Placental Precursor Stem Cells Require Testosterone-Free Environment To Survive - Uncategorized

Trophoblast stem cells (TSCs), cells found in the layer of peripheral embryonic stem cells from which the placenta is formed, are thought to exhibit “immune privilege” that aids cell survivability and is potentially beneficial for cell and gene therapies. Further, the survivability of TSCs has been thought to require the presence of ovarian hormones. However, none of these assumptions has ever been verified. This study, published in the current issue of the journal Cell Transplantation (18:7) – now freely available on-line here – has demonstrated that it is the absence of male hormones, rather than the presence of female hormones, that allows extended transplanted cell survivability.

“Questioning whether a female hormonal environment is one of the physiological requirements for ectopic TSC survival, we surmised that a partially immune-privileged site other than the uterus might also allow TSCs to survive and exert a protective action on other nearby cells, enabling the latter to survive in locations where they normally could not,” said Dr. Bert Binas, co-author of the study.

When the research team injected the livers of both male and female mice with TSCs, the cells survived in female animal livers but did not survive in male animal livers.

“This was not unexpected, given the natural uterine environment for TSCs,” said Dr. Binas. “However, castration of the male mice abolished the sex hormone difference and the livers of the castrated male mice provided a perfect environment for the TSCs.”

The researchers concluded that the presence of male hormones was toxic for the injected TSCs. The injected TSCs survived for three months with little if any proliferation, regardless of their immunological compatibility, but were dependent on a non-male hormonal environment in castrated male mice.

The TSCs were also found to promote survival of another cell type when transplanted together, suggesting that these cells may be able to modify their local environment and enhance the survival of co-transplanted cells. Thus a new “stem cell based trophoblastic approach” to therapeutic cell transplantation may prove to be beneficial.

“Our model provides a starting point for systematically assessing the hormonal and other physiological requirements for trophoblast cells in vivo,” concludes Dr. Binas and his colleagues.

This study, for the first time, demonstrates that long term survival of trophoblast cells in the absence of ovarian hormones is possible.

“These are exciting results and clearly show that the relationship of stem cells with the host or transplant recipient includes a complex interaction between the ’seed and the soil’,” said section editor Dr. Stephen Strom, professor in the Division of Cellular and Molecular Pathology at the University of Pittsburgh. “In the case described here, the “soil” or the natural female environment free of male hormones is an appropriate and supportive environment for TSCs, whereas, the presence of the male hormones proved quite unfavorable for the sustained engraftment of the cells.The good part is that this paper demonstrates that cells such as TSCs confer immunoprotection to another cell type when co-transplanted with the TSCs. However this benefit is only extended to female recipients – males need not apply”.

The editorial offices for Cell Transplantation are at the Center of Excellence for Aging and Brain Repair, College of Medicine, the University of South Florida and the Diabetes Research Institute, University of Miami Miller School of Medicine.

Source: Bert Binas

Cell Transplantation Center of Excellence for Aging and Brain Repair

Placental Precursor Stem Cells Require Testosterone-Free Environment To Survive

Originally from:
http://www.medicalnewstoday.com/articles/169359.php

Physician-researchers at the University of Southern California (USC) received a nearly $16 million grant from the California Institute of Regenerative Medicine (CIRM) to fund the development of a stem cell-based treatment for age-related macular degeneration, the leading cause of vision loss and blindness among the elderly.

Mark Humayun, M.D., Ph.D., professor of ophthalmology, cell and neurobiology, and biomedical engineering at the Keck School of Medicine of USC and the USC Viterbi School of Engineering, and David R. Hinton, M.D., Gavin S. Herbert Professor of Retinal Research and Professor of Pathology and Ophthalmology at the Keck School of Medicine, will lead the four-year study.

CIRM and two international partners awarded more than $250 million to 14 multidisciplinary teams of researchers in California, the UK and Canada to develop stem cell-based therapies for 11 diseases. The Disease Team Research Awards mark the first CIRM funding explicitly expected to result in a filing with the FDA to begin a clinical trial.

The grants received formal approval today from the Independent Citizens Oversight Committee (ICOC), the 29-member governing board of the institute, and were announced at a press conference held in Los Angeles.

USC faculty will also collaborate on grants awarded to other California institutions:

• Paula Cannon, Ph.D., associate professor of molecular microbiology and immunology at the Keck School of Medicine, is a co-investigator on a team that received $14 million to develop a novel therapy that may offer lifetime immunity to HIV infection.

• Thomas Coates, M.D., professor of pediatrics and pathology at the Keck School of Medicine, is a co-investigator on a team that received $9 million to explore treating sickle cell disease using a gene therapy approach to modify patients’ blood-forming stem cell.
• Michael Press, M.D., Ph.D., Harold E. Lee Chair in Cancer Research at the USC Norris Comprehensive Cancer Center and professor of pathology at the Keck School of Medicine, is the co-investigator on a nearly $20 million grant aimed at developing drugs that destroy cancer stem cells in solid tumors.

Age-related macular degeneration (AMD) is a progressive disease that causes distortion in central vision and eventually leads to blindness. It is estimated that by 2020, more than 450,000 Californians will suffer from vision loss or blindness due to AMD. Effective treatment for the disease may be achieved by replacing damaged retinal pigment epithelium – the layer of cells at the back of the eye – and retinal cells with healthy ones derived from human embryonic stem cells, Humayun said.

“The funding from CIRM will be tremendously helpful and will accelerate our research towards achieving a near-term stem cell based therapy for AMD,” he said.

Humayun was elected this month to the prestigious Institute of Medicine for his groundbreaking work to restore sight to the blind. Election to the Institute is considered one of the highest honors in the fields of health and medicine and recognizes individuals who have demonstrated outstanding professional achievement and commitment to service.

CIRM President Alan Trounson said the pace of the Disease Team projects stands in contrast to the decade or more that’s usually required to reach clinical trials.

“Scientists have talked for years about the need to find ways to speed the pace of discovery. By encouraging applicants to form teams composed of the best researchers from around the world we think CIRM will set a new standard for how translational research should be funded,” he said.

Source: Meghan Lewit

University of Southern California

$16 Million Grant From State Stem Cell Agency To Speed Research Of Stem Cell-Based Treatment For Age-Related Macular Degeneration

Originally from:
http://www.medicalnewstoday.com/articles/169320.php

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A team of Cedars-Sinai Heart Institute stem cell researchers led by Eduardo Marbn, M.D., Ph.D. has been awarded a four-year, $5.5 million grant from the California Institute of Regenerative Medicine (CIRM) to fund research leading to clinical trials of new treatments for heart attack patients.

The grant will be used to continue Marbn’s development of cardiac stem cell therapies to strengthen and heal damaged heart muscle caused by cardiac arrest. The grant is part of a new strategy by the California state stem cell agency aimed at speeding the process of moving medical research from the laboratory to patient care.

Generally, it can take a decade or more to develop a new medical treatment to the point of securing federal approval for a clinical trial. The state institute’s Disease Team Research Awards, however, are designed to help researchers develop medical theories into treatments tested by clinical trials in four years or less.

Marbn’s team was one of 11 in California to receive a Disease Team Research Award and is the only team focusing on heart disease. Heart disease is the leading cause of death in the United States. According to the Centers for Disease Control, in 2009, an estimated 785,000 Americans will have a first-time heart attack and about 470,000 will have a recurrent attack.

Earlier this year, Marbn, who is director of the Cedars-Sinai Heart Institute, and his team completed the first procedure in which a patient’s own heart tissue was used to grow specialized heart stem cells that were then injected back into the patient’s heart in an effort to repair and re-grow healthy muscle in a heart that had been injured by a heart attack. The minimally-invasive procedure was completed on the first patient on June 26.

The Disease Team Award will enable Marbn’s team to develop other, new stem cell therapies for heart patients, including a potential treatment for patients with advanced heart failure.

“The support Cedars-Sinai is receiving from the California Institute for Regenerative Medicine will be an important element to succeeding in the fight against heart disease,” Marbn said. “What we work on in our stem cell lab today could translate into tomorrow’s innovative treatment for heart attack patients.”

“We are delighted that Dr. Marbn is receiving CIRM funding to continue his groundbreaking translational science devoted to regenerating diseased myocardial tissue,” said Shlomo Melmed, M.D., Cedars-Sinai Medical Center vice president of academic affairs and dean of the medical faculty. “This award validates the leading role of the Cedars-Sinai Heart Institute in developing cutting-edge treatments for heart disease.”

Source: Sally Stewart

Cedars-Sinai Medical Center

For Development Of Novel Stem Cell Treatments For Heart Attack Patients, Cedars-Sinai Researchers Awarded $5.5 Million

Originally from:
http://www.medicalnewstoday.com/articles/169319.php

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Two teams of UCSF scientists have received grants from the California Institute for Regenerative Medicine to advance their stem cell based strategies for treating diabetes and brain tumors. The intent of the grants is for teams to file new drug applications to the U.S. Food and Drug Administration within four years, driving potential therapies toward clinical trials.

The two grants, awarded to collaborative scientific teams, total $39.2 million.

The diabetes grant is co-led by investigator Jeffrey Bluestone, PhD, director of the UCSF Diabetes Center, in collaboration with Novocell, Inc. Other UCSF members of the team are Michael German, MD, PhD; Matthias Hebrok, PhD; and Qizhi Tang, PhD.

The brain tumor grant is led by Mitchel Berger, MD, chair of the UCSF Department of Neurosurgery, in collaboration with Ludwig Institute for Cancer Research and Burnham Institute for Medical Research. Other UCSF members of the team are C. David James, PhD; Tomoko Ozawa, MD, PhD; Russell Pieper, PhD; Mei-Yin Polley, PhD; Michael Prados, MD; and Elizabeth Read, MD.

The projects are among 14 disease team grants announced by CIRM. The grants focus on conditions ranging from brain tumors and diabetes to HIV, heart damage and amyotrophic lateral sclerosis, among others. They are the first issued by CIRM with the explicit intent of driving the development of therapies for approval by FDA for testing in clinical trials.

The multidisciplinary collaborations are intended to hasten the clinical trial development process, avoiding mistakes sometimes discovered late in the game and ensuring that clinically relevant issues are considered early.

The diabetes team, lauded as a “dream team” by the CIRM working group reviewers, received $19,999,937 over four years. The goal is to encapsulate islet progenitor cells generated from human embryonic stem cells in a durable, retrievable device and implant them into patients. The cells, which differentiate into glucose responsive islet beta cells after transplantation in vivo, have proven to be a successful strategy in treating rodents with chemically-induced diabetes.

“The critical early proof-of-concept milestones have been completed,” says Bluestone. “Now we need to perform the manufacturing and laboratory testing required to assure reliable production of a safe and effective product, thereby generating the data needed to seek Food and Drug Administration approval to test the therapy in humans.”

“This is a very exciting early pre-clinical step, but, as is always the case in science, there are likely to be unexpected hurdles as we move forward,” he says.

If successful, a Phase 1 safety trial in Type 1 diabetic patients could begin in three-four years from the initiation of the project.

The brain tumor team, which received $19,162,435, was characterized by the CIRM working group reviewers as “pioneers and leaders in their respective fields.” The team will refine their strategy of using adult and fetal neural stem cells, as well as mesenchymal stem cells, genetically engineered to contain a tumor-killing gene to home in on glioblastoma multiforme, the most common and aggressive form of brain tumor. The studies in rodents engineered to develop human brain tumors were successful.

The strategy is based on the team’s discovery that neural stem cells naturally seek out brain tumor cells and other types of disease cells. “If successful, this approach would be an important advance in treating brain tumors of all kinds,” says Berger. “Current approaches – surgery, radiation, pharmacological drugs and gene therapies – are unable to reach widely disseminated tumor cells that become dispersed within normal brain structures.”

If the strategy is approved by the FDA, it would be tested first in patients with recurring glioblastoma multiforme.

Diabetes Disease Team grant

In Type 1 diabetes, the body’s immune system turns against itself, destroying pancreatic beta cells. These cells produce insulin, a hormone that controls the amount of sugar in the blood stream. In Type 2 diabetes, caused by lifestyle factors such as obesity, the body’s ability to respond to, or produce insulin is reduced. In both cases, without insulin, blood sugar can increase to toxic levels. While pharmaceutical insulin is commonly used to control diabetes, it does not sufficiently replace beta cells, and the adverse short- and long-term effects of diabetes remain.

The diabetes disease team has developed a strategy in which they prompt human embryonic stem cells to differentiate into islet progenitor cells in the lab and then transplant the cells into rodents, where they differentiate into mature, insulin-producing beta cells.

To prevent the immune system’s reaction to the cells – either the auto-immune attack that would continue to occur in Type 1 diabetics or the normal immune system rejection to foreign cells that occurs in any transplant setting – the team has explored two strategies. One involves administering the cells inside a simple device, implantable under the skin. The other involves using next-generation pharmaceuticals, some of which have been approved recently by the FDA, that enable transplantation between unmatched individuals without major side effects.

The work will include identifying the best means for introducing cells into patients.

More on the grant: http://www.cirm.ca.gov/ReviewReports_DR1-01423

Brain Tumor Disease Team grant

The brain tumor disease team will derive human adult and fetal neural stem cells and mesenchymal stem cell lines, each cell line having been proffered as therapeutic, but never having been compared head-to-head in treating tumors. Each cell line will be modified using two therapeutic genes. One of the genes expresses a protein known as TRAIL that specifically kills tumor cells, but does not harm normal cells and tissues. The other expresses cytosine deaminase, an enzyme that converts a non-toxic chemical into a toxic chemotherapeutic.

The goal is to identify the most effective neural stem cell and therapeutic gene combination to advance for clinical trial in patients with brain tumors.

Source: Jennifer O’Brien

University of California – San Francisco

UCSF Diabetes, Brain Tumor Stem Cell Grants To Drive Development Of Therapies

Originally from:
http://www.medicalnewstoday.com/articles/169316.php

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U.S. District Judge Royce Lamberth on Tuesday dismissed a lawsuit challenging the Obama administration’s move this year to ease federal restrictions on embryonic stem cell research, the AP/Seattle Times reports. In its lawsuit, Nightlight Christian Adoptions alleged that the new federal guidelines would reduce the availability of human embryos for adoptions. However, Lamberth noted that people still could decide if they want to store the embryos or give them to an adoption agency, instead of donating them for research. Lamberth also said that potential embryo donors would have to choose to donate their embryos for research, rather than for adoption, for the agency to have grounds to sue. Ron Stoddart, executive director of the California-based agency, said the organization is considering an appeal (AP/Seattle Times, 10/27).

Reprinted with kind permission from http://www.nationalpartnership.org. You can view the entire Daily Women’s Health Policy Report, search the archives, or sign up for email delivery here. The Daily Women’s Health Policy Report is a free service of the National Partnership for Women & Families, published by The Advisory Board Company.

2009 The Advisory Board Company. All rights reserved.

Judge Dismisses Lawsuit Challenging Federal Guidelines On Embryonic Stem Cell Research

Originally from:
http://www.medicalnewstoday.com/articles/169258.php

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The recent creation of live mice from induced pluripotent stem cells (iPSCs) not only represents a remarkable scientific achievement, but also raises important issues, according to bioethicists at The Johns Hopkins University’s Berman Institute of Bioethics.

In a letter published Oct. 28 in Regenerative Medicine, the authors advocate for clear ethical oversight of this research and pose key questions that warrant careful consideration.

The promise of iPSCs is that they will behave like embryonic stem cells and that their derivation will be both efficient and free of much of the moral controversy that has hampered embryonic stem cell research.

However, the considerable time and resources currently needed to create iPSCs impede their potential use in medicine, state the authors, who caution that there is no guarantee this more efficient approach demonstrated in mice will work in humans.

In addition, “these experiments involved the creation of embryos, from which the live mice were successfully born,” write Jeremy Sugarman, M.D., M.P.H., and Debra J.H, Mathews, Ph.D., both of the Berman Institute of Bioethics. “Paradoxically, this brings us full circle to the knotty questions related to the moral status of the embryo.”

Work on this project was supported in part by a grant from the Stavros Niarchos Foundation, “The Bioethics Rapid Response Initiative.”

Source: Johns Hopkins Medicine

Of Mice And Men: Stem Cells And Ethical Uncertainties

Originally from:
http://www.medicalnewstoday.com/articles/169241.php

The National Institute of General Medical Sciences (NIGMS), part of the National Institutes of Health, is using $5.4 million of Recovery Act funds to accelerate basic studies of induced pluripotent stem cells. These cells, abbreviated iPS, are reprogrammed from skin or other easily obtained adult cells and appear to be similar to stem cells derived from embryos.

In theory, iPS cells could generate any type of cell and be used to treat diseases. But to realize this potential, scientists need a much better understanding of iPS cells’ fundamental properties and how to efficiently derive cells that are safe for therapeutic uses.

To speed iPS research, NIGMS has awarded one-year grant supplements to 22 scientists at 16 institutions in 12 states and the District of Columbia. The investigators already have strong records of accomplishment in a range of research areas and will study iPS cells in varied biological systems.

“Stem cell biology is poised for rapid advances, and we expect our Recovery Act investment to have a catalytic effect. The new awards will contribute to the field’s progress by enhancing the utility of iPS cells as tools for research, for testing the effects of drugs on human tissues and ultimately for patient-specific treatments,” said NIGMS Director Jeremy M. Berg, Ph.D.

The Recovery Act funding will allow the scientists to address such important questions as:

• How does reprogramming work?

• What factors are necessary to create iPS cells efficiently and safely?
• What drives iPS cells toward a desired cell type that can be used to regenerate or repair damaged tissues in a patient?
• Do iPS cells differ from embryonic and adult stem cells, and if so, how?

The investigators receiving supplements are:

• Bruce Beutler, Scripps Research Institute, La Jolla, Calif.

• C. Anthony Blau, University of Washington, Seattle
• Richard Cerione, Cornell University, Ithaca, N.Y.
• Stephen Dalton, University of Georgia, Athens
• Sharon Dent, University of Texas M.D. Anderson Cancer Center, Houston
• Andres Garcia, Georgia Institute of Technology, Atlanta
• David Gilbert, Florida State University, Tallahassee
• Margaret Goodell, Baylor College of Medicine, Houston
• Brenton Graveley, University of Connecticut Health Center, Farmington
• Jeanne Lawrence, University of Massachusetts Medical School, Worcester
• Jeannie Lee, Massachusetts General Hospital, Boston
• Shaohua Li, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, Piscataway
• John Lis, Cornell University, Ithaca, N.Y.
• Nancy Maizels, University of Washington, Seattle
• Sergie Nekhai, Howard University, Washington, D.C.
• Sean Palecek, University of Wisconsin-Madison
• Arnold Rizzino, University of Nebraska Medical Center, Omaha
• Hannele Ruohola-Baker, University of Washington, Seattle
• James Thomson, University of Wisconsin-Madison
• Yi Wang, Baylor College of Medicine, Houston
• Jeffrey Wilusz, Colorado State University, Fort Collins
• Jerome Zack, University of California, Los Angeles

Source: Ann Dieffenbach

NIH/National Institute of General Medical Sciences

Recovery Act Funds Expand Studies Of Stem Cell Biology

Originally from:
http://www.medicalnewstoday.com/articles/169202.php

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The Salk Institute has been awarded a $10.8 million grant by the California Institute for Regenerative Medicine (CIRM) for translational research focusing on developing a novel stem-cell based therapy for Amyotrophic Lateral Sclerosis (ALS) – or Lou Gehrig’s Disease.

Sam Pfaff, Ph.D., a professor in the Salk’s Gene Expression Laboratory and an investigator for the Howard Hughes Medical Institute, will lead the group of researchers who will work on the four-year project announced as part of the $250 million CIRM Disease Team Award.

It marks the first CIRM funding explicitly expected to result in FDA approval for clinical trials. The grants were given to multidisciplinary teams of basic scientists, clinicians and industry in collaboration with two international partners, the Medical Research Council, UK, and the Cancer Stem Cell Consortium, Canada.

ALS is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. When motor neurons die, the ability of the brain to initiate and control muscle movement is lost. The progressive degeneration of motor neurons in ALS eventually leads to paralysis and death.

The research team, which includes co-principal investigators Drs. Larry Goldstein and Don Cleveland, both of UCSD, will focus on astrocytes, the star-shaped support cells that provide nutrients for nearby motor neurons. Working with six different lines of human embryonic stem cells (hESC), Pfaff and the team of researchers will grow clinical-grade astrocyte precursor cells and identify the line that is best suited for implantation in laboratory models.

They hypothesize that the transplanted human astrocyte precursors (hAP) will mature into astrocytes in vivo and provide support for diseased spinal motor neurons. Astrocytes are also capable of clearing excess neurotoxic glutamate and could thereby slow or halt the progression of ALS by preventing motor neuron degeneration.

Once the astrocyte precursors are tested for efficacy and safety to minimize the possibility of tumorigenesis, the next step will be to move forward with human clinical trials after approval by the FDA, says Pfaff.

“This team grant is a natural fit for San Diego because it capitalizes on the strength of neuromuscular disease research from the local scientific community,” says Pfaff. “The standard has been set very high on this project because we are aiming to grow a safe population of astrocytes that can be introduced into patients. Our success will be measured by whether it will help extend the lives of patients suffering from ALS.”

CIRM President Alan Trounson said the pace of the Disease Team projects stands in contrast to the decade or more that’s usually required to reach clinical trials. “Scientists have talked for years about the need to find ways to speed the pace of discovery,” he said. “By encouraging applicants to form teams composed of the best researchers from around the world we think CIRM will set a new standard for how translational research should be funded.”

Source: Mauricio Minotta

Salk Institute

PUrsuing Novel Stem-Cell Derived Therapy For Lou Gehrig’s Disease With $10.8 Million Award

Originally from:
http://www.medicalnewstoday.com/articles/169199.php

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Researchers at the University of Illinois at Chicago College of Medicine have shown that adult stem cells from bone marrow can prevent acute lung injury in a mouse model of the disease.

Their results are reported online in the October issue of the journal Stem Cells.

Acute lung injury (ALI) is responsible for an estimated 74,500 deaths in the U.S. each year. ALI can be caused by any major inflammation or injury to the lungs and is a major cause of death in patients in hospital ICUs. There is no effective drug treatment.

In ALI, the layer of cells that forms the lining of the blood vessels surrounding the lung’s air sacs is damaged, allowing fluid to leak in and fill the sacs. Repair of these breaks in the endothelium, or lining, is complicated by the fact that endothelial cells are long-lived, says Kishore Wary, UIC assistant professor of pharmacology and lead author of the study. Turnover of new cells takes as long as two to five years, and few of the precursor cells needed for replacement circulate in the body at any given time.

“The stem cells that might be able repair the damage caused by ALI are simply not on hand,” he said.

Wary and his colleagues were able to identify progenitor stem cells in the bone marrow of mice that could prevent and treat experimentally-induced ALI. These progenitor stem cells, named Flk-1 and CD34 for the proteins on their surfaces, constitute a very small percentage of the stem cell population in the bone marrow, but the researchers were able to develop a way of culturing the cells that increased their numbers and their “stickiness.”

The stem cells stud their surface with molecules called integrins that allow the cells to stick to their targets and affect the repair. “Increasing this capacity for stickiness in our culture system was likely to make the stem cells more effective in repair,” Wary said.

When mice that had been injected with a compound that causes ALI were injected with the purified and cultured Flk and CD34 stem cells, the progenitor cells were able to repair the lung injury, prevent fluid build-up, and led to improved survival.

The mouse disease model not only demonstrated that stem cell treatment is a promising therapy for ALI, Wary said, “but also provided us with the means to understand how these progenitor cells did their repair work. These therapeutic cells employed integrins to stick to the site of injury and turn on cellular and molecular repair machinery,” he said.

The researchers hope to explore the possibility of using stem cell therapy in human acute lung injury.

The research was supported by grants from the National Institutes of Health. Stephen M. Vogel, Sean Garrean, Yidan D. Zhao and Asrar B. Malik, all of the department of pharmacology in the UIC College of Medicine, also contributed to the study.

Source:
Jeanne Galatzer-Levy

University of Illinois at Chicago

Stem Cell Therapy May Offer Hope For Acute Lung Injury

Originally from:
http://www.medicalnewstoday.com/articles/169163.php

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