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Researchers, with Stem Cells, Advance Understanding of Spinal Muscular Atrophy

Posted: June 20, 2012 at 3:13 pm

Newswise LOS ANGELES (June 19, 2012) Cedars-Sinais Regenerative Medicine Institute has pioneered research on how motor-neuron cell-death occurs in patients with spinal muscular atrophy, offering an important clue in identifying potential medicines to treat this leading genetic cause of death in infants and toddlers.

The study, published in the June 19 online issue of PLoS ONE, extends the institutes work to employ pluripotent stem cells to find a pharmaceutical treatment for spinal muscular atrophy or SMA, a genetic neuromuscular disease characterized by muscle atrophy and weakness.

With this new understanding of how motor neurons die in spinal muscular atrophy patients, we are an important step closer to identifying drugs that may reverse or prevent that process, said Clive Svendsen, PhD, director of the Cedars-Sinai Regenerative Medicine Institute.

Svendsen and his team have investigated this disease for some time now. In 2009, Nature published a study by Svendsen and his colleagues detailing how skin cells taken from a patient with the disorder were used to generate neurons of the same genetic makeup and characteristics of those affected in the disorder; this created a disease-in-a-dish that could serve as a model for discovering new drugs.

As the disease is unique to humans, previous methods to employ this approach had been unreliable in predicting how it occurs in humans. In the research published in PLoS ONE, to the team reproduced this model with skin cells from multiple patients, taking them back in time to a pluripotent stem cell state (iPS cells), and then driving them forward to study the diseased patient-specific motor neurons.

Children born with this disorder have a genetic mutation that doesnt allow their motor neurons to manufacture a critical protein necessary for them to survive. The study found these cells die through apoptosis the same form of cell death that occurs when the body eliminates old, unnecessary as well as unhealthy cells. As motor neuron cell death progresses, children with the disease experience increasing paralysis and eventually death. There is no effective treatment now for this disease. An estimated one in 35 to one in 60 people are carriers and about in 100,000 newborns have the condition.

Now we are taking these motor neurons (from multiple children with the disease and in their pluripotent state) and screening compounds that can rescue these cells and create the protein necessary for them to survive, said Dhruv Sareen, director of Cedars-Sinais Induced Pluripotent Stem Cell Core Facility and a primary author on the study. This study is an important stepping stone to guide us toward the right kinds of compounds that we hope will be effective in the model and then be reproduced in clinical trials.

The study was funded in part by a $1.9 million Tools and Technology grant from the California Institute for Regenerative Medicine aimed at developing new tools and technologies to aid pharmaceutical discoveries for this disease.

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Cedars-Sinai researchers, with stem cells, advance understanding of spinal muscular atrophy

Posted: June 20, 2012 at 3:13 pm

Public release date: 19-Jun-2012 [ | E-mail | Share ]

Contact: Nicole White nicole.white@cshs.org 310-423-5215 Cedars-Sinai Medical Center

LOS ANGELES (June 19, 2012) Cedars-Sinai's Regenerative Medicine Institute has pioneered research on how motor-neuron cell-death occurs in patients with spinal muscular atrophy, offering an important clue in identifying potential medicines to treat this leading genetic cause of death in infants and toddlers.

The study, published in the June 19 online issue of PLoS ONE, extends the institute's work to employ pluripotent stem cells to find a pharmaceutical treatment for spinal muscular atrophy or SMA, a genetic neuromuscular disease characterized by muscle atrophy and weakness.

"With this new understanding of how motor neurons die in spinal muscular atrophy patients, we are an important step closer to identifying drugs that may reverse or prevent that process," said Clive Svendsen, PhD, director of the Cedars-Sinai Regenerative Medicine Institute.

Svendsen and his team have investigated this disease for some time now. In 2009, Nature published a study by Svendsen and his colleagues detailing how skin cells taken from a patient with the disorder were used to generate neurons of the same genetic makeup and characteristics of those affected in the disorder; this created a "disease-in-a-dish" that could serve as a model for discovering new drugs.

As the disease is unique to humans, previous methods to employ this approach had been unreliable in predicting how it occurs in humans. In the research published in PLoS ONE, to the team reproduced this model with skin cells from multiple patients, taking them back in time to a pluripotent stem cell state (iPS cells), and then driving them forward to study the diseased patient-specific motor neurons.

Children born with this disorder have a genetic mutation that doesn't allow their motor neurons to manufacture a critical protein necessary for them to survive. The study found these cells die through apoptosis the same form of cell death that occurs when the body eliminates old, unnecessary as well as unhealthy cells. As motor neuron cell death progresses, children with the disease experience increasing paralysis and eventually death. There is no effective treatment now for this disease. An estimated one in 35 to one in 60 people are carriers and about in 100,000 newborns have the condition.

"Now we are taking these motor neurons (from multiple children with the disease and in their pluripotent state) and screening compounds that can rescue these cells and create the protein necessary for them to survive," said Dhruv Sareen, director of Cedars-Sinai's Induced Pluripotent Stem Cell Core Facility and a primary author on the study. "This study is an important stepping stone to guide us toward the right kinds of compounds that we hope will be effective in the model and then be reproduced in clinical trials."

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Diabetes drug may kill cancer stem cells, study says

Posted: June 20, 2012 at 3:12 pm

Results from a new study suggest low doses of the diabetes drug metformin may effectively destroy pancreatic cancer stem cells, reducing the risk of tumor growth or recurrence.

Metformin has previously shown promise in reducing breast cancer risk, after researchers found women who took the drug were 25 percent less likely to develop breast cancer during their lifetimes than women who did not.

This study, conducted in mice, is the first to suggest metformin may actually target the root of certain cancers the tumor-initiating stem cells.

We didnt have any clue regarding the effects of metformin on pancreatic stem cancer cells, study researcher Dr. Christopher Heeschen, professor for experimental medicine at the Spanish National Cancer Research Centre in Madrid, Spain, told FoxNews.com. Its been implied in past studies of pancreatic cancer that patients who use metformin show better outcomes, but there have been no randomized trials yet.

When metformin was combined with a standard chemotherapy to treat pancreatic cancer, the drugs were able to eradicate both cancer stem cells and the differentiated cells that made up the tumor.

Novel strategies for treating pancreatic cancer have to be multi-modal, Heeschen explained. Right now, metformin is used as a second phase treatment, but I could also envision it as a first phase treatment but it has to be in combination with chemotherapy. I dont think the drug alone could wipe out the primary tumor, which is crucial.

In the study, it appeared that metformin merely arrested cancer cell growth in existing tumors, rather than destroying them.

Metformin targets the root of cancer, which has more of an effect on preventing cancer relapse, Heeschen said.

According to Heeschen, researchers are not yet certain as to why metformin appears to have cancer stem cell-killing properties, but from a pragmatic point of view, you see this striking response with a well-established drug thats safe I think its reasonable to move forward with clinical trials, he said.

One clinical trial is already in the recruitment phase, and Heeschen predicted results of the trial would be available by the end of the year.

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Indian American Doctor Makes Breakthrough in Cancer Research

Posted: June 20, 2012 at 9:20 am

Bangalore: A recent study led by an Indian American researcher Bikul Das, at the Stanford University School of Medicine proved that in times of stress certain human embryonic stem cells produce molecules that benefit themselves along with the helping the nearby cells to survive. Altruism has been reported among bacterial populations and among humans and other animals, like monkeys and elephants, said Stanford postdoctoral scholar Bikul Das, MBBS, PhD. But in mammalian cells at the cellular level the idea of altruism has never been described before.

Das has recently published a research paper documenting altruistic behavior by human embryonic stem cells, in a prominent international magazine 'Stem Cells'.

"Altruism in cells can mean it will be possible to treat cancer without chemotherapy. In future, altruistic stem cells may be cultured and injected into cancerous tissue for treatment, said Dr Chandan J Das, assistant professor in the radio-diagnosis department at AIIMS, Delhi, about the study.

Dr Purna Kurkure, senior paediatric oncologist at Tata Memorial Hospital says "this research will have a bearing on not just cancer research but in the overall understanding of the repair and regeneration mechanism of the human body. Altruism has been observed in bacteria, which is why bacteria are great survivors. So far, we haven't been able to beat cancer because there is a lack of complete understanding about it. Chemotherapy only targets the end cells, not the root. This research is, therefore, a major leap in the battle against cancer'', reports Times of India.

Das has been congratulated by UK scientist Dr Peter W Andrews, one of the two gurus of embryonic stem cell research, for his findings.

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Neuralstem Pioneering Efforts In ALS – Analyst Blog

Posted: June 20, 2012 at 9:20 am

By Jason Napodano, CFA

Neuralstem, Inc. (NYSE MKT: CUR ) has developed a technology that allows large-scale expansion of human neural stem cells ("hNSC") from all areas of the developing human brain and spinal cord. The company owns of has exclusive license to 25 patients and 29 patent applications pending worldwide in the field of regenerative medicine and cell therapy. Management is currently focusing the company's efforts on replacing damaged, malfunctioning, or dead neural cells with fully functional ones that may be useful in treating many central nervous system diseases and neurodegenerative disorders.

Neuralstem's lead development program is for Amyotrophic Lateral Sclerosis ("ALS"), also known as Lou Gehrig 's disease, named after the famous New York Yankee first baseman who was diagnosed with the disease in 1939, and passed in 1941 at the age of only 37.

ALS Background

ALS is a rapidly progressive neurodegenerative disease characterized by weakness, muscle atrophy and twitching, spasticity, dysarthria (difficulty speaking), dysphagia (difficulty swallowing), and respiratory compromise. The disease is almost always fatal, typically due to respiratory compromise or pneumonia, in two to four years. Initial symptoms of ALS include weakness and/or stiffness followed by muscle atrophy in the arms and legs. This is followed by slurred speech or difficulty swallowing, and loss of tongue mobility. Approximately a third of ALS patients also experience pseudobulbar affect (uncontrollable emotions). As the disease progresses, worsening dysphagia and respiratory failure leads to death. A small percentage of patients may also experience cognitive affects such as frontotemporal dementia and anxiety.

The vast majority (~95%) of cases are idiopathic, although there is a known hereditary factor that leads to familial ALS associated with a defect on the 21st chromosome that accounts for approximately 1.5% of all cases. There are also suspected environmental causative factors, including exposure to a dietary neurotoxin called BMAA and cyanobacteria, and use of pesticides. However, in all cases, the defining factor of ALS is rapid and progressive death of upper and lower motor neurons in the motor cortex of the brain, brain stem, and spinal cord. Prior to their destruction, motor neurons develop proteinaceous inclusions in their cell bodies and axons. This may be partly due to defects in protein degradation.

Treatment for ALS is limited, and as of today only riluzole, marketed by Sanofi-Aventis as Rilutek, has been found to improve survival to a modest extent (several months). Riluzole preferentially blocks TTX-sensitive sodium channels, which are associated with damaged neurons. This reduces influx of calcium ions and indirectly prevents stimulation of glutamate receptors. Together with direct glutamate receptor blockade, the effect of the neurotransmitter glutamate on motor neurons is greatly reduced. Riluzole does not reverse the damage already done to motor neurons, and people taking it must be monitored for liver damaged (about 10% incidence).

The remaining treatments for ALS are designed to relieve symptoms and improve quality of life. This supportive care includes a multidisciplinary approach that may include medications to reduce fatigue, control spasticity, reduce excess saliva and phlegm, limit sleep disturbances, reduce depression, and limit constipation. As noted above, median survival is two to four years. In the U.S., approximately 30,000 persons are currently living with ALS.

Neuralstem's Approach For ALS

Neuralstem is seeking to treat the symptoms of ALS via transplantation of its hNSCs directly into the gray matter of the patient's spinal cord. In ALS, motor neurons die, leading to paralysis. In preclinical animal work, Neuralstem cells both made synaptic contact with the host motor neurons and expressed neurotrophic growth factors, which are protective of cells.

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CUR – Neuralstem Pioneering Efforts In ALS

Posted: June 20, 2012 at 9:20 am

As of now, management is planning to conduct the pivotal program on its own, mostly likely seeking funding through grants with the ALS Association and U.S. National Institutes of Health. However, management is also in discussion with potential pharmaceutical partners on the pivotal program. ALS is a highly attractive area for Big Pharma. Depending on the strength of the phase 1 / 2 data, Neuralstem may be able to strike a commercialization partnership in 2014 to help defer the costs of the planned pivotal trial. We expect that any deal with a larger pharmaceutical company would include a substantial upfront payment that Neuralstem would then use to fund expansion of the development platform into new indications, such as spinal cord injury (IND filed) or stroke.

Market Opportunity

In February 2011, the U.S. FDA granted Neuralstem an Orphan Drug designation for its human spinal cord stem cells (HSSC) for the treatment of ALS. As noted above, there are approximately 30,000 patients in the U.S. living with ALS. We estimate that approximately half of these patients are characterized with an FVC > 60% and may be eligible for treatment with Neuralstems hNSCs. Given the Orphan Drug designation, the limited patient population, and the lack of any meaningful treatment options, we think Neuralstem or its commercialization partner could price this therapy at upwards of $100,000. Therefore, the peak market opportunity for Neuralstem is $1.5 billion.

That being said, drug development in ALS has been a graveyard for pharmaceutical companies. One would assume, based on numerous past clinical failures, that Neuralstems chances in ALS are slim. Small molecules including gabapentin, topiramate, celecoxib, tamoxifen, indinavir, minocycline, and xaliproden, many of which are approved for other indications and have posted annual sales over a billion dollars, have all failed human clinical programs for ALS. Even Vitamin E and Creatine have been tested, to little avail, in ALS. Failed mechanisms of action included calcium channel blockers, glutamate regulators, neuroprotectants, immunosuppressants, GABA receptors, anti-inflammatory agents, and antioxidants.

However, there is one thing in common we see in all of the above failures. They are one molecule targeting one mechanism of action or one pathway. ALS is a high complex and largely uncharacterized disease. Neuralstems approach uses human spinal stem cells that, once injected, can provide multiple mechanisms of action on multiple pathways to affect the disease. Plus, Neuralstems approach is highly targeted, with the cells injected directly into the lumbar or cervical spine. Following grafting, the hypothesis is that the cells rebuild circuitry with the patient motor neurons and protect existing neurons from further degradation. Its clearly a unique approach, and one we believe has a better chance of success than many of the previous failed theories enacted over the past decade.

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Neuralstem Pioneering Efforts In ALS

Posted: June 20, 2012 at 9:20 am

By Jason Napodano, CFA

Neuralstem, Inc. (NYSE MKT:CUR) has developed a technology that allows large-scale expansion of human neural stem cells ("hNSC") from all areas of the developing human brain and spinal cord. The company owns of has exclusive license to 25 patients and 29 patent applications pending worldwide in the field of regenerative medicine and cell therapy. Management is currently focusing the company's efforts on replacing damaged, malfunctioning, or dead neural cells with fully functional ones that may be useful in treating many central nervous system diseases and neurodegenerative disorders.

Neuralstems lead development program is for Amyotrophic Lateral Sclerosis ("ALS"), also known as Lou Gehrigs disease, named after the famous New York Yankee first baseman who was diagnosed with the disease in 1939, and passed in 1941 at the age of only 37.

ALS Background

ALS is a rapidly progressive neurodegenerative disease characterized by weakness, muscle atrophy and twitching, spasticity, dysarthria (difficulty speaking), dysphagia (difficulty swallowing), and respiratory compromise. The disease is almost always fatal, typically due to respiratory compromise or pneumonia, in two to four years. Initial symptoms of ALS include weakness and/or stiffness followed by muscle atrophy in the arms and legs. This is followed by slurred speech or difficulty swallowing, and loss of tongue mobility. Approximately a third of ALS patients also experience pseudobulbar affect (uncontrollable emotions). As the disease progresses, worsening dysphagia and respiratory failure leads to death. A small percentage of patients may also experience cognitive affects such as frontotemporal dementia and anxiety.

The vast majority (~95%) of cases are idiopathic, although there is a known hereditary factor that leads to familial ALS associated with a defect on the 21st chromosome that accounts for approximately 1.5% of all cases. There are also suspected environmental causative factors, including exposure to a dietary neurotoxin called BMAA and cyanobacteria, and use of pesticides. However, in all cases, the defining factor of ALS is rapid and progressive death of upper and lower motor neurons in the motor cortex of the brain, brain stem, and spinal cord. Prior to their destruction, motor neurons develop proteinaceous inclusions in their cell bodies and axons. This may be partly due to defects in protein degradation.

Treatment for ALS is limited, and as of today only riluzole, marketed by Sanofi-Aventis as Rilutek, has been found to improve survival to a modest extent (several months). Riluzole preferentially blocks TTX-sensitive sodium channels, which are associated with damaged neurons. This reduces influx of calcium ions and indirectly prevents stimulation of glutamate receptors. Together with direct glutamate receptor blockade, the effect of the neurotransmitter glutamate on motor neurons is greatly reduced. Riluzole does not reverse the damage already done to motor neurons, and people taking it must be monitored for liver damaged (about 10% incidence).

The remaining treatments for ALS are designed to relieve symptoms and improve quality of life. This supportive care includes a multidisciplinary approach that may include medications to reduce fatigue, control spasticity, reduce excess saliva and phlegm, limit sleep disturbances, reduce depression, and limit constipation. As noted above, median survival is two to four years. In the U.S., approximately 30,000 persons are currently living with ALS.

Neuralstems Approach For ALS

Neuralstem is seeking to treat the symptoms of ALS via transplantation of its hNSCs directly into the gray matter of the patients spinal cord. In ALS, motor neurons die, leading to paralysis. In preclinical animal work, Neuralstem cells both made synaptic contact with the host motor neurons and expressed neurotrophic growth factors, which are protective of cells.

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Metformin treatment caused cancer stem cell death in pancreatic cancer cell lines

Posted: June 20, 2012 at 9:20 am

Public release date: 19-Jun-2012 [ | E-mail | Share ]

Contact: Jeremy Moore jeremy.moore@aacr.org 215-446-7109 American Association for Cancer Research

LAKE TAHOE, Nev. Results of some preclinical trials have shown that low doses of the antidiabetic drug metformin may effectively destroy cancer stem cells, a group of cells that are considered to be responsible for tumor initiation and, because they are resistant to standard chemotherapies, tumor relapse.

In addition, when metformin was combined with a standard chemotherapy used for pancreatic cancer, the combination treatment was able to efficiently eradicate both cancer stem cells and more differentiated cancer cells, which form the bulk of the tumor, according to data presented by Christopher Heeschen, M.D., Ph.D., at the American Association for Cancer Research's Pancreatic Cancer: Progress and Challenges conference, held in Lake Tahoe, Nev., from June 18-21, 2012. Heeschen is professor for experimental medicine at the Spanish National Cancer Research Centre in Madrid, Spain.

Most clinical trials of pancreatic cancer conducted during the last 15 years have failed to show marked improvement in median survival, suggesting that the selected approaches were not sufficient for several reasons, according to Heeschen. In recent years, researchers have identified cancer stem cells which, as opposed to the cancer cells that make up the bulk of the tumor, are a small subset of cells that are resistant to conventional therapy.

"Therefore, efficiently targeting these cells will be crucial for achieving higher cure rates in patients with pancreatic cancer," he said. "Our newly emerging data now indicate that metformin, a widely used and well-tolerated drug for the treatment of diabetes, is capable of efficiently eliminating these cells."

Specifically, the researchers found that metformin-pretreated cancer stem cells were particularly sensitive to alterations to their metabolism through the activation of AMPK. In fact, metformin treatment resulted in the death of cancer stem cells. In contrast, treatment of more differentiated cancer cells with metformin only arrested the cells' growth.

"As the cancer stem cells represent the root of pancreatic cancer, their extinction by reprogramming their metabolism with metformin in combination with the stalling of the proliferation of more differentiated cells should result in tumor regression and long-term, progression-free survival," Heeschen said.

The researchers generated data to support this idea when they treated immunocompromised mice implanted with a diverse set of patient-derived tumors with a combination of metformin and gemcitabine, the standard chemotherapeutic treatment for pancreatic cancer. They found that the treatment resulted in reduced tumor burden and the prevention of relapse as compared with treatment with either drug alone.

"Intriguingly, in all tumors treated with metformin to date, relapse of disease was efficiently prevented and there were no noticeable adverse effects," Heeschen said.

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Step closer to stem cell answer for human diseases

Posted: June 20, 2012 at 9:20 am

Development of stem cell research for treating human cells damaged through injury, disease or ageing has taken a step forward in Queensland.

Stem Cells Ltd, based at the Australian Institute for Bioengineering and Nanotechnology at The University of Queensland, is set to receive $470,000 in Queensland Government science funding.

The funding will ensure the growth of stem cell research in Queensland, taking the state's leaders closer to developing cell-based therapies for a host of diseases.

Stem Cells Ltd Queensland manager Victoria Turner said her team would work with stem cell scientists to advance research into diseases such as schizophrenia, Down syndrome, Parkinson's disease and heart disease.

Ms Turner said Stem Cells Ltd would ensure Queensland remained at the forefront of cutting-edge stem cell research.

Stem cell research is an exciting and rapidly expanding field that is vital for basic research and understanding of diseases, she said.

Most importantly, stem cells are set to have a major impact on healthcare and innovation, offering novel scientific insights that can be used to direct the treatment of a multitude of diseases and, ultimately in the future development of cell-based therapies when cells become damaged by illness or injury.

Stem Cells Ltd is a not-for-profit company established to grow the capacity of stem cell research in Australia, providing researchers in the field with highly specialised stem cell products, services and training.

This enables scientists to access valuable stem cell strategies for modeling human diseases, which in many cases represents the only option for gaining a better understanding in order to direct treatment.

Stem Cells Ltd is also expected to break down the barriers for new stem cell scientists to enter the field, providing them with the specialist technical expertise they need for stem cell culture and keeping up with the pace of development.

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Leukemia inhibitory factor may be a promising target against pancreatic cancer

Posted: June 19, 2012 at 11:19 pm

Public release date: 19-Jun-2012 [ | E-mail | Share ]

Contact: Jeremy Moore jeremy.moore@aacr.org 215-446-7109 American Association for Cancer Research

LAKE TAHOE, Nev. Pancreatic cancer is one of the deadliest forms of cancer, defying most treatments. Its ability to evade therapy may be attributable to the presence of cancer stem cells, a subset of cancer cells present in pancreatic tumors that drive tumor growth by generating bulk tumor cells. Cancer stem cells are notorious for their ability to resist traditional chemotherapies.

However, scientists at the University of California, San Francisco (UCSF), have discovered that two proteins KRAS and leukemia inhibitory factor (LIF) help create cancer stem cells and that the latter can be targeted to block them.

These results were presented at the American Association for Cancer Research's Pancreatic Cancer: Progress and Challenges conference, held here from June 18-21.

In many different types of tumors, a constitutively active, mutant form of the signaling protein KRAS helps drive the uncontrolled tumor cell proliferation that is a hallmark of cancer. In fact, more than 90 percent of pancreatic cancers exhibit KRAS mutations, but the link between KRAS and cancer stem cells has been tenuous until now.

Using human pancreatic cancer cell lines and mouse fibroblasts and pancreatic cancer cells, Man-Tzu Wang, Ph.D., a postdoctoral researcher in the McCormick lab at the Helen Diller Family Comprehensive Cancer Center at UCSF, and colleagues showed that KRAS causes cells to acquire and maintain stem cell-like properties.

"We know that KRAS is a very potent driver of pancreatic cancer, but we don't know how to drug it," said Wang. "Our results showed we can block KRAS-mediated cancer stem cells by blocking LIF activity."

KRAS is difficult to target therapeutically. Taking the next logical step, the researchers began looking for proteins that function downstream of KRAS in the generation of pancreatic cancer stem cells to determine if any of them could be potential drug targets. They found a number of candidates but focused on LIF, a protein known to regulate stem cell development. Moreover, they found that LIF is "druggable," making it a potential target for treatment.

Using neutralizing antibodies or shRNA, the team knocked down LIF activity or expression and found that each reduced the in vitro stem cell-like properties of mouse pancreatic cancer cells.

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