Current transplantation therapies rely on the infusion of donor stem cells into a patient’s bone marrow to generate new, healthy blood cells without disease. But that procedure is often risky and can result in fatal complications, due in part to “graft-versus-host disease,” in which transplanted cells react against foreign tissues of the recipient. One means of circumventing this immune rejection problem would be to generate hematopoietic stem cells, or HSCs, using the patient’s own precursor cells. Such cells would be perfectly genetically matched, but in order to generate such cells, scientists must first understand the molecular processes that underlie specification of HSCs.

“If we could generate healthy HSCs from patients and transplant them back into their own bone marrow, it would eliminate many complications,” said David Traver, who headed the research team.

“Our findings are an important step toward this goal because they provide a better understanding of how HSCs, the cell type responsible for the clinical benefits of bone marrow transplants, are first specified during development.

“This improved understanding will aid efforts to instruct pluripotent embryonic stem cells (ESCs), the stem cells that can produce all types of tissue-specific stem cells in the body, to make HSCs; something that is not currently possible. In other words, we are one step closer now to understanding how to clinically generate HSCs for cellular replacement therapies from ESCs,” he added.

Traver and his colleagues made their discoveries in zebrafish, a model laboratory organism for geneticists in which embryos are transparent, allowing the researchers to observe and track individual stem cells with a microscope.

“Using zebra-fish embryos with fluorescently labeled tissues, we were able to demonstrate that HSCs arise directly from cells lining the floor of the dorsal aorta by imaging the process in living embryos.”

The study appears in this week’s early online edition of the journal Nature. (Source-ANI RAS)

Gertrude Elion invented the leukemia-fighting drug 6-mercaptopurine and drugs that facilitated kidney transplants.

Gertrude Elion patented the leukemia-fighting drug 6-mercaptopurine in 1954 and has made a number of significant contributions to the medical field. Dr. Gertrude Elion’s research led to the development of Imuran, a drug that aids the body in accepting transplanted organs, and Zovirax, a drug used to fight herpes.

Including 6-mercaptopurine, Getrude Elion’s name is attached to some 45 patents. In 1988, she was awarded the Nobel Prize in Medicine with George Hitchings and Sir James Black. Dr. Gertrude Elion was inducted into the National Inventors Hall of Fame in 1991, she continued to be an advocate for medical and scientific advancement until her death in February of 1999.

The child of Lithuanian and Polish immigrants, Gertrude Elion decided to become involved in cancer research after losing her grandfather to cancer when she was 15 years old. At age 19, she graduated with the highest undergraduate honors in chemistry from Hunter College. However, 15 institutes rejected her application for graduate school because of the unfair discrimination towards women in the sciences that existed at that time. Elion was forced to work as an unpaid lab assistant in order to have the opportunity to further her research in science. In 1944, Burroughs Wellcome, a pharmaceuticals company, hired Gertrude Elion to work with nucleic acids. During her 39-year career there, Gertrude Elion made most of her scientific advances, including the development of 6-mercaplopurine used in chemotherapy to treat children with leukemia that won her the Nobel Prize.

Timeline:
1918 Born on January 23, in New York City, New York.

1933 Enters Hunter College at the age of 15.

1937 Graduates summa cum laude with a B.S. degree in Chemistry. There were few women working as chemists, and many labs refused to hire women at the time, so Gertrude earned a Masters of Science degree in Chemistry from New York University and taught high school

1944 Is hired by Burroughs-Wellcome and begins a 40 year scientific partnership with George Hitchings. Develops two drugs with Hitchings for the treatment of acute laukemia. Becomes the leader of a large team of scientists that discovers drugs for the treatment of gout and to relieve the side-effects of chemotherapy.

1963 Discovers a drug that makes kidney transplants between unrelated donors possible.

1967 Is named the head of the Department of Experimental Therapy. Develops the world’s first anti-viral medication that is often used for the treatment of herpes.

1983 Retires holding 45 patents. She remains active as a scientific advisor and consultant.

1991 Along with George Hitchings and Sr. James Black, wins the Nobel Prize for Medicine.

1991 Is inducted into the National Inventors Hall of Fame and is presented with the National Medal of Science.

1999 Dies in February, 1999.

cancer cell

Their discovery, published in the November 12 issue of Nature, lays the foundation for a new kind of therapy aimed directly at a critical human protein — one of a few thousand so-called transcription factors — that could someday be used to treat a variety of diseases, especially multiple types of cancer.

“There is a pressing need for drugs that target transcription factors, both for use as scientific tools in the laboratory and as therapies in the clinic,” said senior author James Bradner, a Harvard chemical biologist and oncologist at the Dana-Farber Cancer Institute and an associate member of the Broad Institute of MIT and Harvard. “Our work brings us a step closer toward that goal for a protein with major roles in cancer, cardiovascular disease and stem cell biology.”

If human physiology is like a puppet show, then transcription factors pull the puppet strings. They bind to DNA and turn genes on or off, setting in motion genetic cascades that control how normal cells grow and develop. They also help maintain tumor growth, underscoring their importance as cancer drug targets. Yet transcription factors are counted among the most difficult molecules to neutralize with a drug — in fact, no such drugs are currently available.

Based on his work as an oncologist, Bradner became deeply interested in a human protein called NOTCH. The gene encoding this protein is often damaged, or mutated, in patients with a form of blood cancer, known as T-ALL or T-cell acute lymphoblastic leukemia.

Abnormal NOTCH genes found in cancer patients remain in a state of constant activity, switched on all the time, which helps to drive the uncontrolled cell growth that fuels tumors. Similar abnormalities in NOTCH also underlie a variety of other cancers, including lung, ovarian, pancreatic and gastrointestinal cancers.

Even with this deep scientific knowledge, drugs against NOTCH — or any other transcription factor — have traditionally been extremely difficult, if not impossible, to develop. Most current drugs take the form of small chemicals (known as “small molecules”) or larger-sized proteins, both of which have proven impractical to date for disabling transcription factors.

A few years ago, Bradner and his colleagues hatched a different idea about how to tame the runaway NOTCH protein. Looking closely at its structure as well as the structures of its partner proteins, they noticed a key protein-to-protein junction that featured a helical shape.

“We figured if we could generate a set of tiny little helices we might be able to find one that would hit the sweet spot and shut down NOTCH function,” said Bradner.

Creating and testing these helices involved a team of interdisciplinary researchers, including Greg Verdine, Erving Professor of Chemistry at Harvard University and director of the Chemical Biology Initiative at Dana-Farber Cancer Institute, as well as scientists at Brigham and Women’s Hospital and the Broad Institute’s Chemical Biology Program, which is directed by Stuart Schreiber.

Verdine invented a drug discovery technology that uses chemical braces or “staples” to hold the shapes of different protein snippets. Without these braces, the snippets (called “peptides”) would flop around, losing their three-dimensional structure and thus their biological activity. Importantly, cells can readily absorb stapled peptides, which are significantly smaller than proteins. That means the peptides can get to the right locations inside cells to alter gene regulation.

“Stapled peptides promise to significantly expand the range of what’s considered ‘druggable,’” said Verdine, who is a co-senior author of the study and an associate member of the Broad Institute. “With our discovery, we’ve declared open season on transcription factors and other intractable drug targets.”

After designing and testing several synthetic stapled peptides, the research team identified one with remarkable activity. Not only could it bind to the right proteins and reach the right places inside cells, it also showed the desired biological effect: the ability to disrupt NOTCH function.

Moreover, experiments in cultured cells as well as in mice proved the peptide’s ability to limit the growth of cancer cells fueled exclusively by NOTCH. Interestingly, these effects are also seen at the level of gene activity or “expression.” The researchers looked at the expression levels of genes across the genome, in both cells and mice treated with the peptide, and observed markedly reduced expression of genes that are controlled directly and indirectly by NOTCH. These results offer some early insights into how the peptide works at a molecular level.

In addition to the potential therapeutic applications to NOTCH-dependent cancers, the Nature study also forms the basis of a general strategy for taking aim at other transcription factors. “A variety of key transcription factors assemble in a manner similar to NOTCH,” said first author Raymond Moellering, a graduate student in Harvard University’s Department of Chemistry and Chemical Biology who works with both Verdine and Bradner. “Our approach could offer a template for targeting many other master regulators in cancer.” www.medindia.net

NEW YORK – Genzyme Corp. must collect more data on the leukemia drug Clolar before the Food and Drug Administration will consider expanding the use of the therapy to previously untreated adults with acute myeloid leukemia.

Based on findings from a limited trial, Genzyme sought approval to market the drug to patients with the most common form of blood and bone marrow cancer in adults, the Cambridge, Mass., company said yesterday.

The FDA recommended a randomized, controlled clinical study before it would consider expanding Clolar’s use.

Clolar is approved for children with acute lymphoblastic leukemia (a cancer in which the bone marrow makes too many white blood cells) who have relapsed or are resistant to other treatments.

Genzyme plans to request a meeting with the FDA to discuss which studies will satisfy its requirements to use the drug for untreated adults.

From the Genzyme “About” page:

One of the world’s leading biotechnology companies, Genzyme is dedicated to making a major positive impact on the lives of people with serious diseases. Since 1981, the company has grown from a small start-up to a diversified enterprise with more than 11,000 employees in locations spanning the globe and 2008 revenues of $4.6 billion. In 2007, Genzyme was chosen to receive the National Medal of Technology, the highest honor awarded by the President of the United States for technological innovation.

With many established products and services helping patients in nearly 100 countries, Genzyme is a leader in the effort to develop and apply the most advanced technologies in the life sciences. The company’s products and services are focused on rare inherited disorders, kidney disease, orthopaedics, cancer, transplant and immune disease, and diagnostic testing. Genzyme’s commitment to innovation continues today with a substantial development program focused on these fields, as well as cardiovascular disease, neurodegenerative diseases, and other areas of unmet medical need.

Gainesville City Hall

Gainesville, FL – For his 18th birthday, Patrick Fitzpatrick asked for a pair of flashy track shoes for the upcoming season. For his 50th birthday, he was hoping to find a gift-wrapped ticket to the UF-Tennessee football game. For his 60th birthday, Fitzpatrick wanted to get arrested.

As a light drizzle fell on the large signs that read, “Would Jesus Feed the Homeless?,” “5th Meanest City” and “Homeless Rights are Human Rights,” near the stairs of Gainesville City Hall, Fitzpatrick and a few others broke the law Monday by handing out food to Gainesville’s homeless population. The law, passed in 2003, prohibits the noncity-sponsored distribution of food in front of City Hall.

“We’re breaking this law because we have a conscience,” said Fitzpatrick, who didn’t get his birthday wish. “I don’t care who they are — nobody can tell us who we can or can’t give a sandwich to.”

After the display of civil disobedience, Fitzpatrick, longtime homeless awareness activist, announced that he will run for the 4th District city commissioner seat, which will empty in March when its current holder, Craig Lowe, runs for mayor.

As the homeless munched peanut butter sandwiches and chocolate cake in cadence with faint, live accordion music, Fitzpatrick assured observers and reporters of the seriousness of his campaign and the need to resist the ever-growing power of current officials, who he referred to as “the robber barons.”

“The curve of politics typically goes in favor of the wealthy,” he said. “The curve of justice, however, goes to the poor.”

If elected, one of his first orders of business will be to rescind the 130-person limit on the amount of food served at the St. Francis House shelter. Fitzpatrick plans to establish a permanent place for homeless residents to stay. Danny Griggs, a Hawthorne resident who assists Fitzpatrick in caring for the homeless, believes the restrictions imposed at the St. Francis House need to be addressed immediately.

“I saw with my own eyes a pregnant woman get turned away because she happened to be No. 131,” he said. “That’s just not right.”

According to Griggs, one of the main problems contributing to Gainesville’s homeless problem is a misguided perception that all homeless residents have only themselves to blame for their circumstances.

“They’re smart people,” Griggs said, mentioning innovations made by homeless people to survive such as secretly cultivated gardens in which they grow assortments of vegetables. “Some of them just can’t do it by themselves.”

“Over there are the really stupid people,” he said, pointing to the tall buildings across from City Hall that house local businesses.

To David Wayne, who has been homeless for the past four months, the issue isn’t about politics or winning elections — it’s about getting the next meal. Wayne, whose battle with leukemia made his face jerk and contort as he speaks, sleeps near the courthouse. But despite his problems, Wayne said the efforts of homeless advocates like Fitzpatrick give him hope.

“You won’t see worry in my eyes; I got a secret,” he said, pointing to the sky. “My secret is God.”  (Source www.alligator.org)

Gainesville is the largest city and county seat of Alachua County. It serves as the cultural, educational and commercial center for the North Central Florida Region.

(recent  post by a person with Lupus featured on The Gazette)

In 2007, I was diagnosed with lupus and Lyme disease, and before getting sick, I would have never believed a positive attitude helped “cure” an illness. Then I got sick and brought my unhappy/negative attitude with me. No matter what medications I took, I was not getting well.

I’ve known many people with illness, some as serious as leukemia. Some are in remission, some have died. The ones who are well are the ones who had a positive attitude, the ones who died are the ones who held on to anger. I started to get better when I changed my attitude. I’m still not 100 per cent and I am still working on my happiness, but, in the meantime, I’m close to being fully functional again. And out of the ashes, I was lucky enough to find my passion in natural healing. I’m now working on my naturopathic degree in hopes of sharing my message and to help others who are ill. Anyone who took a human anatomy and physiology course would understand there is a definite connection between mind and body.

We would like to point out the one specific individual that was the first scientist to identify a chromosomal translocation as the cause of leukemia and other cancers which have led to dramatically improved survival rates.

Janet Davison Rowley, M.D., is the Blum Riese Distinguished Service Professor of Medicine, Molecular Genetics & Cell Biology and Human Genetics at The University of Chicago. She is an American human geneticist and the first scientist to identify a chromosomal translocation as the cause of leukemia and other cancers. Rowley is internationally renowned for her studies of chromosome abnormalities in human leukemia and lymphoma, which have led to dramatically improved survival rates for previously incurable cancers and the development of targeted therapies. In 1999 President Clinton awarded her the National Medal of Science–the nation’s highest scientific honor.

Dr. Yaacov Ben-David, a senior scientist at Sunnybrook Research Institute, and colleagues found that the presence of leukemic inhibitory stem cells in the spleens of a mouse model slows the advance of erythroleukemia, a cancer in which a large number of abnormal red blood cells grow in the blood and bone marrow. Prognosis for patients with this type of leukemia is poor.

With this discovery, scientists have a new model for the development of a more efficient drug therapy for this and other forms of leukemia. It also suggests a route for a novel combination therapy, one that targets both genes and cells.

“Many scientists are using targeted therapy for genes that activate or control the growth of cancer cells,” says Ben-David, who is also a professor at the University of Toronto. “But the cellular environment around the tumour, its microenvironment, is the body’s first defence. If we can first strengthen it by the enrichment of inhibitory stem cells, then we may have a better treatment for patients than with targeted therapy alone.”

For their study, the researchers turned to a mouse model of a noncancerous blood disorder, in which the bone marrow makes too many red blood cells. With this condition, despite having an abnormally high number of blood cells, these mice rarely develop erythroleukemia. The researchers thus hypothesized that the inhibitory stem cells have a protective effect. To test their hypothesis, the scientists induced erythroleukemia in mouse models with this noncancerous blood disorder. Upon analysis, they found that the ability of the leukemic inhibitory stem cells to secrete nitric oxide was primarily responsible for the cells’ anti-tumour properties. They also discovered that specific cytokines, signalling molecules that tell cells how to communicate with each other, enriched the stem cells, strengthening the anti-tumour effect.

“I’m very excited about this work,” says Ben-David, whose lab was the first to show, in 2004, that two proteins in the micro-environment of the spleen hasten the growth of leukemic cells, and that removal of the spleen might therefore be a way to halt the spread of leukemia, an approach now being clinically tested at Sunnybrook. Now that we’ve identified a molecular mechanism preclinically, we can look at performing a clinical trial in the near future,” he says.

Erythroleukemia typically affects people aged over 50 years old, though it affects all age groups, including children, and more men than women get it. Risk factors include prior exposure to chemicals, including chemotherapy to treat cancer. (research was supported by the Canadian Institutes of Health Research).

Please Promote Leukemia Awareness Wherever You Can

This finding was quite unexpected, said Michael Cleary, MD, senior author of a paper describing the discovery. GSK3 has never been implicated in promoting cancer. Cleary is a professor of pathology and of pediatrics and a member of the Stanford Cancer Center. The research will appear online in Nature on Sept. 17. Clearys team discovered that inhibiting GSK3 combats leukemias caused by mutated MLL genes. MLL, an acronym for mixed-lineage leukemia, refers to an unusual feature of these deadly cancers. Most leukemias begin in just one of the bodys two white blood cell factories, either the lymph nodes or the bone marrow. But in mixed-lineage leukemias, the bad cells can show markers from both kinds of tissue.

Newly diagnosed leukemia patients have their cancer cells tested to see which genes are driving the cancer. Mutated MLL genes are viewed as a bad prognostic marker, Cleary said. There is intense interest in coming up with better ways to treat these patients, he said. Clearys findings indicate GSK3 may be an effective target for future leukemia drugs.

The first hint of GSK3s role came from petri-dish tests on cancer cells. Postdoctoral scholar Zhong Wang, PhD, treated dishes of different kinds of cancer cells with a battery of chemicals that inhibit various cell signals. When a GSK3 inhibitor clobbered cells with mutant MLL genes, Wang realized his work was cut out for him. I was excited, but I knew I would have to do lots of work to confirm the finding, he said. Most people say GSK3 cannot be a cancer target. That is because of earlier discoveries that showed GSK3 slowed malignancies such as colon cancer.

But Wangs extensive follow-up experiments confirmed GSK3 drove leukemia. For instance, he gave the psychiatric drug lithium, a weak GSK3 inhibitor, to mice with MLL-gene leukemia. Mice that got lithium lived longer than those that did not. Now that the team knows GSK3 is a potential anti-leukemia target, they are studying how the signal revs up cancer.

They are also starting the hunt for high-potency GSK3 inhibitors that could safely be given to humans. The signal is an especially promising leukemia drug target, the researchers said, because GSK3 normally slows the growth of healthy bone marrow stem cells. Thus, it is possible that giving GSK3 inhibitors will have a double-whammy effect on leukemia, killing the cancerous white blood cells and promoting growth of healthy stem cells, such as those given in a bone marrow transplant.

Most current cancer drugs target both the normal and the aberrant cells, Cleary said. It would be a big advantage in cancer treatment if a drug were developed that could selectively kill cancer but help healthy cells grow. Of course, the danger with GSK3 inhibitors would be that they might also cause other cancers if given long-term. Cleary said it is too early to tell if or how a new drug might skirt that problem. There will be a lot of hard work required to get better anti-GSK3 compounds, test them in preclinical models and translate them to human trials, he said. Cleary and Wangs team at Stanford included Kevin Smith, PhD, research associate in pathology, and postdoctoral scholars Mark Murphy, PhD; Obdulio Piloto, PhD; and Tim Somervaille, MD, PhD. The research was supported by grants from the Children™s Health Initiative of the Lucile Packard Foundation for Childrens Health, the Public Health Service, the Leukemia and Lymphoma Society, the Williams Lawrence Foundation and the Stanford Cancer Center. (source mednews.stanford.edu)

New research describes a molecular tool that shows great promise as a therapeutic for human acute myeloid leukemia (AML), a notoriously treatment-resistant blood cancer. The study, published by Cell Press in the July 2nd issue of the journal Cell Stem Cell, describes exciting preclinical studies in which a new therapeutic approach selectively attacks human cancer cells grown in the lab and in animal models of leukemia.

According to a press release issued by EurekAlert, AML is a cancer of the white blood cells that has an extremely poor prognosis and does not respond well to conventional chemotherapy. “The cellular and molecular basis for this dismal picture is unclear,” offers senior study author Associate Professor Richard Lock from the Children’s Cancer Institute Australia and the University of New South Wales. “However, previous research has suggested that leukemia stem cells (LSCs) may lie at the heart of post-treatment relapse and chemoresistance.” LSCs are cells that can initiate AML and are critical for its long-term growth.

Associate Professor Lock and colleagues exploited the fact that the molecule CD123 is expressed at very high levels on LSCs but not on normal blood cells. CD123 is part of the interleukin-3 receptor, a protein that interacts with a growth factor (called a cytokine) that influences cell survival and proliferation. The researchers created a therapeutic antibody that recognized and bound to CD123 with the hope that this antibody would selectively interfere with AML-LSC survival.

When AML-LSCs from human patients were transplanted into mice treated with the antibody, called 7G3, cytokine signaling in the tumor cells was blocked. Further, 7G3 impaired migration of the AML-LSCs to bone marrow and activated the innate immune system of the host mouse to destroy the AML-LSCs. Overall, treatment with 7G3 substantially improved mouse survival when compared with control groups. The researchers go on to report that a CD123-targeting antibody is currently being used in phase 1 clinical trials of advanced AML and that there are no signs of treatment-related toxicity.

These results hold substantial promise for future cancer therapeutics. “The recent characterization of defined populations of cancer stem cells in a range of human malignancies, as well as their relative resistance to conventional chemotherapy and radiotherapy, supports the broad applicability of our approach and provides rationale for the progression of AML-LSC-targeted therapeutics from preclinical evaluation to clinical trials,” concludes Associate Professor Lock. (as reported by “The Hindu”)