New ALS gene and signaling pathways identified

IMAGE:Induced pluripotent stem cell-derived motor neurons from an ALS patient (left) compared with normal cells (right). The cells are being used to study the role of the genes TBK1 and... view more

NEW YORK, NY (February 19, 2015)--Using advanced DNA sequencing methods, researchers have identified a new gene that is associated with sporadic amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease. ALS is a devastating neurodegenerative disorder that results in the loss of all voluntary movement and is fatal in the majority of cases. The next-generation genetic sequencing of the exomes (protein-coding portions) of 2,874 ALS patients and 6,405 controls represents the largest number of ALS patients to have been sequenced in a single study to date.

Though much is known about the genetic underpinnings of familial ALS, only a handful of genes have been definitively linked to sporadic ALS, which accounts for about 90 percent of all ALS cases. The newly associated gene, called TBK1, plays a key role at the intersection of two essential cellular pathways: inflammation (a reaction to injury or infection) and autophagy (a cellular process involved in the removal of damaged cellular components). The study, conducted by an international ALS consortium that includes scientists and clinicians from Columbia University Medical Center (CUMC), Biogen Idec, and HudsonAlpha Institute for Biotechnology, was published today in the online edition of Science.

"The identification of TBK1 is exciting for understanding ALS pathogenesis, especially since the inflammatory and autophagy pathways have been previously implicated in the disease," said Lucie Bruijn, PhD, Chief Scientist for The ALS Association. "The fact that TBK1 accounts for one percent of ALS adds significantly to our growing understanding of the genetic underpinnings of the disease. This study, which combines the efforts of over two dozen laboratories in six countries, also highlights the global and collaborative nature of ALS research today.

"This study shows us that large-scale genetic studies not only can work very well in ALS, but that they can help pinpoint key biological pathways relevant to ALS that then become the focus of targeted drug development efforts," said study co-leader David B. Goldstein, PhD, professor of genetics and development and director of the new Institute for Genomic Medicine at CUMC. "ALS is an incredibly diverse disease, caused by dozens of different genetic mutations, which we're only beginning to discover. The more of these mutations we identify, the better we can decipher--and influence--the pathways that lead to disease." The other co-leaders of the study are Richard M. Myers, PhD, president and scientific director of HudsonAlpha, and Tim Harris, PhD, DSc, Senior Vice President, Technology and Translational Sciences, Biogen Idec.

"These findings demonstrate the power of exome sequencing in the search for rare variants that predispose individuals to disease and in identifying potential points of intervention. We are following up by looking at the function of this pathway so that one day this research may benefit the patients living with ALS," said Dr. Harris. "The speed with which we were able to identify this pathway and begin our next phase of research shows the potential of novel, focused collaborations with the best academic scientists to advance our understanding of the molecular pathology of disease. This synergy is vital for both industry and the academic community, especially in the context of precision medicine and whole-genome sequencing."

"Industry and academia often do things together, but this is a perfect example of a large, complex project that required many parts, with equal contributions from Biogen Idec. Dr. Tim Harris, our collaborator there, and his team, as well as David Goldstein and his team, now at Columbia University, as well as our teams here at HudsonAlpha, said Dr. Myers. "I love this research model because it doesn't happen very frequently, and it really shows how industry, nonprofits, and academic laboratories can all work together for the betterment of humankind. The combination of those groups with a large number of the clinical collaborators who have been seeing patients with this disease for many years and providing clinical information, recruiting patients, as well as collecting DNA samples for us to do this study, were all critical to get this done."

Searching through the enormous database generated in the ALS study, Dr. Goldstein and his colleagues found several genes that appear to contribute to ALS, most notably TBK1 (TANK-Binding Kinase 1), which had not been detected in previous, smaller-scale studies. TBK1 mutations appeared in about 1 percent of the ALS patients--a large proportion in the context of a complex disease with multiple genetic components, according to Dr. Goldstein. The study also found that a gene called OPTN, previously thought to play a minor role in ALS, may actually be a major player in the disease.

"Remarkably, the TBK1 protein and optineurin, which is encoded by the OPTN gene, interact physically and functionally. Both proteins are required for the normal function of inflammatory and autophagy pathways, and now we have shown that mutations in either gene are associated with ALS," said Dr. Goldstein. "Thus there seems to be no question that aberrations in the pathways that require TBK1 and OPTN are important in some ALS patients."

The researchers are currently using patient-derived induced pluripotent embryonic stem cells (iPS cells) and mouse models with mutations in TBK1 or OPTN to study ALS disease mechanisms and to screen for drug candidates. Several compounds that affect TBK1 signaling have already been developed for use in cancer, where the gene is thought to play a role in tumor-cell survival.

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Human skin may harbor obesity cure

Researchers have recently converted human skin cells into appetite controlling neurons for the first time ever, which might eventually provide obesity cure.

The study, led by researchers at Columbia University Medical Center (CUMC) and at the New York Stem Cell Foundation (NYSCF), found that cells provided individualized model for studying obesity and testing treatments.

To make the neurons, human skin cells were first genetically reprogrammed to become induced pluripotent stem (iPS) cells. Like natural stem cells, iPS cells are capable of developing into any kind of adult cell when given a specific set of molecular signals in a specific order.

The iPS cell technology has been used to create a variety of adult human cell types, including insulin-producing beta cells and forebrain and motor neurons.

The CUMC/NYSCF team determined which signals are needed to transform iPS cells into arcuate hypothalamic neurons, a neuron subtype that regulates appetite. The transformation process took about 30 days.

The neurons were found to display key functional properties of mouse arcuate hypothalamic neurons, including the ability to accurately process and secrete specific neuropeptides and to respond to metabolic signals such as insulin and leptin.

The study is published in the Journal of Clinical Investigation. (ANI)

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Human skin may harbor obesity cure

Neurons Controlling Appetite Made From Skin Cells

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Newswise NEW YORK, NY (February 27, 2015) Researchers have for the first time successfully converted adult human skin cells into neurons of the type that regulate appetite, providing a patient-specific model for studying the neurophysiology of weight control and testing new therapies for obesity. The study, led by researchers at Columbia University Medical Center (CUMC) and at the New York Stem Cell Foundation (NYSCF), was published last month in the online issue of the Journal of Clinical Investigation.

In a separate study, which appeared in the February 10 issue of the journal Development, Kevin Eggan, PhD, Florian Merkle, and Alexander Schier of Harvard University have also succeeded in creating hypothalamic neurons from iPS cells. These neurons help to regulate behavioral and basic physiological functions in the human body, including, in addition to appetite, hypertension, sleep, mood, and some social disorders. The investigators at Columbia and Harvard shared ideas during the course of the research, and these studies are co-validating.

Mice are a good model for studying obesity in humans, but it would better to have human cells for testing. Unfortunately, the cells that regulate appetite are located in an inaccessible part of the brain, the hypothalamus. So, until now, weve had to make do with a mouse model or with human cells harvested at autopsy. This has greatly limited our ability to study fundamental aspects of human obesity, said senior author Rudolph L. Leibel, MD, the Christopher J. Murphy Memorial Professor of Diabetes Research, professor of pediatrics and medicine, and co-director of the Naomi Berrie Diabetes Center at CUMC.

To make the neurons, human skin cells were first genetically reprogrammed to become induced pluripotent stem (iPS) cells. Like natural stem cells, iPS cells are capable of developing into any kind of adult cell when given a specific set of molecular signals in a specific order. The iPS cell technology has been used to create a variety of adult human cell types, including insulin-producing beta cells and forebrain and motor neurons. But until now, no one has been able to figure out how to convert human iPS cells into hypothalamic neurons, said co-author Dieter Egli, PhD, assistant professor of pediatrics (in developmental cell biology), a member of the Naomi Berrie Diabetes Center, and a senior research fellow at NYSCF.

This is a wonderful example of several institutions coming together to collaborate and advance research in pursuit of new therapeutic interventions. The ability to make this type of neuron brings us one step closer to the development of new treatments for obesity, said Susan L. Solomon, CEO of NYSCF.

The CUMC/NYSCF team determined which signals are needed to transform iPS cells into arcuate hypothalamic neurons, a neuron subtype that regulates appetite. The transformation process took about 30 days. The neurons were found to display key functional properties of mouse arcuate hypothalamic neurons, including the ability to accurately process and secrete specific neuropeptides and to respond to metabolic signals such as insulin and leptin.

We dont think that these neurons are identical to natural hypothalamic neurons, but they are close and will still be useful for studying the neurophysiology of weight control, as well as molecular abnormalities that lead to obesity, said Dr. Leibel. In addition, the cells will allow us to evaluate potential obesity drugs in a way never before possible.

This shows, said Dr. Eggan, how improved understanding of stem cell biology is making an impact on our ability to study, understand, and eventually treat disorders of the nervous system. Because there are so few hypothalamic neurons of a given type, they have been notoriously difficult to study. The successful work by both groups shows that this problem has been cracked.

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Neurons Controlling Appetite Made From Skin Cells

Li Ka Shing Foundation renews support for Yale Stem Cell Center

The Yale Stem Cell Center (YSCC), under the direction of biologist Haifan Lin, has announced a new generous grant of $1.86 million from the Li Ka Shing Foundation (LKSF), founded by Hong Kong businessman Li Ka-shing, to support education and healthcare initiatives. The contribution builds on a 2011 grant of $1.56 million to secure state-of-the-art equipment for stem cell research at Yale and includes new funding that will strengthen collaborations between Yale and Chinas Shantou University.

One of the fastest growing areas of biomedical science, stem cell research demands the very latest instrumentation and training. Since 2006, Lin has developed the Yale Stem Cell Center as both an incubator for scientific discovery and a training ground for new investigators.

The Yale Stem Cell Center offers a platform where both scientists and clinicians can ask important questions about stem cells and human health, Lin said. Continuing support from the Li Ka Shing Foundation will allow us to accelerate the pace and broaden the scope of our work.

Li said, Training side-by-side with leading scientists in stem cell research will be a transformative experience for the students and faculty at Shantou University Medical College, and I want to express my heart-felt appreciation to Professor Haifan Lin and the YSCC for this amazing opportunity.

Advances in stem cell science can offer basic insights into human development and the promise of new treatments for physical trauma, degenerative conditions, and genetic diseases. Because this research requires specialized instrumentation and expertise beyond what can be afforded by individual investigators, Lin has organized the Yale Stem Cell Center around four core laboratories that serve more than 80 Yale faculty members, along with researchers from other regional institutions.

In the Yale Stem Cell Center, Haifan Lin has developed an approach to collaborative research that truly serves as a model for universities and institutes around the country, said Robert J. Alpern, dean and the Ensign Professor at Yale School of Medicine. By sharing resources, laboratory techniques, and insights into how stem cells function, Haifan and his colleagues opened the door to discoveries that otherwise may not have been possible, for both basic science and clinical applications.

The new round of funding from LKSF will enable Yale investigators to purchase additional equipment to facilitate their research. This instrumentation will also support collaborations with scientists and clinicians in U.S. institutions such as the University of Connecticut Stem Cell Institute, the Massachusetts General Hospital Cancer Center, Albert Einstein College of Medicine, and St. Jude Childrens Research Hospital. Such exchanges can deepen our basic understanding of stem cell biology and help to translate todays technological breakthroughs into tomorrows personalized treatments and cures.

The grant also continues and expands the Yale Stem Cell Centers partnership with Shantou University, a key comprehensive university established through a public-private partnership between the Ministry of Education of Guangdong Province and the Li Ka Shing Foundation.

Yale is enormously grateful to Li Ka Shing Foundation for its continued support of basic science, translational research, and scholarly exchange, said Carolyn Slayman, Sterling Professor of Genetics, professor of cellular and molecular physiology, and deputy dean for academic & scientific affairs. This grant will help expedite the development of therapeutic treatments for some of the worlds most debilitating diseases.

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Cephas Bowles, CEO/President of Jazz Station WBGO, Dies at 62

Cephas Bowles, the president and CEO of Newark, N.J., jazz radio station WBGO, died Feb. 21 at Hackensack University Medical Center, following complications from a stem cell transplant. Bowles, who had been diagnosed with leukemia two years ago and had previously undergone a bone marrow transplant, was 62.

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Joe Lovano (right) greets Lionel Hampton along with Cephas Bowles of WBGO at the Jazz Leadership Society Dinner held at Swing 46, New York City 1999

By Norm Harris

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Bowles, who was affiliated with the station for 21 years, grew up in Newark and returned to his hometown after earning a degree in broadcasting from Syracuse University and working for CBS radio in New York and two NPR stations in Arizona. His first position at WBGO was as station manager. As CEO/president, he was largely responsible for establishing the stations streaming presence on the web, the first jazz station to become available via that medium. Bowles also served on the board of directors of National Public Radio and was active in the Newark community in other areas.

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MD Anderson Names Hwu as Head of Cancer Medicine

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Newswise Patrick Hwu, M.D., chair of Melanoma Medical Oncology and Sarcoma Medical Oncology at The University of Texas MD Anderson Cancer Center, has been named division head of Cancer Medicine effective March 4.

Hwus selection came after a competitive national search to fill the position currently being served by Richard Champlin, M.D., on an ad interim basis. Champlin will continue to serve as chair of Stem Cell Transplantation and Cellular Therapy.

Dr. Hwu is an internationally respected physician-scientist who has 25 years of experience in the fields of tumor immunology, targeted therapies and translational studies, said Ethan Dmitrovsky, M.D., provost and executive vice president. Hes a seasoned leader and has successfully chaired two departments and served as co-director of MD Andersons Center for Cancer Immunology Research and its immunotherapy platform. He has also held endowed positions, including the Sheikh Mohamed Bin Zayed Al Nahyan Distinguished University Chair in Cancer Research. Were delighted that he will be leading this vital division, and are thankful for Dr. Champlins skillful leadership during our search for a new division head.

Hwu earned his medical degree from the Medical College of Pennsylvania in Philadelphia and served as a house officer in internal medicine at The Johns Hopkins Hospital. He completed a fellowship in oncology at the National Cancer Institute, where he continued to work for 10 years as a principal investigator leading tumor immunology studies. He joined MD Anderson in 2003 as the first chair of Melanoma Medical Oncology.

Dr. Hwu is an accomplished clinician, researcher and administrator who is well positioned to take the Division of Cancer Medicine already recognized as a global leader to the next level, said Raymond S. Greenberg, M.D., Ph.D., executive vice chancellor for health affairs, The University of Texas System.

An expert in tumor immunology, Hwu has translated multiple concepts from the laboratory to the clinic and helped to launch the field of gene modified T cells, publishing research on the first chimeric antigen receptor (CAR) directed against cancer. Clinical trials using CAR-transduced T cells now are being studied in many types of cancers, and MD Anderson has established an adoptive T cell therapy program, treating more than 80 melanoma patients with T cells to date.

In addition, Hwu has produced novel, ongoing clinical trials based on his teams findings, including a study of combination T cell and dendritic cell therapy and a study of T cells modified with chemokine receptor genes to enhance their migration to the tumor. His most recent preclinical studies have focused on combinations of immune checkpoint blockade and T cell therapy, as well as rational combinations of targeted therapies and immunotherapies. Both of these concepts are being translated to the clinic.

Dr. Hwu and I worked closely together at the NCI for 13 years. He is one of those rare visionaries when it comes to expanding the frontiers of cancer medicine, said Steven A. Rosenberg, M.D., Ph.D., head of the Tumor Immunology Section and chief of the Surgery Branch at the National Cancer Institutes Center for Cancer Research. He is a brilliant scientist and leader. I congratulate him on this important position and look forward to working with him in his new leadership role at MD Anderson.

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Global warming contrarian researcher investigated for not revealing funding sources

3 hours ago by Bob Yirka

For several years, aerospace engineer Willie Wei-Hock Soon, with the Harvard-Smithsonian Center for Astrophysics (CfA) has been a well known figure in the debate regarding the cause of global warming. While most scientists have maintained that the elevated temperatures are due to increased greenhouse gases in the atmosphere from man-made processes, such as coal and gasoline burning, Soon has insisted that it is instead caused by normal fluctuations of the sun. Taking such a contrarian view has led to praise from those that support his views, and harsh criticism from those who do not.

Soon is in the spotlight again, this time facing accusations that he has not disclosed funding he has received when publishing research papers. His accusers suggest that he has received most of his funding from energy companies which would constitute a conflict of interest. Most respected journals require the authors of research papers to state in their paper that they report no conflict of interest.

Documents obtained via the Freedom of Information Act, by workers with Greenpeace which were subsequently given to investigators at the Climate Investigations Center (CIC) indicate that Soon received approximately $1.2 million in funding over the past fourteen years from companies such as Exxon Mobile, the American Petroleum Institute and most heavily, Southern Company, one of the largest electricity producers (which relies mostly on coal) in the country. Further research by investigators at CIC revealed that Soon did not disclose his ties to such funding organizations on nine research papers published in several different journals, in which he offers contrarian views on the cause of global warming. Also among the documents was a contract between CfA and Southern Company in which representatives with CfA promised to provide notification before publicly disclosing Southern Company as a funding source.

Also, because the CfA is partially funded by the U.S. government, representatives with Greenpeace have written letters to several congressional representatives asking that an investigation be undertaken to ascertain whether public funds were misused.

In light of the recent allegations, the CfA has launched an investigation of its own regarding disclosure issues regarding Soon. And finally, because the investigation is still ongoing, it is not yet clear what action journal editors will take regarding already published articles by Soon, or what will occur going forward.

Explore further: BMJ investigation reveals network of links between public health scientists and sugar industry

2015 Phys.org

Public health scientists and a government committee working on nutritional advice receive funding from the very companies whose products are widely held to be responsible for the obesity crisis, an investigation ...

When federal funding regulations created limitations on human embryonic stem cell research, several states created their own funding programs. A new study analyzed stem cell funding programs in four states that provided their ...

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Global warming contrarian researcher investigated for not revealing funding sources

New Study Sheds Light on Cancer Stem Cell Regulation

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Newswise La Jolla, Calif., February 5, 2015 Researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) have discovered a precise stem cell signaling process that can lead to intestinal tumors if disrupted. The findings add to our understanding of how stem cells give rise to tumors and identify specific stem cell molecules that may be targeted to prevent the onset, progression, and recurrence of intestinal cancers. The results of the study appear online in Cell Reports today.

Accumulating evidence suggests that cancer stem cells are responsible for cancer initiation, progression, metastasis, recurrence, and drug resistance, said Jorge Moscat, Ph.D., program director of the Cell Death and Survival Networks Program at Sanford-Burnham. Our new research provides a better understanding of the signaling cascades that regulate stem cells and is essential for the design of new and more-efficacious therapies for cancer.

We have shown that protein kinase C-zeta (PKC-zeta) normally inhibits stem cell activity through downregulation of two signaling pathways: beta-catenin and Yap, said Maria Diaz-Meco, Ph.D., senior co-author of the paper and professor in the Program. Previously, our lab showed that PKC-zeta acts as a tumor suppressor that maintains homeostasis of intestinal stem cells. The current study reveals the mechanism by which this occurs.

The intestine is covered by a single layer of epithelial cells that are renewed every 3 to 5 days. The pool of cells that replace these epithelial cellsintestinal stem cellsneeds to be regulated to maintain homeostasis.

Disturbing the homeostasis of the stem cell pool can go two waysit can either reduce intestinal epithelial cell regeneration or increase the proliferation of stem cells, said Diaz-Meco. Cancer is produced by the accumulation of mutations in critical genes that control central mechanisms of cell growth. Stem cells are a permanent population in the intestine and a reservoir for those mutations. Therefore, if stem cell activity is increased, as in the case of intestines deficient in PKC-zeta, then the likelihood of developing tumors is much higher, and when the tumor is initiated it becomes more aggressive.

Using a genetically engineered mouse model for intestinal cancer, the research team found that this process is kept under control by direct phosphorylation by PKC-zeta of two essential tumor promoters: beta-catenin and Yap.

Importantly, we confirmed the tumorigenic profiles of PKC-zeta, beta-catenin, and Yap in human colon adenocarcinoma samples. The correlation of human results with our in-vivo mouse studies strongly suggests that Yap and beta-catenin are potential targets of PKC-zeta function and potential targets for new anti-cancer therapies.

"Our results offer new possibilities for the prevention and treatment of intestinal cancers by blocking the pathways that lead to tumors, said Moscat. "They also highlight a new strategy to promote intestinal regeneration after acute or chronic damage, such as that triggered by chemotherapy and radiation.

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Top Swedish center boosts science-hub vision of SAR

Hilary Wong

Tuesday, February 03, 2015

The preeminent Karolinska Institutet will set up its first Asian research center in Hong Kong, which gets a boost in its quest to become a world-class science hub.

Local businessman Lau Ming-wai donated US$50 million (HK$390 million) to set up the Ming Wai Lau Centre for Regenerative Medicine.

The Swedish-Hong Kong center will focus on spinal injuries, a cure for Parkinson's disease, myocardial infarction and stem-cell liver transplant.

Anders Hamsten, vice chancellor of the Stockholm- based institute, said these are extremely critical diseases and groundbreaking research areas.

Karolinska's Nobel Assembly chooses the Nobel laureates in medicine or physiology each year.

The center will recruit 30 scientists through a global recruitment drive, with some of them coming from the institute.

The center's site will be decided in one to two months, with the Science Park one of the sites being considered.

It is expected to be up and running in six months,

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Top Swedish center boosts science-hub vision of SAR

Researchers advance the science behind treating patients with corneal blindness

LOS ANGELES (Jan. 27, 2015) - Researchers in the Cedars-Sinai Board of Governors Regenerative Medicine Institute have devised a novel way to generate transplantable corneal stem cells that may eventually benefit patients suffering from life-altering forms of blindness.

Scientists used human corneal cells to generate pluripotent stem cells that have a capacity to become virtually any body cell. Then, putting these cells on natural scaffolds, researcher's facilitated differentiation of these stem cells back to corneal cells.

"Our research shows that cells derived from corneal stem cells are attractive candidates for generating corneal cells in the laboratory," said Alexander Ljubimov, PhD, director of the Eye Program at the Board of Governors Regenerative Medicine Institute and principal investigator on this research study.

This research, published in the journal Stem Cells Translational Medicine, marks an important first step toward creating a bank of corneal stem cells that may potentially benefit patients who suffer from many forms of corneal blindness. The group is now working to optimize the process with National Institutes of Health funding.

Corneal deficiencies may have genetic or inflammatory roots or be caused by injuries, like burns to the skin in occupational accidents. They result in damage or death of stem cells that renew the outermost part of the cornea. If left untreated, they often cause compromised vision or blindness.

Over 150,000 Americans and more than 3 million individuals worldwide are affected by corneal blindness.

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Study collaborators include Clive Svendsen, PhD, director of the Board of Governors Regenerative Medicine Institute and professor of biomedical sciences and medicine; Dhruv Sareen, PhD, director of the Induced Pluripotent Stem Cell Core and assistant professor of biomedical sciences; Mehrnoosh Saghizadeh, PhD, assistant professor of biomedical sciences; Yaron Rabinowitz, MD, director of the Division of Ophthalmology Research; and Vincent A. Funari, PhD, director of the Genomics Core and assistant professor of pediatrics.

Citation: Sareen D, Saghizadeh M, Ornelas L, et al. Differentiation of human limbal-derived induced pluripotent stem cells into limbal-like epithelium. Stem Cells Transl Med. 2014; 3(9):1002-12.

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Researchers advance the science behind treating patients with corneal blindness