Flavonoids in celery, artichokes kill human pancreatic cancer cells

Main Category: Pancreatic Cancer
Also Included In: Nutrition / Diet
Article Date: 19 Aug 2013 - 1:00 PDT Current ratings for:
Flavonoids in celery, artichokes kill human pancreatic cancer cells

Celery, artichokes, and herbs, especially Mexican oregano, all contain apigenin and luteolin, flavonoids that kill human pancreatic cancer cells in the lab by inhibiting an important enzyme, according to two new University of Illinois studies.

"Apigenin alone induced cell death in two aggressive human pancreatic cancer cell lines. But we received the best results when we pre-treated cancer cells with apigenin for 24 hours, then applied the chemotherapeutic drug gemcitabine for 36 hours," said Elvira de Mejia, a U of I professor of food chemistry and food toxicology.

The trick seemed to be using the flavonoids as a pre-treatment instead of applying them and the chemotherapeutic drug simultaneously, said Jodee Johnson, a doctoral student in de Mejia's lab who has since graduated.

"Even though the topic is still controversial, our study indicated that taking antioxidant supplements on the same day as chemotherapeutic drugs may negate the effect of those drugs," she said.

"That happens because flavonoids can act as antioxidants. One of the ways that chemotherapeutic drugs kill cells is based on their pro-oxidant activity, meaning that flavonoids and chemotherapeutic drugs may compete with each other when they're introduced at the same time," she explained.

Pancreatic cancer is a very aggressive cancer, and there are few early symptoms, meaning that the disease is often not found before it has spread. Ultimately the goal is to develop a cure, but prolonging the lives of patients would be a significant development, Johnson added.

It is the fourth leading cause of cancer-related deaths, with a five-year survival rate of only 6 percent, she said.

The scientists found that apigenin inhibited an enzyme called glycogen synthase kinase-3ß (GSK-3ß), which led to a decrease in the production of anti-apoptotic genes in the pancreatic cancer cells. Apoptosis means that the cancer cell self-destructs because its DNA has been damaged.

In one of the cancer cell lines, the percentage of cells undergoing apoptosis went from 8.4 percent in cells that had not been treated with the flavonoid to 43.8 percent in cells that had been treated with a 50-micromolar dose. In this case, no chemotherapy drug had been added.

Treatment with the flavonoid also modified gene expression. "Certain genes associated with pro-inflammatory cytokines were highly upregulated," de Mejia said.

According to Johnson, the scientists' in vitro study in Molecular Nutrition and Food Research is the first to show that apigenin treatment can lead to an increase in interleukin 17s in pancreatic cells, showing its potential relevance in anti-pancreatic cancer activity.

Pancreatic cancer patients would probably not be able to eat enough flavonoid-rich foods to raise blood plasma levels of the flavonoid to an effective level. But scientists could design drugs that would achieve those concentrations, de Mejia said.

And prevention of this frightening disease is another story. "If you eat a lot of fruits and vegetables throughout your life, you'll have chronic exposure to these bioactive flavonoids, which would certainly help to reduce the risk of cancer," she noted.

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Researchers have developed an experimental therapy that can kill human blood cancer cells in the laboratory and eradicate the disease in mice

Main Category: Lymphoma / Leukemia / Myeloma
Article Date: 15 Aug 2013 - 0:00 PDT Current ratings for:
Researchers have developed an experimental therapy that can kill human blood cancer cells in the laboratory and eradicate the disease in mice

Ottawa researchers have developed unique virus-derived particles that can kill human blood cancer cells in the laboratory and eradicate the disease in mice with few side effects. The study is published in Blood Cancer Journal by co-senior authors Drs. David Conrad and John Bell of the Ottawa Hospital Research Institute (OHRI) and the University of Ottawa (uOttawa).

While Dr. Bell and his colleagues have been investigating replicating viruses for the treatment of solid cancers for many years, with very promising results, this is the first major success they have had treating blood cancer (leukemia). It is also the first success they have had using a non-replicating virus-derived particle as opposed to a replicating virus.

"Our research indicated that a replicating virus might not be the safest or most effective approach for treating leukemia, so we decided to investigate whether we could make virus-derived particles that no longer replicate but still kill cancer," said Dr. Conrad, a hematologist conducting research in the Blood and Marrow Transplant Program at The Ottawa Hospital, and currently completing his PhD at OHRI and uOttawa in the Department of Cellular and Molecular Medicine. "We were delighted to see that this novel therapy was very safe at high doses, and worked extremely well in our laboratory leukemia models. We hope to test this in patients in the near future."

The researchers used a specific method and dose of UV light to transform regular replicating viruses into unique particles that could no longer replicate and spread, but could still enter cancer cells efficiently, kill them and stimulate a strong immune response against the cancer. These particles were able to kill multiple forms of leukemia in the laboratory, including samples taken from local patients who had failed all other therapies. Normal blood cells were not affected. This novel treatment was also successful in mouse models of leukemia. In fact, 80 per cent of the mice that received the therapy had markedly prolonged survival and 60 per cent were eventually cured, while all of the untreated mice died of their leukemia within 20 days.

"Leukemia is a devastating disease that can be very difficult to treat, and new therapies are urgently needed," said Dr. Conrad. "While we're still at the early stages of this research, I think this therapy holds a lot of promise because it appears to have a potent, long-lasting effect on leukemia without the debilitating side effects of many cancer therapies used in the clinic right now. We will likely see even better results once we optimize the dose in our preparations to advance this research into human clinical trials."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our lymphoma / leukemia / myeloma section for the latest news on this subject.

This research was funded by the Ontario Institute for Cancer Research, the Terry Fox Foundation, the Natural Sciences and Engineering Research Council of Canada, the Canadian Institutes of Health Research, Ottawa's Department of Medicine and The Ottawa Hospital Foundation.

Non-replicating rhabdovirus-derived particles (NRRPs) eradicate acute leukemia by direct cytolysis and induction of antitumor immunity. Batenchuk C, Le Boeuf F, Stubbert L, Falls T, Atkins HL, Bell JC, and Conrad DP. Blood Cancer J. 2013 Jul 12;3:e123. doi: 10.1038/bcj.2013.23.

Ottawa Hospital Research Institute

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Decellularized mouse heart beats again after regeneration with human heart precursor cells in Pitt project

Main Category: Cardiovascular / Cardiology
Also Included In: Biology / Biochemistry
Article Date: 15 Aug 2013 - 2:00 PDT Current ratings for:
Decellularized mouse heart beats again after regeneration with human heart precursor cells in Pitt project

For the first time, a mouse heart was able to contract and beat again after its own cells were stripped and replaced with human heart precursor cells, said scientists from the University of Pittsburgh School of Medicine. The findings, reported online in Nature Communications, show the promise that regenerating a functional organ by placing human induced pluripotent stem (iPS) cells - which could be personalized for the recipient - in a three-dimensional scaffold could have for transplantation, drug testing models and understanding heart development.

In the United States, one person dies of heart disease every 34 seconds, and more than 5 million people suffer from heart failure, meaning a reduced ability to pump blood, said senior investigator Lei Yang, Ph.D., assistant professor of developmental biology, Pitt School of Medicine. More than half of heart disease patients do not respond to current therapies and there is a scarcity of donor organs for transplant.

"Scientists have been looking to regenerative medicine and tissue engineering approaches to find new solutions for this important problem," Dr. Yang said. "The ability to replace a piece of tissue damaged by a heart attack, or perhaps an entire organ, could be very helpful for these patients."

For the project, the research team first "decellularized," or removed all the cells, from a mouse heart, a process that takes about 10 hours using a variety of agents. Then, they repopulated the remaining heart framework, or scaffold, with multipotential cardiovascular progenitor (MCP) cells. These replacement cells were produced by reverse engineering fibroblast cells from a small skin biopsy to make induced pluripotent stem cells and then treating the iPS cells with special growth factors to further induce differentiation.

"This process makes MCPs, which are precursor cells that can further differentiate into three kinds of cells the heart uses, including cardiomyocytes, endothelial cells and smooth muscle cells," Dr. Yang explained. "Nobody has tried using these MCPs for heart regeneration before. It turns out that the heart's extracellular matrix - the material that is the substrate of heart scaffold - can send signals to guide the MCPs into becoming the specialized cells that are needed for proper heart function."

After a few weeks, the mouse heart had not only been rebuilt with human cells, it also began contracting again, at the rate of 40 to 50 beats per minute, the researchers found. More work must be done to make the heart contract strongly enough to be able to pump blood effectively, and to rebuild the heart's electrical conduction system correctly so that the heart rate speeds up and slows down appropriately.

In the future, it might be possible to take a simple skin biopsy from a patient to derive personalized MCPs that can be used to seed a biologic scaffold and regenerate a replacement organ suitable for transplantation, Dr. Yang noted. The model also could be used as a lab-based method to preclinically test the effect of new drugs on the heart or to study how the fetal heart might develop.

"One of our next goals is to see if it's feasible to make a patch of human heart muscle," he added. "We could use patches to replace a region damaged by a heart attack. That might be easier to achieve because it won't require as many cells as a whole human-sized organ would."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cardiovascular / cardiology section for the latest news on this subject.

The project was funded by the University of Pittsburgh, the American Heart Association, and the National Science Council (Taiwan).

Repopulation of decellularized mouse heart with human induced pluripotent stem cell-derived cardiovascular progenitor cells

Nature Communications 4, Article number: 2307 doi:10.1038/ncomms3307

Tung-Ying Lu, Bo Lin, Jong Kim, Mara Sullivan, Kimimasa Tobita, Guy Salama & Lei Yang

University of Pittsburgh

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Characterizing stem cells in larval schistosomes may help control the prolific human parasite

Main Category: Infectious Diseases / Bacteria / Viruses
Article Date: 14 Aug 2013 - 0:00 PDT Current ratings for:
Characterizing stem cells in larval schistosomes may help control the prolific human parasite

Ancient Egyptian mummies revealed that humans have been hosting parasitic flatworms called schistosomes for more than 5,000 years. Today the parasites continue to plague millions of people across the world, causing roughly 250,000 deaths each year.

The schistosome reproductive cycle results in exponentially more schistosomes each generation. Not only do the adults lay hundreds to thousands of eggs each day but the larval schistosomes are able to clone themselves thousands of times, with each clone capable of developing into an egg-producing adult.

Researchers at the University of Illinois quickly realized that one key to controlling schistosomes is being able to control their incredibly prolific life cycle. In a recent study published in the journal eLife, Illinois researchers have come one step closer to understanding the unique mechanisms that allow schistosomes' germinal cells, stem cells that multiply into other types of cells, to create thousands of clonal larvae that can then infect humans.

The Disease

This work adds to our understanding of the basic biology of schistosomiasis, a chronic disease caused by schistosome parasites, that robbed at least 243 million people of their productivity in 2011.

"People don't feel well, and so they are not productive in their work," said James Collins III, a postdoctoral researcher in the Department of Cell and Developmental Biology (CDB) at Illinois. "This disease keeps them from being able to realize their full potential, and in turn, they remain poor and are exposed to more diseases like schistosomiasis, which are ultimately diseases of sanitation. It's a disease of poverty that also perpetuates poverty."

Schistosomiasis can result in abdominal pain, diarrhea, and blood in urine or feces. The parasite's eggs, and not the parasite itself, cause these symptoms and others. The bloodstream carries many of the eggs to the liver and other areas of the body where they can trigger a massive immune response.

"When you look at people who have a high level of infection, you see many holes in their liver," said Phillip Newmark, a Professor of Cell and Developmental Biology at Illinois, an Investigator of the Howard Hughes Medical Institute, and an affiliate of the Regenerative Biology and Tissue Engineering research theme at the Institute for Genomic Biology (IGB). "Where there was an egg, a hole is formed where the tissue has been destroyed by the host immune system's inflammatory response."

The Life Cycle

Every day for decades, adult schistosomes can lay hundreds to thousands of eggs. Their life cycle starts over when the eggs are excreted from the human host through urine or feces. When the eggs contact water, they hatch out "miracidia" that seek out the snail intermediate hosts.

Inside the correct species of snail, the miracidia become sporocysts, essentially sacs filled with germinal cells, that undergo clonal expansion, making tens to hundreds of thousands of copies of themselves in the form of "cercariae." The fast-swimming cercariae are shed from the snail, and search for human hosts who find themselves in cercariae-infested fresh water.

"They are attracted by the fatty acids in your skin," said Collins. "In the lab, you can leave your thumbprint on a plastic petri dish, and all the cercariae will swarm to your thumbprint and try to penetrate the plastic."

Once they find a host, they are able to burrow through the skin and enter the bloodstream. Inside the body, they migrate to specific sites in the human host, mature into male or female worms, and find mates with whom they will live, paired together "in copula." If left undetected, they will continue mass producing eggs for decades.

The Research

Illinois researchers are approaching this important problem from a unique perspective, using developmental biology (the study of how organisms grow and develop) and applying the lessons they have learned from studying planarians, non-parasitic relatives of schistosomes.

"When researchers are just focused on targeting diseases and developing drugs, they may wind up limiting their opportunities by not really understanding the biology of the system," Newmark said. "I think fundamental, curiosity-driven research is still vital for developing long-lasting solutions. If anything comes of this, it will be because we were asking very fundamental questions about these parasites, based upon our knowledge of their free-living cousins, the planarians."

The team's research was motivated by the idea that stem cells seem to be key to schistosomes' ability to live within humans, but also to their ability to live and clone themselves within their snail hosts.

They discovered that germinal cells possess a molecular signature - a collection of expressed genes - that is similar to that of neoblasts (adult stem cells) that allow planarians to regrow missing body parts. Among these genes, they identified some that are required for maintaining the germinal cell population.

This evidence suggests that schistosome larvae may have evolved by adapting a developmental program used by non-parasitic flatworms in order to rapidly increase their population - essentially giving them the opportunity to reproduce twice within their life cycle, once asexually inside snail hosts and once sexually inside human hosts.

Illinois researchers believe they can apply this newfound developmental knowledge to future studies that may lead to ways to control, or even eradicate, schistosomes. They have already discovered that they can make the reproductive system of a planarian disappear by removing the function of a neuropeptide; eventually, they hope to do the same in schistosomes.

Still, there's much to still be learned, says Collins. "We have really only scratched the surface of understanding the basic biology of these organisms. In order to be able to treat this disease, we need to know more about the organisms that cause it. That's one of our main motivations for this work."

First author Bo Wang, a postdoctoral fellow at the IGB, said the obvious next step will be to further characterize these schistosome cells on a genomic level. "We really need to improve our understanding of schistosome stem cells," Wang said. "We still don't understand all the mechanisms that really make them unique, that really make them have this tremendous capacity to proliferate, or reproduce."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our infectious diseases / bacteria / viruses section for the latest news on this subject.

The National Institutes of Allergy and Infectious Diseases (NIAID) funded this study. Wang was also supported by the IGB, who sponsored his fellowship. The work was reported in the July 30, 2013 issue of eLife (doi.org/10.7554/eLife.00768).

Institute for Genomic Biology, University of Illinois at Urbana-Champaign

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The human brain spatial map

Main Category: Neurology / Neuroscience
Article Date: 04 Aug 2013 - 10:00 PDT Current ratings for:
The human brain spatial map

Grid-like activity can be seen in the human brain in response to exploring a virtual environment, reports a study published online this week in the journal Nature Neuroscience. These findings imply that our internal navigation system is active even in the absence of movement in physical space.

Previous studies suggest that the sense of place is supported by neurons called place cells, which are active when an animal is in a specific region in an environment, and grid cells that display a spatial pattern of activity that resembles a grid on a map. Though place cells had previously been found in humans, grid cells had been observed only in rodents, bats and monkeys.

Joshua Jacobs and colleagues report evidence for grid-like activity in the human brain, providing the most direct evidence for the existence of grid cells, and suggesting that humans use a coordinate system for navigation similar to that used by other mammalian species. The scientists recorded neuronal activity with electrodes intra-cranially implanted in the brain of patients undergoing treatment for drug-resistant epilepsy. They asked the patients to find objects in a computer-generated virtual environment using a joystick and looked for grid-like features in the recorded activity. In addition to place cell activity in the hippocampus, Jacobs and colleagues found that neurons in the entorhinal and cingulate cortices were active at multiple locations in the environment, forming a lattice covering the entire virtual space. This grid-like pattern strongly resembles the characteristic pattern of activity of grid cells found in animals exploring their physical environment.

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The human brain spatial map

Nature Neuroscience - DOI: 10.1038/nn.3466

Nature

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Liver function regenerated and survival extended in mice with hepatic failure using human stem cell-derived hepatocytes

Main Category: Liver Disease / Hepatitis
Also Included In: Stem Cell Research
Article Date: 30 Jul 2013 - 0:00 PDT Current ratings for:
Liver function regenerated and survival extended in mice with hepatic failure using human stem cell-derived hepatocytes

Researchers have generated functional hepatocytes from human stem cells, transplanted them into mice with acute liver injury, and shown the ability of these stem-cell derived human liver cells to function normally and increase survival of the treated animals. This promising advance in the development of cell-based therapies to treat liver failure resulting from injury or disease relied on the development of scalable, reproducible methods to produce stem cell-derived hepatocytes in bioreactors, as described in an article in Stem Cells and Development, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. The article is available free on the Stem Cells and Development website.

Massoud Vosough and coauthors demonstrate a large-scale, integrated manufacturing strategy for generating functional hepatocytes in a single suspension culture grown in a scalable stirred bioreactor. In the article "Generation of Functional Hepatocyte-Like Cells from Human Pluripotent Stem Cells in a Scalable Suspension Culture" the authors describe the method used for scale-up, differentiation of the pluripotent stem cells into liver cells, and characterization and purification of the hepatocytes based on their physiological properties and the expression of liver cell biomarkers.

David C. Hay, MRC Centre for Regenerative Medicine, University of Edinburgh, U.K., comments on the importance of Vosough et al.'s contribution to the scientific literature in his editorial in Stem Cells and Development entitled "Rapid and Scalable Human Stem Cell Differentiation: Now in 3D." The researchers "developed a system for mass manufacture of stem cell derived hepatocytes in numbers that would be useful for clinical application," creating possibilities for future "immune matched cell based therapies," says Hay. Such approaches could be used to correct mutated genes in stem cell populations prior to differentiation and transplantation, he adds.

"The elephant in the room for stem cell therapy rarely even acknowledged let alone addressed in the literature is that of scalable production of cells for translational application," says Editor-in-Chief Graham C. Parker, PhD, research professor, Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine. "Baharvand's groups' landmark publication not only demonstrates but exquisitely describes the methodology required to scale up stem cell populations for clinical application with a rigor to satisfy necessary manufacturing standards."

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New strategy for fiber tracking in human brain

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Article: " Diffusion tensor imaging fiber tracking with reliable tracking orientation and flexible step size" by Xufeng Yao1, 2, Manning Wang2, Xinrong Chen2, Shengdong Nie1, Zhexu Li1, Xiaoping Xu1, Xuelong Zhang1, Zhijian Song2 (1 Shanghai Medical Instrument College, School of Optical-Electrical and Computer Engineering, University of Shanghai for Science and Technology, Shanghai 200091, China; 2 Digital Medical Research Center, Shanghai Medical School, Fudan University/The Key Laboratory of MICCAI of Shanghai, Shanghai 200032, China)

Yao XF, Wang MN, Chen XR, Nie SD, Li ZX, Xu XP, Zhang XL, Song ZJ. Diffusion tensor imaging fiber tracking with reliable tracking orientation and flexible step size. Neural Regen Res. 2013;8(16):1481-1490.

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Neural Regeneration Research

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New understanding of how Ebola virus suppresses the human immune system

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