadal failure due to abnormal pituitary gonadotropin levels. HH may result from either absent or inadequate hypothalamic GnRH secretion or failure of pituitary gonadotropin secretion. Several congenital and acquired causes, including functional and organic forms, have been associated with this condition. One important aspect of the HH diagnosis is that it may reflect the presence of a tumor of the hypothalamic pituitary region or even a systemic disease. On the other hand, functional forms of HH, characterized by a transient defect in GnRH secretion, are relatively common in women, in response to significant weight loss, exercise, or stress leading to hypothalamic amenorrhea. HH is typically characterized by low circulating sexual steroids associated with low or inappropriately normal gonadotropin levels. The precise and early diagnosis of HH can prevent negative physical and psychological sequelae, preserve normal peak bone mass, and restore the fertility in affected patients.

Accreditation and Credit Designation Statements

The Endocrine Society is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Endocrine Society has achieved Accreditation with Commendation.

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Learning Objectives

Upon completion of this educational activity, participants should be able to:

Recognize the symptoms and signs of hypogonadism throughout different phases of life.

Identify the congenital and acquired causes of hypogonadotropic hypogonadism.

Diagnose hypogonadotropic hypogonadism.

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Leticia Ferreira Gontijo Silveira, M.D., Ph.D, and Ana Claudia Latronico, M.D., Ph.D., have no relevant financial relationships.

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The Editor-in-Chief, Leonard Wartofsky, M.D., is a Consultant for Asurogen, Genzyme, and IBSA, and is on the Speaker's Bureau for Genzyme. Kenneth Burman, M.D., is a Consultant for Medscape and UpToDate; a Reviewer for the Endocrine Fellows Foundation; and has received Institutional Grants for Research from Amgen, Eisei, and Pfizer. Samuel Dagogo-Jack, M.D., is a Consultant for Merck and Novo Nordisk; a Grantee for the American Diabetes Association, AstraZeneca, Boehringer Ingelheim, National Institutes of Health, and Novo Nordisk; and a Grant Reviewer for the American Diabetes Association and National Institutes of Health. Silvio Inzucchi, M.D., is a Consultant/Advisor for Boehringer Ingelheim, Genentech, Janssen, Merck, and Takeda; has DSMB Activity with Amgen, Esai, and Gilead; and receives CME support from Abbott, Amylin, Boeringher-Ingelheim, Merck, and Takeda. Kieren Mather, M.D., received an Investigator-initiated Grant from Novo Nordisk. Lynnette Nieman, M.D., is an Author/Editor for UpToDate, and receives Research Support from HRA-Pharmaceutical.

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Endocrine Society staff associated with the development of content for this activity reported no relevant financial relationships.

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A 19 year-old female, born from nonconsanguineous parents, was referred to the Endocrinology Unit due to primary amenorrhea and poor breast development. Spontaneous partial pubarche and thelarche occurred at 13 and 15 years, respectively. The patient did not report eating disorders or vigorous physical activity. She had no olfactory complaints. She had 2 older brothers with a history of normal pubertal development. At physical examination, she had eunuchoid habitus (height, 155 cm; arm span, 160 cm), weight of 60.7 kg, with normal body mass index of 23 kg/m2. Pubic hair and breast development were Tanner stage II. She had ogival palate and cavus feet, and no other stigmata were observed. Basal hormonal evaluation revealed low serum estradiol (6.8 pg/ml) and suppressed LH (<0.6 IU/L) and FSH (<1.0 IU/L) levels. Upon acute GnRH stimulation test (100 mg iv), peak LH was 1.4 IU/L and peak FSH was 1.7 IU/L. Anterior pituitary function was otherwise normal, including prolactin (9 ng/mL) and thyroid function (TSH, 1.5 IU/L; free T4, 1.1 ng/dL). A formal olfactory test was applied and confirmed normal sense of smell. Her bone age was 13 years. No abnormalities were noticed on abdominal ultrasound examination. Pelvic ultrasound revealed infantile uterus (1.5 cc) and small ovaries (right, 2.6 cc; left, 1.3 cc). Her bone mineral density, corrected for bone age, was reduced, showing osteopenia. Magnetic resonance imaging scan of the hypothalamic-pituitary region was normal.

Pulsatile secretion of GnRH by hypothalamic neurons is a crucial element of the reproductive cascade, initiating the release of pituitary gonadotropins, gonadal secretion of sex steroids, pubertal development, and gametogenesis. Hypogonadotropic hypogonadism (HH) is characterized by failure of gonadal function secondary to deficient gonadotropin secretion (1). This condition is commonly seen in association with other pituitary hormone deficiency states caused by structural lesions of the hypothalamic-pituitary region. However, congenital, acquired, and functional causes have been associated with isolated GnRH deficiency (Tables 1 and 2) (2).

Genes and Their Protein Products Associated With Congenital IHH Phenotype

Genes and Their Protein Products Associated With Congenital IHH Phenotype

Congenital isolated HH (IHH) is characterized by partial or complete lack of pubertal development, secondary to deficient GnRH-induced gonadotropin secretion, in the absence of anatomical abnormalities in the hypothalamic and pituitary region, and normal baseline and reserve testing of the remaining pituitary hormones (1). This genetic condition is classically divided in 2 groups based on the presence or absence of olfaction dysfunction. Around 5060% of the affected individuals exhibit anosmia or hyposmia in association with IHH, defining Kallmann syndrome. Patients with Kallmann syndrome may have additional phenotypic abnormalities including craniofacial defects (cleft lip/palate, high-arched palate, ocular hypertelorism, dental agenesis), neurosensory deafness, digital anomalies (clinodactyly, syndactyly, camptodactyly), unilateral renal agenesis, and neurological defects (oculomotor abnormalities, bimanual synkinesis or mirror hand movements, cerebellar ataxia), whereas normosmic IHH is usually not associated with any other malformations (nonsyndromic condition) (3). In Kallmann syndrome, anosmia is related to hypoplasia or aplasia of the olfactory bulbs, whereas the hypogonadism is due to GnRH deficiency, due to defective migration of olfactory and GnRH neurons. In most vertebrates, the olfactory and GnRH neurons share a common origin in the nasal placode and migrate together across the cribiform plate toward the developing olfactory bulb, explaining the association of HH with olfactory abnormalities (4, 5).

Congenital IHH is a clinically and genetically heterogeneous disorder. Although sporadic cases are the most frequent, families with congenital IHH have been reported with X-linked, autosomal dominant or recessive inheritance. The prevalence of IHH has been estimated at 1/4000 to 1/10 000 males, and it is reported to be 2 to 5 times less frequent in females. The reason for this marked gender discrepancy is not known, and the prevalence of the disease is probably underestimated in females. Male preponderance can be only partially explained by the contribution of men with X-linked disease to the total number of cases (1, 6, 7). Other factors, such as incomplete penetrance, biased referral patterns, with male patients being seen by endocrinologists as opposed to more females being referred and treated by gynecologists, should also be considered.

A growing list of genes has been implicated in the molecular pathogenesis of the congenital IHH, pointing up the heterogeneity and complexity of the genetic basis of this condition (Table 2). These genes encode neuropeptides and proteins involved in the development and migration of GnRH neurons, or in the control of different stages of GnRH function. Mutations in KAL1, FGFR1/FGF8, PROK2/PROKR2, NELF, CHD7, HS6ST1, WDR11, and SEMA3A are associated with defects in neuronal migration, leading to Kallmann syndrome (810). Notably, defects in FGFR1, FGF8, PROKR2, CHD7, and WDR11 have also been associated with normosmic IHH, although in a lower frequency (8, 10). Mutations in KISS1/KISS1R, TAC3/TACR3, and GNRH1/GNRHR, genes that interfere in the secretion and action of GnRH, are described exclusively in patients with normosmic IHH (8, 11). Despite these recent and great advances, the genetic basis of most cases of congenital IHH remains unknown, with the molecular basis of this condition being identified in approximately 30% of patients.

Congenital IHH has been historically defined in traditional Mendelian terms and considered a monogenic disease. However, this concept has been recently reviewed. Pedigrees with great phenotypic variability have been described, and complex genetic transmission (digenic or oligogenic inheritance) has been recently demonstrated (12, 13). Substantial variation in clinical expression of the same genetic defect in families of patients with IHH has been observed, with affected members presenting with Kallmann syndrome, normosmic IHH, isolated anosmia, isolated clefting, simple pubertal delay, or even apparent phenotypic normality, suggesting the possibility that Kallmann syndrome and normosmic IHH may take part of a wider spectrum of disease (3, 10, 13). This variability has been observed mainly in kindreds with mutations in FGF8/FGFR1 and in PROK2/PROKR2 ligand-receptor pairs (3, 13). This type of phenotypic heterogeneity may be ascribed to environmental or epigenetic effects. A second explanation is the coexistence within families of defects in 2 or more different genes that interact functionally, as it has recently been described in a number of families (10, 13).

Acquired causes of HH are mostly due to structural or functional abnormalities involving the hypothalamic-pituitary axis, and most of these patients have multiple pituitary hormone deficiencies. These conditions include infiltrative disorders of the hypothalamic-pituitary tract, such as sarcoidosis, lymphocytic hypophysitis and histiocytosis, space-occupying lesions such as pituitary adenomas, craniopharyngiomas, and other central nervous system tumors (2).

Adult-onset isolated gonadotropin deficiency can be secondary to systemic disorders, drugs, functional abnormalities, or idiopathic. One of the most frequent causes of acquired isolated HH is hyperprolactinemia. Elevated prolactin levels can result mainly from the use of drugs that interfere with the dopaminergic system, lactotroph adenomas (prolactinomas), or from any hypothalamic or pituitary stalk disorder that interrupts hypothalamic inhibition of prolactin secretion. The possibility of nutritional disorders or an undiagnosed chronic illness that may affect the hypothalamic GnRH pulse generator should be evaluated in patients with HH. Hypothyroidism should be ruled out, particularly if growth velocity is below expected and bone age markedly delayed. Hemochromatosis can affect the hypothalamic and pituitary region, leading to progressive isolated gonadotropin deficiency, and should always be ruled out by the presence of normal serum ferritin concentrations. Drugs that can reversibly suppress sex steroid levels include opiates, glucocorticoid, and psychotropic agents such as phenothiazines.

The idiopathic form of adult-onset HH is a rare disorder characterized by an isolated failure of gonadotropin secretion occurring after an otherwise normal sexual maturation in men in whom anatomical, systemic, or functional causes had been ruled out (14). No genetic defect in genes associated with congenital IHH has been identified in this group of patients (15). Long-term follow-up of adult-onset HH individuals revealed that the clinical and hormonal characteristics of these patients did not change over a decade, all of them remaining severely hypogonadal, with testosterone levels below 130 ng/dL, with no spontaneous reversals (15). It is important to differentiate adult-onset HH, characterized by frankly low serum testosterone levels in the presence of low or normal gonadotropins, from the progressive testosterone deficiency observed in a small minority of aging men, known as late-onset hypogonadism. This latter condition has been defined as a syndrome in middle-aged and elderly men reporting sexual symptoms in the presence of moderately low total testosterone levels (<320 ng/dL), with variable levels of gonadotropins, which involves central and mostly gonadal components in its pathogenesis (16, 17).

Functional hypothalamic amenorrhea is a reversible form of GnRH deficiency, usually triggered by stressors such as excessive exercise, nutritional deficits, or psychological distress. Regardless of the specific trigger, functional hypothalamic amenorrhea is characterized by the suppression of GnRH pulsatility (18). Functional hypothalamic amenorrhea is a frequent cause of acquired female infertility, typically manifested as amenorrhea of 6-month duration or longer, low or normal gonadotropin levels, and hypoestrogenemia without organic abnormalities (19, 20). Interestingly, rare variants in the genes associated with congenital IHH were recently found in women with hypothalamic amenorrhea, suggesting that these mutations may contribute to the variable susceptibility of women to functional changes in GnRH secretion (20). Moreover, the importance of low levels of leptin, a hormone secreted by adipocytes that regulates energy homeostasis, in the pathophysiology of hypothalamic amenorrhea was clearly demonstrated by evidence of a significant improvement of the reproductive and neuroendocrine functions in women with hypothalamic amenorrhea after exogenous recombinant leptin replacement (21, 22). Although primarily a disease of females, eating disorders such as anorexia nervosa are increasingly being recognized in males and are associated with hypogonadism. Population-based studies reported that 515% of all patients with anorexia nervosa are males (23, 24).

Clinical presentation of HH depends on the time of onset (ie, congenital vs acquired), the severity of the defect, and the presence of associated conditions. Typically the diagnosis of congenital IHH is made during the second or third decade of life, when the patients present with delayed pubertal onset, absent or poorly developed secondary sexual characteristics, primary amenorrhea, eunuchoid proportions, or infertility. In some cases, the diagnosis may be suspected before puberty. The occurrence of micropenis and/or unilateral or bilateral cryptorchidism in boys, as well as the presence of other associated congenital abnormalities, such as midline defects, suggests congenital GnRH deficiency, especially in the context of a positive family history (25, 26). In contrast, newborn girls have no obvious abnormal findings that might provide clues to the diagnosis. Most commonly, however, the diagnosis cannot be confirmed until the expected time of puberty onset, except in the neonatal period, when gonadotropin and sexual steroid levels are expected to be elevated. The presence of anosmia is suggestive of Kallmann syndrome, and if the child is too young to undergo olfaction tests, magnetic resonance imaging (MRI) scan showing absent or abnormal olfactory bulbs or sulci strongly suggests the diagnosis. Nevertheless, it is important to note that a normal MRI does not rule out the disease because normal olfactory bulbs can be present in up to 20% of Kallmann syndrome patients (2, 3). Adult-onset HH is characterized in women by secondary amenorrhea, decreased libido, infertility, and osteoporosis; in men, symptoms of decreased libido, lack of morning erection, erectile dysfunction, inability to perform vigorous activity, depression, fatigue, and infertility are observed.

The evidence of low/normal gonadotropin levels in the setting of low concentrations of testosterone in men and estradiol in women indicates the diagnosis of HH. Rarely, selective deficiency of LH or FSH can occur due to inactivating mutations of the specific -subunits (2729). The measurement of morning total testosterone by a reliable assay is strongly recommended in the initial diagnosis test (30). In some men, in whom total testosterone is near the lower limit of normal or in whom SHBG abnormality is suspected, measurement of free or bioavailable testosterone levels is then recommended (23). Anterior pituitary function must be investigated to rule out a more complex endocrine disorder with multiple hormone deficiencies.

Although widely used, the practical value of the GnRH test has been questionable because of its low cost-effectiveness. Indeed, the GnRH test provides no extra diagnostic information relative to baseline gonadotropin levels. In HH patients, the response to GnRH test is highly variable and depends on the severity of the gonadotropin deficiency, which is often reflected by the clinical phenotype. Similarly, the pituitary function can be first evaluated by basal hormonal levels (measured by ultrasensitive assays). Thyroid function should be assessed by TSH combined with free T4. IGF-I can be used to evaluate the somatotropic axis, whereas secondary adrenal deficiency can be assessed by measuring a morning cortisol and ACTH. The stimulatory tests should be reserved for the situations in which the basal hormone measurements are not helpful or if there is strong clinical evidence of a multiple pituitary hormone deficiency.

Anosmia can be easily diagnosed by questioning the patient, whereas olfactometry, such as University of Pennsylvania Smell Identification Test, is necessary to determine reliably whether olfaction is normal or partially defective. Indeed, IHH patients display a broad spectrum of olfactory function, with a significant hyposmic phenotype. Accurate olfactory phenotyping in IHH subjects can inform the pathophysiology of this condition and guide genetic testing (31).

MRI of the hypothalamo-pituitary region is very useful in the management of HH. MRI can demonstrate a malformation, an expansive or infiltrative disorder of the hypothalamo-pituitary region. However, the cost-effectiveness of MRI scan to exclude pituitary and/or hypothalamic tumors is unknown according to the recent clinical practice guideline (30). Pituitary and/or hypothalamic tumors should be investigated by MRI in patients with serum testosterone less than 150 ng/dL, multiple pituitary hormone deficiency, persistent hyperprolactinemia, or symptoms of tumor mass effect (headache, visual impairment, or visual field defect). In the presence of suspected functional causes of HH, such as severe obesity, nutritional disorders, and drugs, MRI is not indicated. Additionally, MRI with specific cuts for evaluating the olfactory tract can be helpful in the diagnosis of Kallmann syndrome. Evidence of unilateral or bilateral hypoplastic/agenesis olfactory bulbs and hypoplastic anterior pituitary is pathognomonic of Kallmann syndrome.

Renal ultrasound examination is usually recommended to patients with syndromic IHH, such as Kallmann syndrome, independent of the genetic basis, although it is well known that unilateral kidney agenesis may be more prevalent in patients with KAL1 defects. The genetic study is usually the last step in the congenital IHH investigation, and complete clinical characterization could certainly help in the gene selection. Bone mineral density of the lumbar spine, femoral neck, and hip is recommended at the initial diagnosis of HH and after 1 to 2 years of sex steroid therapy in hypogonadal patients with osteoporosis or low trauma fracture (30).

The goals of therapy for hypogonadal adolescents or young adults are the induction and maintenance of normal puberty and induction of fertility when the patient desires. testosterone therapy for adult men with symptomatic androgen deficiency is recommended to improve sexual function and sense of well-being and to increase muscle mass and strength and BMD. Testosterone is the primary treatment modality used to induce and maintain secondary sexual characteristics and sexual function in men with HH, but it does not restore fertility.

Intramuscular injections of long-acting testosterone esters (testosterone cypionate or enanthate) are commonly used. In adolescents, the initial dose of testosterone esters to induce puberty is 5075 mg/month, which should be gradually increased every 6 months to 100150 mg/month. The maintenance dose for adult males is 200250 mg im every 23 weeks or 1000 mg of testosterone undecanoate every 3 months. Other options are transdermal preparations, including gel formulations (510 g/d) or 5 mg testosterone patches applied nightly over the nongenital skin (30). The long-term goals of testosterone therapy are to maintain the serum concentrations of sex steroids in the midnormal adult range. Testosterone therapy is not indicated in patients with breast or prostate cancer, a palpable prostate nodule, or indurations, or prostate-specific antigen greater than 4 ng/mL or greater than 3 ng/mL in men at high risk for prostate cancer, hematocrit greater than 50%, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms, or uncontrolled or poorly controlled heart failure (30).

When fertility is desired, gonadotropin therapy is necessary to induce spermatogenesis in males with HH (32). Different treatment protocols can be used in male patients with HH. The typical gonadotropin regimen combines human chorionic gonadotropin (hCG) and FSH. One option is to combine hCG 1000 U and FSH 75 U every other day for HH patients without puberty and immature testes (<3 mL). Notably, the intra-subcutaneous route of administration is as effective as im. The hCG doses should be titrated based on testosterone levels, targeting middle normal values. Testosterone levels usually achieve normal range values by 6 months of continuous treatment in most patients, and spermatogenesis is attained in up to 80% of the cases. Another option for patients with partial pubertal development is to start with hCG alone for 6 months and subsequently add FSH if azoospermia persists. Predictive factors of better outcome include larger testicular volume, absence of cryptorchidism, and higher serum inhibin B levels at the initial medical evaluation.

Treatment of adolescent males with exogenous hCG alone or combined with recombinant FSH for induction of puberty may result in testicular growth and hence improvement in potential fertility compared to treatment with testosterone (32). Early induction of spermatogenesis may reduce the time required for appearance of sperm and the need for prolonged cycles of gonadotropin treatment in adult life. Use of hCG alone appears to be less efficient in spermatogenesis induction and final testicular volume when compared to combined treatment with hCG and FSH (32, 33). Side effects of gonadotropin treatment include the inconvenient way of administration, gynecomastia, and the induction of antibodies to hCG, which can impair the response to hCG in the future (34, 35). It is important to note that there are few studies about the use of gonadotropins in adolescents, and most them are small case series of boys with HH who received pubertal induction with gonadotropins at various times, and thus further studies are needed.

The main and most difficult differential diagnosis of congenital IHH in boys is constitutional delay of growth and puberty. Patients with constitutional delay of puberty typically have delayed growth before puberty and delayed bone age, compatible with the height. In contrast, patients with congenital IHH have normal linear growth during childhood, and despite the absence of the pubertal growth spurt, short stature is not a common finding. The absence of long-bone epiphyseal closure explains the presence of eunuchoid proportions and relative high stature. A variety of physiological and stimulation tests have been proposed, such as LH sampling, prolactin response to various stimulating agents, gonadotropin response to GnRH, testosterone response to hCG, and daily urine excretion of FSH and LH (36). Recently, Coutant et al (37) demonstrated that a single measurement of inhibin B level discriminated IHH from constitutional delay of puberty in adolescent boys. The sensibility and specificity were 100% for inhibin B concentration of 35 pg/mL or less in boys with genital stage 1 (testis volume < 3 mL) in this study (26). Other baseline measurements (anti-Mullerian hormone, testosterone, FSH, and LH) were not useful for such discrimination.

It is notable that men with apparent isolated hypothalamic GnRH deficiency may also have primary pituitary and/or testicular defects (a dual defect) as demonstrated by the atypical responses to long-term exogenous pulsatile GnRH treatment (43). The pituitary and/or testicular defects may be initially masked by the GnRH deficiency in these patients. Therefore, the pathophysiology of hypogonadism in a subgroup of patients with IHH could be more complex than previously thought and possibly not limited to an isolated hypothalamic or pituitary defect.

Interestingly, sustained reversal of hypogonadism has been observed in about 10% of congenital IHH patients after discontinuation of treatment. To date, the triggers leading to reversal of IHH are not well understood. Androgen exposure has been suggested to predispose to reversal, and specific genetic backgrounds are especially prone to reversal HH (38). The reversible form of HH should be suspected if testicular volume increases during testosterone administration or in the absence of endocrine therapy. A brief discontinuation of hormonal therapy to assess reversibility is rational in patients with HH. However, the reversibility may not always be lifelong. Interestingly, heterogeneous genetic background (FGFR1, PROK2, GNRH, CHD7, and TAC/TACR3 mutations) has been associated with reversal of congenital HH (38).

Testosterone replacement in older men is another controversial issue in the practice of medicine. Despite the long existence of testosterone as a pharmaceutical medication, few large-scale, double-blind, placebo-controlled, multiple end point studies had been performed on testosterone therapy in men. In fact, older men are more susceptible to risks from testosterone intervention, such as benign prostatic hyperplasia, prostate cancer, and cardiovascular disease. In addition, many men in the middle to older age group do not fit the simple definition of either primary or secondary hypogonadism but have a mixed type of testosterone deficiency with impairment of both testicular and hypothalamic pituitary signals, indicating that the pathogenesis of low testosterone in this group is not well defined (39, 40).

Low gonadotropin and estradiol levels resulting in primary amenorrhea and poor pubertal development suggested the diagnosis of a severe form of HH in this young lady. The normal remaining pituitary function indicated an isolated form of HH. Her history and physical examination ruled out functional hypothalamic amenorrhea. Central anatomic defects and systemic diseases were excluded by routine tests and a normal brain imaging. The early presentation of the hypogonadism, manifesting as primary amenorrhea, and the association with nonreproductive phenotypes (ogival palate and bone abnormalities) contributed to the hypothesis of a congenital defect in this apparently sporadic case of IHH. Additionally, the normal olfaction test confirmed the diagnosis of idiopathic normosmic IHH. More recently, systematic genetic screening revealed a large heterozygous deletion of FGFR1 in this female with IHH (41).

The case depicted here illustrates the typical clinical presentation of severe female GnRH deficiency. Shaw et al (42) recently demonstrated that the clinical presentation of women with GnRH deficiency can vary from primary amenorrhea and absence of any secondary sexual characteristics to spontaneous breast development and occasional menses. In this large series of women with GnRH deficiency, most patients exhibited some degree of breast development (51%), and a small percentage experienced isolated menses (10%). Hypogonadal women with spontaneous thelarche were more likely to have undergone pubarche, suggesting that aromatization of adrenal androgens could contribute to breast development.

Young women with HH are at risk for bone loss and fracture. Congenital hypogonadism may be particularly detrimental to the skeleton because it may lead to failure to achieve peak bone mass, in addition to loss of established bone mass. Estrogen-progesterone replacement, calcium and vitamin D supplementation, and nutritional counseling should be provided. Multiple formulations of estrogen are available and include oral estradiol, oral conjugated estrogen, transdermal estrogen patches, and gel. In patients who have not yet started pubertal development, estrogen therapy should be started at low doses (5 g ethinyl estradiol, 0.3 mg conjugated equine estrogen, or 0.5 mg micronized estradiol daily) to promote breast development. After 6 months or when breakthrough bleeding occurs, cyclical therapy can be initiated by adding a progestogen, and the dose of estrogen is gradually increased over a 2- to 3-year period. Full replacement dose of estrogen and progesterone is attained with 0.6251.25 mg conjugated equine estrogen daily combined with cyclic 510 mg medroxyprogesterone acetate or 200 mg oral micronized progesterone. Other estrogen options are daily 2 mg micronized estradiol orally, 100200 g transdermal 17-estradiol patches or 12 mg estrogen gel. Alternatively, combined contraceptive pills, usually containing ethinyl estradiol, can be conveniently used. However, natural estrogens are preferable to synthetic estrogens because of incomplete metabolization and a greater risk of thromboembolism and arterial hypertension of the synthetic forms. In patients in whom fertility is desired, induction of gonadotropin secretion by pulsatile GnRH or treatment with exogenous gonadotropin is the current hormonal treatment of choice.

Maestre de San Juan was the first to report, in 1856, the association of the absence of olfactory structures in the brain and the presence of small testes in an individual. Although this description took place more than a century ago, the genetics and natural history of Kallmann syndrome are still incompletely understood. Similarly, testosterone has been available as a pharmaceutical medication since 1930, and it has been used since then to treat failure of male secondary sexual development. Definitely, there are still numerous controversial issues in the practice of medicine, requiring individual good sense for taking decisions regarding whom, when, and how to treat. Long-term and well-controlled studies are necessary to solve the current uncertainties in the field of reproductive disorders.

This work was partially supported by a grant from Conselho Nacional de Desenvolvimento Cientfico e Tecnolgico (CNPq, Productivity in Research, process no. 302825/2011-8; to A.C.L.).

Disclosure Summary: The authors have nothing to declare.

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Approach to the Patient With Hypogonadotropic Hypogonadism

Recommendation and review posted by Bethany Smith

Objective:

To formulate clinical practice guidelines for hormonal replacement in hypopituitarism in adults.

Participants:

The participants include an Endocrine Society-appointed Task Force of six experts, a methodologist, and a medical writer. The American Association for Clinical Chemistry, the Pituitary Society, and the European Society of Endocrinology co-sponsored this guideline.

Evidence:

The Task Force developed this evidence-based guideline using the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies.

Consensus Process:

One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, the American Association for Clinical Chemistry, the Pituitary Society, and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines.

Conclusions:

Using an evidence-based approach, this guideline addresses important clinical issues regarding the evaluation and management of hypopituitarism in adults, including appropriate biochemical assessments, specific therapeutic decisions to decrease the risk of co-morbidities due to hormonal over-replacement or under-replacement, and managing hypopituitarism during pregnancy, pituitary surgery, and other types of surgeries.

1.1 We suggest measuring serum cortisol levels at 89 am as the first-line test for diagnosing central adrenal insufficiency (AI). (2|)

1.2 We recommend against using a random cortisol level to diagnose AI. (1|)

1.3 We suggest that a cortisol level <3 g/dL is indicative of AI and a cortisol level >15 g/dL likely excludes an AI diagnosis. (2|)

1.4 We suggest performing a corticotropin stimulation test when morning cortisol values are between 3 and 15 g/dL to diagnose AI. Peak cortisol levels <18.1 g/dL (500 nmol/L) at 30 or 60 minutes indicate AI. (2|)

1.5 We suggest that clinicians perform biochemical testing for the hypothalamic-pituitary-adrenal (HPA) axis at least 1824 hours after the last hydrocortisone (HC) dose or longer for synthetic glucocorticoids (GCs). (2|)

1.6 We recommend measuring serum free T4 (fT4) and TSH to evaluate central hypothyroidism (CH). An fT4 level below the laboratory reference range in conjunction with a low, normal, or mildly elevated TSH in the setting of pituitary disease usually confirms a CH diagnosis. (1|)

1.7 In patients with pituitary disease and low-normal fT4 levels suspected to have mild CH, we suggest starting levothyroxine (L-T4) if suggestive symptoms are present or following fT4 levels over time and starting treatment if the fT4 level decreases by 20% or more. (2|)

1.8 We suggest against using dynamic TSH-secretion testing to diagnose CH. (2|)

1.9 In patients with suspected GH deficiency (GHD), we recommend GH stimulation testing. Single GH measurements are not helpful. (1|)

1.10 We recommend using appropriately controlled body mass index (BMI) cutoffs to assess peak GH values. (1|)

1.11 We suggest against biochemical testing for GHD in patients with clear-cut features of GHD and three other documented pituitary hormone deficits. (2|)

1.12 In males with suspected hypogonadism, we recommend measuring serum T, FSH, and LH to diagnose central hypogonadism. (1|)

1.13 We recommend that clinicians perform hormonal testing for central hypogonadism in males in the absence of acute/subacute illness and before 10 am (after overnight fast) combined with serum prolactin (PRL). (1|)

1.14 In the presence of oligomenorrhea or amenorrhea, we recommend measuring serum estradiol (E2), FSH, and LH. Clinicians should exclude other causes of menstrual irregularities related to impaired ovulation (hyperprolactinemia, hyperandrogenism, and thyroid disease), particularly if no other pituitary hormone deficits are present. In cases of amenorrhea, clinicians should also exclude pregnancy. (1|)

1.15 We suggest against dynamic testing with GnRH, which offers no useful diagnostic information. (2|)

1.16 We recommend that in postmenopausal women, the absence of high serum FSH and LH is sufficient for a diagnosis of gonadotrope dysfunction (provided the patient is not on hormonal replacement therapy [HRT]). (1|)

1.17 We recommend simultaneously measuring serum and urine osmolarity in patients with polyuria (more than 50 mL/kg of body weight/24 hours, 3.5 L/d in a 70-kg person). In the presence of high serum osmolarity (>295 mOsmol/L), urine osmolarity should reach approximately 600 mOsmol/L (urine osmolality/plasma osmolality ratio should be 2), whereas urine dipstick should be negative for glucose. (1|)

2.1 We recommend using HC, usually 1520 mg total daily dose in single or divided doses. Patients using divided doses should take the highest dose in the morning at awakening and the second in the afternoon (two-dose regime) or the second and third at lunch and late afternoon, respectively (three-dose regime). (1|)

2.2 We suggest using longer-acting GCs in selected cases (eg, nonavailability, poor compliance, convenience). (2|)

2.3 We recommend that clinicians teach all patients with AI regarding stress-dose and emergency GC administration and instruct them to obtain an emergency card/bracelet/necklace regarding AI and an emergency kit containing injectable high-dose GC (1|)

2.4 We recommend against using fludrocortisone in patients with secondary AI. (1|)

2.5 We recommend that clinicians treat patients with suspected adrenal crisis (AC) due to secondary AI with an immediate parenteral injection of 50100 mg HC. (1|)

2.6 We recommend L-T4 in doses sufficient to achieve serum fT4 levels in the mid to upper half of the reference range. Appropriate L-T4 doses in CH average 1.6 g/kg/d, with dose adjustments based on clinical context, age, and fT4 levels. (1|)

2.7 We suggest against treating CH with levotriiodothyronine (L-T3), thyroid extracts, or other formulations of thyroid hormones. (2|)

2.8 We recommend against using serum TSH levels to adjust thyroid replacement dosing in patients with CH. (1|)

2.9 We suggest T replacement for adult males with central hypogonadism and no contraindications in order to prevent anemia related to T deficiency; reduce fat mass; and improve bone mineral density (BMD), libido, sexual function, energy levels, sense of well-being, and muscle mass and strength. (2|)

2.10 We recommend gonadal hormone treatment in premenopausal women with central hypogonadism, provided there are no contraindications. (1|)

2.11 We recommend offering GH replacement to those patients with proven GHD and no contraindications. We recommend a starting dose of 0.20.4 mg/d for patients younger than 60 years and 0.10.2 mg/d for patients older than 60 years. (1|)

2.12 We recommend titrating GH doses and maintaining IGF-1 levels below the upper limit of normal and reducing the dose if side effects manifest. (1|)

2.13 We suggest against administering GH to elderly adults with age-adjusted low IGF-1 levels and no history of pituitary or hypothalamic disease. (2|)

2.14 We recommend against using GH to enhance athletic performance because this practice is illegal in the United States, has poor scientific or ethical justification, and does not have substantiated efficacy. (Ungraded Good Practice Statement)

2.15 When administering desmopressin (DDAVP) in diabetes insipidus (DI), we suggest individualized therapeutic schedules. Although clinicians should offer therapy to all patients, some patients with partial DI may not be bothered by polyuria and may prefer no treatment. To reduce the risk of hyponatremia, we recommend that clinicians educate all patients receiving DDAVP about the risk of overdosing. Periodically (at least weekly), patients should experience a phase of polyuria during which the effect of the medication has obviously worn off. (Ungraded Good Practice Statement)

2.16 In postpituitary surgery DI, we suggest that clinicians should make at least one attempt to discontinue DDAVP during the weeks/months after surgery to determine whether posterior pituitary function has recovered. (Ungraded Good Practice Statement)

2.17 In cases of adipsic DI, we suggest careful DDAVP and fluid intake titration that includes frequent weighing and serum sodium level monitoring. (Ungraded Good Practice Statement)

2.18 We suggest that all patients with DI wear an emergency bracelet or necklace to inform clinicians of the patients health problem if incapacitated. (Ungraded Good Practice Statement)

2.19 We suggest testing HPA axis functionality before and after starting GH replacement in patients who are not receiving GC replacement and who have demonstrated apparently normal pituitary-adrenal function. (2|)

2.20 We suggest evaluating patients with CH for AI before starting L-T4 therapy. If this is not feasible, clinicians should prescribe empiric GC therapy in patients with CH who are starting L-T4 therapy until there is a definitive evaluation for AI. (2|)

2.21 We suggest that when clinicians assess adrenal reserve or the adequacy of HC replacement, they take into consideration that total serum cortisol level can be elevated due to the effects of estrogen on corticosteroid-binding globulin (CBG). (2|)

2.22 We recommend that clinicians monitor euthyroid patients with GHD who begin GH therapy for the risk of developing CH, and if fT4 levels decrease below the reference range, these patients should begin L-T4 therapy. CH patients with GHD who are already receiving L-T4 may require increased L-T4 doses when they begin GH therapy to maintain fT4 levels within target ranges. (1|)

2.23 We suggest clinicians treat CH before performing GH stimulation testing because CH may impair the accurate diagnosis of GHD. (2|)

2.24 In patients with CH requiring changes in estrogen therapy, we recommend monitoring fT4 levels and adjusting L-T4 doses to maintain fT4 levels within target ranges. (1|)

2.25 We suggest that women on oral estrogen replacement receive higher GH doses compared with eugonadal females or males. (2|)

2.26 Because AI may mask the presence of partial DI, we suggest monitoring for the development of DI after starting GC replacement. Conversely, patients with improved DI without an AI diagnosis should undergo AI testing. (2|)

2.27 Clinicians should individually assess GC replacement and avoid over-replacement to reduce the risk of osteoporosis. We suggest low-dose HC replacement because this approach might be associated with increased bone formation and a positive bone-remodeling balance. (2|)

2.28 In men with hypopituitarism over-replaced with GC and at risk for fractures, we suggest vertebral fracture assessment (baseline plain spinal x-rays or dual-energy x-ray absorptiometry) to identify patients with unsuspected vertebral fractures. (2|)

2.29 We suggest clinicians monitor L-T4 replacement, as recommended in previous sections, and avoid over-replacement to reduce the risk of fractures. (2|)

2.30 In patients with central AI, we recommend using the lowest tolerable dose of HC replacement to potentially decrease the risks of metabolic and cardiovascular disease. (1|)

2.31 To avoid the possible long-term cardiovascular risks of insufficient or excess thyroid hormone treatment, clinicians should adjust L-T4 doses to avoid low or elevated fT4 levels in CH. (Ungraded Good Practice Statement)

3.1 We recommend GC replacement until full HPA axis recovery after surgically resecting ACTH-secreting tumors. (1|)

3.2 After curative surgery for Cushings disease, we recommend retesting thyroid and GH axes before starting replacement treatment. (1|)

3.3 We recommend reassessing all pituitary axes in patients with macroprolactinoma and central hypogonadism who have had successful dopamine agonist treatments. (1|)

3.4 We suggest low-dose GH replacement in patients with cured acromegaly and documented GHD in the absence of known contraindications. (2|)

3.5 We recommend using stress doses of steroids in AI before surgery and tapered doses after surgery before repeating testing. (1|)

3.6 In patients with normal preoperative adrenal function, we suggest an individualized clinical approach for postoperative GC administration until the HPA axis can be evaluated. (2|)

3.7 With preoperative CH, we recommend using L-T4 therapy before nonemergency surgery and throughout the perioperative period. (1|)

3.8 With intact preoperative thyroid function, we recommend measuring fT4 levels 68 weeks postoperatively to assess for CH. (1|)

3.9 We suggest that initial therapy for DI utilizes short-acting sc aqueous antidiuretic hormone (ADH), allowing for safer use in the vast majority of cases in whom DI resolves spontaneously. (2|)

3.10 We do not suggest prescheduled DDAVP dosages in the first week postsurgery because of the risk of hyponatremia after transient DI resolves and the risk of syndrome of inappropriate ADH secretion that may occur 710 days after surgery. (2|)

3.11 We suggest oral or intranasal DDAVP after discharge, with clear instructions that patients should only use the medication if significant polyuria occurs. (2|)

3.12 We suggest retesting all pituitary axes starting at 6 weeks after pituitary surgery and then periodically to monitor the development or resolution of pituitary deficiencies. (2|)

3.13 On the day of surgery, we recommend adjusting GC doses according to the severity of illness and magnitude of the stressor. (1|)

3.14 In cases of minor to moderate surgical stress, we suggest 2575 mg HC per 24 hours (usually for 12 days). (2|)

3.15 In cases of major surgical stress, we suggest a 100-mg HC per iv injection followed by a continuous iv infusion of 200 mg HC per 24 hours (alternatively 50 mg every 6 hours iv or im). (2|)

3.16 We suggest using HC as the preferred GC in pregnancy and increasing the dose based on the individual clinical course; higher doses may be required, in particular during the third trimester. (Ungraded Good Practice Statement)

3.17 We suggest that pregnant patients with central AI be closely monitored for clinical symptoms and signs of GC over- and under-replacement (eg, normal weight gain, fatigue, postural hypotension or hypertension, hyperglycemia). (Ungraded Good Practice Statement)

3.18 We recommend against using dexamethasone in pregnancy because it is not inactivated in the placenta. (1|)

3.19 We recommend HC stress dosing during the active phase of labor, similar to that used in major surgical stress. (1|)

3.20 We recommend that clinicians monitor fT4 or total T4 levels every 46 weeks for women with CH who become pregnant, and that these women may require increased L-T4 doses to maintain levels within target ranges for pregnancy. (1|)

3.21 In pregnant women with pre-existing DI, we suggest continuing DDAVP during pregnancy and adjusting doses if required. (2|)

3.22 We suggest discontinuing GH replacement during pregnancy because there is no clear evidence yet for efficacy or safety, and the placenta produces GH. (2|)

3.23 We recommend testing for acute pituitary insufficiency in all patients with pituitary apoplexy. (1|)

3.24 Because acute AI is a major cause of mortality, we recommend GC therapy until a laboratory diagnosis is established and the patient maintains normal pituitary function. (1|)

3.25 We recommend that clinicians monitor pituitary axes in pituitary apoplexy patients treated with either surgical decompression or conservative management because hypopituitarism may develop over time. (1|)

3.26 We suggest clinicians educate AI patients that are taking nondexamethasone GCs and who start enzyme-inducing antiepileptic drugs (AEDs) about the early signs and symptoms of AI. (2|)

3.27 In patients with AI on dexamethasone, we suggest increasing dexamethasone replacement doses if enzyme-induced AEDs are coadministered. (2|)

3.28 In CH patients receiving L-T4, we recommend checking fT4 at least 6 weeks after starting an AED and increasing L-T4 doses if fT4 levels decrease below the target range. (1|)

3.29 In women who have started estrogen replacement, we suggest evaluating AED levels and adjusting AED doses as required. (2|)

3.30 We suggest monitoring DDAVP doses and making further adjustments as needed in patients who are started on AEDs. (2|)

The Clinical Guidelines Subcommittee (CGS) of the Endocrine Society deemed hormonal replacement in hypopituitarism a priority area in need of practice guidelines and appointed a Task Force to formulate evidence-based recommendations. The Task Force followed the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation group, an international group with expertise in the development and implementation of evidence-based guidelines (1). A detailed description of the grading scheme has been published elsewhere (2). The Task Force used the best available research evidence to develop the recommendations. The Task Force also used consistent language and graphical descriptions of both the strength of a recommendation and the quality of evidence. In terms of the strength of the recommendation, strong recommendations use the phrase we recommend and the number 1, and weak recommendations use the phrase we suggest and the number 2. Cross-filled circles indicate the quality of the evidence, such that denotes very low quality evidence; , low quality; , moderate quality; and , high quality. The Task Force has confidence that persons who receive care according to the strong recommendations will derive, on average, more good than harm. Weak recommendations require more careful consideration of the persons circumstances, values, and preferences to determine the best course of action. Linked to each recommendation is a description of the evidence and the values that the Task Force considered in making the recommendation. In some instances there are remarks, a section in which the Task Force offers technical suggestions for testing conditions, dosing, and monitoring. These technical comments reflect the best available evidence applied to a typical person being treated. Often this evidence comes from the unsystematic observations of the Task Force and its values and preferences; therefore, one should consider these remarks as suggestions.

In this guideline, the Task Force made several statements to emphasize the importance of shared decision making, general preventive care measures, and basic principles of hormonal replacement in hypopituitarism. The Task Force labeled these as Ungraded Good Practice Statement. Direct evidence for these statements was either unavailable or not systematically appraised; therefore, the Task Force considers these statements out of the scope of this guideline. The intention of these statements is to draw attention to and remind providers of these principles; one should not consider these statements as graded recommendations (3).

The Endocrine Society maintains a rigorous conflict-of-interest review process for developing clinical practice guidelines. All Task Force members must declare any potential conflicts of interest by completing a conflict-of-interest form. The CGS reviews all conflicts of interest before the Societys Council approves the members to participate on the Task Force and periodically during the development of the guideline. All those participating in the guidelines development must also disclose any conflicts of interest in the matter under study, and a majority of these participants must be without any conflicts of interest. The CGS and the Task Force have reviewed all disclosures for this guideline and resolved or managed all identified conflicts of interest.

Conflicts of interest are defined as remuneration in any amount from commercial interest(s) in the form of grants; research support; consulting fees; salary; ownership interest (eg, stocks, stock options [excluding diversified mutual funds]); honoraria or other payments for participation in speakers bureaus, advisory boards, or boards of directors; or other financial benefits. Completed forms are available through the Endocrine Society office.

Funding for this guideline was derived solely from the Endocrine Society; the Task Force received no funding or remuneration from commercial or other entities.

The guideline Task Force commissioned two systematic reviews to assist with summarizing the evidence base for this guideline.

The first review addressed the question of whether adults with panhypopituitarism of any cause have increased all-cause mortality. The review identified 12 studies reporting on 26 017 patients. Studies were observational, with incomplete adjustment for confounders. Meta-analysis suggested increased mortality in patients with panhypopituitarism (RR, 1.55; 95% confidence interval [CI], 1.142.11). Factors associated with increased mortality were female gender, younger age at diagnosis, an underlying diagnosis of a craniopharyngioma or aggressive tumor, the presence of DI, and prior treatment with surgery or radiotherapy. The most common causes of death were malignancies, cardiovascular disease, and cerebrovascular disease.

The second review attempted to answer the question of whether GH replacement is associated with a risk of pituitary tumor recurrence, secondary malignancy, or stroke. The review included seven studies reporting on 22 654 patients. Meta-analysis did not show an association between GH replacement and pituitary tumor recurrence (RR, 0.87; 95% CI, 0.561.33) or the risk of secondary malignancies (RR, 1.24; 95% CI, 0.652.33). There were no data on the outcome of stroke.

Each review addressed a question of association and both demonstrated that the evidence (overall) warrants low certainty in the provided estimates.

Hypopituitarism results from complete or partial deficiency in pituitary hormones and includes AI, hypothyroidism, hypogonadism, GHD, and (more rarely) DI. Not all disorders that affect anterior pituitary function may cause DI, and DI can occur without anterior pituitary dysfunction. Hypopituitarism is the consequence of diseases that either reduce or destroy secretory function or interfere with the hypothalamic secretion of pituitary-releasing hormones.

The prevalence (probably underestimated) is approximately 45 cases per 100 000, with an incidence of about four cases per 100 000 per year (4). Considering evidence from the commissioned systematic review and other evidence extracted mostly from contemporary studies on the management of hypopituitarism due to heterogeneous etiologies, it seems that mortality associated with hypopituitarism is indeed high (510). Recently published evidence indicates that pituitary hormonal deficits managed with the currently used replacement protocols (including nonsupraphysiological doses of HC and appropriate thyroid and gonadal hormone replacement) might not adversely affect mortality (11).

Hypopituitary patients exhibit increased incapacitation and sick days, lower health status, and higher cost of care (12, 13). Those with GHD are less often working full time, more often on sick leave/disability, and often live alone or with parents (14). Despite receiving long-term GH replacement, the working capacity of hypopituitary patients remains lower than the general population (14).

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Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society ...

Recommendation and review posted by Bethany Smith

NAD+ Cell Regenerator and Resveratrol Elite combines NIAGEN nicotinamide riboside and ultra-bioavailable forms resveratrol with quercetin and fisetin to create an innovative nutritional supplement for longevity and youthful cellular energy production.

Resveratrol is a well-known longevity and anti-aging supplement.1 Our Resveratrol Elite formulas contains trans-resveratrol, the form associated with beneficial biological effects.2-5 Resveratrol also promotes healthy insulin sensitivity, supports a healthy inflammatory response and has been shown to promote healthy endothelial function for a healthy cardiovascular system.4,6,7

A more bioavailable resveratrol

Weve combined resveratrol with galactomannan fibers from fenugreek seeds. This makes our Resveratrol Elite formulas up to 10 times more bioavailable. This means that the trans-resveratrol in our supplements reaches higher levels in your bloodstream and circulates longer than traditional, unformulated resveratrol.

Resveratrol and heart health

One way that resveratrol promotes heart health is by helping to shield the body from oxidative stress at the cellular level.8 By inhibiting oxidative stress in your cardiovascular system, resveratrol promotes endothelial healthan essential component of living a long, healthy life.9

Resveratrol and brain health

At the same time, resveratrols ability to support cerebrovascular blood flow may also make it good for your brain: there is clinical evidence that resveratrol can help encourage youthful neurological function and with it, things like cognition. Interestingly, this same trial showed that resveratrol promoted healthy glucose metabolismanother essential aspect of healthy longevity.10

Fight general fatigue with NIAGEN

Nicotinamide riboside increases your bodys levels of NAD+, a coenzyme critical to healthy cellular function.11 In a randomized controlled trial published in 2017, older adults taking a daily dose of 250 mg of nicotinamide riboside had a 40% increase in NAD+ levels after just 30 days.2 Studies in preclinical models have shown that increasing NAD+ also encouraged healthy metabolic and cognitive function.3,4

Fisetin and quercetin

Fisetin and quercetin are phytonutrient compounds that augment trans-resveratrols healthy effects, promote cardiovascular health, support healthy cellular function, fight oxidative stress, promote a healthy inflammatory response and more.9,10

Take the fight against aging to the cellular level with NAD+ Cell Regenerator and Resveratrol Elite.

Read more from the original source:
NAD+ Cell Regenerator and Resveratrol Elite - Life Extension

Recommendation and review posted by Bethany Smith

For many patients battling deadly diseases, getting access to a clinical trial can be life-saving, but it can also be very challenging. Today the governing Board of the California Institute for Regenerative Medicine (CIRM) approved a concept plan to make it financially and logistically easier for patients to take part in CIRM-funded clinical trials.

The plan will create a Patient Support Program (PSP) to provide support to California patients being evaluated or enrolled in CIRM-supported clinical trials, with a particular emphasis on helping underserved populations.

Helping scientists develop stem cell and gene therapies is just part of what we do at CIRM. If those clinical trials and resulting therapies are not accessible to the people of California, who are making all this possible, then we have not fulfilled our mission. says Maria T. Millan, M.D., President and CEO of CIRM.

The Patient Support Plan will offer a range of services including:

The funds for the PSP are set aside under Proposition 14, the voter-approved initiative that re-funded CIRM in 2020. Under Prop 14 CIRM money that CIRM grantees earn from licensing, inventions or technologies is to be spent offsetting the costs of providing treatments and cures arising from institute-funded research to California patients who have insufficient means to purchase such treatment or cure, including the reimbursement of patient-qualified costs for research participants.

Currently, the CIRM Licensing Revenues and Royalties Fund has a balance of $15.6 million derived from royalty payments.

The patient support program and financial resources will not only help patients in need, it will also help increase the likelihood that these clinical trials will succeed, says Sean Turbeville, Ph.D., Vice President of Medical Affairs and Policy at CIRM. We know cell and gene therapies can be particularly challenging for patients and their families. The financial challenges, the long-distance traveling, extended evaluation, and family commitments can make it difficult to enroll and retain patients. The aim of the PSP is to change that.

The overall objective of this funding opportunity is to establish a statewide program that, over five years, is expected to support hundreds of patients in need as they participate in the growing number of CIRM-supported clinical trials. The program is expected to cost between $300,000 to $500,000 a year. That money will come from the Medical Affairs budget and not out of the patient assistance fund.

The first phase of the program will identify an organization, through a competitive process, that has the expertise to provide patient support services including:

You can find more information about the Patient Support Program on our website here and here.

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State Stem Cell & Gene Therapy Agency Sets up Support Program to Help ...

Recommendation and review posted by Bethany Smith

CRISPR is a technology that can be used to edit genes and, as such, will likely change the world.

The essence of CRISPR is simple: its a way of finding a specific bit of DNA inside a cell. After that,the next step in CRISPR gene editing is usually to alter that piece of DNA. However, CRISPR has also been adapted to do other things too, such as turning genes on or off without altering their sequence.

There were ways to edit the genomes of some plants and animals before the CRISPR method was unveiled in 2012 but it took years and cost hundreds of thousands of dollars. CRISPR has made it cheap and easy.

CRISPR is already widely used for scientific research, and in the not too distant future many ofthe plantsandanimalsinour farms, gardens or homes may have been altered with CRISPR. In fact, some people already are eating CRISPRed food.

CRISPR technology also has the potential to transform medicine, enabling us to not onlytreatbut alsopreventmany diseases. We may even decide to use it tochange the genomesofour children. An attempt to do this in Chinahasbeen condemned as premature and unethical, but some think it could benefit children in the future.

CRISPR is being used for all kinds of other purposes too, from fingerprinting cells andlogging what happensinside them todirecting evolutionand creatinggene drives.

The key to CRISPR is the many flavours of Cas proteins found in bacteria, where they help defend against viruses. The Cas9 protein is the most widely used by scientists. This protein can easily be programmed to find and bind to almost any desired target sequence, simply by giving it a piece of RNA to guide it in its search.

When the CRISPR Cas9 protein is added to a cell along with a piece of guide RNA, the Cas9 protein hooks up with the guide RNA and then moves along the strands of DNA until it finds and binds to a 20-DNA-letter long sequence that matches part of the guide RNA sequence. Thats impressive, given thatthe DNA packed into each of our cellshas six billion letters and is two metres long.

What happens next can vary. The standard Cas9 protein cuts the DNA at the target. When the cut is repaired, mutations are introduced that usually disable a gene. This is by far the most common use of CRISPR. Its called genome editing or gene editing but usually the results arenot as preciseas that term implies.

CRISPR can also be used tomake precise changessuch as replacing faulty genes true genome editing but this is far more difficult.

Customised Cas proteins have been created that do not cut DNA or alter it in any way,but merely turn genes on or off: CRISPRa and CRISPRi respectively. Yet others, called base editors,change one letter of the DNA code to another.

So why do we call it CRISPR? Cas proteins are used by bacteria to destroy viral DNA. They add bits of viral DNA to their own genome to guide the Cas proteins, and the odd patterns of these bits of DNA are what gave CRISPR its name: clustered regularly interspaced short palindromic repeats. Michael Le Page

Read more:
What is CRISPR? | New Scientist

Recommendation and review posted by Bethany Smith

Many bacterial clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) systems employ the dual RNA-guided DNA endonuclease Cas9 to defend against invading phages and conjugative plasmids by introducing site-specific double-stranded breaks in target DNA. Target recognition strictly requires the presence of a short protospacer adjacent motif (PAM) flanking the target site, and subsequent R-loop formation and strand scission are driven by complementary base pairing between the guide RNA and target DNA, Cas9-DNA interactions, and associated conformational changes. The use of CRISPR-Cas9 as an RNA-programmable DNA targeting and editing platform is simplified by a synthetic single-guide RNA (sgRNA) mimicking the natural dual trans-activating CRISPR RNA (tracrRNA)-CRISPR RNA (crRNA) structure. This review aims to provide an in-depth mechanistic and structural understanding of Cas9-mediated RNA-guided DNA targeting and cleavage. Molecular insights from biochemical and structural studies provide a framework for rational engineering aimed at altering catalytic function, guide RNA specificity, and PAM requirements and reducing off-target activity for the development of Cas9-based therapies against genetic diseases.

Keywords: CRISPR; Cas9; genome engineering; mechanism; off-target; structure.

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CRISPR-Cas9 Structures and Mechanisms - PubMed

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In July, an HIV-positive man became the first volunteer in a clinical trial aimed at using Crispr gene editing to snip the AIDS-causing virus out of his cells. For an hour, he was hooked up to an IV bag that pumped the experimental treatment directly into his bloodstream. The one-time infusion is designed to carry the gene-editing tools to the mans infected cells to clear the virus.

Later this month, the volunteer will stop taking the antiretroviral drugs hes been on to keep the virus at undetectable levels. Then, investigators will wait 12 weeks to see if the virus rebounds. If not, theyll consider the experiment a success. What were trying to do is return the cell to a near-normal state, says Daniel Dornbusch, CEO of Excision BioTherapeutics, the San Francisco-based biotech company thats running the trial.

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Crispr isbeing used in several other studiesto treat a handful of conditions that arise from genetic mutations. In those cases, scientists are using Crispr to edit peoples own cells. But for the HIV trial, Excision researchers are turning the gene-editing tool against thevirus. The Crispr infusion contains gene-editing molecules that target two regions in the HIV genome important for viral replication. The virus can only reproduce if its fully intact, so Crispr disrupts that process by cutting out chunks of the genome.

This is an excerpt. Read the full article here

More here:
A CRISPR cure for HIV? Gene-editing technology may be able stop viral replication in its tracks and wipe out infections - Genetic Literacy Project

Recommendation and review posted by Bethany Smith

Studies in non-human primates demonstrated nearly 100% gene editing and knockout of endogenous RHO gene and more than 30% replacement protein levels using a dual vector AAV approach

Treated eyes showed morphological and functional photoreceptor preservation

EDIT-103 advancing towards IND-enabling studies

CAMBRIDGE, Mass., Oct. 13, 2022 (GLOBE NEWSWIRE) -- Editas Medicine, Inc. (Nasdaq: EDIT), a leading genome editing company, today announced ex vivo and in vivo preclinical data supporting its experimental medicine EDIT-103 for the treatment of rhodopsin-associated autosomal dominant retinitis pigmentosa (RHO-adRP). The Company reported these data in an oral presentation today at the European Society of Gene and Cell Therapy 29th Annual Meeting in Edinburgh, Scotland, UK.

EDIT-103 is a mutation-independent CRISPR/Cas9-based, dual AAV5 vectors knockout and replace (KO&R) therapy to treat RHO-adRP. This approach has the potential to treat any of over 150 dominant gain-of-function rhodopsin mutations that cause RHO-adRP with a one-time subretinal administration.

These promising preclinical data demonstrate the potential of EDIT-103 to efficiently remove the defective RHO gene responsible for RHO-adRP while replacing it with an RHO gene capable of producing sufficient levels of RHO to preserve photoreceptor structure and functions. The program is progressing towards the clinic, said Mark S. Shearman, Ph.D., Executive Vice President and Chief Scientific Officer, Editas Medicine. EDIT-103 uses a dual AAV gene editing approach, and also provides initial proof of concept for the treatment of other autosomal dominant disease indications where a gain of negative function needs to be corrected.

Key findings include:

Full details of the Editas Medicine presentations can be accessed in the Posters & Presentations section on the Companys website.

About EDIT-103EDIT-103 is a CRISPR/Cas9-based experimental medicine in preclinical development for the treatment of rhodopsin-associated autosomal dominant retinitis pigmentosa (RHO-adRP), a progressive form of retinal degeneration. EDIT-103 is administered via subretinal injection and uses two adeno-associated virus (AAV) vectors to knockout and replace mutations in the rhodopsin gene to preserve photoreceptor function. This approach can potentially address more than 150 gene mutations that cause RHO-adRP.

AboutEditas MedicineAs a leading genome editing company, Editas Medicine is focused on translating the power and potential of the CRISPR/Cas9 and CRISPR/Cas12a genome editing systems into a robust pipeline of treatments for people living with serious diseases around the world. Editas Medicine aims to discover, develop, manufacture, and commercialize transformative, durable, precision genomic medicines for a broad class of diseases. Editas Medicine is the exclusive licensee of Harvard and Broad Institutes Cas9 patent estates and Broad Institutes Cas12a patent estate for human medicines. For the latest information and scientific presentations, please visit http://www.editasmedicine.com.

Forward-Looking StatementsThis press release contains forward-looking statements and information within the meaning of The Private Securities Litigation Reform Act of 1995. The words "anticipate," "believe," "continue," "could," "estimate," "expect," "intend," "may," "plan," "potential," "predict," "project," "target," "should," "would," and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. The Company may not actually achieve the plans, intentions, or expectations disclosed in these forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various factors, including: uncertainties inherent in the initiation and completion of preclinical studies and clinical trials and clinical development of the Companys product candidates; availability and timing of results from preclinical studies and clinical trials; whether interim results from a clinical trial will be predictive of the final results of the trial or the results of future trials; expectations for regulatory approvals to conduct trials or to market products and availability of funding sufficient for the Companys foreseeable and unforeseeable operating expenses and capital expenditure requirements. These and other risks are described in greater detail under the caption Risk Factors included in the Companys most recent Annual Report on Form 10-K, which is on file with theSecurities and Exchange Commission, as updated by the Companys subsequent filings with theSecurities and Exchange Commission, and in other filings that the Company may make with theSecurities and Exchange Commissionin the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and the Company expressly disclaims any obligation to update any forward-looking statements, whether because of new information, future events or otherwise.

Original post:
Editas Medicine Presents Preclinical Data on EDIT-103 for Rhodopsin-associated Autosomal Dominant Retinitis Pigmentosa at the European Society of Gene...

Recommendation and review posted by Bethany Smith

Gene editing has long been primarily used for research, treatment, and disease prevention. Currently, this technology is increasingly being applied to modify agricultural products to create more perfect species. More and more genetically edited foods are appearing on the market, including high-nutrient tomatoes and zero-trans-fat soybean oil.

Some argue that gene-edited foods are safer than genetically modified (GM) foods (pdf). The U.S. Department of Agriculture (USDA) specified in 2018 that most genetically edited foods do not need to be regulated. However, are these foods, which will increasingly appear on the table, really risk-free?

In September 2021, the first gene-edited foodSicilian Rouge tomatoesmade with CRISPR-Cas9 technology were officially on sale.

This gene-edited tomato contains high levels of gamma-aminobutyric acid (GABA), which helps lower blood pressure and aids relaxation.

Japanese researchers remove a gene from the genome of the common tomato. After the gene is removed, the activity of an enzyme in tomatoes increases, promoting the production of GABA. The GABA content in this tomato is four to five times higher than that of a regular tomato.

Warren H. J. Kuo, an emeritus professor of the Department of Agronomy at National Taiwan University, explains that both gene editing and transgenic organisms are genetic modification, also known as genetic engineering.

The earliest technique was genetic modification, that is, transgenicin which a plant or animal is being inserted a gene from another species, such as a specific bacterial gene. The purpose of artificially modifying plants and animals is to improve their resistance against diseases and droughts, promote growth rates, increase yields, or improve nutrient content. However, the finished product will exhibit the foreign species genes.

Kuo says that transgenic modification is genetic modification 1.0, while gene editing is genetic modification 2.0. Gene editing is directly modifies the genes of the organism itself, so most of them do not exhibit foreign genes. However, the most common gene editing technique, CRISPR-Cas9, introduces foreign genes as the editing tool, and then removes the transplanted foreign genes.

While gene-edited tomatoes were on the market, Japan also approved two types of fish genetically edited with CRISPRtiger pufferfish and red seabream. These fish are genetically edited to accelerate muscle growth. Among them, the gene-edited tiger pufferfish weighs nearly twice that of the ordinary species.

Back in 2019, the United States had used another earlier gene-editing technique to create soybean oil with zero trans fat and introduced it into the market.

Gene-edited foods which have also been approved for sale worldwide by now include soybeans, corn, mushrooms, canola, and rice.

The number of genetically edited foods on the market is likely to increase. Patent applications relating to CRISPR-edited commercial agricultural products have skyrocketed since the 2014/2015 period.

Proponents ofgenetic modification believe this is a method to perfect agricultural produce and solve problems such as pests, droughts, and nutritional deficiencies. But the technology is still a double-edged sword.

Genetic engineering indeed has its benefits in the short term, but it may bring long-term pitfalls, said Joe Wang, molecular biologist. Wang is currently a columnist with The Epoch Times.

Hornless cattle were once the celebrity of the animal kingdom, appearing in news stories one after another.

Many breeds of dairy cattle have horns, but they are dehorned to prevent them from harming humans and other animals, and to save more feeding trough space. To solve the problem of horns, the gene editing company Recombinetics successfully produced hornless cattle with gene-editing techniques many years ago.

The company simply added a few letters of DNA to the genome of ordinary cattle and their offspring didnt grow horns, either.

However, a few years later, an accident happened.

The FDA found that a modified genetic sequence of a bull contained a stretch of bacterial DNA including a gene conferring antibiotic resistance, which has been one of the global health crises in recent years. Scientists arent clear whether this gene in gene-edited cattle will pose a greater risk than expected or not, and the FDA has stressed that its hazard-free. However, John Heritage, a retired microbiologist from Leeds University, told MIT Technology Review that the antibiotic resistance gene could be absorbed by gut bacteria in cattle and could create unpredictable opportunities for its spread.

In fact, this is one of the currently perceived risks of genetically edited foods.

The problem with unexpected accidents in the genetic modification process occurs in GM foods because transgenic techniques cannot control where the foreign gene is embedded in the chromosome.

Kuo used the example of a study that compared the protein of transgenic soybeans and non-transgenic soybeans. These transgenic soybeans were initially embedded with one foreign gene, and should have had only one protein that didnt exist before. However, the comparison showed that there was a difference of about 40 proteins between the two: Half of the proteins were originally present, but disappeared after transgenic modification; the other half were not present but were added after the transgenic modification.

In contrast, emerging gene editing techniques allow for more precise modification of specific genes (pdf). Its like a tailor modifying a section of a zipper by cutting off a specific segment and replacing it with a new one. However, there may be mistakes and unexpected changes in the process of cutting and repairing, and another similar section of the zipper may also be cut off.

Kuo says that this process may have unforeseen side effects; for example, if during this, new allergy-causing proteins or new toxins are produced.

The genetic engineering procedure, and this includes gene editing, has the potential to damage DNA, said molecular geneticist Dr. Michael Antoniou, head of the Gene Expression and Therapy Group at Kings College London, in an interview in April 2022. If you alter gene function, you automatically alter the biochemistry of the plant included within that altered biochemistry can be the production of novel toxins and allergens that is my main concern.

Another major concern with GM foods is herbicide residue.

Most crops, whether genetically edited or genetically modified, have herbicide-resistant genes incorporated into them. This is done so that when herbicides are applied to crops for weed control, the crops themselves wont be harmed.

When planting herbicide-resistant crops, farmers can use herbicides rather liberally. But, long term, the weeds the farmers are targeting become increasingly herbicide-resistant as well, resulting in a cycle of increased herbicide use and resistance.

Since the introduction of herbicide-resistant GM crops in 1996, herbicides have experienced a significant growth in application every year. The herbicides residue in the crops grown are increasing as well.

One of the most widely used herbicides is glyphosate under the trade name Roundup. The International Agency for Research on Cancer (IARC) classifies glyphosate as a Group 2A carcinogen that is probably carcinogenic to humans.

Massachusetts Institute of Technology (MIT) researcher Stephanie Sene and scientific consultant Anthony Samsel said in their study that 80 percent of GM crops, especially corn, soybeans, canola, cotton, sugar beets, and alfalfa, are specifically introduced with glyphosate resistance genes.

In addition to carcinogenic concerns, glyphosate may have more harmful effects. They have collected and reviewed 286 studies and indicated that glyphosate inhibits the activity of an enzyme in the mitochondria of liver cellscytochrome P450which has the ability to detoxify and decompose foreign toxic substances. Moreover, glyphosate also has adverse effects on the gut microbiota.

These effects are not immediately apparent, but in the long run may contribute to inflammatory bowel disease, obesity, depression, attention deficit hyperactivity disorder (ADHD), autism, Alzheimers, Parkinsons, amyotrophic lateral sclerosis (ALS), multiple sclerosis, cancer, infertility, and developmental abnormalities.

An animal study published in Environmental Health shows that long-term exposure to ultra-low doses of glyphosate still causes liver and kidney diseases in rats.

The debate over whether GM food is safe or not has not yet settled. Many advocates of transgenic modification and gene editing believe that people have been eating GM crops for 20-plus years and still there is no evidence that they have caused problems to human health. Other argue they contribute to long term harm that is still being measured.

Kuo said that GM food is not a highly toxic drug causing immediate problems. Health problems can be the result of something cumulative, and hard to relate back to a single food cause. Whether GM foods are the culprit of such health problems has not been proven, nor ruled out.

At present, various countries have adopted an early warning principle for GM foods, stipulating that merchants label their products. It is the consumers decision to purchase them or not.

Will gene-edited food require specific labeling? Some argue that because these foods do not exhibit foreign genes, there should not be such regulation. Kuo believes this is a misleading argument, given that the tool used to edit the original genes were in fact foreign genes, and the method carries the risk that these foreign genes may not be completely removed.

Currently, the regulations for gene-edited foods in various countries are much looser than those for GM foods.

The USDA has consistently stated that gene-edited agricultural products are not regulated. Plant technologists are usually given the green light within months after submitting inquiries to the agency, allowing them to grow gene-edited foods without oversight.

In addition to the United States, Brazil and Australia and other countries have also adopted similar regulatory approaches. European regulations are still more stringent.

Antoniou argues that since these GM agricultural products are not monitored, the unexpected genes that they carry are released into the environment and will cause harm to it. They may also cause harm to the public due to the scientific communitys insufficient understanding of their risks.

Wang said that scientists who support gene editing believe that what they are doing now will also happen in nature, albeit at a slower pace. They simply speed it up. However, humans are not gods and cannot control everything. When humans do such things, the odds of mistakes and danger are definitely higher than what happens naturally, Wang said.

We humans have violated the laws of nature for a long time, Kuo said.

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Camille Su is a health reporter covering disease, nutrition, and investigative topics. Have a tip? kuanmi.su@epochtimes.com

Read more here:
More Foods Will Be Gene-Edited Than You Think - The Epoch Times

Recommendation and review posted by Bethany Smith

USAs Alcor Life Extension Foundation has claimed that it will soon develop the scientific way to rebirth. The company, in USAs Arizona, has preserved the dead bodies of around 199 people only with the hope that once the technique is developed, they will get respite from their illnesses, and they will come back to life. With this hope of these people getting their lives back, Alcor has reserved their dead bodies in nitrogen tanks and the company calls them patients who lost their lives because of illnesses like cancer, paralysis, amyotrophic lateral sclerosis, etc.

Dead bodies preserved this way are called cryopreserved. Among these bodies, the youngest is that of a Thai child, who had lost her life at the age of 2 because of brain cancer in the year 2015. Alcors CEO, Max Moor has said that both of the childs parents are doctors and despite getting multiple brain surgeries performed on her, nothing helped. Hal Finney, who pioneered bitcoin, is also a patient at Alcor. After he lost his life in 2014 due to paralysis, his body is being preserved here.

The process of cryopreservation is highly different, after the legal announcement of a persons death, the blood and other fluids from the body are ejected out, which are then replaced with special chemicals, which prevent the boy from getting damaged, after which the dead body is preserved in extremely cold temperatures like glass.

View original post here:
Alcor Life Extension Foundation preserves 199 dead bodies in nitrogen - Goa Chronicle

Recommendation and review posted by Bethany Smith

Oct. 15Kauai County will give out thousands of free home test kits next week at various neighborhood centers.

The county, in partnership with the state Health Department, is offering about 6, 000 COVID-19 tests kits on a first-come, first-served basis, starting Wednesday. There will be a limit of five tests per person or household.

"Mahalo to our partners with the Kauai District Health Office, the Department of Parks and Recreation, and the Kauai Emergency Management Agency for making these free tests available to our community, " said Mayor Derek Kawakami in a news release. "Home test kits are one of the many tools at our disposal to reduce the risk of spreading COVID."

These COVID-19 tests have an expiration date of November 2022, officials said, but have received a seven-month shelf-life extension from the U.S. Food and Drug Administration. They are set to expire in June.

The distribution schedule will be as follows :

Wednesday9 a.m. to noon, Hanalei Neighborhood Center1 to 4 p.m., Kilauea Neighborhood Center Thursday9 a.m. to noon, Waimea Neighborhood Center1 to 4 p.m., Hanapepe Neighborhood Center Friday9 a.m. to noon, Bryan J. Baptiste Sports Complex1 to 4 p.m., Lihue Neighborhood Center COVID-19 testing is also available islandwide on Kauai, with sites listed at.

Read this article:
Kauai County to hand out thousands of free COVID home test kits - Yahoo News

Recommendation and review posted by Bethany Smith

In this article:

Everyone knows vitamin D -- it's the nutrient we get from the sun. Vitamin D is important for several bodily functions, the main ones being bone and muscle strength and immune function. Still, about 35% of Americans are vitamin D deficient. Research has found that vitamin D deficiencies and diseases like depression, diabetes and cancer are correlated.

Vitamin D is essential. But with winter coming and food source limitations, getting vitamin D isn't always as easy as walking out in the sun. Supplements are used to combat such deficiencies.

A note on units of measurement for vitamin D supplements -- different brands use different units in their marketing. Some measure in micrograms (mcg), while others use international units (IU). The nutritional label typically has both units and the percentage of the daily recommended value. It can get confusing.

Quick conversions that will help you read this list:

Vitamin D supplements span quality, dosage and price point. There are many options, but we narrowed it down to the top eight best vitamin D supplements.

Hum Nutrition Here Comes the Sun is the best overall vitamin D supplement because of its vitamin content and rigorous testing. According to the Hum Nutrition website, this vitamin D supplement boosts mood, maintains your immune system and aids calcium absorption.

It's a non-GMO and gluten-free vitamin D supplement free of artificial flavors, colors or sweeteners. With the serving size of one softgel, you get 250% of your recommended daily value of vitamin D. The vitamin D source was derived from lichen, which makes this vitamin D supplement great for vegans and vegetarians.

Hum Nutrition's vitamin D supplements are sustainably sourced and feature third-party testing.

Price: $19 for a 30-day supply

Vitamin D per serving: 50 mcg or 250% of the daily value

Serving size: One softgel, daily

Hum Nutrition's best features:

Things to consider:

Nature Made vitamin supplements are often my choice for budget shoppers because of the price, vitamin content and company reputation. The Nature Made Vitamin D3 Softgels are available in multiple dosages, so you can choose which works best for you. They have dosages from 25 mcg to a maximum of 250 mcg.

You really can't beat the price of Nature Made. You can get up to a 250-day supply for under $20. Not to mention that the softgels are small and easy to swallow -- and you only have to take one per day.

Price: $16.93 for a 250-day supply

Vitamin D per serving: 50 mcg or 250% of the daily value

Serving size: one softgel, daily

Nature Made's best features:

Things to consider:

If you have trouble swallowing pills, liquid vitamin D options are available the best of which is Pure Encapsulations Vitamin D3 liquid.

It's a small bottle that's easy to transport, which allows you to add it to food anywhere. It's also flavorless. Liquid supplements give you the flexibility that capsule or pill supplements can't. You can also alter the dosage based on seasons and needs. Remember to always pay close attention to how much you're ingesting.

This vitamin D supplement is sourced from lichen. It includes no artificial flavors and is gluten-free and non-GMO. Pure Encapsulation products are third-party tested by organizations like Advanced Laboratories, Eurofins and Intertek.

Price: $29.55 for 22.5 ml bottle

Vitamin D per serving: 25 mcg or 125% of vitamin D of the daily value

Serving size: One drop, daily

Pure Encapsulations' best features:

Things to consider:

For people who need a higher dose of vitamin D, -- those with malabsorption syndromes, osteoporosis or liver failure -- Life Extension Vitamin D3 supplement is a good choice. Most vitamin D supplements have 25 mcg to 50 mcg. The vitamin D supplement from Life Extension offers 125 mcg or 5,000 IU, which is significantly more than other brands.

Given this vitamin D supplement has such a high dosage, it's important to speak to your doctor before taking it. It shouldn't be taken by the average person who doesn't need a huge boost of vitamin D. Life Extension's bottle label advises you to meet with your doctor for regular blood tests to determine your vitamin D levels.

Price: $15.17 for a 120-day supply

Vitamin D per serving: 125 mcg or 625% of the daily value

Serving size: one softgel, daily

Life Extension's best features:

Things to consider:

Many vitamin D supplements happen to be vegan. However, Truvani is the best vegan vitamin D supplement. It's a plant-based and USDA-certified organic supplement sourced from organic lichens that doesn't include additives or processed ingredients. This vitamin D supplement has an average amount of vitamin D at 50 mcg. This vitamin D supplement comes in a small, uncoated tablet. It's easy to swallow, but you can also add it to smoothies or drinks and let it dissolve.

Price: $14.99 for a 30-day supply

Vitamin D per serving: 50 mcg or 250% of the daily value

Serving size: one tablet, daily

Truvani's best features:

Things to consider:

Nordic Naturals Vitamin D3 Gummies are an all-natural supplement free of artificial sugars or additives. With this vitamin D supplement, you get a solid dose of vitamin D without all the extras that gummy vitamins tend to have.

This gummy vitamin D supplement features a wild berry flavor with organic sucrose and fumaric acid sour berry coating. An important thing to note is that while the sugars included are not artificial (organic sugar cane and organic tapioca syrup), there are still two grams of added sugar in this product. It's not the highest I've seen, but it's something to consider if you watch your sugar intake closely. Added sugars are extremely common in the gummy industry -- that's how they get their delicious flavors. Unlike other brands, Nordic Naturals also offers a zero-sugar version sweetened with xylitol.

Price: $12.07 for a 30-day supply

Vitamin D per serving: 25 mcg or 125% of the daily value.

Serving size: 1 gummy, daily

Nordic Naturals' best features:

Things to consider:

Ritual is a well-known vitamin subscription service. It's the best multivitamin with vitamin D because of its traceable ingredients and dense nutrient content. According to Ritual, the Essential Multivitamin helps bone health, brain health and immune function.

Ritual multivitamins include a vegan D3 ingredient made from UK-sourced lichen. With each serving, you get 50 mcg of vitamin D, double what some supplements offer. Since it's a multivitamin, you get additional nutrients like folate and iron.

Ritual supplements are backed by a clinical study that found that the Ritual Essential Multivitamin for Women resulted in a 43% increase in vitamin D levels. It's worth noting that Ritual was involved in the study.

Price: $30 for a 30-day supply

Vitamin D per serving: 50 mcg or 250% of the daily value.

Serving size: two capsules, daily

Ritual's best features:

Things to consider:

Vitamin D is essential for pregnancy as it aids in the development of a baby's bones. Vitamin D deficiencies during pregnancy have been linked to newborns' disordered skeletal homeostasis or fractures. Experts recommend that pregnant women intake up to 4,000 IU (100 mcg) of vitamin D3 daily to prevent preterm births and infections.

Most vitamin D supplements don't offer that much vitamin D3 per serving. However, the FullWell Prenatal Multivitamin does. Developed by a fertility nutrition expert, FullWell supplements are non-GMO and free of common allergens like nuts, dairy, gluten and shellfish.

FullWell Prenatal Multivitamin includes the recommended 4,000 IU of vitamin D and all other nutrients a pregnant person needs -- like vitamins A, V, E and B6. This supplement also offers a hefty dose of pantothenic acid at 2,143% daily value and biotin at 1,429%.

Price: $49.95 for a 30-day supply

Vitamin D per serving: 100 mcg or 667% of the daily value

Serving size: eight capsules, daily

FullWell's best features:

Things to consider:

When choosing the best vitamin D supplements for this list, we considered factors like price, dosage and vitamin D source. We also paid close attention to third-party certifications that the products carry. Due to the limited FDA regulations in the vitamin and supplement industry, third-party testing and certifications are essential to determine product quality and purity. We did not test these products in-house. We relied on customer reviews for things like taste and ease of swallowing.

Our bodies need vitamin D, and as a result, there are a ton of supplements out there with vitamin D in them. From pure vitamin D supplements to multivitamins or prenatal supplements, there tends to be vitamin D in all of them. So which vitamin D supplement should you buy?

When shopping for vitamin D supplements, keep these key factors in mind:

What's the difference between vitamin D and D3?

Vitamin D is broken down into two main forms -- vitamin D2 and D3. The difference is where they come from. Vitamin D2 (ergocalciferol) is found in plant sources like mushrooms or fungi. Vitamin D3 (cholecalciferol is derived from animal sources.

How often should you take vitamin D supplements?

Unlike other nutrients, our bodies store vitamin D in fat cells, which allow them to release it when needed. Many supplements with higher doses of vitamin D are not designed to be taken each day since there likely already is some stored in the body. Taking too much vitamin D can result in stomach discomfort, weight loss and kidney issues. A lower vitamin D supplement is considered safe, particularly if you're deficient in vitamin D.

The information contained in this article is for educational and informational purposes only and is not intended as health or medical advice. Always consult a physician or other qualified health provider regarding any questions you may have about a medical condition or health objectives.

Excerpt from:
8 Best Vitamin D Supplements to Take This Winter - CNET

Recommendation and review posted by Bethany Smith

Cryobiology illustration generated using Midjourney generative AI

Have you ever thought about what would happen if you suddenly need organ transplantation, but no one you know who is willing to donate is a match? An integral part of organ transplantation is, of course, donors and recipients, or people who donate the organs for matching people in need. They are registered within the Organ Procurement and Transplantation Network, an organization that arranges everyone on donor-recipient lists taking into consideration the severity of their illnesses. Their database contains all detailed information on blood and tissue types, organ sizes, medical urgency, and the geographical distance between the donor and the recipient. As soon as there is a newly available organ, a match is found throughout their database and shipped as soon as possible. Or at least thats how the system aims to work.

But there is a hidden player - cold. From Ancient Greece and Rome to modern days, our society has utilized cold in many ways, mostly to preserve food. However, in modern medicine, cold was also found in quite a few applications, such as freezing human sperm and embryos in the process of in vitro fertilization. Intuitively, modern medicine also futuristically looks at cold as a useful agent that could save our lives many years ahead, in the sense of preserving (freezing) our bodies now, and reviving them once we find the cures for untreatable diseases that may have impacted us.

But, coming back to organ transplantation, cold plays a huge role in this process. Once the organ has been removed from the donor's body, it needs to come to the recipient in the exact same functional state. Several external and environmental conditions can severely damage the organ until it's no longer of use. One of the key factors is temperature, which needs to be low enough to slow down biochemical reactions happening in the organ after extraction to prevent further damage. To successfully transport and deliver organs, they need to be kept on ice (a term called hypothermic storage), with an average temperature of +4C. Unfortunately, the heart and lungs can survive on ice for only about 4-5 hours, after which theyre no longer usable. Human organ transplantation requires intense immunological screening of both the donor and the recipient, and this period is usually insufficient to perform it. Finally, 4-5 hours is not enough for an organ to travel from Europe to the United States, for example. It's not even enough to travel within the United States, depending on the ending location, and in many cases, when paired with other logistical constraints, not even sufficient to travel from hospital to hospital. Therefore, geographical location plays a huge role in organ transplantation, and organs that cannot be delivered in a timely manner in optimal conditions will simply be lost. And that's exactly what happens because about 28 thousand organs are wasted in the United States only per year, due to poor performance of currently available preservation methods.

French Blood Bank In Bordeaux. Blood Transfusion Center, Storage Room For Stem Cells In Nitrogen ... [+] 196C. Open Vat Containing Bags Of Stem Cells. Stock Room For Cellular Therapy. (Photo By BSIP/UIG Via Getty Images)

The field of science that investigates the application of cold on biological samples is called cryobiology, whereas the process of using cold to preserve those samples is called cryopreservation. There are quite a few scientific groups, working both in academia and industry, that keep expanding the knowledge in these fields every day. The process of cryopreservation entails many steps, mainly cooling, storage, and rewarming. Each one of these steps can be divided into multiple reactions, and all of them could be performed in multiple ways. It is, however, vital that all of them are performed in an optimal way such that the biological sample that's being preserved does not get damaged, or lose its functionality upon reviving. The main problem in cryopreservation is the formation of ice crystals, that can happen at any step of the way, but mostly when samples are being either cooled to or warmed from subzero temperatures. This is a major issue because the largest part of all biological samples is water. Therefore, many research groups in cryobiology are working on ways to avoid ice crystal formation.

If successful cryopreservation and reviving of complex biological samples, e.g. human organs, was made possible without the interference of ice crystals, organs could be easily transported throughout the world without considering the time it would take to get them to their final destination or be stored for a long time until somebody would need them, as opposed to discarding and losing hundreds of them on a daily basis. Similarly, even if their functionality could be prolonged to a few days instead of a few hours, tens of thousands of human lives could be saved every year. Some researchers dedicated their whole careers to making this happen, and today I will introduce you to one of them.

In my last article on cryopreservation, I had the pleasure of interviewing the group of Dayong Gao, that works on methods to improve reviving of frozen biological samples using single-mode electromagnetic resonance rewarming. Today, I'm interviewing Matthew J. Powell-Palm, an Assistant Professor of Mechanical Engineering and Materials Science at Texas A&M University, and a co-founder of BioChoric Inc. Following in the footsteps of his mentor Boris Rubinsky, he works on understanding the underpinnings of cryopreservation and manipulating the first major part of this process, i.e., freezing itself. The method they are establishing is called isochoric cryopreservation, a technique that could improve transplantation medicine immensely.

Cryobilogy in cancer

The History of Cryopreservation: Major Breakthroughs

By providing you a little bit of historical context, well have a look over the major breakthroughs that happened in the field of cryobiology, and that instigated the modern use of cold in medicine. The start of the modern field of cryobiology is thought to have happened in 1948, when Christopher Polge discovered the cryoprotective effects of glycerol, a cryoprotective agent (CPA) that prevents ice crystal formation through the creation of bonds with free water molecules. Since then, a huge aspect of cryobiology and cryopreservation technologies was that we can modulate a given system's chemistry by involving CPAs, which could, in theory, allow us to preserve a live biologic sample for a long time. Many more CPAs, like dimethyl sulfoxide (DMSO), appeared on the scene afterwards, revolutionizing the subfield of human sperm cryopreservation. In 1972, scientists Peter Mazur, Stanley Leibo, and David Whittingham published evidence of the first-ever successful cryopreservation of mammalian embryos using slow-freezing. Eleven years later, the first-ever human embryo was cryopreserved.

A turning point in cryobiology happened in the 1980s, the so-called golden era of cryopreservation. Building on seminal early work by Father Basile J. Luyet, a Catholic priest and professor who helped to establish the thermodynamic foundation of modern cryobiology, Gregory M. Fahy and William R. Fall introduced the process of vitrification to medical cryopreservation. Vitrification is a process of rapid cooling of liquid medium until it becomes a glass-like non-crystalline amorphous solid. It requires the protective effect of CPAs, which lower the freezing point of water, as a major part of biological systems. In its vitrified state, water is locked in place, preventing the formation of ice crystals, and the entire sample becomes a glass-like solid. Vitrification is used widely today in the cryopreservation of very small biological samples (specifically in in vitro fertilization and other reproductive applications), and many cryobiologists believe it could eventually be applied to freeze any biological materials, even organs and whole organisms.

Human kidney frozen in ice cube, 3D rendering isolated on white background

Using vitrification, many research groups have already been able to successfully preserve and revive different cells and tissues, showing that there is major potential in cryopreserving and reviving organs as well. One of the major focus in cryobiology research is, in fact, centered around the process of vitrification and how much and which CPAs to add during this stage, or how to remove them in the rewarming stages. But, so far, CPA-aided vitrification only enabled the routine preservation of cells and cell suspensions and failed to produce any clinically translatable technique on how to preserve any complex biological systems like organs outside of the human body.

Isochoric Cryopreservation: Out With the Old, In With the New?

Methods in cryopreservation havent changed much in the last few years but there is a different approach currently available called isochoric cryopreservation. The term stands for cryopreservation of biological tissues at a constant volume, versus the more traditional way of cryopreservation that's done at constant pressure, called isobaric cryopreservation. During isochoric preservation, the cooling process happens in a confined, constant-volume chamber, representing one of the biggest differences between isochoric and isobaric conditions. Another difference is minimized role of CPAs, which are very much needed in the classical isobaric cryopreservation, but not in several modes of isochoric cryopreservation. The advantage of isochoric freezing is that it completely avoids the question of the toxicity associated with CPA usage as well as the amount of CPAs needed to be present in the biological sample you might want to freeze. Even if there is a need to use CPAs, their concentrations would be dramatically decreased. Under isochoric conditions, a biological sample is confined within a container with high rigidity and strength, usually made out of titanium. The container is completely absent of the bulk gas phase, and is denied any access to the atmosphere, which changes both the thermodynamic equilibrium and the ice nucleation kinetics within the system inside.

Isochoric cryopreservation is a technique conceived initially by Boris Rubinsky, a Professor at the University of California at Berkeley. Prof. Rubinsky obtained his Ph.D. at MIT in 1981 and has been engaged in the field of cryobiology ever since. His major research interests include heat and mass transfer in biomedical engineering and biotechnology and, in particular, low-temperature biology, as well as the development of bio-electronics and biomedical devices for clinical purposes. He has also pioneered in the fields of medical imaging, cryoablation, and non-thermal electroporation. Prof. Rubinsky has been involved with more than 470 peer-reviewed scientific papers since the beginning of his career and holds more than 30 US-issued patents.

The aim of isochoric cryopreservation at Prof. Rubinsky's group is not strictly preservation of biological samples (to be revived) per se, but rather about further developing the technique to offer the world a chance for a more successful general process of cryopreserving biological samples and decreasing the using toxic CPAs. Some of their latest research includes the creation of a quantitative approach to develop a general framework for the design of metastable supercooling protocols which incorporate the phase transformation and biochemical kinetics of the system. You can find the paper here. The group has also played with carbohydrate polymer protectants, as opposed to the small-molecular weight chemical ones mostly in use nowadays, and found that they can be used to manipulate the metastable-equilibrium phase change kinetics of the system at subzero temperatures. This approach has revealed that a carbohydrate polymer can be used to help modulate the stochasticity of ice nucleation in the supercooling system, which is important to designing supercooled biopreservation protocols for practical use. This research can be read here.

It seems the group is really striving to develop and optimize an application of supercooling and freezing techniques that could be used in biomedical devices already today. Some of Prof. Boris Rubinsky's technologies were already used to treat tens of thousands of patients, and the companies he founded were acquired by the big fish, such as Cryomedical Sciences which became a $300 million NASDAQ company. A new name in the field of isochoric cryopreservation is eager to follow in these steps, and to further develop the field in his own way: Matthew J. Powell-Palm.

Future Players in Cryo-thermodynamics: Professor Matthew J. Powell-Palm

Matt Powell-Palm is one of Boris Rubinsky's former PhD students and a leader in the field of isochoric cryopreservation. He is currently an Assistant Professor of Mechanical Engineering and Materials Science at Texas A&M University, and a co-founder of BioChoric Inc. (along with his former PhD supervisor), a medtech startup that is working on transforming transplant medicine by developing methods to prolong organ preservation. He obtained his Master's degree in 2016 at Carnegie Mellon University under the supervision of Jon Malen, and his Ph.D. in 2020 at UC Berkeley.

Currently, a central focus of Matt's research is within the field of isochoric thermodynamics and cryopreservation. His expertise revolves around the applications of isochoric supercooling and vitrification protocols and devices to improve organ preservation, conserve endangered marine animals, and improve global food storage and transportation. Even though he completed his Ph.D. only two years ago, he's already established himself as one of the leaders in the field of isochoric thermodynamics and cryopreservation with more than 25 published peer-reviewed scientific papers and numerous patents. I was honored to share the online space for some time with Matt and pick his brain on all things cryo, plus ask some additional futuristic questions.

Alex Zhavoronkov, PhD interviewing professor Matthew Powell-Palm via Zoom, September, 2022

First, I wanted to see what Matt's perspective was on different terms in cryobiology, and what he considers the differences between them.

Alex: Can you describe the differences between cryonics, cryobiology, and cryopreservation?

Matt: Cryopreservation is the application of cryobiology, and the biggest difference between it and cryonics is the end goal. The field of cryopreservation is not particularly interested in existential or societal aspects of life prolongation and is solving daily problems in medicine, conservation biology, agriculture, and in any application where the elongated shelf life is important. Cryonics is the application of cryobiology where the end goal is to prolongate a human life by freezing and reviving it in the future.

Alex: Can you talk about your current research and, specifically, the concept of isochoric cryopreservation?

Matt: Looking back on the many successes and failures of modern cryopreservation, I have been asking myself the past few years if there are any new non-chemical ways in which we can manipulate the thermodynamic behaviors of water to achieve the goal of preventing ice crystal formation below the systems melting point, which is the main problem in cryopreservation.

The umbrella technique the Rubinsky Lab has come up with leverages the effect of confinement or constant volume thermodynamic properties to manipulate phase transitions and equilibria of water. In the world around us, we are always in communication with the atmosphere as this constant and infinite pressure reservoir, and the core premise of isochoric cryopreservation processes is that we may be able to affect the phase equilibria and kinetics of water and ice by denying them access to this constant atmospheric pressure. When we do that, the natural variables that describe their existence are now constant volume and temperature, not pressure and temperature. When we confine the volume of a given system, it has a huge effect on the relationship between water and ice. We all know water expands almost 10% upon freezing, and weve all left a bottle of water or beer in the freezer only to come back and find it exploded. So lets imagine what would happen if instead of having liquid in a glass bottle, we held it in an unbreakable titanium flask. Ice will form and try to expand, but now it can't break the container or push the water out. What happens? Ice will start to expand, but the flask won't break and will instead push back on the contents within, pressurizing the growing ice and the remaining water. As a result, only a small portion of the liquid will end up as ice, even at temperatures well below the freezing point.

And isochoric conditions affect not only the equilibrium between water and ice, but also the metastability of water, the vitrification process of water, and the ice nucleation and growth process. So we are working on a broad suite of thermodynamic techniques that arent dependent on chemical intervention but enable us to reach sub-zero temperatures without ice formation in a stored biologic, which opens up many new avenues for exploration in cryobiology.

Alex: Among the classical isobaric approaches used in cryopreservation with antifreeze agents, vitrification, and rapid reheating, how is isochoric preservation better?

Matt:

You can think of the isochoric effect as being a value-add to any system. Speaking generically, our data and research suggest that if you take any classical technique or system and conduct the same protocol not under atmospheric pressure, but instead under isochoric conditions, you will encounter a lower chance for ice crystal formation. For conventional vitrification for example, you need incredibly high concentrations of cryoprotectants, usually 7 to 10 mol/L, or up to 40-50 % of the weight ratio. By using isochoric conditions, we can relieve some of the work that the chemistry needs to do in aiding glass formation, facilitating the same process of vitrification using a lower concentration of cryoprotectants, but under isochoric conditions. Similarly we can supercool metastable systems with higher reliability by confining them, we can hold equilibrium systems in a passively pressurized ice-free state, and so on.

Ill note too that a lot of the classical cryobiology literature and techniques have focused on ultra-low temperature preservation that targets months or years-long preservation, but there are all kinds of pressing medical cryobiology problems that dont necessarily require that, the most obvious being full organ preservation, where shelf-life extension on the order of even a single day would be transformative. So theres been a notable shift in the last decade towards what the community calls high subzero methods, which operate in the 0 20C range and leverage processes that aim to be much less physically and chemically intensive on the biologic than something like vitrification. Were finding that isochoric techniques can be particularly useful in this domain too, because you enter the realm where totally-CPA free isochoric supercooling or isochoric freezing protocols are very possible.

Alex: What about rapid reheating by using microwaves? How does the isochoric approach help with this?

Matt: Our goal is to build our protocol so that we ultimately wont need rapid reheating, which is required to escape the high probability of ice crystal formation when rewarming biological samples. If we can decrease the probability of ice crystal formation across the board, we would decrease the need to use rapid reheating. For example, and although I can't talk about it in too much detail, we are collaborating with the Smithsonian Conservation Biology Institute on vitrifying whole fragments of endangered corals under isochoric conditions, which has never before been achievable. In preliminary data, we are able to reheat the system without problems at a ballpark rate of 100s of degrees C per minute. The more sophisticated electromagnetic heating techniques achieves warming up rates of thousands of degrees and up in small systems, and those methods are indeed very cool, but so far unneeded for our systems. Ill note too that another aspect of the rewarming challenge is heating the system without building up significant thermal stress, which can lead to cracking throughout the sample because of uneven heating. One advantage that the isochoric system appears so far to offer is that physically confining the volume can help stabilize the system against cracking. If your system is open to the atmosphere, as it warms, the outermost layer that's open to the environment can expand freely, and cracking can happen easily. In the isochoric system, the boundaries of the sample are constrained, and it can help with reducing thermal cracking.

Matt's answers really intrigued me. I have been looking at cryopreservation through the eyes of cryonics and improving medicine by being able to extend the time until we find cures for untreatable diseases, which would imminently save so many human lives. However, it seems one part of the field, which Matt is intensively developing with his colleagues, could help to save so many lives in the present time very soon. It seems like a real, graspable possibility.

However, this made me wonder about the field of cryopreservation I have been interested in for months now. We saw some major breakthroughs in the field a long time ago, but lately, it seems as if the progress has been really slow. Is it because the field has been focused on the complicated process of vitrification by using cryopreserving agents too much, or is there something else at play? I was interested in what Matt had to say about this.

Alex: Clearly, the field of cryopreservation has been around for quite soe time. Why did it not yet pick up?

Matt: This is a fascinating question thats obviously affected by many different factors both historical and contemporary, but one of the biggest as always is funding, plain and simple. In the 90s and early 2000s, there was vanishingly little money available for research on cryopreservation, and what money there was was sort of narrowly focused. In the last decade however, cryopreservation, which we now include under the larger umbrella of biopreservation, has become something of a space race, and funders as varied as NIH, USDA, DOD, and even NASA are now giving out money for low-temperature biopreservation research. For example, NASA is looking for ways to protect astronauts in the theoretical manned missions to Mars. Even though using cryopreservation techniques to achieve goals like that seemed like sci-fi only a few years ago, we are now seeing more and more adventurous cryopreservation ideas getting funded, and funded well, and this has enabled the modern cryobiology field to start operating at the pace expected of a cutting-edge, super-impactful branch of science.

Alex: What happened in the last 5 years in cryopreservation research that may result in a major breakthrough in industrial applications?

Matt: Oh yeah, the last 5 years have been huge. Im lucky to get to see watch this progress unfold from both the academic angle, as a professor, and the industrial and clinical angles, as a startup founder. The suite of core technologies driving cryopreservation these days has just exploded in the last half-decade or so, driven by key advances in our understanding of aqueous metastability and supercooling of bulk volume liquids, uses of electromagnetic effects and nanoparticles for rapid and uniform warming, new thermodynamic configurations like isochoric, and many more. These fresh approaches are driving work in all sorts of new applications, and bringing new interdisciplinary physical science angles to the field.

Supercooling alone is a potentially transformative technology for large clinical applications, e.g. to extend the shelf-lives of transplantable livers, hearts, kidneys, etc. Id put my money on that technique seeing the light of day in the clinic within the next 5 years, as some kind of self-contained supercooling device. In my company, we have an isochoric supercooling technique that I think can be ready for pre-clinical trials very soon, though I can't say too much there. But the potential public health benefit of stable supercooling is just tremendous. I mean, if you could extend the preservability of a heart by just 4-8 hours, you might save a thousand lives next year. Extend it by a day or two and you could potentially be saving tens of thousands of lives around the globe.

As a field, we don't need technologies that will take ten more years to develop and will enable indefinite storage of a human heartwe need technologies that will take ten more months to develop and will enable storage of a heart for just long enough to get it from the donor to the recipient!

Although Matthew didn't point it out now, he is also doing a lot of work on preserving and extending the shelf life of food, which is another pressing societal issue, given the rising problems of food waste in some regions of the world, and the lack of food in other regions at the same time. In one of the groups latest research papers, isochoric supercooling and freezing have been applied to freshly harvested pomegranate, with its shelf-life being successfully extended for a month. You can read the publication here.

At his young age, Matthew is already wearing two hats (as he candidly points out), one of an academic professor and researcher, and the other as a co-founder and owner of a start-up company called BioChoric Inc. The company carries on with its research on isochoric preservation and aims at putting applicable devices and methods on the medical market as soon as possible, with everything being rooted in peer-reviewed and solid-proof research. Matt shared with me what the first days of starting the company looked like, and what their main future goals are.

Alex: When did you start BioChoric Inc. and what drove you to it?

Matt: We started the company in 2020 during the COVID pandemic. It was a spinout out of UC Berkeley, with me and Boris Rubinsky as founders, and the impetus was a crop of data we got on the effects of isochoric conditions on the supercooling of water, which suggested to us that an isochoric supercooling approach may be immediately applicable to organ and tissue preservation. We have a couple of integral patents and papers that describe the premise that, by confining the system, we can stabilize water in a metastable supercooled state, and predict the behaviors of this state in a rigorous quantitative sense, which has so far proven very difficult in unconfined systems.

The underlying philosophy of BioChoric Inc. is the obligation we feel to make rapid if incremental progress in full organ preservation. The degree of donor organ waste and the number of people dying on organ transplanting lists every day is huge, and that made us look at everything with a more clinical perspective. That's what we're pushing forward with BioChoric, even though the company is very small for now. One unique thing about the company is that it represents most of the thermodynamic expertise surrounding isochoric systems in the world today, and we rely heavily on interdisciplinary academic collaborations to help us further build the confidence and evidence we need to start pushing our techniques to clinical markets. We haven't taken any outside funding and it's fully internal equity, even though we've been approached by investors several times. We want to make sure we are scientifically sterling, peer-reviewed, bullet-proof before we start trying for the clinic.

One of the side hats BioChoric wears is also building isochoric biopreservation platforms and devices for other labs interested in advancing the science, and the small profit we generate from that helps to sustain our early R&D efforts.

It seems Matt is fully focused on improving human lives in the sense of prolonging the time transplantation-ready organs can be preserved, and that's the main goal of BioChoric. However, Matt and Boris's company is not the only one out there that offers cryo-products, although it may be the only one with a focus on isochoric cryopreservation, at least for now. Let's see what Matt thinks about how his company compares to similar ones in the field of cryobiology.

Alex: How do you compare and compete with companies like Lorentz Bio or X-Therma? When do you think BioChoric Inc. will be ready to fundraise and go industrial-scale?

Matt: I think there are many great young companies popping up in this space, but I'm glad you bring up Lorentz Bio because it has sparked quite a bit of chatter in the community, and they're taking an approach opposite to ours I think. My generic observation is that they have tackled raising the big money first, presuming they can fill in the scientific blanks later. In our case, its the scientists who have built the company, and built it on a core piece of new science, and were presuming we can fill in the money blanks later! Both fine ways to approach the problem. But personally, Im not really in the business of speculation or gambling I'm here to make sure were producing rock-solid, air-tight science, and the fundraising aspects don't worry me as much. Maybe that's just my academic side coming out. I think historically though, companies with really high checkbook-to-scientist ratios often end up coming to companies with really high scientist-to-checkbook ratios, like ours, to license our scientifically-established techniques and products. So suffice it to say, were focused on the science first and everything else second, and we're shooting for both fundraising and expansion to industrial scale in the next two years.

As my final question, I asked Matt the same futuristic question I asked Dayong Gao's research group at the University of Washington's Center for Cryo-Biomedical Engineering and Artificial Organs in my first article on cryopreservation, which you can read here. Matt was brave enough to offer me a timeline in which we could see some real breakthroughs in cryonics, as opposed to only preservation.

Alex: When do you think we will be able to see isochoric cryopreservation being used to cryopreserve and revive a small mammal?

Matt: Interesting question! I would say within the next 5 years, we will certainly see isochoric preservation of endangered marine species. Marine biodiversity is such an unbelievably urgent problem, and we are thinking about expanding our research on coral to other marine organisms in the next few months. If things continue to go well, we may be looking at trying to deploy field-ready isochoric devices at every marine research station on Earth, as bombastic as that sounds! The problems there are just too pressing to wait. On the human organ scale, I think we will see the preservation of organs extended to at least single days within the next 5 years. And I also want to take this opportunity to give a shoutout to each and every research group working on this problem right now, because the many often divergent results from differing corners of the field each move us all forward.

I admittedly havent thought much about preserving small live mammals, so I cant speculate in a properly scientific fashion, but Ill speculate for fun! Current approaches would require us to preserve each organ of the mammal separately because the preservation process gets more complicated the more complex you go. Based on the progress in the last 5 years, we will probably see a supercooling approach to preserve every major organ separately within the next 5 years. I don't know what happens at one step higher if you would want to preserve a multiorgan construct, and what would be different about it in comparison to just one organ. The relationship of these animals with air is also more complex than with marine animals that live submerged in a liquid anyway. But as a cop-out, Ill go ahead and say that the timeline will once again depend really acutely on potential increases in funding, and it will depend on which aspects of the field will get the most funding. So, I would speculate we could see a small mammal preserved and revived in about 20 years if the funding goes in that direction. But in my opinion, there is much more pressing research to be done.

With such young and bright-minded scientists led by the field's giants, like the combination of Matthew J. Powell-Palm and Boris Rubinsky, cryopreservation is definitely looking at several major breakthroughs coming from all areas of the field in the next few years. Also, as Matt also smartly pointed out, progress coming from different areas of cryopreservation actually helps developing all areas of cryopreservation, as the complex process of cryopreservation itself is made of various tightly-bound and regulated steps that cannot work alone.

See more here:
Think Outside The (Titanium) Box: Isochoric Cryopreservation Could Save Lives - Forbes

Recommendation and review posted by Bethany Smith

A recent report commissioned by the Chamber of Commerce for Greater Philadelphia and researched by economic consulting firm Econsult Solutions, Inc. ranked the city No. 2 overall for cell and gene therapy (CGT) hubs. The analysis evaluated 14 US CGT hubs across five categories, including research infrastructure, human capital, innovation output, commercial activity, and value proposition. The only region to eclipse Philadelphia was Boston. New York and San Francisco ranked third and fourth, respectively.

According to the report, Greater Philadelphia researchers have been awarded at least $1 billion in NIH funding in each of the past five years. Focusing in more closely on research projects related to CGTs, more than $317 million in NIH funding has been awarded to Philadelphia investigators during that time period. Funding for CGT comprised 6% of total NIH funding in Philadelphia compared to a range of 0.7% to 5.2% in the comparison regions.

The volume of research funding is an indicator of the potential pipeline of discoveries and innovation that can be generated from basic academic research in the coming years.

In addition to the Pennsylvania citys second-place showing in CGT hub prowess, the Chamber of Commerce for Greater Philadelphias CEO Council for Growth, along with its partners in the Cell and Gene Therapy Initiative, have released a new video (https://bit.ly/3EnUfXU) on the Philadelphia regions connected CGT startup ecosystem. Titled Greater Philadelphia: Discovery Starts Here, the 90-second video animation shares a snapshot of several of the regions research institutions and a number of the CGT-focused companies that have licensed technologies.

The video highlights five of the regions leading research institutions: Childrens Hospital of Philadelphia, Temple University, Thomas Jefferson University, University of Pennsylvania, and The Wistar Institute. It then shifts the focus to 15 companies that have direct links to one or more of those five research institutions. The video also distinguishes the organizations in four categories: emerging, privately held, publicly traded, or acquired.

The 15 CGT companies highlighted in the video include: Adaptimmune; Aevi Genomic Medicine, Inc. (acquired by Avalo Therapeutics, Inc.); Cabaletta Bio; Carisma Therapeutics; Cartio Therapeutics; Imvax; INOVIO; Interius BioTherapeutics; KOP Therapeutics; Passage Bio; Renovacor; Scout Bio; Spark Therapeutics, a member of the Roche Group; Verismo Therapeutics; and Virion Therapeutics.

For more information on the video and the Chamber of Commerce for Greater Philadelphias CEO Council for Growth, the full press release can be found here.

Link:
Philadelphia Shines in Cell and Gene Therapy Research Pursuits - Applied Clinical Trials Online

Recommendation and review posted by Bethany Smith

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Read more from the original source:
Selection and Evaluation of Ancillary Materials for Cell and Gene Therapy Research - Inside Precision Medicine

Recommendation and review posted by Bethany Smith

BEIJING & BURLINGTON, Mass.--(BUSINESS WIRE)--CANbridge Pharmaceuticals Inc. (HKEX:1228), a leading global biopharmaceutical company, with a foundation in China, committed to the research, development and commercialization of transformative rare disease and rare oncology therapies, announced that data from its gene therapy research agreement with the Horae Gene Therapy Center, at the UMass Chan Medical School, was presented at the 29th European Society of Gene and Cell Therapy Annual Congress in Edinburgh, Scotland, today.

In an oral presentation, Guangping Gao, Ph.D., Co-Director, Li Weibo Institute for Rare Diseases Research, Director, the Horae Gene Therapy Center and Viral Vector Core, Professor of Microbiology and Physiological Systems and Penelope Booth Rockwell Professor in Biomedical Research at UMass Chan Medical School, discussed the study that was led by the investigator Jun Xie, Ph.D., and his team from Dr. Gaos lab, and titled Endogenous human SMN1 promoter-driven gene replacement improves the efficacy and safety of AAV9-mediated gene therapy for spinal muscular atrophy (SMA) in mice.

The study showed that a novel second-generation self-complementary AAV9 gene therapy, expressing a codon-optimized human SMN1 gene. under the control of its endogenous promoter, (scAAV9-SMN1p-co-hSMN1), demonstrated superior safety, potency, and efficacy across several endpoints in an SMA mouse model, when compared to the benchmark vector, scAAV9-CMVen/CB-hSMN1, which is similar to the vector used in the gene therapy approved by the US Food and Drug Administration for the treatment of SMA. The benchmark vector expresses a human SMN1 transgene under a cytomegalovirus enhancer/chicken -actin promoter for ubiquitous expression in all cell types, whereas the second-generation vector utilizes the endogenous SMN1 promoter to control gene expression in different tissues. Compared to the benchmark vector, the second-generation vector resulted in a longer lifespan, better restoration of muscle function, and more complete neuromuscular junction innervation, without the liver toxicity seen with the benchmark vector.

This, the first data to be presented from the gene therapy research collaboration between CANbridge and the Gao Lab at the Horae Gene Therapy Center, was also presented at the American Society for Cellular and Gene Therapy (ASGCT) Annual Meeting in May 2022. Dr. Gao is a former ASCGT president.

Oral Presentation: Poster #: 0R57

Category: AAV next generation vectors

Presentation Date and Time: Thursday, October 13, 5:00 PM BST

Authors: Qing Xie, Hong Ma, Xiupeng Chen, Yunxiang Zhu, Yijie Ma, Leila Jalinous, Qin Su, Phillip Tai, Guangping Gao, Jun Xie

Abstracts are available on the ESGCT website: https://www.esgctcongress.com/

About the Horae Gene Therapy Center at UMass Chan Medical School

The faculty of the Horae Gene Therapy Center is dedicated to developing therapeutic approaches for rare inherited disease for which there is no cure. We utilize state of the art technologies to either genetically modulate mutated genes that produce disease-causing proteins or introduce a healthy copy of a gene if the mutation results in a non-functional protein. The Horae Gene Therapy Center faculty is interdisciplinary, including members from the departments of Pediatrics, Microbiology & Physiological Systems, Biochemistry & Molecular Pharmacology, Neurology, Medicine and Ophthalmology. Physicians and PhDs work together to address the medical needs of rare diseases, such as alpha 1-antitrypsin deficiency, Canavan disease, Tay-Sachs and Sandhoff diseases, retinitis pigmentosa, cystic fibrosis, amyotrophic lateral sclerosis, TNNT1 nemaline myopathy, Rett syndrome, NGLY1 deficiency, Pitt-Hopkins syndrome, maple syrup urine disease, sialidosis, GM3 synthase deficiency, Huntington disease, and others. More common diseases such as cardiac arrhythmia and hypercholesterolemia are also being investigated. The hope is to treat a wide spectrum of diseases by various gene therapeutic approaches. Additionally, the University of Massachusetts Chan Medical School conducts clinical trials on site and some of these trials are conducted by the investigators at The Horae Gene Therapy Center.

About CANbridge Pharmaceuticals Inc.

CANbridge Pharmaceuticals Inc. (HKEX:1228) is a global biopharmaceutical company, with a foundation in China, committed to the research, development and commercialization of transformative therapies for rare disease and rare oncology. CANbridge has a differentiated drug portfolio, with three approved drugs and a pipeline of 11 assets, targeting prevalent rare disease and rare oncology indications that have unmet needs and significant market potential. These include Hunter syndrome and other lysosomal storage disorders, complement-mediated disorders, hemophilia A, metabolic disorders, rare cholestatic liver diseases and neuromuscular diseases, as well as glioblastoma multiforme. CANbridge is also building next-generation gene therapy development capability through a combination of collaboration with world-leading researchers and biotech companies and internal capacity. CANbridges global partners include Apogenix, GC Pharma, Mirum, Wuxi Biologics, Privus, the UMass Chan Medical School and LogicBio.

For more on CANbridge Pharmaceuticals Inc., please go to: http://www.canbridgepharma.com.

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CANbridge-UMass Chan Medical School Gene Therapy Research in Oral Presentation at the European Society of Gene and Cell Therapy (ESGCT) 29th Annual...

Recommendation and review posted by Bethany Smith