Psoriasis Corrected in stem cell cultures with Vitamin C

Psoriasis Corrected in stem cell cultures with Vitamin C

Psoriasis Corrected in stem cell cultures with Vitamin C

Lian and Murphy have previously shown that 5-hmC loss in the skin epigenome can be reprogrammed using agents as fundamental as ascorbic acid (vitamin C). They reasoned that therapeutic correction of the epigenomic defect in psoriasis might reverse the entire process. Based on experiments using skin stem cell cultures in the lab, the team presents promising preliminary data suggesting that 5-hmC levels can be restored to correct the deficiency seen in psoriasis.

Loss of the Epigenetic Mark, 5-hmC, in Psoriasis: Implications for Epidermal Stem Cell Dysregulation Li, Feng et al. Journal of Investigative Dermatology DOI:https://doi.org/10.1016/j.jid.2019.10.016

https://www.jidonline.org/article/S0022-202X(19)33467-0/abstract

#psoriasis #vitaminc #ascorbicacid

Psoriasis, vitaminc, ascorbicacid, stemcells, 5-hmc, corrected, treated, reversed, stem cell, vitamin c, ascorbic acid, keratinocyte, 5-hydroxymethylcytosine, treatment

How Good Fats Build Bone

How Good Fats Build Bone

How Good Fats Build Bone
Researchers discover how DHA helps stem cells become bone forming cells

ω-3 polyunsaturated fatty acids direct differentiation of the membrane phenotype in mesenchymal stem cells to potentiate osteogenesis/ Science Advances  08 Nov 2017: Vol. 3, no. 11, eaao1193 DOI:10.1126/sciadv.aao1193

Several FDA-approved anti-cancer drugs induce stem cell tumors, perhaps thwarting therapy

Several FDA-approved anti-cancer drugs induce stem cell tumors, perhaps thwarting therapy
Drosophila intestines provide ‘ready-made stem cell microenvironments’ that are ‘difficult-to-impossible’ to create in petri dishes, offering an unconventional screen that allows researchers to test drugs in vivo. Credit: University of Massachusetts Amherst        

                                

Using a new approach to systematically test chemotherapy drugs in an unusual animal model, a research team led by University of Massachusetts Amherst molecular biologist Michele Markstein, with Norbert Perrimon at Harvard Medical School, report that several have a serious side effect: Inducing hyper proliferation in stem cells that could lead to tumor recurrence.

Markstein says, “We discovered that several chemotherapeutics that stop fast growing tumors have the opposite effect on stem cells in the same animal, causing them to divide too rapidly. This was a surprise, because it showed that the same drug could have opposite actions on cells in the same animal: Suppressing tumor growth on one cell population while initiating growth in another. Not only is the finding of clinical interest, but with this study we used an emerging new non-traditional tool for assessing drugs using stem cells in the fruit fly gut.” Continue reading “Several FDA-approved anti-cancer drugs induce stem cell tumors, perhaps thwarting therapy”

Immortal ‘Snail Fur’ may lead to Cancer Research Breakthroughs / Regenerates and Does Not biologically age

Hydractinia echinata on the carapace of a hermit crab.
Hydractinia echinata on the carapace of a hermit crab.

A marine hydroid common off the coasts of Ireland and Britain has shown remarkable regeneration properties which effectively allow it to live forever, and researchers hope studying it will garner new revelations which can be applied to stem cell biology.

Hydractinia echinata, also sometimes known as snail fur because of the fuzzy appearance it gives the surfaces where it colonizes, is an organism related to jellyfish and and sea anemones. It tends to accumulate on the shells of other marine creatures such as hermit crabs and sea snails.

Uri Frank, who specializes in hydractinia research at the National University of Ireland at Galway, told the Irish Times that hydractinia have the power to regenerate any lost body part, can clone themselves and do not biologically age.

These remarkable attributes make the tiny creatures “perfect for understanding the role of stem cells in development, aging and disease,” Frank told the Irish Times.

“Hydractinia has some stem cells which remain at an embryonic-like stage throughout its life. It sounds gruesome, but if it has its head bitten off, it simply grows another one within a few days using its embryonic or ‘pluripotent’ stem cells,” Frank said, adding, “the potential for research is immense.”

Pluripotent stem cells have the ability to transform in to any cell type, which has proven to be of great interest to researchers studying congenital defects and the biology of cancer.

Frank and his team an NUI Galway have discovered a previously unknown link between two genetic signalling  mechanisms: heat-shock proteins, which function as a sort of intra-cellular chaperone for other proteins, and a cell signalling pathway known as Wnt signalling which aids in governing basic cell activity. Both heat-shock proteins and Wnt signalling are known to be associated with cell growth and cancer.

“These two cellular signalling mechanisms are known to play important roles in development and disease, so they have been widely, though separately, studied. We have shown that they talk to each other, providing a new perspective for all scientists in this field,” Frank told the Times.

By further studying the immortal hydractina, the stem cells of which Frank believes should be similar to human stem cells, the researchers hope to gain even more information which may prove useful in future cancer studies.

 

http://www.natureworldnews.com/articles/3586/20130821/immortal-snail-fur-lead-cancer-research-breakthroughs.htm

There’s life after radiation for brain cells

Contact: Stephanie Desmon sdesmon1@jhmi.edu 410-955-8665 Johns Hopkins Medicine

Johns Hopkins researchers suggest neural stem cells may regenerate after anti-cancer treatment

Scientists have long believed that healthy brain cells, once damaged by radiation designed to kill brain tumors, cannot regenerate. But new Johns Hopkins research in mice suggests that neural stem cells, the body’s source of new brain cells, are resistant to radiation, and can be roused from a hibernation-like state to reproduce and generate new cells able to migrate, replace injured cells and potentially restore lost function.

“Despite being hit hard by radiation, it turns out that neural stem cells are like the special forces, on standby waiting to be activated,” says Alfredo Quiñones-Hinojosa, M.D., a professor of neurosurgery at the Johns Hopkins University School of Medicine and leader of a study described online today in the journal Stem Cells. “Now we might figure out how to unleash the potential of these stem cells to repair human brain damage.”

The findings, Quiñones-Hinojosa adds, may have implications not only for brain cancer patients, but also for people with progressive neurological diseases such as multiple sclerosis (MS) and Parkinson’s disease (PD), in which cognitive functions worsen as the brain suffers permanent damage over time.

In Quiñones-Hinojosa’s laboratory, the researchers examined the impact of radiation on mouse neural stem cells by testing the rodents’ responses to a subsequent brain injury. To do the experiment, the researchers used a device invented and used only at Johns Hopkins that accurately simulates localized radiation used in human cancer therapy. Other techniques, the researchers say, use too much radiation to precisely mimic the clinical experience of brain cancer patients.

In the weeks after radiation, the researchers injected the mice with lysolecithin, a substance that caused brain damage by inducing a demyelinating brain lesion, much like that present in MS. They found that neural stem cells within the irradiated subventricular zone of the brain generated new cells, which rushed to the damaged site to rescue newly injured cells. A month later, the new cells had incorporated into the demyelinated area where new myelin, the protein insulation that protects nerves, was being produced.

“These mice have brain damage, but that doesn’t mean it’s irreparable,” Quiñones-Hinojosa says. “This research is like detective work. We’re putting a lot of different clues together. This is another tiny piece of the puzzle. The brain has some innate capabilities to regenerate and we hope there is a way to take advantage of them. If we can let loose this potential in humans, we may be able to help them recover from radiation therapy, strokes, brain trauma, you name it.”

His findings may not be all good news, however. Neural stem cells have been linked to brain tumor development, Quiñones-Hinojosa cautions. The radiation resistance his experiments uncovered, he says, could explain why glioblastoma, the deadliest and most aggressive form of brain cancer, is so hard to treat with radiation.

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The research was supported by grants from the National Institutes of Health’s National Institute of Neurological Disorders and Stroke (RO1 NS070024), the Maryland Stem Cell Research Fund, the Robert Wood Johnson Foundation, the Howard Hughes Medical Institute, the PROMETEO grant, the Red de Terapia Celular (TerCel) from Instituto de Salud Carlos III, and the Consejo Nacional de Ciencia y Tecnología.

Other Johns Hopkins researchers involved in the study include Vivian Capilla-Gonzalez, Ph.D.; Hugo Guerrero-Cazares, M.D., Ph.D.; Janice Bonsu; Oscar Gonzalez-Perez, M.D.; Pragathi Achanta, Ph.D.; John Wong, Ph.D.; and Jose Manuel Garcia-Verdugo, Ph.D.

For more information: http://tinyurl.com/ofqkea3

JOHNS HOPKINS MEDICINE

Johns Hopkins Medicine (JHM), headquartered in Baltimore, Maryland, is a $6.7 billion integrated global health enterprise and one of the leading health care systems in the United States. JHM unites physicians and scientists of the Johns Hopkins University School of Medicine with the organizations, health professionals and facilities of The Johns Hopkins Hospital and Health System. JHM’s mission is to improve the health of the community and the world by setting the standard of excellence in medical education, research and clinical care. Diverse and inclusive, JHM educates medical students, scientists, health care professionals and the public; conducts biomedical research; and provides patient-centered medicine to prevent, diagnose and treat human illness. JHM operates six academic and community hospitals, four suburban health care and surgery centers, more than 38 primary health care outpatient sites and other businesses that care for national and international patients and activities. The Johns Hopkins Hospital, opened in 1889, was ranked number one in the nation for 21 years by U.S. News & World Report.

Johns Hopkins Medicine Media Relations and Public Affairs

Media Contact:

Stephanie Desmon 410-955-8665; sdesmon1@jhmi.edu

Helen Jones 410-502-9422, hjones49@jhmi.edu

Digest This: Cure for Cancer May Live in Our Intestines / People will not die from cancer, if our prediction is true

The discovery of Robo1 protein in the intestinal stem cells (depicted in yellow) leads to tolerance of higher doses of chemoradiation for cancer patients. (Credit: Dr. Wei-Jie Zhou)

July 31, 2013 — Treating a cancerous tumor is like watering a houseplant with a fire hose — too much water kills the plant, just as too much chemotherapy and radiation kills the patient before it kills the tumor.

However, if the patient’s gastrointestinal tract remains healthy and functioning, the patient’s chances of survival increase exponentially, said Jian-Guo Geng, associate professor at the University of Michigan School of Dentistry. Recently, Geng’s lab discovered a biological mechanism that preserves the gastrointestinal tracts in mice who were delivered lethal doses of chemotherapy.

The findings, which will appear in the journal Nature, could revolutionize cancer therapy, Geng said.

“It’s our belief that this could eventually cure later-staged metastasized cancer. People will not die from cancer, if our prediction is true,” said Geng, who emphasized that the findings had not yet been proven in humans. “All tumors from different tissues and organs can be killed by high doses of chemotherapy and radiation, but the current challenge for treating the later-staged metastasized cancer is that you actually kill the patient before you kill the tumor.

“Now you have a way to make a patient tolerate to lethal doses of chemotherapy and radiotherapy. In this way, the later-staged, metastasized cancer can be eradicated by increased doses of chemotherapy and radiation.”

Geng’s lab found that when certain proteins bind with a specific molecule on intestinal stem cells, it revs intestinal stem cells into overdrive for intestinal regeneration and repair. Stem cells naturally heal damaged organs and tissues, but so-called “normal” amounts of stem cells in the intestine simply cannot keep up with the wreckage left behind by the lethal doses of chemotherapy and radiation required to successfully treat late-stage tumors.

However, the phalanx of extra stem cells protect the intestine and gastrointestinal tract, which means the patient can ingest nutrients, the body can perform other critical functions and the bacterial toxins in the intestine are prevented from entering the blood circulation, Geng said.

These factors could give the patient just enough of an extra edge to survive the stronger doses of chemotherapy and radiation, until the tumor or tumors are eradicated.

In the study, 50-to-75 percent of the mice treated with the molecule survived otherwise lethal doses of chemotherapy. All of the mice that did not receive the molecule died, Geng said.

“If you can keep the gut going, you can keep the patient going longer,” Geng said. “Now we have found a way to protect the intestine. The next step is to aim for a 100-percent survival rate in mice who are injected with the molecules and receive lethal doses of chemotherapy and radiation.”

Geng’s lab has worked with these molecules, called R-spondin1 and Slit2, for more than a decade. These molecules repair tissue in combination with intestinal stem cells residing in the adult intestine.

Vitamin C Helps Control Gene Activity in Stem Cells

Vitamin C, in a natural source such as an orange and as a supplement. Vitamin C affects whether genes are switched on or off inside mouse stem cells, and may thereby play a previously unknown and fundamental role in helping to guide normal development in mice, humans and other animals. (Credit: © brozova / Fotolia)

July 1, 2013 — Vitamin C affects whether genes are switched on or off inside mouse stem cells, and may thereby play a previously unknown and fundamental role in helping to guide normal development in mice, humans and other animals, a scientific team led by UC San Francisco researchers has discovered.

The researchers found that vitamin C assists enzymes that play a crucial role in releasing the brakes that keep certain genes from becoming activated in the embryo soon after fertilization, when egg and sperm fuse.

The discovery might eventually lead to the use of vitamin C to improve results of in vitro fertilization, in which early embryos now are typically grown without the vitamin, and also to treat cancer, in which tumor cells abnormally engage or release these brakes on gene activation, the researchers concluded in a study published June 30, 2013 in the journal Nature.

In the near term, stem-cell scientists may begin incorporating vitamin C more systematically into their procedures for growing the most healthy and useful stem cells, according to UCSF stem-cell scientist Miguel Ramalho-Santos, PhD, who led the study. In fact, the unanticipated discovery emerged from an effort to compare different formulations of the growth medium, a kind of nutrient broth used to grow mouse embryonic stem cells in the lab.

Rather than building on any previous body of scientific work, the identification of the link between vitamin C and the activation of genes that should be turned on in early development was serendipitous, Ramalho-Santos said. “We bumped into this result,” he said.

Working in Ramalho-Santos’ lab, graduate student Kathryn Blaschke and postdoctoral fellow Kevin Ebata, PhD, were comparing different commercial growth media for mouse stem cells. The researchers began exploring how certain ingredients altered gene activity within the stem cells. Eventually they discovered that adding vitamin C led to increased activity of key enzymes that release the brakes that can prevent activation of an array of genes.

The brakes on gene activation that vitamin C helps release are molecules called methyl groups. These methyl groups are added to DNA at specific points along the genome to prevent specific genes from getting turned on.

During the development of multicellular organisms, humans among them, different patterns of methylation arise in different cells as methyl groups are biochemically attached to DNA at specific points along the genome during successive cell divisions. Normally this gradual methylation, a key part of the developmental program, is not reversible.

But after fertilization and during early development, a class of enzymes called “Tet” acts on a wide array of the methyl groups on the DNA to remove these brakes, so that genes can be activated as needed.

The UCSF researchers demonstrated that Tet enzymes require vitamin C for optimal activity as they act to remove the methyl groups from the DNA and to stimulate gene activity that more faithfully mimics in cultured stem cells what occurs at early stages of development in the mouse embryo.

“Potential roles for vitamin C in the clinic — including in embryo culture media used during in vitro fertilization, which currently do not contain vitamin C, and in cancers driven by aberrant DNA methylation — deserve exploration,” Ramalho-Santos, said.

In addition, scientists previously have found that many adult tissues also have stem cells, which can generate a variety of cell types found within a specific tissue. This raises the possibility that vitamin C might help maintain healthy stem cell populations in the adult, according to Ramalho-Santos.

“Although we did not in this paper address the function of Vitamin C in adult tissues, given the roles that Tet enzymes are now known to play in adult tissues, we anticipate that Vitamin C might also regulate Tet function in the adult,” Ramalho-Santos said. “This remains to be determined.”

Vitamin C already has become a popular supplement in recent decades, and potential health benefits of vitamin C supplementation continue to be investigated in clinical trials. It has been more than 80 years since vitamin C was first recognized as vital to prevent scurvy, a now rare connective-tissue disease caused by the failure of another enzyme that also relies on vitamin C.

The function of vitamin C as an antioxidant to prevent chemical damage is the likely reason why some commercial suppliers of growth media have included it in their products, Ramalho-Santos said, but other antioxidant molecules cannot replace Vitamin C in the enhancement of the activity of Tet enzymes.

Despite its importance, humans, unlike most animals and plants, cannot synthesize their own Vitamin C and must obtain it through their diet. The mouse makes vitamin C, but that fact does not diminish the expectation that the new findings will also apply to human development, according to Ramalho-Santos. Only adult liver cells in the mouse make vitamin C, he said.

Ramalho-Santos now aims to explore the newly discovered phenomenon in the living mouse. “The next step is to study vitamin C and gene expression in vivo,” he said.

 

http://www.sciencedaily.com/releases/2013/07/130701163755.htm

Compound found in rosemary protects against macular degeneration in laboratory model

Contact: Heather Buschman, Ph.D. hbuschman@sanfordburnham.org 858-795-5343 Sanford-Burnham Medical Research Institute

Sanford-Burnham researchers discover that carnosic acid, a component of the herb rosemary, promotes eye health in rodents—providing a possible new approach for treating conditions such as age-related macular degeneration

      IMAGE:   Left: This shows control cells exposed to hydrogen peroxide. Right: This shows cells treated with carnosic acid are protected from hydrogen peroxide. Live cells are stained green, dead cells are…Click here for more information.

 

LA JOLLA, Calif., November 27, 2012 – Herbs widely used throughout history in Asian and early European cultures have received renewed attention by Western medicine in recent years. Scientists are now isolating the active compounds in many medicinal herbs and documenting their antioxidant and anti-inflammatory activities. In a study published in the journal Investigative Ophthalmology & Visual Science, Stuart A. Lipton, M.D., Ph.D. and colleagues at Sanford-Burnham Medical Research Institute (Sanford-Burnham) report that carnosic acid, a component of the herb rosemary, promotes eye health.

Lipton’s team found that carnosic acid protects retinas from degeneration and toxicity in cell culture and in rodent models of light-induced retinal damage. Their findings suggest that carnosic acid may have clinical applications for diseases affecting the outer retina, including age-related macular degeneration, the most common eye disease in the U.S.

Age-related macular degeneration

Age-related macular degeneration likely has many underlying causes. Yet previous studies suggest that the disease might be slowed or improved by chemicals that fight free radicals—reactive compounds related to oxygen and nitrogen that damage membranes and other cell processes.

Lipton’s team first discovered a few years ago that carnosic acid fights off free radical damage in the brain. In their latest study, Lipton and colleagues, including Tayebeh Rezaie, Ph.D. and Takumi Satoh, Ph.D., initially investigated carnosic acid’s protective mechanism in laboratory cultures of retinal cells.

The researchers exposed the cells growing in the dish to hydrogen peroxide in order to induce oxidative stress, a factor thought to contribute to disease progression in eye conditions such as macular degeneration and retinitis pigmentosa. They found that cells treated with carnosic acid triggered antioxidant enzyme production in the cells, which in turn lowered levels of reactive oxygen and nitrogen species (cell-damaging free radicals and peroxides).

Rosemary’s therapeutic potential

Lipton, Rezaie, Satoh and colleagues next tested carnosic acid in an animal model of light-induced damage to photoreceptors—the part of the eye that converts light to electrical signals, enabling visual perception. As compared to the untreated group, rodents pre-treated with carnosic acid retained a thicker outer nuclear layer in the eye, indicating that their photoreceptors were protected. The carnosic acid-treated rodents also exhibited better electroretinogram activity, a measure of healthy photoreceptor function.

What’s next for carnosic acid? “We’re now developing improved derivatives of carnosic acid and related compounds to protect the retina and other brain areas from a number of degenerative conditions, including age-related macular degeneration and various forms of dementia,” said Lipton, director of Sanford-Burnham’s Del E. Webb Neuroscience, Aging, and Stem Cell Research Center and an active clinical neurologist.

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Note to members of the media: Please contact Heather Buschman at hbuschman@sanfordburnham.org to schedule on-site, phone, or Skype interviews with Stuart A. Lipton, M.D., Ph.D. Images are also available upon request.

This research was funded by the U.S. National Institutes of Health: Eunice Kennedy Shriver National Institute of Child Health & Human Development grant P01 HD29587; National Institute of Environmental Health Sciences grant P01 ES016738; National Institute of Neurological Disorders and Stroke grant P30 NS076411; National Eye Institute grant R01 EY05477

The study was co-authored by Tayebeh Rezaie, Sanford-Burnham; Scott R. McKercher, Sanford-Burnham; Kunio Kosaka, Nagase & Co., Ltd.; Masaaki Seki, Sanford-Burnham; Larry Wheeler, Allergan, Inc.; Veena Viswanath, Allergan, Inc.; Teresa Chun, Allergan, Inc.; Rabina Joshi, Sanford-Burnham; Marcos Valencia, Sanford-Burnham; Shunsuke Sasaki, Iwate University; Terumasa Tozawa, Iwate University; Takumi Satoh, Sanford-Burnham and Iwate University; and Stuart A. Lipton, Sanford-Burnham.

About Sanford-Burnham Medical Research Institute

Sanford-Burnham Medical Research Institute is dedicated to discovering the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. The Institute consistently ranks among the top five organizations worldwide for its scientific impact in the fields of biology and biochemistry (defined by citations per publication) and currently ranks third in the nation in NIH funding among all laboratory-based research institutes. Sanford-Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, and infectious, inflammatory, and childhood diseases. The Institute is especially known for its world-class capabilities in stem cell research and drug discovery technologies. Sanford-Burnham is a U.S.-based, non-profit public benefit corporation, with operations in San Diego (La Jolla), California and Orlando (Lake Nona), Florida. For more information, news, and events, please visit us at sanfordburnham.org.

Vitamin C boosts the reprogramming of adult cells into stem cells

2009 study posted for filing

Contact: Cathleen Genova cgenova@cell.com 617-397-2802 Cell Press

Famous for its antioxidant properties and role in tissue repair, vitamin C is touted as beneficial for illnesses ranging from the common cold to cancer and perhaps even for slowing the aging process. Now, a study published online on December 24th by Cell Press in the journal Cell Stem Cell uncovers an unexpected new role for this natural compound: facilitating the generation of embryonic-like stem cells from adult cells.

Over the past few years, we have learned that adult cells can be reprogrammed into cells with characteristics similar to embryonic stem cells by turning on a select set of genes. Although the reprogrammed cells, called induced pluripotent stem cells (iPSCs), have tremendous potential for regenerative medicine, the conversion is extremely inefficient.

“The low efficiency of the reprogramming process has hampered progress with this technology and is indicative of how little we understand it. Further, this process is most challenging in human cells, raising a significant barrier for producing iPSCs and serious concerns about the quality of the cells that are generated,” explains senior study author Dr. Duanqing Pei from the South China Institute for Stem Cell Biology and Regenerative Medicine at the Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences.

Dr. Pei and colleagues measured the production of reactive oxygen species or ROS during reprogramming and discovered a potential link between high ROS and low reprogramming efficiency. They became particularly interested in antioxidants, hypothesizing that they might suppress ROS and cell senescence, which seems to be a major roadblock for the generation of iPSCs.

The researchers found that adding vitamin C, an essential nutrient that is abundant in citrus fruits, enhanced iPSC generation from both mouse and human cells. Vitamin C accelerated gene expression changes and promoted a more efficient transition to the fully reprogrammed state. Somewhat to their surprise, they found that other antioxidants do not have the same effect, but vitamin C does seem to act at least in part through slowing cell senescence.

“Our results highlight a simple way to improve iPSC generation and provide additional insight into the mechanistic basis of reprogramming,” concludes Dr. Pei. “It is also of interest that a vitamin with long-suspected anti-aging effects has such a potent influence on reprogramming, which can be considered a reversal of the aging process at the cellular level. It is likely that our work may stimulate further research in this area as well.”

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The researchers include Miguel Angel Esteban, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; Tao Wang, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; Baoming Qin, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; Jiayin Yang, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; Dajiang Qin, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; Jinglei Cai, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; Wen Li1, Zhihui Weng, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; Su Ni, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; Keshi Chen, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; Yuan Li, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; Xiaopeng Liu, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; Jianyong Xu, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; Shiqiang Zhang, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; Feng Li, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; Wenzhi He1, Krystyna Labuda, Ludwig Boltzmann Institute for Clinical and Experimental Traumatology, Vienna, Austria, Austrian Cluster for Tissue Regeneration, Vienna, Austria, Yancheng Song, Austrian Cluster for Tissue Regeneration, Vienna, Austria; Anja Peterbauer, Austrian Cluster for Tissue Regeneration, Vienna, Austria, Red Cross Blood Transfusion Service of Upper Austria, Linz, Austria; Susanne Wolbank, Ludwig Boltzmann Institute for Clinical and Experimental Traumatology, Vienna, Austria, Austrian Cluster for Tissue Regeneration, Vienna, Austria, Heinz Redl, Ludwig Boltzmann Institute for Clinical and Experimental Traumatology, Vienna, Austria, Austrian Cluster for Tissue Regeneration, Vienna, Austria, Daozhang Cai, Austrian Cluster for Tissue Regeneration, Vienna, Austria; Lingwen Zeng, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; and Duanqing Pei, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.

73rd Health Research Report 05 JAN 2010 – Reconstruction

 

In this issue:

1. Growing evidence suggests progesterone should be considered a treatment option for traumatic brain injuries

2. Alzheimer’s disease may protect against cancer and vice versa

3. Citrus surprise: Vitamin C boosts the reprogramming of adult cells into stem cells

4. Chlorophylls effective against aflatoxin

5. New year, new vitamin C discovery: It ‘cures’ mice with accelerated aging disease

6. (glycyrrhizin extracted from licorice root) A trip to the candy store might help ward off rare, but deadly infections

7. Running shoes may cause damage to knees, hips and ankles

8. Natural compound ( Quercetin) blocks hepatitis C infection

9. Caffeine consumption associated with less severe liver fibrosis

 

Public release date: 22-Dec-2009

Growing evidence suggests progesterone should be considered a treatment option for traumatic brain injuries

Researchers at Emory University in Atlanta, GA, recommend that progesterone (PROG), a naturally occurring hormone found in both males and females that can protect damaged cells in the central and peripheral nervous systems, be considered a viable treatment option for traumatic brain injuries, according to a clinical perspective published in the January issue of the American Journal of Roentgenology.

“Traumatic brain injury (TBI) is an important clinical problem in the United States and around the world,” said Donald G. Stein, PhD, lead author of the paper. “TBI has received more attention recently because of its high incidence among combat casualties in Iraq and Afghanistan. Current Department of Defense statistics indicated that as many as 30 percent of wounded soldiers seen at Walter Reed Army Hospital have suffered a TBI, a finding that has stimulated government interest in developing a safe and effective treatment for this complex disorder,” said Stein.

“Growing evidence indicates that post-injury administration of PROG in a variety of brain damage models can have beneficial effects, leading to substantial and sustained improvements in brain functionality. PROG given to both males and females can cross the blood-brain barrier and reduce edema (swelling) levels after TBI; in different models of cerebral ischemia (restriction of blood supply), significantly reduce the area of necrotic cell death and improve behavioral outcomes; and protect neurons distal to the injury that would normally die,” said Stein.

PROG was recently tested in two phase 2 clinical trials for traumatic brain injury and will begin a phase 3 NIH sponsored trial soon.

“Given its relatively high safety profile, its ease of administration, its low cost and ready availability, PROG should be considered a viable treatment option — especially because, in brain injury, so little else is currently available,” said Stein.

 

Public release date: 23-Dec-2009

Alzheimer’s disease may protect against cancer and vice versa

Embargoed for release until 4 p.m. ET, Wednesday, Dec. 23, 2009

ST. PAUL, Minn. – People who have Alzheimer’s disease may be less likely to develop cancer, and people who have cancer may be less likely to develop Alzheimer’s disease, according to a new study published in the December 23, 2009, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“Discovering the links between these two conditions may help us better understand both diseases and open up avenues for possible treatments,” said study author Catherine M. Roe, PhD, of Washington University School of Medicine in St. Louis, MO, and a member of the American Academy of Neurology.

For the study, researchers looked at a group of 3,020 people age 65 and older who were enrolled in the Cardiovascular Health Study and followed them for an average of five years to see whether they developed dementia and an average of eight years to see whether they developed cancer. At the start of the study, 164 people (5.4 percent) already had Alzheimer’s disease and 522 people (17.3 percent) already had a cancer diagnosis.

During the study, 478 people developed dementia and 376 people developed invasive cancer. For people who had Alzheimer’s disease at the start of the study, the risk of future cancer hospitalization was reduced by 69 percent compared to those who did not have Alzheimer’s disease when the study started. For Caucasian people who had cancer when the study started, their risk of developing Alzheimer’s disease was reduced by 43 percent compared to people who did not have cancer at the start of the study, although that finding was not evident in minority groups.

Public release date: 24-Dec-2009

Citrus surprise: Vitamin C boosts the reprogramming of adult cells into stem cells

Famous for its antioxidant properties and role in tissue repair, vitamin C is touted as beneficial for illnesses ranging from the common cold to cancer and perhaps even for slowing the aging process. Now, a study published online on December 24th by Cell Press in the journal Cell Stem Cell uncovers an unexpected new role for this natural compound: facilitating the generation of embryonic-like stem cells from adult cells.

Over the past few years, we have learned that adult cells can be reprogrammed into cells with characteristics similar to embryonic stem cells by turning on a select set of genes. Although the reprogrammed cells, called induced pluripotent stem cells (iPSCs), have tremendous potential for regenerative medicine, the conversion is extremely inefficient.

“The low efficiency of the reprogramming process has hampered progress with this technology and is indicative of how little we understand it. Further, this process is most challenging in human cells, raising a significant barrier for producing iPSCs and serious concerns about the quality of the cells that are generated,” explains senior study author Dr. Duanqing Pei from the South China Institute for Stem Cell Biology and Regenerative Medicine at the Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences.

Dr. Pei and colleagues measured the production of reactive oxygen species or ROS during reprogramming and discovered a potential link between high ROS and low reprogramming efficiency. They became particularly interested in antioxidants, hypothesizing that they might suppress ROS and cell senescence, which seems to be a major roadblock for the generation of iPSCs.

The researchers found that adding vitamin C, an essential nutrient that is abundant in citrus fruits, enhanced iPSC generation from both mouse and human cells. Vitamin C accelerated gene expression changes and promoted a more efficient transition to the fully reprogrammed state. Somewhat to their surprise, they found that other antioxidants do not have the same effect, but vitamin C does seem to act at least in part through slowing cell senescence.

“Our results highlight a simple way to improve iPSC generation and provide additional insight into the mechanistic basis of reprogramming,” concludes Dr. Pei. “It is also of interest that a vitamin with long-suspected anti-aging effects has such a potent influence on reprogramming, which can be considered a reversal of the aging process at the cellular level. It is likely that our work may stimulate further research in this area as well.”

 

Public release date: 29-Dec-2009

Chlorophylls effective against aflatoxin

CORVALLIS, Ore. – A new study has found that chlorophyll and its derivative chlorophyllin are effective in limiting the absorption of aflatoxin in humans. Aflatoxin is produced by a fungus that is a contaminant of grains including corn, peanuts and soybeans; it is known to cause liver cancer – and can work in concert with other health concerns, such as hepatitis.

Levels of aflatoxin are carefully regulated in the United States, but are often found in the food supplies of developing nations, especially those with poor storage facilities.

OSU scientist George Bailey, a distinguished professor of environmental and molecular toxicology, pioneered studies of aflatoxin in China, where he found that in one region, one out of every 10 adults died from liver cancer.

But what has the science world particularly intrigued with this follow-up study is the methodology used by the researchers – a new “Phase 0” approach that safely tests low levels of carcinogens in human volunteers to measure the total aflatoxin exposure and to determine the effect of dietary chlorophlls on reducing this exposure.

Results of the study were just published in the journal Cancer Prevention Research.

Bailey and several other researchers, including lead author Carole Jubert, were part of the recent study. The journal also included a perspective written by a pair of Johns Hopkins researchers – Thomas Kensler and John Groopman – who praise the methodology and suggest that these Phase 0 “microdosing” studies should be expanded.

They wrote: “…microdosing studies with carcinogens have the potential to provide important insights into chemopreventive interventions and to enhance the overall clinical development and safety evaluation of preventive agents.”

The Phase 0 study “…may open the door for all kinds of new research,” said Jubert, a former researcher in Bailey’s lab at OSU’s Linus Pauling Institute. Jubert now works for Life Microsystems, an OSU spinoff company that hopes to continue work with natural products grown in Oregon, including pure chlorophylls.

“The technology is not particularly difficult,” she added. “It’s just a novel approach to evaluate toxin exposure in humans.”

In their study, Jubert and her colleagues gave very low doses of aflatoxin labeled with carbon-14 isotopes as a tracer to four human volunteers. They then gave the volunteers the same doses of aflatoxin along with doses of either chlorophyll or chlorophyllin, which previously had been shown to reduce carcinogen bioavailability in trout and rats. Using an accelerator mass spectrometer, they measured the rate of aflaxtoxin bioavailability. This technique is extremely sensitive, the researchers say, allowing measurement of minute amounts of any labeled compound.

Their research revealed rapid absorption of aflatoxin, which was significantly limited after the chlorophyll and chlorophyllin treatments.

“The beauty of this kind of ‘Phase 0’ study is the use of ultra-sensitive technology and ‘microdoses’ of environmental carcinogens to study toxicokinetics within the human body,” said John Mata, an OSU pharmacologist and second author on the study. “These measurements can be important because they allow us to better design future studies to understand the effects of dietary constituents on cancer risk.

“In this case, clearly the results merit further study,” Mata added. “We showed that aflatoxin is absorbed quite rapidly and that chlorophyll and chlorophyllin have an ameliorating effect, preventing the toxin from getting into the bloodstream. Further studies can more precisely explore the interactions, as well as dosage levels.”

Jubert and Mata also have tested the feasibility of using similar technology on human exposure to other toxins, including smokers who ingest carcinogens through cigarette smoke.

Mata, a professor in OSU’s College of Veterinary Medicine, is a pharmacologist who previously worked in the drug industry. He said Phase 1 studies are designed to see if a compound is safe; Phase 2 expands the scope of the project, and Phase 3 looks at the compounds’ efficacy. Phase 0 represents a new concept – a way to measure the kinetics of a drug by using extremely small doses that pose little risk to the volunteers.

In this case, the amount of radiation given the human volunteers was equal to that you would encounter from a one-hour airplane ride; the level of aflatoxin administered was 1/30th the amount the Food and Drug Administration allows in a peanut butter sandwich.

Public release date: 4-Jan-2010

New year, new vitamin C discovery: It ‘cures’ mice with accelerated aging disease

New research in the FASEB Journal reports vitamin C reverses abnormalities caused by Werner syndrome gene, including cancer, obesity, diabetes, heart failure and high cholesterol

A new research discovery published in the January 2010 print issue of the FASEB Journal (http://www.fasebj.org) suggests that treatments for disorders that cause accelerated aging, particularly Werner’s syndrome, might come straight from the family medicine chest. In the research report, a team of Canadian scientists show that vitamin C stops and even reverses accelerated aging in a mouse model of Werner’s syndrome, but the discovery may also be applicable to other progeroid syndromes. People with Werner’s syndrome begin to show signs of accelerated aging in their 20s and develop age-related diseases and generally die before the age of 50.

“Our study clearly indicates that a healthy organism or individuals with no health problems do not require a large amount of vitamin C in order to increase their lifespan, especially if they have a balanced diet and they exercise,” said Michel Lebel, Ph.D., co-author of the study from the Centre de Recherche en Cancerologie in Quebec, Canada. “An organism or individual with a mutation in the WRN gene or any gene affected by the WRN protein, and thus predisposes them to several age-related diseases, may benefit from a diet with the appropriate amount of vitamin C.”

Scientists treated both normal mice and mice with a mutation in the gene responsible for Werner’s syndrome (WRN gene) with vitamin C in drinking water. Before treatment, the mice with a mutated WRN gene were fat, diabetic, and developing heart disease and cancer. After treatment, the mutant mice were as healthy as the normal mice and lived a normal lifespan. Vitamin C also improved how the mice stored and burned fat, decreased tissue inflammation and decreased oxidative stress in the WRN mice. The healthy mice did not appear to benefit from vitamin C.

“Vitamin C has become one of the most misunderstood substances in our medicine cabinets and food,” said Gerald Weissmann, M.D., Editor-in-Chief of the FASEB Journal. “This study and others like it help explain how and why this chemical can help to defend some, but certainly not all, people from premature senescence.”

Ralph’s note – “ The healthy mice did not appear to benefit from vitamin C” If the mice were healthy, What benefit were they looking for Specifically (I.e. Immortality, Laser Vision, etc..)

 

Public release date: 4-Jan-2010

(glycyrrhizin extracted from licorice root) A trip to the candy store might help ward off rare, but deadly infections

New research in the Journal of Leukocyte Biology shows that glycyrrhizin extracted from licorice root helps the body defend against Pseudomonas aeruginosa infection

As it turns out, children were not the only ones with visions of sugar plums dancing in their heads over this past holiday season. In a new research report published in the January 2010 issue of the Journal of Leukocyte Biology (http://www.jleukbio.org), a team of scientists from the University of Texas Medical Branch and Shriners Hospitals for Children show how a compound from licorice root (glycyrrhizin from Glycyrrhiza glabra) might be an effective tool in battling life-threatening, antibiotic-resistant infections resulting from severe burns. Specifically, they found that in burned mice, glycyrrhizin improved the ability of damaged skin to create small proteins that serve as the first line of defense against infection. These proteins, called antimicrobial peptides, work by puncturing the cell membranes of bacteria similar to how pins pop balloons.

“It is our hope that the medicinal uses of glycyrrhizin will lead to lower death rates associated with infection in burn patients,” said Fujio Suzuki, Ph.D., one of the researchers involved in the work. Suzuki also said that more research is necessary to determine if this finding would have any implications for people with cystic fibrosis, who can develop Pseudomonas aeruginosa infections in their lungs.

To make this discovery, Suzuki and colleagues used three groups of mice. The first group was normal, the second group was burned and untreated, and the third group was burned and treated with glycyrrhizin. The skin of the untreated burned mice did not have any detectable antimicrobial peptides that prevent bacteria from growing and spreading, but the normal mice did. The skin of the untreated burned mice also had immature myeloid cells, which indicate an inability of the skin to produce antimicrobial peptides needed to prevent infection. The mice treated with glycyrrhizin, however, were more like the normal mice as they had the antimicrobial peptides and no immature myeloid cells.

“Burns are the most painful of all injuries,” said John Wherry, Ph.D., Deputy Editor of the Journal of Leukocyte Biology, “and the deadly Pseudomonas infections that can result from severe burns do more than add insult to those injuries. This research should serve as an important stepping stone toward helping develop new drugs that help prevent or treat Pseudomonas.”

 

Public release date: 4-Jan-2010

Running shoes may cause damage to knees, hips and ankles

Greater stresses on joints than running barefoot or walking in high-heeled shoes observed

New York, NY, January 4, 2010 – Knee osteoarthritis (OA) accounts for more disability in the elderly than any other disease. Running, although it has proven cardiovascular and other health benefits, can increase stresses on the joints of the leg. In a study published in the December 2009 issue of PM&R: The journal of injury, function and rehabilitation, researchers compared the effects on knee, hip and ankle joint motions of running barefoot versus running in modern running shoes. They concluded that running shoes exerted more stress on these joints compared to running barefoot or walking in high-heeled shoes.

Sixty-eight healthy young adult runners (37 women), who run in typical, currently available running shoes, were selected from the general population. None had any history of musculoskeletal injury and each ran at least 15 miles per week. A running shoe, selected for its neutral classification and design characteristics typical of most running footwear, was provided to all runners. Using a treadmill and a motion analysis system, each subject was observed running barefoot and with shoes. Data were collected at each runner’s comfortable running pace after a warm-up period.

The researchers observed increased joint torques at the hip, knee and ankle with running shoes compared with running barefoot. Disproportionately large increases were observed in the hip internal rotation torque and in the knee flexion and knee varus torques. An average 54% increase in the hip internal rotation torque, a 36% increase in knee flexion torque, and a 38% increase in knee varus torque were measured when running in running shoes compared with barefoot.

These findings confirm that while the typical construction of modern-day running shoes provides good support and protection of the foot itself, one negative effect is the increased stress on each of the 3 lower extremity joints. These increases are likely caused in large part by an elevated heel and increased material under the medial arch, both characteristic of today’s running shoes.

Writing in the article, lead author D. Casey Kerrigan, MD, JKM Technologies LLC, Charlottesville, VA, and co-investigators state, “Remarkably, the effect of running shoes on knee joint torques during running (36%-38% increase) that the authors observed here is even greater than the effect that was reported earlier of high-heeled shoes during walking (20%-26% increase). Considering that lower extremity joint loading is of a significantly greater magnitude during running than is experienced during walking, the current findings indeed represent substantial biomechanical changes.” Dr. Kerrigan concludes, “Reducing joint torques with footwear completely to that of barefoot running, while providing meaningful footwear functions, especially compliance, should be the goal of new footwear designs.”

Public release date: 4-Jan-2010

Natural compound ( Quercetin) blocks hepatitis C infection

Finding may lead to a new treatment

Researchers have identified two cellular proteins that are important factors in hepatitis C virus infection, a finding that may result in the approval of new and less toxic treatments for the disease, which can lead to liver cancer and cirrhosis.

An estimated 270 to 300 million people worldwide are infected with hepatitis C and the conventional treatments – interferon and ribavirin – can have significant side effects. A new drug targeting cellular proteins rather than viral proteins would be a valuable addition to the treatment arsenal, said Samuel French, an assistant professor of pathology and senior author of the study.

French and his team set out to identify the cellular factors involved in hepatitis C replication and, using mass spectrometry, found that heat shock proteins (HSPs) 40 and 70 were important for viral infection. HSP 70 was previously known to be involved, but HSP 40 was linked for the first time to hepatitis C infection, French said. They further showed that the natural compound Quercetin, which inhibits the synthesis of these proteins, significantly inhibits viral infection in tissue culture.

“This is an important finding because we can block these proteins with the idea of reducing the level of the virus in people and, ideally, completely eliminate it,” said French, who also is a researcher at UCLA’s Jonsson Comprehensive Cancer Center.

The study appeared in the most recent issue of the journal Hepatology.

Since Quercetin has been shown to inhibit hepatitis C infection, French said, a Phase I clinical trial will be launched at UCLA to determine if the compound is safe and effective.

Quercetin is a plant-derived bioflavonoid, and is used by some people as a nutritional supplement. Laboratory studies show it may have anti-inflammatory and antioxidant properties, and it is being investigated for a wide range of potential health benefits. Currently, there are early-stage clinical trials testing quercetin for safety and efficacy against sarcoidosis, asthma and glucose absorption in obesity and diabetes.

“Because Quercetin targets cellular proteins rather than viral proteins, there is less likelihood of developing viral resistance,” French said. “Cellular proteins cannot change like viral proteins can.”

Many patients in the United States have a type of hepatitis C virus that does not respond to the standard treatments. In these cases, if the virus can’t be blocked, end-stage liver disease and, ultimately, death may occur. Once HSP 40 and 70 were identified, French and his team used Quercetin in an attempt to block the proteins and found that the compound “reduced infectious particle production at non-toxic concentrations,” according to the study.

“Quercetin may allow for the dissection of the viral life cycle and has potential therapeutic use to reduce virus production with low associated toxicity,” the study states.

The UCLA clinical trial will most likely target those with type 1 hepatitis C, which is the non-responsive type prevalent in this country. Only about 50 percent of those with type 1 hepatitis C respond to treatment, French said.

Volunteers with type 1 hepatitis C who opt not to undergo conventional therapies would be recruited for the study. In other studies in other diseases, Quercetin has resulted in no significant side effects, French said.

“A non-toxic treatment for chronic hepatitis C would be great because our current therapies have significant side effects and only a certain percentage of the patient population responds,” French said.

Public release date: 5-Jan-2010

Natural compounds in pomegranates may prevent growth of hormone-dependent breast cancer

Eating fruit, such as pomegranates, that contain anti-aromatase phytochemicals reduces the incidence of hormone-dependent breast cancer, according to results of a study published in the January issue of Cancer Prevention Research, a journal of the American Association for Cancer Research.

Pomegranate is enriched in a series of compounds known as ellagitannins that, as shown in this study, appear to be responsible for the anti-proliferative effect of the pomegranate.

“Phytochemicals suppress estrogen production that prevents the proliferation of breast cancer cells and the growth of estrogen-responsive tumors,” said principal investigator Shiuan Chen, Ph.D., director of the Division of Tumor Cell Biology and co-leader of the Breast Cancer Research Program at City of Hope in Duarte, Calif.

Previous research has shown that pomegranate juice — punica granatum L — is high in antioxidant activity, which is generally attributed to the fruit’s high polyphenol content. Ellagic acid found in pomegranates inhibits aromatase, an enzyme that converts androgen to estrogen. Aromatase plays a key role in breast carcinogenesis; therefore, the growth of breast cancer is inhibited.

Chen, along with Lynn Adams, Ph.D., a research fellow at Beckman Research Institute of City of Hope, and colleagues, evaluated whether phytochemicals in pomegranates can suppress aromatase and ultimately inhibit cancer growth.

After screening and examining a panel of 10 ellagitannin-derived compounds in pomegranates, the investigators found that those compounds have the potential to prevent estrogen-responsive breast cancers. Urolithin B, which is a metabolite produced from ellagic acid and related compounds, significantly inhibited cell growth.

“We were surprised by our findings,” said Chen. “We previously found other fruits, such as grapes, to be capable of the inhibition of aromatase. But, phytochemicals in pomegranates and in grapes are different.”

According to Gary Stoner, Ph.D., professor in the Department of Internal Medicine at Ohio State University, additional studies will be needed to confirm the chemopreventive action of Urolithin B against hormone-dependent breast cancer.

“This is an in vitro study in which relatively high levels of ellagitannin compounds were required to demonstrate an anti-proliferative effect on cultured breast cancer cells,” said Stoner, who is not associated with this study. “It’s not clear that these levels could be achieved in animals or in humans because the ellagitannins are not well absorbed into blood when provided in the diet.”

Stoner believes these results are promising enough to suggest that more experiments with pomegranate in animals and humans are warranted.

Powel Brown, M.D., Ph.D., medical oncologist and chairman of the Clinical Cancer Prevention Department at the University of Texas M. D. Anderson Cancer Center, agreed with Stoner’s sentiments and said these results are intriguing. He recommended that future studies focus on testing pomegranate juice for its effect on estrogen levels, menopausal symptoms, breast density or even as a cancer preventive agent.

“More research on the individual components and the combination of chemicals is needed to understand the potential risks and benefits of using pomegranate juice or isolated compounds for a health benefit or for cancer prevention,” Brown said. “This study does suggest that studies of the ellagitannins from pomegranates should be continued.”

Until then, Stoner said people “might consider consuming more pomegranates to protect against cancer development in the breast and perhaps in other tissues and organs.”

Public release date: 5-Jan-2010

Caffeine consumption associated with less severe liver fibrosis

Study finds caffeine in sources other than coffee does not have similar effect

Researchers from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) determined that patients with chronic hepatitis C virus (HCV) who consumed more than 308 mg of caffeine daily had milder liver fibrosis. The daily amount of caffeine intake found to be beneficial is equivalent to 2.25 cups of regular coffee. Other sources of caffeine beyond coffee did not have the same therapeutic effect. Details of this study are available in the January 2010 issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases.

Liver fibrosis or scaring of the liver is the second stage of liver disease and characterized by a degradation of liver function due to accumulated connective tissue. Past studies have looked at modifiable behaviors, such as coffee consumption, that mitigate the progression of liver disease. A number of studies have looked at the benefits of higher coffee intake with results that include: lower prevalence of chronic liver disease, reduced risk of hepatocellular carcinoma (liver cancer), and lower risk of death from cirrhosis complications. “From data collected to date it remains unclear whether coffee itself, or caffeine provides the beneficial effect,” said Apurva Modi, M.D. and lead author of the current study that focuses on caffeine intake and its impact on liver fibrosis.

From January 2006 to November 2008 all patients evaluated in the Liver Disease Branch of the National Institutes of Health were asked to complete a questionnaire to determine caffeine consumption. Questions were asked pertaining to all sources of caffeine including regular and diet soft drinks; regular and decaffeinated coffee; black, green, Chinese and herbal teas; cocoa and hot chocolate; caffeine-fortified drinks; chocolate candy; caffeine pills; and medications with caffeine. Participants were asked about their frequency of caffeine consumption, which was quantified as never; 1-3 times per month; 1, 2-4, or 5-6 times per week; 1, 2-3, 4-5, and 6 or more times per day.

The analysis included 177 participants who were undergoing liver biopsy with a mean age of 51 years and mean body mass index (BMI) of 27.5. Of those in the cohort 56% were male, 59% Caucasian, 19% Black, 19% Asian, 3% Hispanic, and 68% had chronic HCV. Daily consumption of caffeine from food and beverages raged from none to 1028 mg/day with an average of 195 mg/day, which is equivalent to 1.4 cups of coffee daily. Most caffeine consumed came from regular coffee (71%) followed by caffeinated soda (13%), and black tea (4%). Repeated administration of the questionnaire within a 6-month period displayed consistent responses suggesting caffeine intake does not significantly change over time.

Patients with an Ishak fibrosis score of less than 3 had a mean caffeine intake of 212 mg/day compared with 154 mg/day for those with more advanced fibrosis. The Ishak fibrosis score is the preferred system that measures degree of liver scarring with 0 representing no fibrosis through 6 indicating cirrhosis. For each 67 mg increase in caffeine consumption (about one half cup of coffee) there was a 14% decrease in the odds of advanced fibrosis for patients with HCV. “Our data suggest that a beneficial effect requires caffeine consumption above a threshold of approximately 2 coffee-cup equivalents daily,” noted Dr. Modi. The protective effects of consuming more than 308 mg of caffeine daily persisted after controlling for age, sex, race, liver disease, BMI and alcohol intake for all study participants.

Researchers further evaluated caffeine and coffee separately to determine the individual effect of each on fibrosis. Results showed that consumption of caffeinated soda, green or black tea was not associated with reduced liver fibrosis. However, a significant protective effect could have been missed due to small numbers, as 71% of total caffeine consumed came from coffee. Caffeinated coffee had the most pronounced effect on reduced liver fibrosis. The authors suggest that further research is needed to determine if the protective benefits of coffee/caffeine intake plateau at amounts beyond the daily consumption threshold.

________________________________

 

These reports are done with the appreciation of all the Doctors, Scientist, and other

Medical Researchers who sacrificed their time and effort. In order to give people the

ability to empower themselves. Without the base aspirations for fame, or fortune.

Just honorable people, doing honorable things.

Health Research Report

73rd  Issue 05 JAN 2010

Compiled By Ralph Turchiano

www.healthresearchreport.me www.vit.bz

www.youtube.com/vhfilm www.facebook.com/engineeringevil

www.engineeringevil.com

Spices halt growth of breast stem cells, U-M study finds ( Curcumin, piperine )

2009 study posted for filing

Contact: Nicole Fawcett nfawcett@umich.edu 734-764-2220 University of Michigan Health System

ANN ARBOR, Mich. — A new study finds that compounds derived from the spices turmeric and pepper could help prevent breast cancer by limiting the growth of stem cells, the small number of cells that fuel a tumor’s growth.

Researchers at the University of Michigan Comprehensive Cancer Center have found that when the dietary compounds curcumin, which is derived from the Indian spice turmeric, and piperine, derived from black peppers, were applied to breast cells in culture, they decreased the number of stem cells while having no effect on normal differentiated cells.

“If we can limit the number of stem cells, we can limit the number of cells with potential to form tumors,” says lead author Madhuri Kakarala, M.D., Ph.D., R.D., clinical lecturer in internal medicine at the U-M Medical School and a research investigator at the VA Ann Arbor Healthcare System.

Cancer stem cells are the small number of cells within a tumor that fuel the tumor’s growth. Current chemotherapies do not work against these cells, which is why cancer recurs and spreads. Researchers believe that eliminating the cancer stem cells is key to controlling cancer. In addition, decreasing the number of normal stem cells – unspecialized cells that can give rise to any type of cell in that organ – can decrease the risk of cancer.

In this study, a solution of curcumin and piperine was applied to the cell cultures at the equivalent of about 20 times the potency of what could be consumed through diet. The compounds are available at this potency in a capsule form that could be taken by mouth. (Note: This work has not been tested in patients, and patients are not encouraged to add curcumin or piperine supplements to their diet at this time.)

The researchers applied a series of tests to the cells, looking at markers for breast stem cells and the effects of curcumin and piperine, both alone and combined, on the stem cell levels. They found that piperine enhanced the effects of curcumin, and that the compounds interrupted the self-renewal process that is the hallmark of cancer-initiating stem cells. At the same time, the compounds had no affect on cell differentiation, which is the normal process of cell development.

“This shows that these compounds are not toxic to normal breast tissue,” Kakarala says. “Women at high risk of breast cancer right now can choose to take the drugs tamoxifen or raloxifene for prevention, but most women won’t take these drugs because there is too much toxicity. The concept that dietary compounds can help is attractive, and curcumin and piperine appear to have very low toxicity.”

Curcumin and piperine have been explored by other researchers as a potential cancer treatment. But this paper, published online in the journal Breast Cancer Research and Treatment, is the first to suggest these dietary compounds could prevent cancer by targeting stem cells.

In addition, tamoxifen or raloxifene are designed to affect estrogen, which is a factor in most, but not all breast cancers. In fact, the aggressive tumors that tend to occur more often in women with a family history or genetic susceptibility are typically not affected by estrogen. Because curcumin and piperine limit the self renewal of stem cells, they would impact cancers that are not estrogen sensitive as well as those that are.

Researchers are planning an initial Phase I clinical trial to determine what dose of curcumin or piperine can be tolerated in people. The trial is not expected to begin accruing participants until spring.

###

Breast cancer statistics: 194,280 Americans will be diagnosed with breast cancer this year and 40,610 will die from the disease, according to the American Cancer Society

Additional authors: Dean Brenner, Hasan Korkaya, Connie Cheng, Karim Tazi, Christophe Ginestier, Suling Liu, Gabriel Dontu and Max Wicha, all from U-M

Funding: National Institutes of Health; curcumin and piperine were donated by Sabinsa Co.

Reference: Breast Cancer Research and Treatment, DOI: 10.1007/s10549-009-0612-x

Resources: U-M Cancer AnswerLine, 800-865-1125 U-M Comprehensive Cancer Center, www.mcancer.org Cancer’s Stem Cell Revolution, www.mcancer.org/stemcells

71st Health Research Report 08 DEC 2009 – Reconstruction

 

Editors Top Five:

 

1. Aspirin, Tylenol May Decrease Effectiveness of Vaccines (actually all antibodies, vaccinated or not) MUST READ

2. Popular diabetes drugs linked to increased risk of heart failure and death

3. Coffee consumption associated with reduced risk of advanced prostate cancer

4. Spices halt growth of breast stem cells, U-M study finds

5. Young adults’ blood lead levels linked to depression, panic disorder

 

In this issue:

 

1. Chicken capsules good for aching joints

2. Long-term physical activity has an anti-aging effect at the cellular level

3. To keep muscles strong, the ‘garbage’ has to go

4. Will copper keep us safe from the superbugs?

5. Are the effects of pornography negligible?

6. Aspirin, Tylenol May Decrease Effectiveness of Vaccines (actually all antibodies, vaccinated or not) MUST READ

7. Young adults who exercise get higher IQ

8. Toy recall of 2007 hurt innocent companies

9. Childhood lead exposure causes permanent brain damage

10. Green tea chemical combined with another may hold promise for treatment of brain disorders

11. Popular diabetes drugs linked to increased risk of heart failure and death

12. Researchers find increased dairy intake reduces risk of uterine fibroids in black women

13. Mayo Clinic and collaborators find vitamin D levels associated with survival in lymphoma patients

14. Antioxidant compound reduced incidence of colorectal metachronous adenomas

15. Exercise reduces death rate in prostate cancer patients

16. Coffee consumption associated with reduced risk of advanced prostate cancer

17. Young adults’ blood lead levels linked to depression, panic disorder

18. Spices halt growth of breast stem cells, U-M study finds

19. Most antidepressants miss key target of clinical depression

Health Research Report

71st  Issue Date 08 DEC 2009

Compiled By Ralph Turchiano

www.healthresearchreport.me www.vit.bz

www.youtube.com/vhfilm www.facebook.com/engineeringevil

www.engineeringevil.com

Stem Cells Not Needed for Cancer

Fully developed neurons can revert to stem cell-like states and give rise to brain tumors.

By Ruth Williams |October 18, 2012

The prevailing view that stem cells are the principle originators of brain cancer may be incorrect, according to a report out today (October 18) in Science.The new study suggests that terminally differentiated brain cells, including neurons, can be reprogrammed by oncogenic factors to become progenitor-like cells that then develop into brain tumors, or gliomas.

“What’s provocative about these experiments is that they challenge the notion that only stem cells can give rise to cancers of the brain,” said David Gutmann, a professor of neurology at Washington University in St Louis, Missouri, who did not participate in the study. “While we were all very excited 10 years ago when the cancer stem cell hypothesis came out, I think it was perhaps wishful thinking for us to believe that that was the only path to cancer.” The researchers were “able to demonstrate that you can get gliomas from these terminally differentiated neurons,” agreed Ronald DePinho, president of the MD Anderson Cancer Center at the University of Texas, Houston. “[The finding] is very exciting and basically teaches us that cells maintain an extraordinary level of plasticity.”

The potential for multiple cell types to give rise to brain cancer may also account for the variety of glioma subclasses observed, Gutmann added.

Inder Verma, a geneticist at the Salk Institute in La Jolla, California made the discovery as part of a larger effort to create mouse models of glioma. The team had injected lentiviral vectors that activated Ras signaling—a pathway that promotes cell growth and division—into the brains of mice that were deficient in the cell cycle protein p53 to induce gliomas.

The cellular origin of these gliomas was unknown, but the researchers assumed the most likely candidates were neural progenitor cells, because such cells are more easily reprogrammable and share many features with cancer cells. In the latest study, however, Verma’s team used an approach to specifically target mature neurons and astrocytes, and found both cell types were able to produce gliomas.

The neuron and astrocyte-derived gliomas expressed high levels of stem and progenitor cell marker proteins. And in vitro studies confirmed that the lentiviral vectors induced differentiated adult brain cells to adopt progenitor like features—similar to those found in neural and induced pluripotent stem cells. Transplanting these reprogrammed cells into receptive mice resulted in tumor growth, confirming the cells were cancerous.

“What we’re saying is, any cell in the brain that gets an oncogenic insult has the ability to dedifferentiate [and form tumors],” said Verma. This might seem a rather bleak outlook, but “by knowing the mechanism, we at least have a handle to start thinking about [treatments],” Verma said.

Of course, just because differentiated neurons can be induced to give rise to tumors experimentally doesn’t mean the process occurs in human patients, Gutmann pointed out. But Verma and colleagues found evidence to suggest that it might.  An analysis of the molecular profiles of the tumors derived from adult neurons revealed a striking similarity to that of a particularly aggressive subtype of human glioma.  “It is possible that these human tumors might also have originated from neurons,” said Verma.

The finding also suggested that different cells-of-origin give rise to different types of glioma. “It’s like German Americans and Italian Americans,” said Gutmann. “They’re both American citizens but still retain their heritage.” Importantly, he added, those subtle ancestral differences “may make a huge difference in terms of response to therapy and outcome.”

D. Friedmann-Morvinski et al., “Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice,” Science, doi: 10.1126/science.1226929, 2012

http://www.the-scientist.com/?articles.view/articleNo/32899/title/Stem-Cells-Not-Needed-for-Cancer/

 

Moriguchi broadly admits to lying about trailblazing stem cell trial

News On Japan via Mainichi — Oct 14
 

Hisashi Moriguchi, a Japanese researcher who had said he implemented the world’s first clinical trial using a trailblazing stem cell technology, admitted Saturday most of what he claimed in an academic conference presentation about the procedure was false.

 

At a news conference in New York, Moriguchi said, “While the treatment was implemented, it was only one procedure. At the end of the day, I lied.”He earlier said treatment using induced pluripotent stem cells was conducted on a total of six people, including the first case on a man with a failing heart in February this year. He also corrected the timing of the trial to June last year.

He said he was present during the procedure allegedly undertaken in the United States and showed his passport record to reporters.

Massachusetts General Hospital in Boston, where he claimed that the trial was conducted, said Friday there are no records of him having undertaken the procedure or of applying for approval to carry it out.

iPS細胞(人工多能性幹細胞)を使った臨床応用について、虚偽の発表をした森口尚史氏は、13日、滞在先のアメリカ・ニューヨークで会見し、6例行ったと主張した手術の­うち、5例についてはうそだったと認めた。

Reprogramming of Pericyte-Derived Cells of the Adult Human Brain into Induced Neuronal Cells

  • Reprogramming of somatic cells into neurons provides a new approach toward cell-based therapy of neurodegenerative diseases (Vierbuchen and Wernig, 2011). Previous studies have shown that postnatal astroglia from the mouse cerebral cortex can be directly converted into functional neuronal cells in vitro by forced expression of a single transcription factor (Heinrich et al., 2010, Heinrich et al., 2011; Heins et al., 2002) and that the synergistic action of three or four transcription factors can induce neurogenesis from rodent and human fibroblasts (Caiazzo et al., 2011; Pang et al., 2011; Qiang et al., 2011; Son et al., 2011; Vierbuchen et al., 2010; Yoo et al., 2011). However, a major challenge for the translation of neuronal reprogramming into therapy is whether direct conversion of somatic cells into neuronal cells can be achieved from cells residing within the adult human brain. To address this question, we prepared adherent cultures from 30 human specimens that were derived from surgical approaches through the cerebral cortex to deep-seated nontraumatic nonmalignant lesions, i.e., epileptic foci and nonruptured vascular lesions. In order to characterize the cellular composition of the cultures obtained from these specimens, we performed immunocytochemistry and fluorescence-activated cell sorting (FACS) analyses at different stages of culturing. Intriguingly, the majority of cells expressed platelet-derived growth factor receptor-β (PDGFRβ) (Daneman et al., 2010) (Figures 1C and 1D and Figure S1A available online), which is detected within the human brain tissue exclusively on microvessel-associated pericytes (Figure 1A), a cell type involved in the establishment and maintenance of the blood-brain barrier and regulation of local blood flow (Armulik et al., 2011). Consistent with a pericyte identity, we also observed expression of NG2 (Karram et al., 2005) (Figure 1B and S1B), smooth muscle actin (SMA) (Figures S1A and S1B) (Hellström et al., 1999), CD146 (Crisan et al., 2008), and CD13 (Crisan et al., 2008) (Figure 1E), though with some heterogeneity with regard to coexpression of these markers (Figures 1E, S1A, and SB). In contrast, the number of glial acidic fibrillary protein (GFAP)-positive cells was extremely low in these cultures (<1%), although astrocytes were readily detected within the human tissue (data not shown). Quantitative RT-PCR experiments confirmed the enriched expression of pericytic marker genes and the virtual absence of astroglial (gfap) and oligodendroglial cells (olig2) in these cultures compared to human brain tissue from which the cells had been isolated (Figure S1C). Importantly, βIII-tubulin could not be detected at any stage of culturing (assessed from 2 days to 8 weeks after plating), demonstrating that these cultures were devoid of neuroblasts or surviving neurons (data not shown). Furthermore, these cultures were completely devoid of expression of neural stem cell markers such as sox2 or prom1 or neurogenic fate determinants such as ascl1 or pax6 (Figure S1C). Moreover, Sox2, Mash1, Olig2, and Pax6 were also not detected on the protein level by immunocytochemistry (data not shown). The few CD34-positive cells (Figures 1D and S1C) of hematopoietic or endothelial origin were lost upon passaging. Thus, these cultures are enriched for cells exhibiting pericyte characteristics.
    • Figure 1 Characterization and In Vitro Conversion into Induced Neuronal Cells of Human and Mouse Adult Brain Pericyte-like Cells (A) PDGFRβ expression in microvessel-associated cells in the adult human cerebral cortex. Scale bar: 100 μm. (B) NG2 expression in microvessel-associated cells in the adult human cerebral cortex. Microvessels were visualized by CD31 (green) immunoreactivity and DAPI (blue). Scale bar: 100 μm. (C) Immunocytochemical analysis for pericyte marker PDGFRβ (red) in cell cultures obtained from human cerebral tissue; DAPI is in blue. Scale bar: 100 μm. See also Figures S1A and S1D. Scale bar: 100 μm. (D) Example of FACS analysis from an adult human brain culture. Depicted are the isotype controls (ctrl, left and middle panel) for establishing the gating conditions for sorting the PDGFRβ- and CD34-positive populations. See also Figure S1I. (E) Relative coexpression of pericyte markers as analyzed by FACS analysis. Each data point represents the relative coexpression of PDGFRβ and CD146 (mean 40.7% ± 28.1%) or CD13 (mean 46.4% ± 29.1%). (F) Quantification of the effect on βIII-tubulin expression and morphology following DsRed only for control, Sox2, Mash1, and combined Sox2 and Mash1 expression. Cells were categorized for exhibiting a flat polygonal morphology, round morphology without processes, or neuronal morphology with processes. Each value represents the mean of βIII-tubulin-positive cells from six different patients. For each patient and treatment, at least three experimental replicates were analyzed. For each condition >1,000 cells were analyzed. Error bars are SEM. (G) Live imaging of the conversion of a PDGFRβ-positive FACS-sorted cell (blue arrow, see also Figure S1I) into an induced neuronal cell following coexpression of Sox2 and Mash1. Pictures show phase contrast and fluorescence (Mash1-DsRed and Sox2-GFP) images at different time points (Days-Hours:Minutes) during the reprogramming process. Note the change of the cotransduced cell from a protoplasmic to a neuron-like morphology. See also Movie S1Download (20.51 MB)Movie S1. Direct Observation of Neuronal Reprogramming of PDGFRβ- Sorted Pericyte-Derived Cells from the Adult Human Brain by Continuous Live Imaging in Culture Note the change in morphology of a cell coexpressing Sox2 and Mash1 (blue arrow) during reprogramming. Postimaging immunocytochemistry for βIII-tubulin (white) confirms the neuronal identity of the reprogrammed cell at the end of live imaging (see also Figure 1F).. (G′) Depicted is the last recorded time point in phase contrast (LT) and the postimmunocytochemistry (Post IC) of the reprogrammed cell for GFP (green), DsRed (red), and βIII-tubulin (white). (H) Example of MAP2 and βIII-tubulin coexpression after 5 weeks following transduction. See also Figure S1G. (I) Specific β-galactosidase expression associated with CD31-positive blood vessels in the cerebral cortex of Tg:TN-AP-CreERT2:R26RNZG mice. β-galactosidase-positive cells express the pericyte marker PDGFRβ. Note the restricted expression around microvessels. β-galactosidase, green; PDGFRβ, red; CD31, blue. Scale bars: left panel, 50 μm; right panels, 10 μm. (J) Reprogramming of EYFP-positive cells isolated from the cerebral cortex of adult Tg:TN-AP-CreERT2:R26REYFP mice into induced neuronal cells. EYFP-positive cells (green) transduced with Mash1 (red) and Sox2 (without reporter) display a neuronal morphology and express βIII-tubulin; 14 days postinfection. Scale bar: 100 μm. For the efficiency of reprogramming of mouse pericytic cells, see Figures S1J–S1K.
  • Previous work has identified Mash1 (mammalian achaete-scute homolog 1, encoded by the gene ascl1) as a powerful reprogramming factor for direct conversion of somatic cells into neuronal cells (Berninger et al., 2007; Caiazzo et al., 2011; Vierbuchen et al., 2010). When we assessed the response of our cultures to retrovirus-mediated expression of Mash1 (CAG-ascl1-IRES-dsred), we observed the reduction of PDGFRβ expression to 23% (n[cells] = 219), indicating a loss of pericyte-specific protein expression (Figure S1D). Moreover, a subset of Mash1-transduced cells responded with the induction of βIII-tubulin, suggesting some degree of neuronal respecification (Figure 1F). Previous work has suggested that Sox2 expression may facilitate neuronal reprogramming of postnatal astrocytes by neurogenic fate determinants (Heinrich et al., 2010). As there was no endogenous Sox2 expression in these cultures (Figure S1C), we hypothesized that forced expression of sox2 may enhance the efficiency of neuronal reprogramming by Mash1. Expression of Sox2 (CAG-sox2-IRES-gfp) alone had no overt effect on βIII-tubulin expression (Figure 1F) or morphology of pericyte-like cells (Figure S1F). In contrast, coexpression of Sox2 and Mash1 significantly increased the proportion of βIII-tubulin-expressing cells to 48% ± 9% SEM (n[cells] = 1,500, analyzed after 4–5 weeks following transduction, cultures from six different patients; compared to 10% ± 4% SEM after Mash1 transduction alone, p = 0.0038, Figure 1F). Most strikingly, many of the double-transduced cells (28% ± 5% SEM) exhibited neuronal morphology (Figure S1F) and induced expression of MAP2 (46% ± 11% SEM, n[cells] = 296 from three different patients, analyzed after 5–6 weeks; Figures 1H and S1G) and NeuN (Figure S1H), indicating a high degree of reprogramming efficiency of cells from adult human tissue. Consistent with the acquisition of a neuronal phenotype and a loss of pericyte identity, Sox2- and Mash1-coexpressing cells downregulated PDGFRβ (Figure S1E). Of note, some cultures contained virtually only (97%) PDGFRβ-positive cells (Figure 1D), of which 46% of the Mash1 and Sox2 cotransduced cells differentiated into βIII-tubulin-positive cells, with 26% exhibiting neuronal morphology (n[cells] = 203). In the following we refer to these neuronal cells derived from human pericyte-like cells as human pericyte-derived induced neuronal cells (hPdiNs).
  • Despite the high frequency of PDGFRβ-positive cells infected by the retroviral vectors, the remainder of PDGFRβ-negative cells may still act as the main source of induced neuronal cells upon Mash1 and Sox2 transduction. Thus, we proceeded to follow the fate conversion of pericytes by live imaging (Rieger et al., 2009). Cultured cells were FACS-sorted for surface expression of PDGFRβ (Figure S1I), transduced 48 hr later with retroviral vectors encoding sox2 and ascl1, and subsequently imaged by time-lapse video microscopy (Movie S1Download (20.51 MB)Movie S1. Direct Observation of Neuronal Reprogramming of PDGFRβ- Sorted Pericyte-Derived Cells from the Adult Human Brain by Continuous Live Imaging in Culture Note the change in morphology of a cell coexpressing Sox2 and Mash1 (blue arrow) during reprogramming. Postimaging immunocytochemistry for βIII-tubulin (white) confirms the neuronal identity of the reprogrammed cell at the end of live imaging (see also Figure 1F).). Figure 1G shows an example of an anti-PDGFRβ FACS-sorted cell undergoing Sox2- and Mash1-induced neurogenesis. The cell acquired a polarized morphology within 12 days following transduction and could be shown to express βIII-tubulin at the end of the live imaging (Figure 1G′). Intriguingly, following the onset of reporter expression, this PDGFRβ-sorted cell did not undergo any cell division, providing evidence for direct conversion from an adult human nonneuronal somatic cell into an hPdiN. Likewise, only 1 of 36 (3%) Sox2- and Mash1-coexpressing cells that we followed over time underwent cell division, in sharp contrast to untransduced (n[cells] = 11/30; 36%], Mash1-only (n[cells] = 8/30; 26%), and Sox2-only transduced cells (n[cells] = 13/30; 46%), indicating that Sox2- and Mash1-induced reprogramming does not only not require cell division, but is accompanied by immediate cell cycle exit. Of all the tracked cells coexpressing Sox2 and Mash1, 36% endured cell death. This percentage was considerably higher than that of untransduced cells (3%) and Sox2-only transduced cells (7%). Of note, Mash1-only transduced cells also exhibited a higher rate of cell death (33%), suggesting that Mash1 or Sox2 and Mash1 coexpression can induce a catastrophic conflict of cell fates in pericyte-derived cells. Counting of βIII-tubulin-positive cells after imaging revealed that none of the Sox2-only cells (n[cells] > 300), 7% of Mash1-only (n[cells] = 88) cells, and 25% of double-positive cells (n[cells] = 786; two independent experiments) expressed βIII-tubulin. In an additional experiment, in which cells had been sorted simultaneously for PDGFRβ and CD146 and had been time-lapsed, a reprogramming efficiency of 37% was observed (n[cells] = 209). Combining all time-lapse experiments, the overall reprogramming efficiency was 19% of the coinfected cells, taking proliferation and cell death into account.
  • To unequivocally determine the origin of the reprogrammed cells from pericytes in vivo, we turned to genetic fate-mapping in mice. We took advantage of a transgenic mouse that expresses an inducible Cre recombinase (CreERT2) under control of the tissue-nonspecific alkaline phosphatase (TN-AP) promoter for genetic fate mapping of pericytes (Dellavalle et al., 2011). These mice were crossed to reporter lines (Tg:TN-AP-CreERT2:R26RNZG and Tg:TN-AP-CreERT2:R26REYFP) to aid identification of cells of pericytic origin either by β-galactosidase or yellow fluorescent protein (YFP) immunoreactivity following tamoxifen-induced Cre-mediated excision of the stop cassette. As expected β-galactosidase expression was confined to microvessel-associated cells coexpressing PDGFRβ (Figure 1I) and NG2 (data not shown) (Dellavalle et al., 2011) in the cerebral cortex of young adult mice following induction at postnatal stages, indicating that the TN-AP promoter allows reliable fate-mapping of pericyte-derived cells in the adult brain. Next we prepared cultures from the adult cerebral cortex of Tg:TN-AP-CreERT2:R26REYFP mice under the same culture conditions as used for human samples. As in the adult cerebral cortex, reporter-positive cells coexpressed the pericytic markers PDGFRβ, NG2, and CD146 and could be expanded in vitro (data not shown). In contrast to control vector-transduced reporter-positive pericyte-derived cells (data not shown), Sox2- and Mash1-expressing cells gave rise to βIII-tubulin-positive PdiNs (Figure 1J). Neuronal reprogramming of wild-type mouse pericyte-derived cells occurred at an even higher frequency compared to adult human pericyte-derived cells: coexpression of Sox2 and Mash1 significantly increased the proportion of βIII-tubulin-positive cells to 92% ± 3% SEM (compared to 41% ± 10% SEM after Mash1 transduction alone, p = 0.0028) (Figure S1K), and most of the double-transduced cells (73% ± 7% SEM) exhibited neuronal morphology (Figure S1J) and were capable of repetitive action potential firing (Figure S2F and Table S1).
  • We next analyzed whether the hPdiNs expressing neuron-specific proteins also acquire the functional membrane properties of neurons. In Mash1 (n[cells] = 7) and Sox2 (n[cells] = 6) singly transduced cells, step-current injection failed to elicit any action potentials (Figures S2A, S2A′, S2B, and S2B′), indicating that neither transcription factor alone induces neuronal electrical properties. In sharp contrast, a substantial proportion of cells (71% of 17 cells tested, cultures from five different patients) coexpressing both factors responded typically with the generation of a single action potential that could be blocked by the sodium channel antagonist tetrodotoxin (TTX) (Figures S2C and S2C′). Moreover, in voltage-clamp these cells exhibited clearly discernible sodium (Figure S2C″) and potassium (data not shown) currents. However, these hPdiNs exhibited immature properties, as reflected by the relatively high input resistances, low action potential, and peak sodium current amplitudes, even after prolonged time in culture, consistent with the slow maturation of human neurons (Table S1). In order to further promote maturation and to investigate whether hPdiNs can integrate into a neuronal network, we cocultured hPdiNs with neurons from the mouse embryonic neocortex. Under these conditions hPdiNs exhibited a more complex morphology (Figures 2A, 2B, and 2E) and were capable of repetitive action potential firing (Figure 2C), although input resistances were still high (Table S1). Importantly, hPdiNs were found to receive functional glutamatergic input from cocultured neurons (4 out of 12 cells analyzed, Figures 2D–2D″), demonstrating that they express functional transmitter receptors, are capable of assembling a postsynaptic compartment, and can be recognized by other neurons as functional targets. Consistent with functional glutamatergic input, dendrites of hPdiNs were decorated with presynaptic terminals containing vesicular glutamate transporters (Figure 2F). Of note, hPdiNs exhibited immunoreactivity for the inhibitory neurotransmitter β-aminobutyric acid (GABA, 14/14 hPdiNs analyzed) (Figure S2D). Moreover, qRT-PCR showed the expression of the interneuron calcium binding protein pvalb (Figure S2E), pointing toward acquisition of an interneuron-like phenotype. In contrast, none of the Sox2 and Mash1 cotransduced cells expressed the glutamatergic lineage marker tbr1 (T-box brain gene 1; data not shown) or slc17a7 (encoding the vesicular glutamate transporter [vGluT]-1; Figure S2E). However, a definitive proof for a GABAergic interneuron-like identity awaits the demonstration of functional GABAergic transmission.
    • Figure 2 Neuronal Morphology and Membrane Properties of hPdiNs (A) Bright-field micrograph depicts an hPdiN (red arrowhead) after 26 days of coculture with E14 mouse cerebral cortical neurons, 46 days following retroviral transduction. (B) DsRed fluorescence indicating transduction with ascl1 and dsred-encoding retroviruses. Inset: GFP fluorescence indicating transduction with sox2– and gfp-encoding retrovirus. (C) Step current injection in current-clamp results in repetitive action potential firing. For comparison with cells transduced with a single transcription factor or cotransduced, but cultured without mouse cortical neurons, see Figures S2A–S2C″. (D) The graph depicts spontaneous synaptic events recorded from the same hPdiN as shown in (C). The enlarged trace shows individual synaptic events. (D′) The synaptic events are blocked by the application of CNQX (10 μM). (D″) Recovery of spontaneous synaptic input following washout of CNQX. For a summary of the electrophysiological properties, see Table S1. (E) Micrograph depicting an hPdiN stained for DsRed and GFP, after 22 days of coculture with E14 neurons, 42 days following retroviral transduction. (F) High-magnification view of a single dendrite (magenta, GFP) from the same hPdiN as shown in (E), illustrating the high density and the distribution of vGluT1-immunoreactive puncta (green, Cy5).
  • Here we provide evidence for high-efficiency reprogramming of pericyte-derived cells of the adult human cerebral cortex into induced neuronal cells by coexpression of only two transcription factors. The fact that only coexpressing cells convert into neuronal cells provides direct evidence for a cell-autonomous effect. Different scenarios may account for the synergism of these two transcription factors. Sox2 may facilitate Mash1-induced reprogramming by rendering the somatic genome more susceptible to the neurogenic activity exerted by Mash1. Alternatively, Sox2 may be required to directly interact with Mash1 on common target genes. While we can currently not discern between these two modes of action, the fact that Neurog2 failed to reprogram cells in culture from the adult human cerebral cortex (data not shown) argues partially against the first mechanism as the solely important one. Recent studies on the role of Mash1 and Neurog2 during cortical development suggest that these factors activate distinct programs in neural progenitors (Castro et al., 2011). Mash1 also has been found as a key transcription factor in the direct reprogramming of fibroblasts (Pang et al., 2011; Vierbuchen et al., 2010) and hepatocytes (Marro et al., 2011) where it synergizes with Brn2 and Myt1l. This may suggest that Mash1 acts as a core factor in direct neuronal reprogramming. Interestingly, we observed a very slight induction of endogenous ascl1 mRNA expression (Figure S2E). It is noteworthy that, while fibroblasts coexpressing different combinations of transcription factors have been shown to give rise to induced neuronal cells of glutamatergic identity (Pang et al., 2011; Vierbuchen et al., 2010), dopaminergic (Caiazzo et al., 2011; Kim et al., 2011; Pfisterer et al., 2011) and cholinergic motor neuron identity (Son et al., 2011), the combination of Sox2 and Mash1 appears to favor a GABAergic phenotype in hPdiNs. It will be important to understand whether this is largely dependent on the factor combination used or the cellular context determined by the origin and nature of the reprogrammed cell.
  • Local CNS pericytes have been recently recognized as a major source of proliferating scar-forming cells following CNS injury (Göritz et al., 2011). A key finding of the present study is that progeny of brain pericytes represent a potential target for direct reprogramming. While much needs to be learned about adapting a direct neuronal reprogramming strategy to meaningful repair in vivo, e.g., by using a noninvasive approach to activate these transcription factors (Kormann et al., 2011), our data provide strong support for the notion that neuronal reprogramming of cells of pericytic origin within the damaged brain may become a viable approach to replace degenerated neurons

Common cancer treatments may create dangerous cancer stem cells

By Charles Q. Choi Published September 27, 2012| MyHealthNewsDaily

 

Radiation  therapy and chemotherapy aimed at killing cancer cells may have the undesirable  effect of helping to create cancer stem cells, which are thought to be  particularly adept at generating new tumors and are especially resistant to  treatment, researchers say.

The  finding might help explain why late-stage  cancers are often resistant to both radiation therapy and  chemotherapy, and it could point to new strategies to fight tumors.

Past  studies hint that cancer  stem cells give rise to new  tumors. Researchers suggest they are ultimately responsible for the recurrence  of cancers and the dangerous spread of a cancer throughout the body. Scientists  also have found that cancer stem cells are more likely than other cancer cells  to survive chemotherapies and radiation therapies, probably becausetheir  “stemness” allows them to self-replenish by repairing their damaged DNA and  removing toxins.

The  exact origin of cancer stem cells is debated. One possibility is that normal  stem cells — which are valued for their ability to give rise to other cell types  in the body — mutate to become cancerous. Another is that regular cancer cells  somehow acquire stem cell properties.

The  new study suggests regular cancer cells can indeed give  rise to cancer stem cells, and that the radiation commonly used to  treat cancer can trigger their stemness.

“Radiotherapy  has been a standard treatment for cancer for so long, so we were quite surprised  that it could induce stemness,” said study researcher Dr. Chiang Li, of Harvard  Medical School in Boston.

The  scientists exposed regular cancer cells to gamma-rays, one form of ionizing  radiation. They found that under the conditions that normally foster stem cell  growth, regular cancer cells formed balls of cells — a hallmark  of cancer stem cells.

Additionally,  analysis of these irradiated cancer cells revealed activity of genes linked with  stem cell behaviors, according to the findings the scientists detailed online  Aug. 21 in the journal PLoS ONE.

Chemotherapy  may have similar effects, according to previous findings that Li and his  colleagues detailed in July in the journal Cell Cycle.

“So  radiation and chemotherapy not only might create cancer stem cells, any  pre-existing cancer stem cells in a tumor were veryresistant  to radiation and chemotherapy, so they remain as well,” Li said. “This could  help explain why these therapies are sometimes not as effective as we might  hope.”

Li  cautioned these lab findings might not prove relevant in patients in real life.  “This was all carried out in the petri dish,” he said. “There is a long way we  have to go before we can be sure about its clinical implications for patients,  if any.”

Still,  this research suggests that if scientists find a way to inhibit stemness in  cancers, radiation therapy and chemotherapy then might cleanly finish off  tumors.

“There  are lots of projects both in academia and industry right now to develop cancer  stem cell inhibitors, although those are still in early stages,” Li said.

Read more: http://www.foxnews.com/health/2012/09/27/common-cancer-treatments-may-create-dangerous-cancer-stem-cells/print#ixzz27oZgvkXP

Researchers detail chemotherapy’s damage to the brain” Chemotherapy drugs used to treat a wide range of cancers were more toxic to healthy brain cells than the cancer cells they were intended to treat

Re-post from 2008: This is not the watered down Chemo brain article released 5 Sep 2012..4 years later

contact: Mark Michaud
mark_michaud@urmc.rochester.edu
585-273-4790
University of Rochester Medical Center

A commonly used chemotherapy drug causes healthy brain cells to die off long after treatment has ended and may be one of the underlying biological causes of the cognitive side effects – or “chemo brain” – that many cancer patients experience. That is the conclusion of a study published today in the Journal of Biology.

A team of researchers at the University of Rochester Medical Center (URMC) and Harvard Medical School have linked the widely used chemotherapy drug 5-fluorouracil (5-FU) to a progressing collapse of populations of stem cells and their progeny in the central nervous system.

“This study is the first model of a delayed degeneration syndrome that involves a global disruption of the myelin-forming cells that are essential for normal neuronal function,” said Mark Noble, Ph.D., director of the University of Rochester Stem Cell and Regenerative Medicine Institute and senior author of the study. “Because of our growing knowledge of stem cells and their biology, we can now begin to understand and define the molecular mechanisms behind the cognitive difficulties that linger and worsen in a significant number of cancer patients.”

Cancer patients have long complained of neurological side effects such as short-term memory loss and, in extreme cases, seizures, vision loss, and even dementia. Until very recently, these cognitive side effects were often dismissed as the byproduct of fatigue, depression, and anxiety related to cancer diagnosis and treatment. Now a growing body of evidence has documented the scope of these conditions, collectively referred to as chemo brain. And while it is increasingly acknowledged by the scientific community that many chemotherapy agents may have a negative impact on brain function in a subset of cancer patients, the precise mechanisms that underlie this dysfunction have not been identified.

Virtually all cancer survivors experience short-term memory loss and difficulty concentrating during and shortly after treatment. A study two years ago by researchers with the James P. Wilmot Cancer Center at the University of Rochester showed that upwards of 82% of breast cancer patients reported that they suffer from some form of cognitive impairment.

While these effects tend to wear off over time, a subset of patients, particularly those who have been administered high doses of chemotherapy, begin to experience these cognitive side effects months or longer after treatment has ceased and the drugs have long since departed their systems. For example, a recent study estimates that somewhere between 15 and 20 percent of the nation’s 2.4 million female breast cancer survivors have lingering cognitive problems years after treatment. Another study showed that 50 percent of women had not recovered their previous level of cognitive function one year after treatment.

Two years ago, Noble and his team showed that three common chemotherapy drugs used to treat a wide range of cancers were more toxic to healthy brain cells than the cancer cells they were intended to treat. While these experiments were among the first to establish a biological basis for the acute onset of chemo brain, they did not explain the lingering impact that many patients experience.

The scientists conducted a similar series of experiments in which they exposed both individual cell populations and mice to doses of 5-fluorouracil (5-FU) in amounts comparable to those used in cancer patients. 5-FU is among a class of drugs called antimetabolites that block cell division and has been used in cancer treatment for more than 40 years. The drug, which is often administered in a “cocktail” with other chemotherapy drugs, is currently used to treat breast, ovarian, stomach, colon, pancreatic and other forms of cancer.

The researchers discovered that months after exposure, specific populations of cells in the central nervous – oligodendrocytes and dividing precursor cells from which they are generated – underwent such extensive damage that, after 6 months, these cells had all but disappeared in the mice.

Oligodendrocytes play an important role in the central nervous system and are responsible for producing myelin, the fatty substance that, like insulation on electrical wires, coats nerve cells and enables signals between cells to be transmitted rapidly and efficiently. The myelin membranes are constantly being turned over, and without a healthy population of oligodendrocytes, the membranes cannot be renewed and eventually break down, resulting in a disruption of normal impulse transmission between nerve cells.

These findings parallel observations in studies of cancer survivors with cognitive difficulties. MRI scans of these patients’ brains revealed a condition similar to leukoencephalopathy. This demyelination – or the loss of white matter – can be associated with multiple neurological problems.

“It is clear that, in some patients, chemotherapy appears to trigger a degenerative condition in the central nervous system,” said Noble. “Because these treatments will clearly remain the standard of care for many years to come, it is critical that we understand their precise impact on the central nervous system, and then use this knowledge as the basis for discovering means of preventing such side effects.”

Noble points out that not all cancer patients experience these cognitive difficulties, and determining why some patients are more vulnerable may be an important step in developing new ways to prevent these side effects. Because of this study, researchers now have a model which, for the first time, allows scientists to begin to examine this condition in a systematic manner.

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Other investigators participating in the study include Ruolan Han, Ph.D., Yin M. Yang, M.D., Anne Luebke, Ph.D., Margot Mayer-Proschel, Ph.D., all with URMC, and Joerg Dietrich, M.D., Ph.D., formerly with URMC and now with Harvard Medical School. The study was funded by the National Institutes of Neurological Disorders and Stroke, the Komen Foundation for the Cure, and the Wilmot Cancer Center

Stem-cell-protecting drug could prevent the harmful side effects of radiation therapy: mTOR inhibitor rapamycin

Contact: Elisabeth Lyons elyons@cell.com 617-386-2121 Cell Press

Radiation therapy is one of the most widely used cancer treatments, but it often damages normal tissue and can lead to debilitating conditions. A class of drugs known as mammalian target of rapamycin (mTOR) inhibitors can prevent radiation-induced tissue damage in mice by protecting normal stem cells that are crucial for tissue repair, according to a preclinical study published by Cell Press in the September issue of the journal Cell Stem Cell.

“We can exploit the emerging findings for the development of new preventive strategies and more effective treatment options for patients suffering this devastating disease,” says senior study author J. Silvio Gutkind of the National Institute of Dental and Craniofacial Research.

In response to radiation therapy, cancer patients often develop a painful condition called mucositis—tissue swelling in the mouth that can leave these patients unable to eat or drink and force them to rely on opioid-strength pain killers. Radiation therapy may cause this debilitating condition by depleting normal stem cells capable of repairing damaged tissue.

In the new study, Gutkind and his team found that the mTOR inhibitor rapamycin protects stem cells taken from the mouths of healthy individuals (but not cancer cells) from radiation-induced death and DNA damage, dramatically extending the lifespan of these normal stem cells and allowing them to grow. Rapamycin exerted these protective effects by preventing the accumulation of harmful molecules called reactive oxygen species. Moreover, mice that received rapamycin during radiation treatment did not develop mucositis.

Because rapamycin is approved by the Food and Drug Administration and is currently being tested in clinical trials for the prevention and treatment of various types of cancer, the new findings could have immediate and important implications for a large proportion of cancer patients. “Mucositis prevention would have a remarkable impact on the quality of life and recovery of cancer patients and at the same time would reduce the cost of treatment,” Gutkind says. “Our study provides the basis for further testing in humans, and we hope that these findings can be translated rapidly into the clinic.”

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Iglesias-Bartolome et al.: “mTOR inhibition prevents epithelial stem cell senescence  and protects from radiation-induced mucositis.”

Finkel et al.: “Relief with Rapamycin: mTOR Inhibition Protects against Radiation-Induced Mucositis”(In Translation Article

Paralyzed patients regain some sensory function after neural stem cell treatment

By Michelle Castillo
 
 

StemCells’ human neural stem cell

(Credit: StemCells Inc.)

(CBS News) For most people who are paralyzed, there is no treatment available to help them regain full function of their limbs. 

 

But, promising new research from a phase 1 study conducted at the University of Zurich sponsored by StemCells, Inc. shows that six months after the implantation of neural stem cells, two out of three complete injury patients – meaning they had no neurological function below the point of injury – were able to gain some sensory function.

 

“We haven’t made progress in how to address injury after they occur, but using neural stem cells in a transplant lets us, for the first time, think we can repair this,” Dr. Stephen Huhn, a neurosurgeon and the vice president and head of the CNS program at StemCells, Inc. said to HealthPop.

 

The phase 1 study was intended to see if the implantation treatment had any unwanted side effects. For the procedure, 20 million neural stem cells were implanted directly into the spinal cord, something that has never been done before. Then, any reactions were monitored including complex examinations of sensory function – for example light touch, sensitivity to temperature and sensitivity to subtle electronic stimulation – as well as electrostimulation of the spinal cord itself.

 

What researchers were surprised to find was that the neural stem cell implantation was able to return some sensation to these paralyzed patients, who were all injured at the thoracic or chest level.

 

Hugh explained that if you think of the spinal cord and its 31 segments as a building with a series of floors, these patients could not access the floor below the point of the initial trauma. However, after the implantation, one patient was able to access three to four floors (or spinal cord segments below the paralysis point) and the other was able to reach five or six floors.

 

“These patients have had such an injury to their spinal cord that to see this kind of effect is amazing. They contain the worst of the worst injuries,” he explained.

 

While the other patient did not regain sensation, none of the patients had any negative side effects. Huhn believes this means that the treatment may be able to work even better for people who have limited function after a traumatic injury. Since the treatment has been deemed to be safe, the next phase is to test the implantation on nine other people who have incomplete injuries or some limited sensation or function after an injury.

 

Huhn recognizes that the field of stem cell research is controversial. The world’s only other trial using stem cells to treat spinal injury – which used embryonic stem cells – was ended in 2011 for financial reasons, according to the New Scientist. But, Huhn feels that the unique properties of neural stem cells and potential benefits warrant their use in medical treatment. Neural stem cells have the unique ability to divide and replicate themselves though cell culture. This means that for this trial, the team was able to use only one donated brain source to supply all the material needed for the study.

 

“This is a very delicate area, and we appreciate that neural stem cells are one of the first discoveries that we’ve had in which we can think about biologically repairing the nervous system,” “Now we have a tool, a technology – something we can think about repairing the central nervous system with.”

 

The information was presented at the International Spinal Cord Society’s (ISCoS) annual meeting in London on Sept. 3

http://www.cbsnews.com/8301-504763_162-57505238-10391704/paralyzed-patients-regain-some-sensory-function-after-neural-stem-cell-treatment/?tag=contentMain;contentBody

Binding sites for LIN28 protein found in thousands of human genes

Contact: Debra Kain ddkain@ucsd.edu 619-543-6163 University of California – San Diego

Protein expression also causes changes in gene splicing

IMAGE:This is Gene Yeo, Ph.D.

Click here for more information.

A study led by researchers at the UC San Diego Stem Cell Research program and funded by the California Institute for Regenerative Medicine (CIRM) looks at an important RNA binding protein called LIN28, which is implicated in pluripotency and reprogramming as well as in cancer and other diseases.  According to the researchers, their study – published in the September 6 online issue of Molecular Cell – will change how scientists view this protein and its impact on human disease.

Studying embryonic stem cells and somatic cells stably expressing LIN28, the researchers defined discrete binding sites of LIN28 in 25 percent of human transcripts.  In addition, splicing-sensitive microarrays demonstrated that LIN28 expression causes widespread downstream alternative splicing changes –variations in gene products that can result in cancer or other diseases.

“Surprisingly, we discovered that LIN28 not only binds to the non-coding microRNAs, but can also bind directly to thousands of messenger RNAs,” said first author Melissa Wilbert, a doctoral student in the UC San Diego Biomedical Sciences graduate program.

Messenger RNA or mRNA, are RNA molecules that encode a chemical “blueprint” for the synthesis of a protein.  MicroRNAs (miRNAs) are short snippets of RNA that are crucial regulators of cell growth, differentiation, and death.  While they don’t encode for proteins, miRNAs are important for regulating protein production in the cell by repressing or “turning off” genes.

“The LIN28 protein is linked to growth and development and is important very early in human development,” said principal investigator Gene Yeo, PhD, MBA, of the Department of Cellular and Molecular Medicine, the Stem Cell Research Program and the Institute for Genomic Medicine at UC San Diego. “It is usually turned off in adult tissue, but can be reactivated, for instance, in certain cancers or metabolic disorders, such as obesity.”

Using genome-wide biochemical methods to look at the set of all RNA molecules across the transcriptome, the researchers found that LIN28 recognizes and binds to a known hairpin-like structure found on the let-7 family of miRNA, but surprisingly, this same structure is also found on mRNAs, allowing LIN28 to directly regulate thousands of targets.

“One of these targets actually encodes for the LIN28 protein itself. In other words, LIN28 helps to make more of itself,” said Yeo.  This process, known as autoregulation, helps to maintain a so-called “steady-state” system in which a protein positively regulates its own production by binding to a regulatory element of the mRNA for the gene coding it.

“Since these mRNA targets include those known to be involved in gene splicing, we also implicate LIN28 in the regulation of alternative splicing,” said Wilbert, adding that abnormal variations in splicing are often implicated in cancer and other disorders.

In the splicing process, fragments that do not typically code for protein, called introns, are removed from gene transcripts, and the remaining sequences, called exons, are reconnected.  The splicing factor proteins themselves, as well as the location where these proteins bind, dictate which pieces of the RNA are included or excluded in the final gene transcript – in much the same way that removing and inserting scenes, or splicing, can alter the plot of a movie.

The discovery of thousands of precise binding sites for LIN28 within human genes offers a novel look at the role this protein plays in development and disease processes.  For example, scientists had looked at targeting a particular miRNA called let-7 to halt cancer growth.  “But we now see that LIN28 can, in essence, bypass let-7 and find many, many other binding sites – perhaps with the same adverse effect of uncontrolled cell overgrowth,” said Yeo.  “This suggests that LIN28 itself should be the therapeutic target for diseases, rather than let-7 or other miRNAs.”

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Additional contributors to the study include, Stephanie C. Huelga, Katannya Kapeli, Thomas J. Stark, Tiffany Y. Liang, Stella X. Chen, Bernice Y. Yan, Jason L. Nathanson, Kasey R. Hutt, Michael T. Lovci, and Anthony Q. Vu, UC San Diego; Hilal Kazan and Quaid Morris, University of Toronto; Katlin B. Massirer, UC San Diego and State University of Campinas, Brazil; and Shawn Hoon, A*Star and National University of Singapore.

This study was supported in part by the National Institutes of Health (HG004659, GM084317 and NS075449), the National Institute of General Medical Sciences (T32 GM008666), and the California Institute for Regenerative Medicine (RB1-01413).

Daisies lead scientists down path to new leukemia drug – DMAPT can kill both dormant cells and cells that are busy dividing

Contact: Leslie Orr Leslie_Orr@urmc.rochester.edu 585-275-5774 University of Rochester Medical Center

OCT 2007

Rochester team develops compound to attack cancer stem cells

A new, easily ingested form of a compound that has already shown it can attack the roots of leukemia in laboratory studies is moving into human clinical trials, according to a new article by University of Rochester investigators in the journal, Blood.

The Rochester team has been leading the investigation of this promising therapy on the deadly blood cancer for nearly five years. And to bring it from a laboratory concept to patient studies in that time is very fast progress in the drug development world, said Craig T. Jordan, Ph.D., senior author of the Blood article and director of Translational Research for Hematologic Malignancies at the James P. Wilmot Cancer Center, at the University of Rochester Medical Center.

Clinical trials are expected to begin in England by the end of 2007. Investigators expect to initially enroll about a dozen adult volunteers who’ve been diagnosed with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) or other types of blood or lymph cancers, Jordan said.

Under development is dimethylamino-parthenolide (DMAPT), a form of parthenolide (PTL) that is derived from a daisy-like plant known as feverfew or bachelor’s button. DMAPT is a water-soluble agent that scientists believe will selectively target leukemia at the stem-cell level, where the malignancy is born. This is significant because standard chemotherapy does not strike deep enough to kill cancer at the roots, thus resulting in relapses. Even the most progressive new therapies, such as Gleevec, are effective only to a degree because they do not reach the root of the cancer.

DMAPT appears to be unique. It’s mechanism of action is to boost the cancer cell’s reactive oxygen species – which is like pushing the stress level of the cell over the edge – to the point where the cell can no long protect itself and dies, said Monica L. Guzman, Ph.D., the lead researcher on the DMAPT project and a senior instructor at the University of Rochester Medical Center.

Leukemia is different from most cancers and particularly hard to eradicate because leukemia stem cells lie dormant. Standard cancer treatments are designed to seek out actively dividing cells. But in studies so far, DMAPT can kill both dormant cells and cells that are busy dividing, Guzman said

Rochester investigators looked at whether DMAPT could eliminate leukemia in donated human cells, and in mice and dogs. In all cases, DMAPT induced rapid death of AML stem and progenitor cells, without harming healthy blood cells.

DMAPT also has shown potential as a treatment for breast and prostate cancer, melanoma, and multiple myeloma, Guzman said, although those studies have only been conducted in cell cultures to date.

“Once we begin seeing evidence from the clinical trials, it will give us more insight into the pharmacological properties of DMAPT and it will be easier to figure out its potential for other cancers,” Guzman said.

In addition to the studies of DMAPT, Guzman and Jordan also reported in the same issue of Blood on another new type of leukemia drug known as TDZD-8.  Although this agent is at a much earlier stage of development, it also shows the ability to kill leukemia stem cells and may some day lead to better forms of treatment.

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The National Cancer Institute RAID program (Rapid Access to Interventional Development) is funding the fast-track research into DMAPT at the University of Rochester. RAID attempts to push promising new therapeutics into the marketplace more quickly. Additional funding came from the Leukemia and Lymphoma Society and the U.S. Department of Defense. Co-authors and partners include chemists at the University of Kentucky, who contributed to developing the analog form of parthenolide

Reposted For Filing….

Ovaries continue to produce eggs during adulthood? Yes, they may….

A compelling new genetic study tracing the origins of immature egg cells, or ‘oocytes’, from the embryonic period throughout adulthood adds new information to a growing controversy

A compelling new genetic study tracing the origins of immature egg cells, or ‘oocytes‘, from the embryonic period throughout adulthood adds new information to a growing controversy. The notion of a “biological clock” in women arises from the fact that oocytes progressively decline in number as females get older, along with a decades-old dogmatic view that oocytes cannot be renewed in mammals after birth. After careful assessment of data from a recent study published in PLoS Genetics, scientists from Massachusetts General Hospital and the University of Edinburgh argue that the findings support formation of new eggs during adult life; a topic that has been historically controversial and has sparked considerable debate in recent years.

Eggs are formed from progenitor germ cells that exit the mitotic cycle, thereby ending their ability to proliferate through cell division, and subsequently enter meiosis, a process unique to the formation of eggs and sperm which removes one half of the genetic material from each type of cell prior to fertilization.

While traditional thinking has held that female mammals are born with all of the eggs they will ever have, newer research has demonstrated that adult mouse and human ovaries contain a rare population of progenitor germ cells called oogonial stem cells capable of dividing and generating new oocytes. Using a powerful new genetic tool that traces the number of divisions a cell has undergone with age (its ‘depth’) Shapiro and colleagues counted the number of times progenitor germ cells divided before becoming oocytes; their study was published in PLoS Genetics in February this year.

If traditional thinking held true, all divisions would have occurred prior to birth, and thus all oocytes would exhibit the same depth regardless of age. However, the opposite was found – eggs showed a progressive increase in depth as the female mice grew older.

In their assessment of the work by Shapiro and colleagues – published recently in a PLoS Genetics Perspective article – reproductive biologists Dori Woods, Evelyn Telfer and Jonathan Tilly conclude that the most plausible explanation for these findings is that progenitor germ cells in ovaries continue to divide throughout reproductive life, resulting in production of new oocytes with greater depth as animals age.

Although these investigations were performed in mice, there is emerging evidence that oogonial stem cells are also present in the ovaries of reproductive-age women, and these cells possess the capacity, like their mouse counterparts, to generate new oocytes under certain experimental conditions. While more work is needed to settle the debate over the significance of oocyte renewal in adult mammals, Woods and colleagues emphasize that “the recent work of Shapiro and colleagues is one of the first reports to offer experimental data consistent with a role for postnatal oocyte renewal in contributing to the reserve of ovarian follicles available for use in adult females as they age.”

Fish oil may hold key to leukemia cure

This is a Repost from 6 months ago. What is Evil about it, is that none of this information is being conveyed to patients…Hence a rare re-post for me…
A compound produced from fish oil that appears to target leukemia stem cells could lead to a cure for the disease, according to Penn State researchers. The compound — delta-12-protaglandin J3, or D12-PGJ3 — targeted and killed the stem cells of chronic myelogenous leukemia, or CML, in mice, said Sandeep Prabhu, associate professor of immunology and molecular toxicology in the Department of Veterinary and Medical Sciences. The compound is produced from EPA — Eicosapentaenoic Acid — an Omega-3 fatty acid found in fish and in fish oil, he said.

“Research in the past on fatty acids has shown the health benefits of fatty acids on cardiovascular system and brain development, particularly in infants, but we have shown that some metabolites of Omega-3 have the ability to selectively kill the leukemia-causing stem cells in mice,” said Prabhu. “The important thing is that the mice were completely cured of leukemia with no relapse.”

The researchers, who released their findings in the current issue of Blood, said the compound kills cancer-causing stem cells in the mice’s spleen and bone marrow. Specifically, it activates a gene — p53 — in the leukemia stem cell that programs the cell’s own death. “p53 is a tumor suppressor gene that regulates the response to DNA damage and maintains genomic stability,” Prabhu said.

IMAGE:Penn State researchers initially tested a compound produced from fish oil on a type of leukemia found in mice called the Friend Virus. This slide shows a Friend Virus Leukemia…Click here for more information.

Killing the stem cells in leukemia, a cancer of the white blood cells, is important because stem cells can divide and produce more cancer cells, as well as create more stem cells, Prabhu said.

The current therapy for CML extends the patient’s life by keeping the number of leukemia cells low, but the drugs fail to completely cure the disease because they do not target leukemia stem cells, said Robert Paulson, associate professor of veterinary and biomedical sciences, who co-directed this research with Prabhu.

“The patients must take the drugs continuously,” said Paulson. “If they stop, the disease relapses because the leukemia stem cells are resistant to the drugs.”

Current treatments are unable to kill the leukemia stem cells, Paulson noted. “These stem cells can hide from the treatment, and a small population of stem cells give rise to more leukemia cells,” said Paulson. “So, targeting the stem cells is essential if you want to cure leukemia.”

IMAGE:Penn State researchers Sandeep Prahbu (right) and Robert Paulson (left) sketch out a delta-12-protaglandin J3, or D12-PGJ3. The compound, derived from fish oil, targeted and killed the stem cells of…Click here for more information.

During the experiments, the researchers injected each mouse with about 600 nanograms of D12-PGJ3 each day for a week. Tests showed that the mice were completely cured of the disease. The blood count was normal, and the spleen returned to normal size. The disease did not relapse.

In previous experiments, the compound also killed the stem cells of Friend Virus-induced leukemia, an experimental model for human leukemia.

The researchers focused on D12-PGJ3 because it killed the leukemia stem cells, but had the least number of side effects. The researchers currently are working to determine whether the compound can be used to treat the terminal stage of CML, referred to as Blast Crisis. There are currently no drugs available that can treat the disease when it progresses to this stage.

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The researchers, who applied for a patent, are also preparing to test the compound in human trials

The real culprit behind hardened arteries? Stem cells, says landmark study (NC)

Berkeley — One of the top suspects behind killer vascular diseases is the victim of mistaken identity, according to researchers from the University of California, Berkeley, who used genetic tracing to help hunt down the real culprit.

The guilty party is not the smooth muscle cells within blood vessel walls, which for decades was thought to combine with cholesterol and fat that can clog arteries. Blocked vessels can eventually lead to heart attacks and strokes, which account for one in three deaths in the United States.

Instead, a previously unknown type of stem cell — a multipotent vascular stem cell — is to blame, and it should now be the focus in the search for new treatments, the scientists report in a new study appearing June 6 in the journal Nature Communications.

“For the first time, we are showing evidence that vascular diseases are actually a kind of stem cell disease,” said principal investigator Song Li, professor of bioengineering and a researcher at the Berkeley Stem Cell Center. “This work should revolutionize therapies for vascular diseases because we now know that stem cells rather than smooth muscle cells are the correct therapeutic target.”

The finding that a stem cell population contributes to artery-hardening diseases, such as atherosclerosis, provides a promising new direction for future research, the study authors said.

“This is groundbreaking and provocative work, as it challenges existing dogma,” said Dr. Deepak Srivastava, director of the Gladstone Institute of Cardiovascular Disease at UC San Francisco, who provided some of the mouse vascular tissues used by the researchers. “Targeting the vascular stem cells rather than the existing smooth muscle in the vessel wall might be much more effective in treating vascular disease.”

It is generally accepted that the buildup of artery-blocking plaque stems from the body’s immune response to vessel damage caused by low-density lipoproteins, the bad cholesterol many people try to eliminate from their diets. Such damage attracts legions of white blood cells and can spur the formation of fibrous scar tissue that accumulates within the vessel, narrowing the blood flow.

The scar tissue, known as neointima, has certain characteristics of smooth muscle, the dominant type of tissue in the blood vessel wall. Because mature smooth muscle cells no longer multiply and grow, it was theorized that in the course of the inflammatory response, they revert, or de-differentiate, into an earlier state where they can proliferate and form matrices that contribute to plaque buildup.

However, no experiments published have directly demonstrated this de-differentiation process, so Li and his research team remained skeptical. They turned to transgenic mice with a gene that caused their mature smooth muscle cells to glow green under a microscope.

In analyzing the cells from cross sections of the blood vessels, they found that more than 90 percent of the cells in the blood vessels were mature smooth muscle cells. They then isolated and cultured the cells taken from the middle layer of the mouse blood vessels.

After one month of cell expansion, the researchers saw a threefold increase in the size of the cell nucleus and the spreading area, along with an increase in stress fibers. Notably, none of the new, proliferating cells glowed green, which meant that their lineage could not be traced back to the mature smooth muscle cells originally isolated from the blood vessels.

“Not only was there a lack of green markers in the cell cultures, but we noticed that another type of cell isolated from the blood vessels exhibited progenitor traits for different types of tissue, not just smooth muscle cells,” said Zhenyu Tang, co-lead author of the study and a Ph.D. student in the UC Berkeley-UCSF Graduate Program in Bioengineering.

The other co-lead author of the study, Aijun Wang, was a post-doctoral researcher in Li’s lab.

“The different phenotypes gave us the clue that stem cells were involved,” said Wang, who is now an assistant professor and the co-director of the Surgical Bioengineering Laboratory at the UC Davis Medical Center. “We did further tests and detected proteins and transcriptional factors that are only found in stem cells. No one knew that these cells existed in the blood vessel walls because no one looked for them before.”

Further experiments determined that the newly discovered vascular stem cells were multipotent, or capable of differentiating into various specialized cell types, including smooth muscle, nerve, cartilage, bone and fat cells. This would explain why previous studies misidentified the cells involved in vessel clogs as de-differentiated smooth muscle cells after vascular injury.

“In the later stages of vascular disease, the soft vessels become hardened and more brittle,” said Li. “Previously, there was controversy about how soft tissue would become hard. The ability of stem cells to form bone or cartilage could explain this calcification of the blood vessels.”

Other tests in the study showed that the multipotent stem cells were dormant under normal physiological conditions. When the blood vessel walls were damaged, the stem cells rather than the mature smooth muscle cells became activated and started to multiply.

The researchers analyzed human carotid arteries to confirm that the same type of multipotent vascular stem cells are found in human blood vessels.

“If your target is wrong, then your treatment can’t be very effective,” said Dr. Shu Chien, director of the Institute of Engineering in Medicine at UC San Diego, and Li’s former adviser. “These new findings give us the right target and should speed up the discovery of novel treatments for vascular diseases.”