Category Archives: Kentucky Stem Cells

http://www.stemcellresearch.org

The ethical controversy surrounding human embryonic stem cell research (hESCR) arises from one fact: the research requires the destruction of a living human embryo in order to acquire the stem cells. That the human embryo is a human life is agreed upon by all sides. Indeed, if the human embryo were not a human life, and recognized as such, the research would be ethically non-contentious.

Proponents of the research base their support for it on a utilitarian proposition: the benefits such research may produce in treating numerous diseases and conditions diabetes, spinal cord injuries, Alzheimers, heart disease and Parkinsons are among the most frequently cited outweighs and justifies the necessary destruction of the embryo. The embryo is here recognized as a form of human life that is worthy of respect and the ethical concerns to which its destruction give rise are acknowledged. Nonetheless, this form of human life does not rise to a level that would require its protection whatever the potential benefits that might result from its destruction.

This outlook on embryo-destructive research was enshrined in the conditions first laid out for publicly funding such research in the United States. In its final report before he left office, President Clintons National Bioethics Advisory Committee first recommended federal funding for hESCR. But it did so conditionally: In our judgment, the derivation of stem cells from embryos remaining following infertility treatments is justifiable only if no less morally problematic alternatives are available for advancing the researchThe claim that there are alternatives to using stem cells derived from embryos is not, at the present time, supported scientifically. We recognize, however, that this is a matter that must be revisited continually as science advances.[1]

That is, the research admittedly is morally problematic precisely because it requires destroying a human life. However, the destruction of human life at the embryonic stage is justifiable because the value of that life is outweighed by the researchs potential benefits. Thus, proponents of the research begin with the possibility of therapeutic benefits to make the fact of human embryonic life conditional and therefore of lesser value than other human life.

Opponents of the research, on the other hand, begin with the fact that the human embryo, from a purely scientific perspective, is unconditionally a human life, as attested by every standard textbook on embryology. The human embryo at conception is a fully integrated, genetically unique self-directed human life that can only develop into a more mature member of the species Homo sapiens and no other. Thus, as a unique human life it has an inherent dignity and therefore cannot be used as a means to another persons ends much less another persons merely potential ends however nobly those ends are cast. In this view, human life cannot be used or manipulated to become a condition for the good of another human life.

Many who take this position, though not all, ground this inherent human dignity in the belief that the human being is created by God and possesses an eternal soul, and this dignity of the individual is thus inviolate from those who would use others as means to their own ends. Theological perspectives are legitimate and have a necessary place in considering issues of bioethics. But in addition, there are nonsectarian grounds for rejecting destructive human embryonic stem cell research, as such research represents the commodification and commercialization of human life.

Throughout the public policy debate in the United States, the main point of contention has been government funding of destructive hESCR (contrary to widespread belief, such research was never banned in the United States; the private sector was always free to pursue it and public funding at the state level was always at the discretion of the states.) The main public policy debate in the United States was whether the federal government, as a matter of national policy, should endorse embryo research by funding such ethically contentious research.) Senator Sam Brownback, a leading opponent of federal funding for hESCR, would raise the question of whether the human embryo was a person or property. From a non-sectarian standpoint, this is a crucial question in confronting the ethics of hESCR. If human life is viewed as property, than it becomes a mere commodity to be exploited for whatever purposes one deems worthy (and worthy can be as mundane as desiring smoother skin, as some cosmetic companies now boast the use of fetal cells in their preparations). This commodification and commercialization of some human life has the very real potential to degrade and diminish our sense of the inherent value of the human individual throughout all of society. For example, the pursuit of hESCR has been closely related to human cloning in order to produce embryos for stem cells theoretically genetically matched to patients. Creating and destroying a human embryo is one form of commodification of human life to produce a potential medical product. But human cloning requires human eggs, thus raising the very real specter of some women donors almost certainly lower-income and disadvantaged women being exploited as producers of a needed commodity, just as in some areas of the world the poor are exploited as donors of organs.

Nor are there any guarantees that such commodification will remain limited to embryonic life at seven days or less after conception (the time at which embryonic stem cells are usually harvested). This is because while science may be competent to tell us what we are able to do, and the most efficient way to do it, it not within the competence of science to tell us what we should or should not do. Science is a method for obtaining a specific form of knowledge about the natural world, a way of observing and learning about the physical properties of the natural world. When it comes to questions of value it is inherently neutral. Value judgments as to which avenues of medical research should or should not be pursued must come from disciplines outside of science. For example we may find that tissue taken from embryos beyond the seven-day point have greater therapeutic potential than embryonic stem cells. If that is the case, why not grow the embryo to 14 days, or 21 days, or even beyond, if from a purely scientific viewpoint that is the most efficient way to obtain the tissue most promising for treating disease? Most of us would cringe at this scenario not because of scientific reasons, but rather for ethical ones.

We have already witnessed the chilling results when some human life comes to be seen as a scientific commodity useful for conducting experiments. Researchers conducting the Tuskegee syphilis experiment (begun in 1932) believed they were acting on a sound scientific basis when they refused African-American men with syphilis the standard treatment, which then was risky and of questionable value. But they continued to deny treatment even after penicillin proved available and beneficial for syphilis patients, and they did so because of the scientific knowledge they believed they could gain from observing the diseases progression. Again, while it may have been scientifically sound for the Tuskegee researchers to carry on their study this way, we now have laws against such research because we understand it to be ethically unsound.

One final point brings us back to the condition laid down by the NBAC for conducting hESCR: that it should be pursued only if there were no less morally problematic alternatives to achieve the research goals those goals being the curing or alleviating of various diseases and conditions. Of course, opponents of the research reject any scenario for destroying human life, however noble the stated goal. But of those who would agree to such a condition, the question goes begging: is it ethically acceptable to continue such research if such ethically non-contentious alternatives are discovered? In terms of actually providing therapeutic benefits to patients, the advance of science shows adult stem cells to be far more efficacious than embryonic. To date, adult stem cells have provided therapeutic benefits to patients for some 73 diseases and conditions, while embryonic stem cells provide none.[2] And the discovery of the method to produce induced pluripotent stem cells (iPSCs) from ordinary somatic cells has given researchers an easily obtainable and virtually inexhaustible supply of fully pluripotent, embryonic-like stem cells to work with without having to destroy embryos or resort to human cloning.[3] We would argue that in light of these developments, and with these ethically non-contentious alternatives readily available, it is unethical for proponents to continue hESCR. In continuing to do so, and in devising other rationales for the research, proponents of hESCR are providing an apt illustration of how easily, once one set of ethical boundaries on scientific research are reasoned away, others soon follow.

[1] Ethical Issues in Human Stem Cell Research, National Bioethics Advisory Commission, September, 1999, p. 55

[2] Prentice DA and Tarne G, Adult versus embryonic stem cells: Treatments. Science 316, 1422-1423, 2007; also see stemcellresearch.org/facts/asc-refs.pdf for a list of sample references.

[3] Takahashi K et al., Induction of pluripotent stem cells from adult human fibroblasts by defined factors, Cell 131, 861-872, 2007; Yu J et al., Induced pluripotent stem cell lines derived from human somatic cells, Science 318, 1917-1920, 2007

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Stem Cell Research | Central Kentucky Right to Life

NewsBeat

November 4, 2016 - Dr. Gary Gibbons,Director of the National Heart, Lung, and Blood Institute (NHLBI) at the National Institutes of Health presented the 2016 Leonard Leight Lecture - Read More | Photos

October 24, 2016 - Drs. Rakesh Gopinathannair and Michael Flaherty lead newly approved WATCHMAN Left Atrial Appendage Closure (LAAC) Implant program at Jewish Hospital - Read More

September 29, 2016 - Dr. Aruni Bhatnagar, other health experts make case against e-cigs, hookah - Read More

August 9, 2016 - Dr. Ali. Marian tabbed to deliver the 2016 Leonard Leight Lecture - Read More

June 1, 2016 - Bradford Hill, Ph.D., was awarded a $1.8 million grant from the NIH to study the role of metabolism in cardiac cell therapy.

June 1, 2016 - Steven Jones, Ph.D., was awarded a $2.1 million grant from the NIH to study the regulation of metabolic genes in the heart.

May 18, 2016 - Aruni Bhatnagar, Ph.D., and the UofL Diabetes & Obesity Center are part of an air pollution reduction project - Read More

Oct. 29, 2015 - Roberto Bolli, M.D., FAHA, honored with the Schottenstein Prize in Cardiovascular Sciences from The Ohio State University - Read More

Incredible! That's how Mike Jones describes his life three and a half years after receiving stem cells as part of Dr. Roberto Bolli's groundbreaking SCIPIO trial. The study, in which twenty patients received their own cardiac stem cells, has transformed Mike Jones' life.Read more.

November 15, 2016 - Dr. Emma Birks presents evidence showing that an artificial heart assist device along with medications may actually help heal the heart - Read More

October 25, 2016 -UofL research team co-authors American Heart Association Rapid Access Journal Report on air pollution linked to blood vessel damage in healthy young adults - Read More

September 27, 2016 - Dr. Aruni Bhatnagar part of Mayor's forum on possible e-cigarette, hookah ban - Read More

August 12, 2016 - Participants sought by UofL for FACTT trial researching e-cigarette flavors. For more information, e-mail ATRAC@louisville.edu - Read More

April 25, 2016 - Dr. Lorrel Brown earns American College of Cardiology award for CPR training at the Kentucky State Fair - Read More

April 12, 2016 - Dr. Andrew DeFilippis was recently honored with the Multi-Ethnic Study of Atherosclerosis (MESA) Early Career Investigator Award - Read More

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Division of Cardiovascular Medicine School of Medicine ...

Laura Ungar of the Louisville Courier-Journal reports on one of the worlds first recipients of an infusion of cardiac stem cells as a part of a Phase 1 clinical trial being conducted by a team of University of Louisville physicians at Jewish Hospital.

After two heart attacks, Michael Jones of Louisville suffered heart failure that made him so weak he could manage only a few football passes now and then with his grandson. But after becoming one of the world's first heart patients to get an infusion of cardiac stem cells, Jones said he works out on a treadmill and bike and feels invigorated.

I hope to have as normal a life as anyone, the self-employed painting and remodeling contractor said at a news conference Friday. I might even start jogging again.

Jones, 66, received an infusion of his own stem cells through a minimally invasive catheterization procedure on July 17 as part of a clinical trial being conducted by a team of University of Louisville physicians at Jewish Hospital. The doctors, who announced the trial and started recruiting patients in February, are using adult cardiac stem cells to heal hearts. They said they were infusing the second patient Friday. A similar procedure, involving slightly different cells, was performed last month in California, doctors said.

It is an important, historic announcement, U of L President James Ramsey said. The No. 1 killer is heart disease, and we in Kentucky have a higher incidence than the national average.

American Heart Association statistics rank Kentucky seventh-worst in the nation for cardiovascular deaths, with about 14,000 a year. Study leader Dr. Roberto Bolli said heart failure is one of the worst cardiovascular conditions, afflicting about 6 million Americans. Often, the only options for patients are transplants, heart-assist devices or palliative care. Mortality rates are high and the treatments we have are, by and large, unsatisfactory, said Bolli, Jewish Hospital Heart and Lung Institute Distinguished Chair in Cardiology. Jones, who had his first heart attack 4 years ago, said he was diagnosed with heart failure about three or four months after that, with blocked arteries that caused permanent scarring of his heart muscle. Doctors said he was a good candidate for the stem cell procedure because he had not yet had bypass surgery.

On March 23, Dr. Mark Slaughter, chief of U of L's division of cardiothoracic surgery, performed coronary artery bypass surgery, removing Jones' cardiac stem cells from a portion of the upper chamber of the heart. The tissue was then frozen and sent to colleagues at Brigham and Women's Hospital in Boston and Harvard University. There, stem cells were isolated and expanded before being sent back to Jewish Hospital for infusion. After Jones' heart attacks, doctors said his ejection fraction, a measurement of the amount of blood pumped out of the left ventricle with each heartbeat, was lower than 25 percent, compared with 50 percent or more for healthy people. Now, doctors said, it's about 30 percent, and they hope it continues to increase. Doctors said they have enrolled 14 patients in the clinical trial so far and hope to treat a total of 20 patients who are suffering from heart failure, have had a heart attack and need to undergo cardiac surgery. They will compare these against 20 control subjects. Bolli said the hospital and doctors are donating their services and facilities, so the costs of the trial are reduced, totaling about $10,000 to $20,000 a patient from U of L research funds. Doctors said this is a Phase I trial, which tests the safety and feasibility of a treatment. At this point, side effects from the stem cells are unknown because they are being used for the first time, doctors said, adding that there's no risk of rejection because they are using a patient's own cells. Potential side effects of the catheterization, which reaches the heart through a large artery in the leg, include infection, bleeding, heart attack and stroke. Another clinical trial is being conducted at the Cedars-Sinai Heart Institute in Los Angeles. The difference, Bolli said, is that U of L doctors have injected a pure population of stem cells called c-kit-positive cells, while California doctors injected cardiosphere-derived cells, which are a mixture of primitive and partially differentiated cells. If U of L's stem cell procedure succeeds, doctors said, it will be at least three to five years before it becomes a routine treatment. Jones, who said Friday that he has been married for more than 44 years to his high school sweetheart, Shirley, and has two grown children, said he never feared getting the therapy, even though it is experimental.

I am very, very grateful and honored to be chosen as the first recipient, said Jones, who lives in southeastern Jefferson County. This really seemed natural. It just made sense to use the body to regenerate itself.

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Louisville Man is Worlds First Cardiac Stem Cell Recipient

A promise to your child, peace of mind for you

The Family Link Cord Blood Storage Program lets you take steps to preserve your child's health now and in the future. While most babies are born healthy and grow up without the threat of serious illness, medical conditions can surface at any time. For a number of serious illnesses, one of the best treatments is stem cell transplants.

Every year, 17,000 people in North America require a stem cell/ bone marrow transplant for life-threatening diseases.

While most patients are able to receive transplant donations from a family member, 70 percent are unable to find a suitable match. To combat the shortage of available bone marrow donors, physicians have started using umbilical cord blood as an alternative source for stem cells. The ideal time to obtain stem cells from the umbilical cord and placenta is after delivery.

What is the Family Link Cord Blood Storage Program? The Family Link program is a private facility started in 1998 for storage of umbilical cord blood from a newborn infant. Serving families delivering within a four-hour driving distance from Metro Louisville, through Family Link a baby's stem cells can be taken from the umbilical cord and placenta at birth and preserved at ultra-low temperatures in the Blood and Marrow Transplant Service Laboratory of Norton Healthcare for up to 20 years. Because the blood cells are collected after the baby is born, the process doesn't interfere with delivery or the early intimate moments following birth. It is an entirely painless procedure for both mother and child, and state-of-the-art medical technology is used to retrieve and preserve the blood cells for future use.

Benefits of Cord Blood Storage Stem cells can be used by your baby or other members of your family for the future treatment of a variety of Diseases treatable by stem cell transplant. Major diseases and serious medical conditions, including cancers such as leukemia or lymphoma, solid tumors, sickle cell disease, rare types of anemia, and Hurler's syndrome may be treated using cord blood stem cells. If a person's blood cells have been damaged or destroyed by chemotherapy or disease, a stem cell transplant can help the body rebuild healthy blood cells.

Cord Blood Storage Helps Babies and Family Members If your child requires a bone marrow or stem cell transplant later in life, the frozen cord blood is a perfect match for your child. The frozen cord blood also may be used for members of your child's immediate family if it is a match. The chance that stem cells will be a suitable match for a child's biological brother or sister is one in four. (The odds of finding a suitable match outside the family can be thousands of times greater.)

Read more about the cost, procedure details and frequently asked questions about cord blood storage.

More Information about Family Link Cord Blood Storage

Detailed information, resources and enrollment packets are available online or call (502) 629-1234 or (888) 4-U-NORTON.

To speak with a member of the laboratory or clinical staff, call (502) 629-7771.

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Cord Blood - Louisville, Kentucky(KY), Cord Blood Storage ...

The Addison Jo Blair Cancer Care Center is home to Kentucky's only stem cell and bone marrow transplant program specifically for children. An eight-bed unit with HEPA-filtered rooms is designed for the care of patients with compromised immune systems. A multidisciplinary team of attending physicians, residents, nurse practitioners, nurses and ancillary staff provide daily patient care. In addition to the primary transplant clinical team, a child life therapist, social worker, chaplain, physical therapist, nutritionist, pharmacist, expressive and art therapists, and a schoolteacher are involved in each child's care.

We perform stem cell transplants for patients with various blood disorders such as sickle cell anemia and we have a large sickle cell treatment program. We provide transplants using stem cells from related and unrelated cord blood donors and autologous stem cell transplants. All national and international cord blood banks and the National Marrow Donor Program are extensively searched to find matches for our patients.

Kosair Children's Hospital has an on-site private facility for cord blood storage. A service of Norton Healthcare, the Family Link Cord Blood Storage Program began in 1998 for storage of umbilical cord blood from newborn infants. Through Family Link, families delivering within a four-hour driving distance from Louisville Metro can have their baby's stem cells taken from the umbilical cord and placenta at birth and preserved at ultra-low temperatures through a process called cryopreservation. Visit the Family Link Program for more information.

The Kosair Children's Hospital stem cell and bone marrow transplant program is a member of the Pediatric Blood and Marrow Transplant Consortium, the Blood and Marrow Transplant Clinical Trials Network and the Children's Oncology Group.

In 1999, Kosair Children's Hospital became the first hospital in the country to perform a bone marrow transplant for Kostmann syndrome with nonmatching bone marrow.

Parents are encouraged to stay at the Ronald McDonald Family Room provided for families of transplant patients in the Addison Jo Blair Cancer Care Center, where they can remain important team members in their child's care. This room includes a full bathroom, kitchenette, sitting area and four bunk beds. In addition, one parent may sleep in their child's room. Outpatient follow-up is done at Kosair Children's Hospital, where children can get their medicines and transfusions as needed. Out-of-town patients and families can stay at the Ronald McDonald House just two blocks away from the hospital. A room especially for families of our patients is reserved there but based on availability.

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Bone Marrow Transplant - Louisville, Kentucky(KY), Stem ...

Best Pract Res Clin Haematol. Author manuscript; available in PMC 2008 Mar 1.

Published in final edited form as:

PMCID: PMC1988840

NIHMSID: NIHMS28836

Craig T. Jordan, James P. Wilmot Cancer Center, University of Rochester School of Medicine, Rochester, NY;

Malignant stem cells have recently been described as the source of several types of human cancer. These unique cell types are typically rare and possess properties that are distinct from most other tumor cells. The properties of leukemic stem cells indicate that current chemotherapy drugs will not be effective. The use of current cytotoxic agents is not effective in leukemia because the agents target both the leukemic and normal stem cell populations. Consequently, new strategies are required that specifically and preferentially target the malignant stem cell population, while sparing normal stem cells. Several well known agents are lethal for the leukemic stem cell in preclinical testing. They include parthenolide, commonly known as feverfew, and TDZD-8. They have undergone various levels of preclinical development, but have not been used in patients as yet in the cancer setting. These drugs and combinations of existing therapies that target the leukemic stem cell population may provide a cure in this disease. This article summarizes recent findings in the leukemic stem cell field and discusses new directions for therapy.

Keywords: leukemic stem cell, parthenolide, TDZD-8

Approximately 50 years ago the concept was introduced that a stem cell may be connected to the origin and evolution of myeloid leukemia. To hypothesize the evolution of this disease, some form of normal stem or progenitor cell undergoes a mutation, giving rise to an entity that is functionally defined as a leukemic stem cell. The normal stem cells continue to differentiate into the hematopoietic lineage giving rise to erythrocytes, platelets, leukocytes, and granulocytes. The mutated stem cells have properties similar to the normal stem cells and can also differentiate into the hematopoietic lineage carrying the defect/s or can remain and accumulate as immature progenitor cells, also known as blast cells ().

Hypothesis of myeloid leukemia development

The chemotherapeutic agents used today effectively eradicate the blast cells in many patients. However, those same agents have very little if any activity at the level of the blast progenitor cell, the leukemic stem cell (LSC), which is biologically distinct from most of the cells that are found in a typical patient. An LSC is a functionally defined entity not necessarily named because it arises from a normal stem cell, but because it fulfills the same criteria used to define normal stem cells. These cells can undergo self renewal, are multipotent, and highly proliferative. The origin of the LSC has been the subject of considerable research in recent years.1

During normal developmental progression from stem cell to progenitor cell to mature cell, mutations may potentially occur at any point during this evolution, giving rise to a malignant entity. A mutation in a normal stem cell might give rise to a unit that could be considered an LSC. However, there is experimental evidence that suggests that mutations in a progenitor cell that no longer has all the characteristics of a stem cell can also give rise to an entity that can initiate and maintain leukemic disease.2 By extrapolation, it can be seen that more differentiated cells with the appropriate mutations may also give rise to the leukemic stem cell.

From a therapeutic perspective, the nature of the LSC may vary depending upon the stage during which it arose. Accordingly, drug resistance and various characteristics that are relevant to therapy may also differ, based on the origin of the diseased cell. Thus, it is possible to speculate that certain forms of leukemia that are relatively amenable to current therapies may derive from more differentiated cells that have certain intrinsic properties that are more readily addressed by conventional therapy. A plethora of new agents is available for treating leukemias, including kinase inhibitors, histone deacetylase inhibitors, cyclin D kinase inhibitors, heat shock protein inhibitors, methylation inhibitors, farnesyltransferase inhibitors, NF-kB inhibitors, and proteasome inhibitors.3,4 All of these agents affect specific mechanisms that may have gone awry. Despite the excitement and potential of all of these agents, there is not a single drug that has yet been validated as useful for eradicating the human LSC. An extremely important undertaking will be to fill this gap and to understand if and how all these new therapies are acting at the level of the stem cell.

Because anthracyclines, alkylating agents, nucleoside analogs, and topoisomerase inhibitors currently used in the treatment of acute myeloid leukemia (AML) often fail, they may not be targeting LSCs very effectively.5 In fact, there is no evidence that there is any selectivity or specific targeting of a leukemic versus normal stem cell by these agents. For example, Ara-C, which is a cycle-active agent commonly used in treating leukemia, shows virtually no activity with isolated LSCs.6 In contrast, this agent is effective when tested on blast cells from the same patient. There is a distinct difference in treating these two cell populations. When anthracyclines are tested in vitro, they are extremely cytotoxic both to LSCs and normal stem cells and there is no selectivity. However, there are ways that conventional therapies can be used in the appropriate combinations and appropriate methodologies, some of which have been previously published, to enhance the selective targeting and killing of leukemic stem cells.

LSCs can be isolated based on their cell surface markers using the currently available cell-sorting technologies. Once the leukemic stem cells have been isolated, they can be analyzed using the same techniques applied in any type of cancer cell to understand the specific mutations and pathways that propel growth and survival. Tumor-associated properties in the LSC could include mutations in the kinase domains, transcription factors, and tumor suppressors, or alterations in the growth and survival mechanisms mediated through NF-kappa B (NF-B) or PI3 kinase, or changes in physiology, glucose metabolism, or responses to oxidative stress, to name a few. The results obtained from these analyses of LSCs can be compared to the unique properties of normal stem cells, which are relatively rare, have a quiescent cell cycle status, can efflux drug, and have self-renewal properties. Based on these findings we will be able to effectively develop regimens that will target LSCs.2

From this relatively broad perspective, it is difficult to choose the most effective pathways to target. A great deal of knowledge has been amassed on agents that target mitogenic tyrosine kinase mutations, such as the BCR/ABL mutation by imatinib mesylate, which induces apoptosis of primary chronic myeloid leukemia (CML) cells.7 Another example is the Flt3 inhibitor CEP701, which induces apoptosis of primary AML blasts.8 However, there is no evidence that inhibiting these pathways is relevant to inhibiting the proliferating LSC.

As an alternative to inhibiting the activity of specific mutations in a cancer cell, it might be appropriate to consider the physiology of other unique mechanisms that maintain the viability and survival of these cells. Two such mechanisms have been suggested in the literature: the constitutive activation of the PI3 kinase pathway9 and NF-B,10 which are evident in LSCs. Inhibiting these two pathways might have therapeutic relevance. While no particular mutations or specific genetic events are associated with activation of the NF-B or PI3-kinase pathways, converging events, such as multiple different mutations, may feed into these pathways. However, such pathway modification may not be the only mechanism to produce leukemia.

Primitive human LSC populations can be selected by cell surface markers containing CD34+/CD38/CD123+ antigens. These cells are almost entirely quiescent, mimicking normal stem cells. As a result, cell cycle agents that are active in dividing cells will not be effective with this population. To characterize unique properties of LSCs, these purified populations have been examined using molecular analyses that look for activation of the NF-B pathway. As shown in , activation of the NF-B pathway can be readily detected. Normal hematopoietic stem cells do not show activation of NF-B. We believe that this is a leukemia-specific phenomenon.

NF-kB activity in primitive AML cells

Idarubicin with a proteasome inhibitor, parthenolide, and TDZD-8 are three examples of regimens that selectively target the leukemic stem cell. All three are able to inhibit NF-B activity. The combination of idarubicin with various classes of proteasome inhibitors mediates selective apoptosis in LSCs while sparing normal cells.10 The second agent, parthenolide, is a naturally occurring sesquiterpene lactone11 that also selectively kills LSC populations with minimal activity in normal stem cells. Continuing studies with this agent in colony-forming assays have been used to measure progenitor cell function. This pattern of selectivity continues with the third agent, TDZD-8, which is lethal only to the leukemic population. Data on TDZD-8 is yet unpublished. From a preclinical standpoint, these types of molecules appear promising.

Parthenolide is a small molecule that is the active compound in the plant known as feverfew, which has been used for centuries in herbal remedies to treat headache and inflammation. It is a potent inhibitor of NF-B. Parthenolide selectively ablates myeloid leukemia cells at an IC50 of 2.5 M and causes apoptosis in primary human AML cells and blast crisis CML (bcCML) cells. AML progenitor and stem cells were analyzed in in vitro colony forming assays in a nonobese diabetic/severe combined immunodeficient (NOD/SCID) xenograft mouse model. Parthenolide preferentially targeted both AML progenitor and LSC populations.11 The only drawback is that parthenolide is not a good candidate for pharmacologic development because it is not particularly water soluble. We have collaborated with Peter A. Crooks, PhD, at the University of Kentucky to develop analogs of parthenolide. The best candidate so far is a fumarate salt of dimethylaminoparthenolide. Its solubility in water is ~1000-fold greater than parthenolide and maintains its LSC-specific activity. It has been picked up by the NCIs RAID program and is currently undergoing further preclinical development. We hope to see this agent entering trials relatively soon.

TDZD-8 (4-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione) belongs to a family of molecules with an interesting history. A research group from the University of Madrid tested agents to inhibit the enzymatic activity of glycogen synthase kinase-3 beta (GSK-3 with the aim of treating neurologic diseases, such as Alzheimers, in which the enzyme GSK-3 is very active. The agents they tested also have NF-B inhibitory activity. One of these compounds, TDZD-8, is a non-ATP competitive inhibitor of GSK-3 (IC50=2M), binds to the active site of GSK-3, and inhibits the activities of Cdk1/cyclin B, casein kinase-II, and protein kinase A and C (IC50>100M). Preliminary data show that TDZD-8, similar to parthenolide, selectively induces the death of primary AML progenitor cells.

Further preliminary studies compared the efficacy of treating the AML progenitor cells with either parthenolide or TDZD-8. An overnight culture of AML progenitor cells expressing CD34+CD38- treated with either parthenolide or TDZD-8 showed that survival is rapidly impaired by TDZD-8 in comparison to parthenolide (half life of 120 minutes for cells in the presence of TDZD-8 vs > 360 minutes for those in the presence of parthenolide), relative to untreated controls. By contrast, there was very little to no activity in normal patient specimens.

In terms of the kinetics of these two agents, cells were treated with TDZD-8 or parthenolide at intervals of 30, 60, 120 1440 minutes and then assayed for viability. It became readily apparent between 6 and 12 hours that cells were dying in the presence of parthenolide. With TDZD-8, these cells were killed in as little as 30 minutes. When AML progenitor cells were introduced into NOD/SCID mice to rigorously assess stem cell potential, TDZD-8 inhibited the engraftment of AML leukemic stem cells, but did not significantly inhibit engraftment of normal hematopoietic stem cells. In a phenotypic analysis, cells were taken from the cell viability assay and introduced at each of the same time points into a functional assay such as progenitor cell colony-forming assays with striking results. The cells from the previous assay that were transferred into a functional assay had no detectable colony forming activity in as little as 30 minutes in the presence of TDZD-8. By comparison, parthenolide required an overnight time lapse before readily evident cell kill was observable. The mechanism of TDZD-8 is being investigated; however, from an empirical perspective, the extremely fast cell death with this agent is a very exciting development.

The two different agents discussed in this paper, parthenolide and TDZD-8, are chemically distinct entities. These compounds have the property of mediating cell death and inhibiting leukemic stem cell-specific activity. The empirical observation is that there are two types of stimuli required to bring about leukemia-specific cell death. The first is the inhibition of a survival pathway. The NF-kappa B and PI3 kinase pathways are affected by these drugs, but there could be others. Yet inhibiting pathways alone is not particularly toxic. However, when combined with a stimulus in the form of oxidative and/or genotoxic stress, the two signals together appear to be highly selective in killing leukemic stem cells, but are not particularly toxic at the normal stem cell level. Agents like parthenolide and TDZD-8 appear to simultaneously deliver both signals (). A general criterion for selecting therapeutic regimens could be the ability of the agent to deliver both signals simultaneously.

Hypothesis to propel selective death in leukemic stem cells

In developing regimens that are more selective to leukemic stem cells, these agents should be developed for patient use and their activity should be validated at the level of stem cells. Similarly, when these regimens are used in patients, patient outcomes should be assessed in terms of the relative efficacy of targeting leukemic stem cells in vivo. The assays are currently available and can be applied to determine this.

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The leukemic stem cell - PubMed Central (PMC)

Dr. Bennett, has for years, been quietly using adult stem cells to regenerate cartilage. Cartilage is the cap of tissue that is on the ends of each long bone in all of our joints. If you have ever had a chicken drumstick and noticed a white cap on the end of the bone, this is what human articular cartilage also looks like. Cartilage provides for a sliding mechanism so our joints glide and move smoothly and provides for a shock-absorbing mechanism.

Types of Stem cells

Stem cells include fetal, embryonic, placental and adult, to name just a few. Interestingly, all humans have adult stem cells. In fact tissue in the human body has some type of stem celleven heart and brain tissue. Adult stem cells, unless engineered cant create sperm or egg and thus avoid any ethical discussion. In fact, adult stem cells can be readily available in our bodies.

There are 3 main types of stem cells utilized in orthopedics, albeit, many orthopedic surgeons dont use stem cells. Bone marrow derived, fat or adipose derived and synovial stem cells are utilized. Some advertising promotes PRP as stem cell therapy. In fact, PRP, or platelet enriched plasma, a concentration of platelets from your own blood, does indeed have stem cells, blood or hematopoietic stem cells. However, these cells are not good for cartilage, ligament or tendon repair.

Bone Marrow derived stem cells in orthopedics

At Bennett Orthopedics and Sportsmedicine. Regenerating the Youth in You! We use only bone marrow derived stem cell, presently for cartilage, ligament and tendon repair.

So! How did we get here? Early use of adult or equine(horse-derived) stem cells have been successfully utilized in some of the Kentucky Derby, Preakness and Belmont stakes competitors.

While this is an arthroscopic photo of a knee surgery in a 24 year old athlete, this depicts what an acute cartilage injury looks like.

From there, animal models have been developed. Interestingly, aside from using too many stem cells-which can contribute to loose bodies in the joint, Dr. Bennett notes that he has never seen a negative study with respect to tissue healing. See below, Dr. Fortier a Veterinarian from Cornell University has actually, and because of her contributions in this area, been the President of the International Cartilage Repair Society-for humans and based out of Switzerland.

Concentrated Bone Marrow Aspirate Improves Full-Thickness Cartilage Repair Compared with Microfracture in the Equine Model. Investigation performed at Cornell University College of Veterinary Medicine, Ithaca, and the Hospital for Special Surgery, New York, NY Conclusions: Delivery of bone marrow concentrate can result in healing of acute full-thickness cartilage defects that is superior to that, after microfracture alone, in an equine model. Clinical Relevance: Delivery of bone marrow concentrate to cartilage defects has the clinical potential to improve cartilage healing, providing a simple, cost-effective, arthroscopically applicable, and clinically effective approach for cartilage repair. J Bone Joint Surg Am. 2010;92:1927-37

Stem cells often are mixed with a scaffold so the cells stay in the general vicinity of the damaged tissue. A study from Singapore has shown that Adipose Derived Stem Cells, which are fat derived, can aid in cartilage regeneration when used with a resorbable scaffold.

Evaluation of Intra-Articular Mesenchymal Stem Cells to Augment Healing of Microfractured Chondral Defects-Steadman/Philippon Research Institute- Conclusions: This study confirms that intra-articular BMSCs enhance cartilage repair quality with increased aggrecan content and tissue firmness. Clinical Relevance: Clinical use of BMSCs in conjunction with microfracture of cartilage defects may be potentially beneficial.

Dr. Bennett has performed simple stem cell injections into joints for patients who do not want surgery with very promising results. However, he notes that given the opportunity to combine adult bone marrow derived stem cells with various types of cartilage surgery that he performs, he can regenerate near normal cartilage. Some of these techniques include using stem cells with microfracture of substituting stem cells for a MACI or AMIC procedure, a type of carticel procedure which incorporates a membrane over the cells to hold the cells in place.

Outcomes After a Single-Stage Procedure for Cell-Based Cartilage Repair A Prospective Clinical Safety Trial With 2-year Follow-up Brian J. Cole -Conclusion: The first clinical experience in using CAIS for treating patients with focal chondral defects indicates that it is a safe, feasible, and effective method that may improve long-term clinical outcomes. Keywords: cartilage; knee; arthroscopy; tissue engineering; magnetic resonance. American Journal of Sports Medicine, Vol. 39, No. 6

Autologous Bone Marrow-Derived Mesenchymal Stem Cells Versus Autologous Chondrocyte Implantation An Observational Cohort Study Singapore-Conclusion: Using BMSCs in cartilage repair is as effective as chondrocytes for articular cartilage repair. American Journal of Sports Medicine, Vol. 38, No. 6

The Use of Bone Marrow Aspirate Concentrated for Full-thickness Knee Cartilage Lesions in a One-step Procedure: A Prospective Study-Alberto W. Gobbi MD-Milan,Italy,-Conclusion: This study showed that the use of autologous bone marrow derived and collagen I/Ill matrix in a one-step procedure could represent an improvement on the currently available techniques for cartilage transplantation could be a viable technique in the treatment of grade IV knee chondral lesions.

So, locations from New York to Vail, Colorado to Milan, Italy, to Singapore are in communion with this approach. Come to Sarasota, Florida, home of one of the best beaches in the World and have Dr. Bennett administer state of the art adult stem cells for your injuries.

Call 941-404-2703 or fill out our online form.

Excerpt from:
Can Stem Cells Really Repair Regenerate Cartilage Injuries ...

Rob Waddell Defeats Kidney Disease

Rob Waddell knew at an early age that he would need a kidney transplant. His mother has had two transplants and polycystic kidney disease runs in his family. "Ive had two uncles thatve died from this disease. At early ages. I mean they went on dialysis, they had a transplant, something happened, theyre no longer here. Their kids are, without, without a dad!", Rob said.

So when his doctor told him he had to go on dialysis and that a transplant was imminent it was no surprise. Having watched his mother suffer the ups and downs of taking anti-rejection drugs her whole life, he was thrilled to find out there was another option. He entered a clinical trial whereby he would receive an adult stem cell transplant from his kidney donor at the time of the kidney transplant surgery. The donors adult stem cells would allow Rob to accept the same donors kidney, essentially re-training his immune system so that it would recognize the donor kidney as part of Robs own body.

Rob says, "Well, I decided to do the stem cell transplant because I didnt want to live the rest of my life on immune rejection drugs. The good and the bad of immune suppressant drugs is they let the kidney stay in your body. The bad part is that slowly over time it kills the kidney. Its toxic to the kidney. So those drugs, over time, will cause the kidney to fail. My wife, Karen, she, when I proposed the idea of me doing this stem cell study, she was really kind of concerned. I mean she didnt want me to do it because it was new."

Karen Waddell remembers what she said when she heard about the adult stem cell transplant, "I told him I was totally against it from the beginning. Didnt like it. I said, you can just have a normal transplant. Your mom has lived through it. You know, well just adjust."

Rob says, "Seeing my mother go through the repercussions of having kidney disease and the transplant and immune rejection drugs, probably was the number one foundation for me pursuing this."

After the stem cell infusion, Karen says, Rob was like a new man. "Its like hes rejuvenated. Its amazing. He's alert. All his faculties are working great. And for him to be just drug-free, oh its wonderful!

"We call him my fifth child and other people that know us too, theyll tease, because you will see him rip-sticking around the neighborhood, or on the trampoline. So Im thankful that he was able to just be determined and have that drive and the foresight to know that he was going to get those stem cells.

Today Rob lives a full and active life chasing four kids around the soccer, baseball and lacrosse fields of Louisville, Kentucky.

"I feel so fortunate, because Ive been blessed with this. I mean truly a new lease on life. I feel fantastic. My kids could tell you that. I mean I wear them out half the time and I didnt before.

Actually, almost every day since then, I just walk around and Im like, Wow! I feel so goodI mean is this really happening? These adult stem cells to me were a chance to live a normal life.and its amazing."

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Rob Waddell Defeats Kidney Disease - Adult Stem Cells

Regenerative medicine is a relatively new concept in the U.S., although research into the use of stem cells to treat disease is more established in Europe. Since stem cells have the ability to differentiate into any type of cell, they have the potential to foster the repair of damaged tissue. As such, stem cell therapy offers great promise in the development of medical treatments for a wide range of conditionsincluding heart attacks.

"When someone has a heart attack, we shift into maintenance mode by prescribing medicines and other treatments to prevent another heart attack, but we can't reverse the damage that's already done," said Dr. Ahmed Abdel-Latif, assistant professor at the University of Kentucky's Gill Heart Institute. "With all of our advances in cardiovascular medicine, there is currently only one approved way to repair damaged heart tissue after a heart attack: with a heart transplant."

An average of21 peopledie every day in the U.S. waiting for an organ transplant, according to the Organ Procurement and Transplantation Network (OPTN) and the Gift of Life Donor Program.Clearly, transplant isn't a very elegant solution due to the limited number of donor hearts available and the lifetime of maintenance required to avoid complications post-transplantation, Latif said. Furthermore, heart transplants often aren't a viable option for the very sick or those with co-morbidities such as pulmonary hypertension. But stem cells which have the potential to grow into a variety of heart cell types might repair and regenerate damaged heart tissue, and research at the Gill Heart Institute is looking into that concept.

"There are very few U.S. centers offering regenerative medicine for cardiovascular disease," Latifsaid. "We are an active lab with a full spectrum of studies exploring translational opportunities for stem cell therapy."

One such study, called ALLSTAR (ALLogenic cardiac Stem cells to Achieve myocardial Regeneration) is looking into the possibility that stem cell therapy can repair damaged heart tissue after a recent heart attack. These patients often suffer long-term consequences of their heart attack, slipping into heart failure and potentially requiring an expensive and risky heart transplant.

Eric Mason is one of the first patients to enroll in the ALLSTAR trial at the Gill. He was just 35 years old when he had a life-threatening heart attack.

"In order for the heart to function properly, it needs to be supplied with sufficient amounts of oxygen-rich blood," Latif said. "The left coronary artery is tasked with this responsibility as it supplies blood to large areas of the heart. When this artery becomes blocked, it will cause a massiveattack that will likely lead to sudden death."

Mason had blockages in all three of his arteries80 percent, 90 percent and, in the left coronary artery, 100 percent. His type of heart attack is nicknamed "the widow maker" because so few patients survive.

Luckily, Eric's wife, Misty, was alert and acted quickly.

"Eric's father died of a heart attack at age 41, and Eric's symptoms were the same as a friend of ours who also had a heart attack," Misty Mason said. "So when he called to tell me it felt like an elephant was sitting on his chest, I told him to take two baby aspirin and get to the emergency room."

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Gill Heart Institute Researcher Explores Stem Cell Therapy ...