THURSDAY June 25, 2009---------------------------News Archive / Return to News Alerts


Human Placenta Abundant Source of Hematopoietic Cells
Investigators at Children's Hospital Oakland Research Institute, Oakland, California found a way to obtain large numbers of hematopoietic stem cell from human term placentas

Their results appear in the July 2009 issue of Experimental Biology and Medicine, describing in detaile a practical way to obtain hematopoietic stem cells from placenta in numbers that are several-fold higher than could be obtained from cord blood.

The research team consisted of Dr. Vladimir Serikov, MD, PhD, D.Sci, Assistant Staff Scientist, Catherin Hounshell, research associate, Sandra Larkin, research associate, Mr. William Green, student, Dr. Hurokazy Ikeda, MD, Visiting Scientist, Dr. Mark Walters, Medical Director of Children's Hospital Oakland Hematology and Oncology Programs, and Dr. Frans Kuypers, Senior Scientist.

The team performed studies of human term placentas, human cord blood, and immunodeficient mice. Dr. Serikov said that the human term placenta is a hematopoietic organ. A fact shown by his team more then a year ago. This year's finding were confirmed by UCSF scientists headed by Dr. S. Fisher.

In his report, Dr. Serikov demonstrated that human placentas could provide abundant amounts of CD34+ CD133+ colony-forming cells, as well as other primitive hematopoietic progenitors, suitable for transplantation in humans.

Hematopoietic stem cells maintain their differentiation capacity, and stromal stem cells (that support long-term culture of hematopoietic cells). Live hematopoietic cells can similarly be obtained from whole cryopreserved placentas.

Cells derived from placental tissue differentiated into all blood lineages in vitro. Animal experiments further demonstrated successful engraftment of placenta-derived HSC in immunodeficient mice.

Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology and Medicine said "the outstanding importance of these results for practical hematology is determined by the fact that the total number of stem cells that can be harvested from cord blood limits the efficacy of this stem cell source for transplants only to small children."

The novel findings of the Children's Hospital reseach demonstrates that placentas may provide a source of autologous stem cells sufficient for reconstitution of hematopoiesis in adult patients.

The methods used to obtain hematopoietic cells from placentas, developed by Dr. Serikov and Dr. Kuypers, can augument umbilical cord blood-based therapy in replacing bone marrow transplantation, and will dramatically change the whole field of transplantology."

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Child Psychologists Discuss How Parents of Preemies Sometimes Develop PTSD
Cocooned in tubes and wires, too fragile to be held, small, sick newborns fight for life in neonatal intensive care units. Though many go home healthy, the babies' harrowing starts leave indelible marks on their parents

To learn exactly how parents are affected, Richard Shaw, MD, a child psychiatrist at Lucile Packard Children's Hospital and an associate professor at the Stanford University School of Medicine, is studying post-traumatic stress disorder among moms and dads whose infants stayed in a NICU. (His latest paper on the subject was published in the March-April issue of the journal Psychosomatics.) He recently sat down for a Q&A session on the topic.

Question: How could PTSD interfere with a parent's ability to be a good caregiver?
Shaw: Parents with PTSD tend to be highly anxious and prone to overinterpret mild distress in their children as indicating possible serious illness. They may constantly expect their child to become ill, recreating the feelings of anxiety and distress they experienced at the time of their child's birth. They may repeatedly bring their children to the doctor - often unnecessarily - and, in so doing, foster a pattern in which their child manifests physical symptoms as a way to express emotion.

Parents may also develop symptoms of what has been termed the "vulnerable child syndrome." In this syndrome, parents with a history of having a medically fragile infant become overprotective, limiting their child's independence, because they want to make up for their child's trauma. This may result in children becoming oppositional and defiant as they get older.

Q: What were the most important aspects of your recent findings?
Shaw: We found very high rates of symptoms of traumatic stress in parents of NICU infants in the first few weeks after birth. The parents' symptoms may include nightmares about their child's birth and hospital stay, intrusive memories, a tendency to be jumpy or on edge, sleep difficulties and attempts to avoid reminders of the trauma. In our sample of parents, mothers tended to be more symptomatic, possibly because they are more likely to be at the bedside, and are therefore more likely to experience the traumatic aspects of their child's medical problems.

Q: Did any of your findings surprise you?
Shaw: We were surprised to find that fathers had a delayed reaction in terms of their trauma response. By four months, maternal trauma symptoms had diminished, but fathers' symptoms had increased, and in fact exceeded those of the mothers. It appeared that fathers tend to keep their emotional reactions in check for the first few months, perhaps to allow full support to be given to the mothers. However, by four months, when the mothers are recovering, the fathers go through a very difficult period. Awareness of this phenomenon is essential to ensure that the fathers' needs are not overlooked or neglected.

Q: In your research, the severity of the infants' illness did not correlate to parents' stress levels. Why not?
Shaw: In trauma research in general, the severity of the response tends to depend more on the characteristics of the victim, and less on the circumstances of the trauma. Some individuals seem to be quite resilient and less likely to develop symptoms of PTSD. Others, especially those with prior history of trauma exposure, or those with poor coping abilities, are more vulnerable. These factors appear to be more important than the severity of the child's illness.

Q: What follow-up care should we provide for parents after an infant's NICU stay ends?
Shaw: Parents should be carefully evaluated and offered appropriate psychological support. They should be educated about warning signs in themselves - insomnia, nightmares, irritability, etc. - and involved in hospital-based parent support groups. They also benefit greatly from advice from other parents who have gone through similar NICU experiences. Packard Children's, for example, has a Parent Mentor Program to provide support of this nature. In addition, to advance research in this area, we have recently submitted a grant to study the usefulness of brief, supportive psychotherapy for NICU parents.



Genetic Finding that Could Lead to Therapy for Neuroblastoma
Researchers have identified a genetic glitch that could lead to development of neuroblastoma, a deadly form of cancer that typically strikes children under 2

Two University of Florida scientists are part of the multicenter team of researchers that made the discovery, which could pave the way for better treatments that target the disease, according to findings published Wednesday in the journal Nature.

"What makes our study so important is that although neuroblastoma accounts for 7 percent of childhood cancers, it is responsible for 15 percent of deaths in children with cancer," said Wendy London, Ph.D., a research associate professor of epidemiology, biostatistics and health policy research at the UF College of Medicine and a member of the UF Shands Cancer Center. "This paper adds yet another gene in the pathway that could lead to tumorigenesis (tumor formation) of neuroblastoma."

Neuroblastoma forms in developing nerve cells, with tumors most often found on a child's adrenal gland. It's the most common form of cancer in babies and the third most common childhood cancer, according to the American Cancer Society.

Led by John J. Maris, M.D., director of the Cancer Center at The Children's Hospital of Philadelphia, researchers performed what's known as a genome-wide association study to uncover errors in DNA that could be associated with neuroblastoma.

To do this, researchers analyzed the genetic makeup of 846 patients with neuroblastoma, whose samples were derived from the Children's Oncology Group Neuroblastoma Tumor Bank, and 803 healthy patients in a control group.

On the basis of their initial findings, the researchers performed a second validation analysis, pinpointing that a glitch called a "copy number variation" in a single chromosome is associated with neuroblastoma. Copy number variation has to do with the gain, loss or duplication of snippets of DNA.

"This is part of series of papers that creates the bigger picture, an understanding of the genetic mechanisms that lead to neuroblastoma," said London, the principal investigator for the Children's Oncology Group Statistics and Data Center at UF. "We are searching for genetic targets to treat with therapy."

The researchers reported additional genetic links in Nature Genetics in May. The team discovered that on the gene called BARD1, six single-nucleotide polymorphisms — variations in tiny pieces of DNA — were also associated with neuroblastoma.

"Only two years ago we had very little idea of what causes neuroblastoma," said Maris, who led both studies. "Now we have unlocked a lot of the mystery of why neuroblastoma arises in some children and not in others."

Although neuroblastoma is one of the more common childhood cancers, it is relatively rare overall when compared with more common adult cancers, which has proved to be a challenge for researchers trying to uncover its causes, said Peter Zage, M.D., Ph.D., an assistant professor of pediatrics at the Children's Cancer Hospital at the University of Texas M.D. Anderson Cancer Center.

"Dr. Maris' group has been able to collect a relatively large number of cases for a neuroblastoma study and so has been able to identify these genetic variations and specific genes to provide us with some new avenues for therapy that we probably would not have been able to identify looking at the smaller cohorts of patients we each see at our individual institutions. In that sense, it's certainly an amazing leap forward in our understanding of the disease."

The discovery does hold promise for developing treatments, but London cautions that these potential "targeted therapies" won't work on all neuroblastoma patients. Not all neuroblastoma patients have this particular genetic anomaly, and not all children with this anomaly will develop neuroblastoma. Development of neuroblastoma is complicated and can occur because of multiple reasons, arising after a complex chain of events, London said.

"What's amazing is there are so many different ways for tumorigenesis to occur," London said. "That's the reason it is so hard to treat and cure cancer, or even to understand why it happens and how it happens."

All the researchers involved in the study are members of the Children's Oncology Group, the only National Institutes of Health/National Cancer Institute pediatric cancer cooperative group. The group performs clinical trials, collects specimens and performs statistical analysis related to pediatric cancers. UF is one of three institutions with a COG Statistics and Data Center, where study design, data collection and statistical analysis for COG research occurs.

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New Way that Cells Fix Damage to DNA
A team of researchers at The Scripps Research Institute and other institutions has discovered a new way by which DNA repairs itself, a process that is critical to the protection of the genome, and integral to prevention of cancer development

Scientists who study the repair of the DNA bases, which make up the information in the human genome, had known of only one type of method that cells use to fix a specific kind of damage to their DNA, but in the June 11, 2009 issue of Nature, the team found a novel way—one that combines elements from the known mechanisms and an unrelated second method that was previously not known to play a role in this type of DNA repair.

"We found a connection between the known DNA repair processes that people did not know was there," says Professor John Tainer, a member of the Skaggs Institute for Chemical Biology at Scripps Research, who led the study with Geoffrey P. Margison of the University of Manchester (United Kingdom) and Anthony E. Pegg of the Pennsylvania State University College of Medicine. "This changes the game, and gives us something important to look for in cancers that are resistant to chemotherapy."

This new mechanism is controlled by alkyltransferase-like proteins (ATLs), whose structure and function had been unknown and which had been identified only in bacteria and yeast. In addition to describing the function of ATLs, in the new study the scientists showed that ATLs exist in a multicellular organism, the sea anemone, which suggests this protein or its cousins in terms of repair activity also exist in other species, including humans.

Known Strategies for DNA Repair
Damage occurs to a cell's DNA on a continuing basis from outside sources, such as radiation and UV light, and from activities that go on day by day inside the cell. Most of this damage consists of damage to the DNA bases adenine, cytosine, guanine, and thymine. These bases pair up together inside the DNA double helix—adenine and thymine join together, and guanine and cytosine link to each other and their sequence forms the information in the human genome.

These bases can be chemically modified in a number of ways, including by alkylation, in which an alkyl group (or "adduct") is transferred onto a guanine base. When this happens, one of the hydrogen bonds holding guanine and cytosine together is removed, increasing the chances that thymine will be inserted across from guanine during DNA replication. If DNA is replicated with this "transition" error, a mutated gene results, so the information is changed. This can lead to harmful results, like cell death or cancer.

As shown in the reported work, this kind of damage occurs, for example, when chemicals derived from cigarette smoke stick to guanine, or when chemotherapy agents put an alkyl adduct onto guanine.

But that is where DNA repair mechanisms come in, which is good in the case of chemicals from cigarettes, but not so desirable when they repair genetic damage purposely induced by chemotherapy drugs intended to kill cancer cells.

The DNA repair process that removes such toxic "lesions" is known as base repair, and uses a protein called AGT (O6-alkylguanine DNA-alkytransferase) to remove the alkyl group before DNA replicates. The protein essentially sticks a chemical finger inside the DNA to flip the damaged guanine out from the DNA helix structure so that its adduct is exposed and can be transferred from the guanine to a part of its protein structure. The guanine is now repaired and can rejoin cytosine with three hydrogen bonds linking them.

AGT is believed to act alone, but there is another, unrelated repair process—nucleotide excision repair (NER)—that uses lots of proteins in its pathway. This repair occurs when bulky adducts stuck to bases distort the sleek shape of the DNA helix. Then a whole group of proteins come in and remove a patch of bases that includes the adduct, and DNA polymerase follows and fills in the patch while adding the correct base back.

A New Way
Before the new study, ATLs were believed to be involved in DNA damage responses, because they protected cells from DNA alkylation damage in lab experiments, but no one understood how they worked or what they did. In the new study, the team describes ATLs' role.

The scientists undertook a series of structural, genetic, and biochemistry experiments on the protein and determined its structure, both alone and with a guanine that had a methyl adduct and another with a smoking-derived adduct stuck on it. They found that the ATL structure looks like AGT. It, too, had a chemical finger that can rotate a damaged guanine base out from the DNA helix, but it doesn't remove the adduct like AGT does. Instead, ATL binds tightly to the damaged guanine and bends the DNA in a way that is more pronounced than what AGT does for repair.

"Base flipping by ATL is like a switch that activates the NER pathway, which then removes the alkyl adduct from the guanine," says first author Julie Tubbs, a research associate at Scripps Research. "So we believe that ATL is conceptually acting like a bridge, connecting the two DNA repair pathways—base and NER—together. This is a surprisingly general mechanism to channel specific base damage into the general NER pathway."

Before the new study, scientists also didn't know if ATLs functioned outside of single celled organisms. In the new study, however, the scientists discovered ATLs in two types of ancient organisms, archaeal bacteria and in sea anemone, suggesting this new bridging pathway may be general to most cells and organisms.

"What's especially important about these newly discovered ATLs is that we now know that ATLs exist in all domains of life, so it is very likely that ATL was common to the evolutionary branches before complex eukaryotes [single-celled or multicellular organisms whose cells contain a distinct membrane-bound nucleus]," Tainer says. "This suggests higher eukaryotes, including mammals and humans, will either have an ATL or have lost or replaced it with a protein of analogous function."

If ATLs are found in humans, Tainer sees that either inhibiting or bolstering their function could aid cancer therapy. Inhibiting DNA repair would help chemotherapy effectively destroy cancer cells. Augmenting ATL function could help protect sensitive tissue, such as bone marrow, that is easily destroyed during cancer treatment.

"There are all kinds of exciting ideas to emerge from this research," says Tainer. "For one thing, we now know what to look for when we see resistance to some chemotherapies."

WEDNESDAY June 24, 2009---------------------------News Archive / Return to News Alerts



Weed Killer Kills Embryonic, Placental and Umbilical Cord Cells
Used in yards, farms and parks throughout the world, Roundup has long been a top-selling weed killer. But now researchers have found that one of Roundup’s inert ingredients can kill human cells, particularly embryonic, placental and umbilical cord cells

The new findings intensify a debate about so-called “inerts” — the solvents, preservatives, surfactants and other substances that manufacturers add to pesticides. Nearly 4,000 inert ingredients are approved for use by the U.S. Environmental Protection Agency.

Glyphosate, Roundup’s active ingredient, is the most widely used herbicide in the United States. About 100 million pounds are applied to U.S. farms and lawns every year, according to the EPA.

Until now, most health studies have focused on the safety of glyphosate, rather than the mixture of ingredients found in Roundup. But in the new study, scientists found that Roundup’s inert ingredients amplified the toxic effect on human cells—even at concentrations much more diluted than those used on farms and lawns.

One specific inert ingredient, polyethoxylated tallowamine, or POEA, was more deadly to human embryonic, placental and umbilical cord cells than the herbicide itself – a finding the researchers call “astonishing.”

“This clearly confirms that the [inert ingredients] in Roundup formulations are not inert,” wrote the study authors from France’s University of Caen. “Moreover, the proprietary mixtures available on the market could cause cell damage and even death [at the] residual levels” found on Roundup-treated crops, such as soybeans, alfalfa and corn, or lawns and gardens.

The research team suspects that Roundup might cause pregnancy problems by interfering with hormone production, possibly leading to abnormal fetal development, low birth weights or miscarriages.

Monsanto, Roundup’s manufacturer, contends that the methods used in the study don’t reflect realistic conditions and that their product, which has been sold since the 1970s, is safe when used as directed. Hundreds of studies over the past 35 years have addressed the safety of glyphosate.

“Roundup has one of the most extensive human health safety and environmental data packages of any pesticide that's out there,” said Monsanto spokesman John Combest. “It's used in public parks, it's used to protect schools. There's been a great deal of study on Roundup, and we're very proud of its performance.”

The EPA considers glyphosate to have low toxicity when used at the recommended doses.

“Risk estimates for glyphosate were well below the level of concern,” said EPA spokesman Dale Kemery. The EPA classifies glyphosate as a Group E chemical, which means there is strong evidence that it does not cause cancer in humans.

In addition, the EPA and the U.S. Department of Agriculture both recognize POEA as an inert ingredient. Derived from animal fat, POEA is allowed in products certified organic by the USDA. The EPA has concluded that it is not dangerous to public health or the environment.

The French team, led by Gilles-Eric Seralini, a University of Caen molecular biologist, said its results highlight the need for health agencies to reconsider the safety of Roundup.

“The authorizations for using these Roundup herbicides must now clearly be revised since their toxic effects depend on, and are multiplied by, other compounds used in the mixtures,” Seralini’s team wrote.

Controversy about the safety of the weed killer recently erupted in Argentina, one of the world’s largest exporters of soy.

Last month, an environmental group petitioned Argentina’s Supreme Court, seeking a temporary ban on glyphosate use after an Argentine scientist and local activists reported a high incidence of birth defects and cancers in people living near crop-spraying areas. Scientists there also linked genetic malformations in amphibians to glysophate. In addition, last year in Sweden, a scientific team found that exposure is a risk factor for people developing non-Hodgkin lymphoma.

Inert ingredients are often less scrutinized than active pest-killing ingredients. Since specific herbicide formulations are protected as trade secrets, manufacturers aren’t required to publicly disclose them. Although Monsanto is the largest manufacturer of glyphosate-based herbicides, several other manufacturers sell similar herbicides with different inert ingredients.

The term “inert ingredient” is often misleading, according to Caroline Cox, research director of the Center for Environmental Health, an Oakland-based environmental organization. Federal law classifies all pesticide ingredients that don’t harm pests as “inert,” she said. Inert compounds, therefore, aren’t necessarily biologically or toxicologically harmless – they simply don’t kill insects or weeds.

Kemery said the EPA takes into account the inert ingredients and how the product is used, whenever a pesticide is approved for use. The aim, he said, is to ensure that “if the product is used according to labeled directions, both people’s health and the environment will not be harmed.” One label requirement for Roundup is that it should not be used in or near freshwater to protect amphibians and other wildlife.

But some inert ingredients have been found to potentially affect human health. Many amplify the effects of active ingredients by helping them penetrate clothing, protective equipment and cell membranes, or by increasing their toxicity. For example, a Croatian team recently found that an herbicide formulation containing atrazine caused DNA damage, which can lead to cancer, while atrazine alone did not.