This entry is in regards to an interesting review article in the October, 2013 Stem Cells journal, by Darwin J. Prockop, M.D., Ph.D from Texas A&M University. He writes about two specific negative feedback loops that stem cells introduce into generic pathways of inflammation.
(I apologize about the technical aspect of this blog entry, but I found it difficult to put a lot of the medical terminology into layperson terms.)
The first feedback loop is brought about by pro-inflammatory mediators from certain sensor cells that activate stem cells and upregulate the expression of COX2 and other parts of the arachidonic acid pathway. This then causes the stem cells to secrete more prostaglandin E2 (PGE2) which then appears to cause pro-inflammatory macrophages to instead secrete anti-inflammatory mediators (including interleukin-10 and interleukin-1).
The second negative feedback loop also involves stem cell activation from mediators. This activation causes stem cells to increase the expression of certain genes, specifically the anti-inflammatory protein TNF-alpha stimulated gene/protein 6 (TSG-6). This results in a decrease in TNF-alpha and other mediators that stimulate inflammation.
These two loops provide evidence that stem cells have a definite effect in decreasing inflammation, a finding that once again shows promise for stem cells as a treatment modality.
The lab testing evidence for these two loops was developed primarily in experiments wherein the stem cells were given after an acute tissue injury that induced the inflammatory response. The author notes that further investigation is needed to determine if these feedback loops exist in situations such as mild inflammation or unresolved inflammation due to a chronic disease process. It is also intriguing to note if these negative feedback loops would exist in all patients, or if genetic differences would influence them.
These negative feedback loops are only one portion of the role that stem cells have in the healing response. There are many other factors involved, including stimulation of growth factors, increased vascularization, recruitment of more host stem cells, modulation of the immune response, reduction of reactive oxygen species, transdifferentiation of cell types, and increased paracrine signaling, among many other methods.
Friday, December 13, 2013
Tuesday, October 1, 2013
Stem Cell Mechanism of Action
A recent study from Laura Shin and Daniel Peterson in Stem Cells Translational Medicine (2013; 2:33-42) attempts to clarify exactly how stem cells given as a treatment actually induce healing. The conventional theory has been that these cells act by differentiating once inside the body, as in they change into the cell types that the body needs to repair and heal itself. This equates to the analogy that they act as seeds that then grow into the new tissue.
However, this recent study seems to point to a different mechanism of action.The researchers used human mesenchymal stem cells in mice that were given excisional wounds that were splinted open. The splint wound model more closely duplicates how human wounds heal by granulation and re-epithelialization (rather than by skin contraction, the normal repair mechanism in rodents). The treated mice were given a pair of these wounds, one that received an engraftment of stem cells and the other left untreated. The stem cells were genetically modified so the researchers could trace the cells after giving them to the mice. There was also a control group who had similar paired wounds, but received no stem cells.
The results of this study showed that the animals that received stem cell therapy had accelerated healing when compared to the control group. However, the stem cells themselves did not seem to be the cells directly involved in the wound repair. The traced stem cells were abundantly evident in the treated wound just one day after delivery, but the numbers were dramatically reduced by day 5, and these cells were not even detectable in the wound bed by day 10.
The wounds that received no stem cells showed a rather significant delay in closure compared to those receiving stem cells. The stem cells were also only engrafted into one of the paired wounds on each treated mouse, but the non-treated wound on that mouse showed a moderate improvement in healing over the non-stem cell mice as well.
The results seem to indicate that the improved closure of the wounds despite the relatively rapid decrease in engrafted stem cell numbers may be due to signalling within the wound bed that helps to modulate and direct the host's own cells. The injected stem cells appear to recruit the patient's own stem cells to the area of injury, both at the engrafted site as well as distant sites in the body to some degree. These signals also seem to be maintained after the engrafted stem cells are gone. Thus the authors propose that while the stem cells are useful for healing, it is the subsequent healing response that they induce that ultimately leads to wound repair. If this is truly the manner that stem cells are involved in the healing process, it is the signals they produce that are the key to success with future therapies.
However, this recent study seems to point to a different mechanism of action.The researchers used human mesenchymal stem cells in mice that were given excisional wounds that were splinted open. The splint wound model more closely duplicates how human wounds heal by granulation and re-epithelialization (rather than by skin contraction, the normal repair mechanism in rodents). The treated mice were given a pair of these wounds, one that received an engraftment of stem cells and the other left untreated. The stem cells were genetically modified so the researchers could trace the cells after giving them to the mice. There was also a control group who had similar paired wounds, but received no stem cells.
The results of this study showed that the animals that received stem cell therapy had accelerated healing when compared to the control group. However, the stem cells themselves did not seem to be the cells directly involved in the wound repair. The traced stem cells were abundantly evident in the treated wound just one day after delivery, but the numbers were dramatically reduced by day 5, and these cells were not even detectable in the wound bed by day 10.
The wounds that received no stem cells showed a rather significant delay in closure compared to those receiving stem cells. The stem cells were also only engrafted into one of the paired wounds on each treated mouse, but the non-treated wound on that mouse showed a moderate improvement in healing over the non-stem cell mice as well.
The results seem to indicate that the improved closure of the wounds despite the relatively rapid decrease in engrafted stem cell numbers may be due to signalling within the wound bed that helps to modulate and direct the host's own cells. The injected stem cells appear to recruit the patient's own stem cells to the area of injury, both at the engrafted site as well as distant sites in the body to some degree. These signals also seem to be maintained after the engrafted stem cells are gone. Thus the authors propose that while the stem cells are useful for healing, it is the subsequent healing response that they induce that ultimately leads to wound repair. If this is truly the manner that stem cells are involved in the healing process, it is the signals they produce that are the key to success with future therapies.
Thursday, August 1, 2013
Stem Cells From Fat Versus Bone Marrow
A recent study published in the journal "Stem Cells Translational Medicine" seems to indicate that adipose-derived stem cells are more potent than bone marrow derived cells when comparing how they each modulate the immune system.
Functionally, both cell types responded similarly. They each had the capacity to differentiate toward both osteogenic and adipogenic lineages. In terms of the immune system response, both had similar surface marker expression. However, the adipose-derived stem cells showed a significantly higher level of suppression of peripheral blood mononuclear cell proliferation when used in equal numbers. Approximately three times the number of bone marrow derived stem cells were necessary to get the same suppressive effect.
This effect appears to be related to a decrease in inflammatory cytokines and an increase in certain anti-inflammatory cytokines. Cytokines are immunomodulating agents, such as interleukins and interferons.
This marks a significant finding in using stem cells for therapeutic applications. The frequency of stem cells in bone marrow is comparatively low, with stem cells accounting for only 0.001% - 0.01% of the total mononuclear cell fraction. Also, bone marrow aspiration is relatively invasive. Adipose tissue, however, contains approximately 500-fold greater frequency of stem cells, and collection via lipoaspiration is simple and easily tolerated.
The study also showed that adipose cells secrete higher levels of a multitude of cytokines that have been implicated in how stem cells modulate our immune systems.
Because of these many factors, adipose-derived stem cells appear to be a much better choice for cell-based therapies.
-from Stem Cells Translational Medicine 2013;2:455-463
Functionally, both cell types responded similarly. They each had the capacity to differentiate toward both osteogenic and adipogenic lineages. In terms of the immune system response, both had similar surface marker expression. However, the adipose-derived stem cells showed a significantly higher level of suppression of peripheral blood mononuclear cell proliferation when used in equal numbers. Approximately three times the number of bone marrow derived stem cells were necessary to get the same suppressive effect.
This effect appears to be related to a decrease in inflammatory cytokines and an increase in certain anti-inflammatory cytokines. Cytokines are immunomodulating agents, such as interleukins and interferons.
This marks a significant finding in using stem cells for therapeutic applications. The frequency of stem cells in bone marrow is comparatively low, with stem cells accounting for only 0.001% - 0.01% of the total mononuclear cell fraction. Also, bone marrow aspiration is relatively invasive. Adipose tissue, however, contains approximately 500-fold greater frequency of stem cells, and collection via lipoaspiration is simple and easily tolerated.
The study also showed that adipose cells secrete higher levels of a multitude of cytokines that have been implicated in how stem cells modulate our immune systems.
Because of these many factors, adipose-derived stem cells appear to be a much better choice for cell-based therapies.
-from Stem Cells Translational Medicine 2013;2:455-463
Tuesday, July 16, 2013
Stem Cell Transplants and HIV Patients
I recently came across a very intriguing story about HIV patients who had undergone chemotherapy and stem cell transplants as part of lymphoma therapy. This is a story about the potential involved in stem cell treatments, and something that continues to reveal the vast array of diseases that may one day be treated this way.
The story is about HIV-positive patients who have undergone what is being called the "sterilizing cure", wherein the above-mentioned medical therapy removes all traces of the virus. These HIV-positive patients developed lymphoma that required chemotherapy followed by bone marrow transplants as a cure for the cancer. The bone marrow (stem cell) transplants effectively removed the virus from their bodies. These two patients represent the second and third known cases where the sterilizing cure has apparently worked. An earlier patient had a similar result after treatment for leukemia.
Most recently, the two patients with HIV were being treated with long-term antiretroviral therapy when they developed lymphoma. The antiretroviral medications were continued through the duration of chemotherapy and also the bone marrow transplants. After these treatments, both patients have shown no traces of virus. Lead researcher Dr. Timothy Henrich, from Harvard Medical School and Brigham and Women's Hospital in Boston, said that "we have been unable to detect virus in either the blood cells or the plasma of these patients." He also biopsied intestinal tissue from one of the patients and could not detect virus there either.
The research team withdrew the patients' antiretroviral medications in order to test how effective the cancer therapy had worked to eliminate the virus. One patient has been off medication for 15 weeks, and the other for 7 weeks, both without showing any rebound of the virus.
The researchers are not calling it a true cure as of yet, as the virus could still be present in extremely low amounts that just aren't detectable.
In bone marrow transplants, donor cells replace the host's blood cells, and in these patients, the antiretroviral medications seemed to allow the donor stem cells to replace the host cells without becoming infected with the virus.
These results were presented at the International AIDS Society Conference in Kuala Lumpur, Malaysia and are considered preliminary findings.
The story is about HIV-positive patients who have undergone what is being called the "sterilizing cure", wherein the above-mentioned medical therapy removes all traces of the virus. These HIV-positive patients developed lymphoma that required chemotherapy followed by bone marrow transplants as a cure for the cancer. The bone marrow (stem cell) transplants effectively removed the virus from their bodies. These two patients represent the second and third known cases where the sterilizing cure has apparently worked. An earlier patient had a similar result after treatment for leukemia.
Most recently, the two patients with HIV were being treated with long-term antiretroviral therapy when they developed lymphoma. The antiretroviral medications were continued through the duration of chemotherapy and also the bone marrow transplants. After these treatments, both patients have shown no traces of virus. Lead researcher Dr. Timothy Henrich, from Harvard Medical School and Brigham and Women's Hospital in Boston, said that "we have been unable to detect virus in either the blood cells or the plasma of these patients." He also biopsied intestinal tissue from one of the patients and could not detect virus there either.
The research team withdrew the patients' antiretroviral medications in order to test how effective the cancer therapy had worked to eliminate the virus. One patient has been off medication for 15 weeks, and the other for 7 weeks, both without showing any rebound of the virus.
The researchers are not calling it a true cure as of yet, as the virus could still be present in extremely low amounts that just aren't detectable.
In bone marrow transplants, donor cells replace the host's blood cells, and in these patients, the antiretroviral medications seemed to allow the donor stem cells to replace the host cells without becoming infected with the virus.
These results were presented at the International AIDS Society Conference in Kuala Lumpur, Malaysia and are considered preliminary findings.
Thursday, July 11, 2013
Organ Growth from Stem Cells
Here is an NPR story about stem cells...
http://www.npr.org/2013/07/05/199025495/building-a-liver-from-stem-cells
http://www.npr.org/2013/07/05/199025495/building-a-liver-from-stem-cells
Tuesday, May 21, 2013
Stem Cells and Brain Lesions
The current issue of the STEM CELLS Translational Medicine journal contains a study involving a novel way of increasing the survival rate of stem cells injected into the brain.
Researchers harvested neural stem cells (NSC's) from baby mice and sorted the cells to find a predominance of stem cells containing CD15, a carbohydrate found on the surface of the cells that plays a very important role in cellular migration and adhesion, and in growth factor signaling that helps in cell maintenance and differentiation. This sorting process allowed them to harvest a population of NSC's in which 98% of them were positive for the CD15 marker, approximately six times more than when the sorting method is not used.
These CD15 -positive cells were then differentiated in the lab, eventually resulting in neurons, astrocytes, and oligodendrocytes - these are specific types of cells found in our brain and spinal cord. Neurons are the cells that process and transmit information, astrocytes are the most abundant cells that provide stuctural and metabolic support, and the oligodendrocytes provide support to and insulate our nerve cells. These developed cells were then introduced into the brains of baby mice and studied over time, along with a control group of non-sorted neural cells. Initially, both groups of cells were similar in the baby mice - one week later, when the brain was still growing, the cells in both groups had achieved similar population levels. However, in adult mice the CD15-positive grafts showed significantly higher survival rates. The cells with CD15 also tended to significantly differentiate into oligodendrocytes, cells that have a protective role for neurons.
The significance of this study is that it shows a potential method for improved deliverance of therapeutic cells to our brain and spianl cord. Anthony Atala, MD, edior of the journal and director of the Wake Forest Institute for Regenerative Medicine said "the fact that the CD15-positive cells show a significant increase in oligodendrocyte differentiation suggests that they may be particularly useful for treating diseases involving white matter lesions." White matter lesions are commonly associated with Alzheimer's Disease, multiple sclerosis, and stroke. These types of lesions have also been found with infectious and inflammatory conditions, and even associated with patients experiencing migraine headaches.
Yet another bold step in the research of stem cells and possible therapeutic benefits!
Researchers harvested neural stem cells (NSC's) from baby mice and sorted the cells to find a predominance of stem cells containing CD15, a carbohydrate found on the surface of the cells that plays a very important role in cellular migration and adhesion, and in growth factor signaling that helps in cell maintenance and differentiation. This sorting process allowed them to harvest a population of NSC's in which 98% of them were positive for the CD15 marker, approximately six times more than when the sorting method is not used.
These CD15 -positive cells were then differentiated in the lab, eventually resulting in neurons, astrocytes, and oligodendrocytes - these are specific types of cells found in our brain and spinal cord. Neurons are the cells that process and transmit information, astrocytes are the most abundant cells that provide stuctural and metabolic support, and the oligodendrocytes provide support to and insulate our nerve cells. These developed cells were then introduced into the brains of baby mice and studied over time, along with a control group of non-sorted neural cells. Initially, both groups of cells were similar in the baby mice - one week later, when the brain was still growing, the cells in both groups had achieved similar population levels. However, in adult mice the CD15-positive grafts showed significantly higher survival rates. The cells with CD15 also tended to significantly differentiate into oligodendrocytes, cells that have a protective role for neurons.
The significance of this study is that it shows a potential method for improved deliverance of therapeutic cells to our brain and spianl cord. Anthony Atala, MD, edior of the journal and director of the Wake Forest Institute for Regenerative Medicine said "the fact that the CD15-positive cells show a significant increase in oligodendrocyte differentiation suggests that they may be particularly useful for treating diseases involving white matter lesions." White matter lesions are commonly associated with Alzheimer's Disease, multiple sclerosis, and stroke. These types of lesions have also been found with infectious and inflammatory conditions, and even associated with patients experiencing migraine headaches.
Yet another bold step in the research of stem cells and possible therapeutic benefits!
Tuesday, April 9, 2013
Arterial Growth
Here are 2 sets of arteriograms (or angiograms, which are x-rays taken with the use of special dyes to visualize arteries):
The left side of both images show very poor arterial blood flow in the leg due to vascular disease. These patients often end up needing amputations due to the lack of blood flow.
The right side of each image shows vastly improved arterial supply after stem cell therapy. The stem cells were injected intramuscularly, meaning into the calf and other lower leg muscles. The stem cells allow for growth of new blood vessels and essentially save these patients' limbs.
Tuesday, April 2, 2013
Case Report #1 - T. M. PATIENT UPDATE
In August of 2012 I wrote about a 35 y.o. female who was our first stem cell orthopedic injection patient (see entry "Case Report #1 - T.M."). She has continued to do extremely well after her treatment and is now over one year out from the procedure. She continues to exercise in a manner that she could not prior to her stem cell therapy, including sports, hiking, and P-90-X. She denies pain and swelling in her right knee, and reports discomfort only in her left knee which has not had a stem cell injection.
On March 7, 2013 she underwent a repeat MRI of her right knee which was then compared to a prior MRI obtained on December 8, 2011.
In the time between the studies, her only treatment was the stem cell injection into the right knee joint which was done in February of 2012. Prior to the cell therapy, this patient's pain was most prominent in the inside aspect of the knee near her knee cap, which coincides with the anterior medial meniscus.
Important excerpts of the recent radiology report read as follows:
"Comparison is made to a prior study of the right knee dated 12/8/2011."
"An improved appearance of the marrow of the distal femur and tibia is noted when compared to the prior study.
Postoperative repair of the anterior horn of the medial meniscus has occurred since the prior exam."
The radiologist did not know that this patient had stem cell therapy, but obviously could detect changes that showed improvement in her primary orthopedic issue. We are very pleased to share these MRI findings and the fact that the radiologist saw evidence of meniscal repair.
On March 7, 2013 she underwent a repeat MRI of her right knee which was then compared to a prior MRI obtained on December 8, 2011.
In the time between the studies, her only treatment was the stem cell injection into the right knee joint which was done in February of 2012. Prior to the cell therapy, this patient's pain was most prominent in the inside aspect of the knee near her knee cap, which coincides with the anterior medial meniscus.
Important excerpts of the recent radiology report read as follows:
"Comparison is made to a prior study of the right knee dated 12/8/2011."
"An improved appearance of the marrow of the distal femur and tibia is noted when compared to the prior study.
Postoperative repair of the anterior horn of the medial meniscus has occurred since the prior exam."
The radiologist did not know that this patient had stem cell therapy, but obviously could detect changes that showed improvement in her primary orthopedic issue. We are very pleased to share these MRI findings and the fact that the radiologist saw evidence of meniscal repair.
Thursday, March 21, 2013
The Basics - What Exactly Is A Stem Cell?
A very common question happens to be one that goes back to the basics - what is a stem cell?
Stem cells are essentially building blocks that are found in all multicellular organisms. These cells can divide (through a process called mitosis), self renew, and differentiate into many different cell types.
Again, the classic definition of a stem cell requires that it possess the following properties:
In general, there are two broad types of stem cells: embryonic, which are isolated from blastocysts (a product of early gestation that leads to the development of the embryo), and adult stem cells, found in various tissues throughout the body. In the developing embryo, stem cells can differentiate into all specialized cells (these are called pluripotent cells) and also maintain the normal turnover of regenerative organs/tissues, such as blood, skin, or intestinal tissues. In adults, stem cells serve as the repair system for the body, replenishing adult tissues after injury or through the normal process of aging. Adult stem cells are multipotent, meaning they can differentiate into many cell types, but not all.
There are three readily-accessible sources of autologous (meaning from one's own body) adult stem cells in humans:
1. Bone marrow - requires extraction by drilling into bone (typically the iliac crest)
2. Adipose tissue (fat) - requires extraction by liposuction
3. Blood - requires extraction through the process of pheresis, wherein blood is drawn from the donor, passed through a machine that extracts the stem cells, then returns other portions of the blood back to the donor
Stem cells can also be found in umbilical cord blood just after birth.
Autologous harvesting involves the least risk when working with stem cells, as the cells are obtained from the patient's own body. Thus, there is no chance of an auto-immune reaction or tissue rejection. This also eliminates the risk of acquring an infection from another person.
Stem cells are essentially building blocks that are found in all multicellular organisms. These cells can divide (through a process called mitosis), self renew, and differentiate into many different cell types.
Again, the classic definition of a stem cell requires that it possess the following properties:
- Self-renewal: the ability to go through continued cycles of cell division while maintaining the undifferentiated state.
- Potency: the ability to differentiate into specialized cell types.
In general, there are two broad types of stem cells: embryonic, which are isolated from blastocysts (a product of early gestation that leads to the development of the embryo), and adult stem cells, found in various tissues throughout the body. In the developing embryo, stem cells can differentiate into all specialized cells (these are called pluripotent cells) and also maintain the normal turnover of regenerative organs/tissues, such as blood, skin, or intestinal tissues. In adults, stem cells serve as the repair system for the body, replenishing adult tissues after injury or through the normal process of aging. Adult stem cells are multipotent, meaning they can differentiate into many cell types, but not all.
There are three readily-accessible sources of autologous (meaning from one's own body) adult stem cells in humans:
1. Bone marrow - requires extraction by drilling into bone (typically the iliac crest)
2. Adipose tissue (fat) - requires extraction by liposuction
3. Blood - requires extraction through the process of pheresis, wherein blood is drawn from the donor, passed through a machine that extracts the stem cells, then returns other portions of the blood back to the donor
Stem cells can also be found in umbilical cord blood just after birth.
Autologous harvesting involves the least risk when working with stem cells, as the cells are obtained from the patient's own body. Thus, there is no chance of an auto-immune reaction or tissue rejection. This also eliminates the risk of acquring an infection from another person.
Thursday, February 14, 2013
Stem Cells and Heart Function
On November 6, 2012, at the American Heart Association Scientific Sessions meeting, Drs. Bolli (from the University of Louisville) and Anversa (from Brigham and Women's Hospital in Boston) presented updated data from their SCIPIO trial (Stem Cell Infusion in Patients with Ischemic CardiomyOpathy). This trial was a randomized open-label trial using cardiac stem cells in patients with heart failure after a heart attack, or myocardial infarction. The data they presented was the follow-up after 2 years.
The trial followed 33 patients who suffered a heart attack with measurable damage to the cardiac muscle. The patients all had a decreased LVEF (left ventricular ejection fraction), a standard measure of the heart's function measuring the blood ejected from the left ventricle during contraction of the heart muscle. In the study, the patients' LVEF had to be equal to or under 40%, with a normal LVEF being 50% or more. The trial involved harvesting patients' stem cells from their hearts during coronary artery bypass surgery and then multiplying these cells in the research team's lab. When approximately 1 million cells had been produced, the stem cells were then reintroduced into the region of the heart that had been scarred as a result of the heart attack.
Of the 33 patients, 20 actually received the stem cell therapy while the other 13 were in the control group receiving no stem cells. The researchers report that the 20 patients receiving stem cell therapy had marked improvement in cardiac function. Four months after the stem cell infusion, these pateints' average LVEF rose from 29% to 36%. At the one year mark, LVEF increased by 8.1%, while at the 2 year mark by 12.9%. The 13 control patients showed no improvement, on average.
Additionally, nine of the patients who received stem cells underwent MRI's and showed marked reduction in the size of the heart muscle scarring and resultant increase in viable muscle tissue. On average, the infarct size was 33.9 grams prior to treatment and 18.2 grams at the 2 year mark. The viable left ventricle tissue rose from 146.3 to 164.2 grams.
One patient in particular had suffered from two heart attacks prior to the study. His LVEF went from 38% to 58% after stem cell therapy, with his heart now showing essentially no ill effects from the prior myocardial infarctions.
The investigators plan to continue following these patients for two more years, and hopefully expand their resaerch with further funding.
The trial followed 33 patients who suffered a heart attack with measurable damage to the cardiac muscle. The patients all had a decreased LVEF (left ventricular ejection fraction), a standard measure of the heart's function measuring the blood ejected from the left ventricle during contraction of the heart muscle. In the study, the patients' LVEF had to be equal to or under 40%, with a normal LVEF being 50% or more. The trial involved harvesting patients' stem cells from their hearts during coronary artery bypass surgery and then multiplying these cells in the research team's lab. When approximately 1 million cells had been produced, the stem cells were then reintroduced into the region of the heart that had been scarred as a result of the heart attack.
Of the 33 patients, 20 actually received the stem cell therapy while the other 13 were in the control group receiving no stem cells. The researchers report that the 20 patients receiving stem cell therapy had marked improvement in cardiac function. Four months after the stem cell infusion, these pateints' average LVEF rose from 29% to 36%. At the one year mark, LVEF increased by 8.1%, while at the 2 year mark by 12.9%. The 13 control patients showed no improvement, on average.
Additionally, nine of the patients who received stem cells underwent MRI's and showed marked reduction in the size of the heart muscle scarring and resultant increase in viable muscle tissue. On average, the infarct size was 33.9 grams prior to treatment and 18.2 grams at the 2 year mark. The viable left ventricle tissue rose from 146.3 to 164.2 grams.
One patient in particular had suffered from two heart attacks prior to the study. His LVEF went from 38% to 58% after stem cell therapy, with his heart now showing essentially no ill effects from the prior myocardial infarctions.
The investigators plan to continue following these patients for two more years, and hopefully expand their resaerch with further funding.
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