Bone marrow transplantation can be a life-saving procedure, but also a grueling one. Once a compatible donor is found, a recipient must undergo nonspecific radiation or chemotherapy to destroy their own bone marrow, which may leave them weak and vulnerable to infection.
Immune cells, like this T lymphocyte, are generated by stem cells in the bone marrow. Stem cell transplantation can be curative when immune cells are faulty because of inherited mutations, or because of acquired diseases like cancer.
Credit: NIAID
Bone marrow recipients usually also require lifelong treatment with immunosuppressive agents that help them tolerate the donation but may increase their risk of infection and cancer.
In a new paper(link is external) published February 6 in Nature Communications, researchers from NIAID and Harvard University describe a way to better prepare a recipient to tolerate bone marrow donation, using an antibody-drug conjugate that combines a cell-targeting antibody with a cell toxin, which the antibody carries as cargo. Using this approach, they were able to selectively kill bone marrow stem cells in mice, making the mice much more likely to tolerate donor stem cells in bone marrow and to accept skin grafts, without complications or the need for long-term immunosuppression.
The technique uses a combination of a monoclonal antibody and a cell toxin to kill off the recipient’s original stem cells. The monoclonal antibody binds to a protein, CD117, which is common on the outside of the recipient’s blood-producing stem cells. This allows the drugs to selectively kill the stem cells while leaving most other cells unharmed, clearing the way for the donor stem cells to take hold after the transplant.
In a separate paper(link is external) also published in the same issue of Nature Communications, the Harvard team used NIAID funding to test the same antibody-drug combination on mice whose immune system proteins were very similar to those of donor mice. In the recipient mice, one dose of the antibody-drug combination removed over 99 percent of bone marrow stem cells, allowing new donor cells to easily take hold without serious complications. The recipient immune systems were later shown to function well when challenged with fungal spores and viruses.
In their collaborative study, NIAID and Harvard researchers took this idea a step further by testing the antibody-drug combination on mice whose immune system proteins were very different from those of the donor mice, a situation that can make rejection symptoms more likely. Fourteen out of fifteen mice that received bone marrow transplants using the antibody-drug combination remained healthy for almost two years—nearly the entire normal lifespan of a mouse. Most of the mice that were given the antibody-drug combination treatments before receiving skin grafts also did well. In mice receiving no treatments, the skin grafts were rapidly rejected.
Although the antibody-drug combination technique has not yet been tested in humans, these early results are remarkable, the researchers say, and the technique merits further investigation. Content last reviewed on February 26, 2019
Analysis of genetic data from more than 94,000 individuals has revealed five new risk genes for Alzheimer’s disease, and confirmed 20 known others.
Newly identified (red) and known (blue) genes linked to Alzheimer’s disease spike in this table plotting results from genome-wide association analysis of 94,437 individuals with late onset Alzheimer’s.Kunkle et al and Nature Genetics.
An international team of researchers also reports for the first time that mutations in genes specific to tau, a hallmark protein of Alzheimer’s disease, may play an earlier role in the development of the disease than originally thought. These new findings support developing evidence that groups of genes associated with specific biological processes, such as cell trafficking, lipid transport, inflammation and the immune response, are “genetic hubs” that are an important part of the disease process. The study, which was funded in part by the National Institute on Aging (NIA) and other components of the National Institutes of Health, follows results from 2013. It will be published online February 28, 2019 in the journal Nature Genetics.
“This continuing collaborative research into the genetic underpinnings of Alzheimer’s is allowing us to dig deeper into the complexities of this devastating disease,” said Richard J. Hodes, M.D., director of the NIA. “The size of this study provides additional clarity on the genes to prioritize as we continue to better understand and target ways to treat and prevent Alzheimer’s.”
The researchers, members of the International Genomic Alzheimer’s Project (IGAP), analyzed both rare and common gene variants in 94,437 individuals with late onset Alzheimer’s disease, the most common form of dementia in older adults. IGAP is made up of four consortia in the United States and Europe that have been working together since 2011 on genome-wide association studies (GWAS) involving thousands of DNA samples and shared datasets. GWAS are aimed at detecting variations in the genome that are associated with Alzheimer’s. Understanding genetic variants is helping researchers define the molecular mechanisms that influence disease onset and progression.
In addition to confirming the known association of 20 genes with risk of Alzheimer’s and identifying five additional Alzheimer’s-associated genes, these genes were analyzed to see what cellular pathways might be implicated in the disease process. The pathway analysis implicated the immune system, lipid metabolism and amyloid precursor protein (APP) metabolism. Mutations in the APP gene have been shown to be directly related to early onset Alzheimer’s. The present study, done in late onset Alzheimer’s subjects, suggests that variants affecting APP and amyloid beta protein processing are associated with both early-onset autosomal dominant Alzheimer’s and with late onset Alzheimer’s. In addition, for the first time, the study implicated a genetic link to tau binding proteins. Taken together, data suggest that therapies developed by studying subjects with early-onset disease could also be applied to the late-onset form of Alzheimer’s.
The research was led by an international team of experts including Brian Kunkle, Ph.D. and Margaret Pericak-Vance, Ph.D., from the Miller School of Medicine’s John P. Hussman Institute for Human Genomics at the University of Miami, and Benjamin Grenier-Boley, Ph.D. and Jean-Charles Lambert, Ph.D., from INSERM, Lille, France.
Once the functions of the five genes newly associated with Alzheimer’s—IQCK, ACE, ADAM10, ADAMTS1 and WWOX—are understood and examined in conjunction with the functions of the 20 known genes, researchers will be in a better position to identify where the genetic hubs of Alzheimer’s are clustering. Armed with these findings, researchers can look more deeply into these genetic hubs to reveal disease mechanisms and potential drug targets.
A key to these discoveries was the sample size, the largest to date for this kind of Alzheimer’s study. A large sample is especially important to find rare genes that might be involved with a disease.
“Having more and more samples in GWAS data sets is like adding more and more pixels to a photograph—it helps researchers see details that they otherwise wouldn’t and helps them decide where to focus further study,” explained Marilyn Miller, Ph.D., director of the Genetics of Alzheimer’s Disease program in the Division of Neuroscience at NIA. “If the genes only appear in one out of ten thousand people, you need to find several samples containing those genes for results to be statistically significant.”
The research was funded by multiple NIH grants, including AG032984, AG036528, AG21886, AG041689, AG016976, AG049505 and AG056270 from NIA. Other NIH institutes involved were the National Heart, Lung and Blood Institute, National Human Genome Research Institute, National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, National Institute of Diabetes and Digestive and Kidney Disease, and National Institute of Neurological Disorders and Stroke.
The National Institutes of Health (NIH) is the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases.
Partnership will ensure provision of latest technology to enable early diagnostics and better treatment for cancer patients; NSIA- LUTH Cancer Center (NLCC) is the first hospital in West Central Africa to install GE Healthcare’s Discovery RT CT.
2nd Right: Eyong Ebai, General Manager for West Central and French Sub-Sahara Africa at GE Healthcare and his team during the commission event
GE Healthcare has partnered with the Nigeria Sovereign Investment Authority (NSIA) to supply latest technology in computed tomography (CT), Discovery RT, to Lagos University Teaching Hospital for its modern NSIA- LUTH Cancer Center, commissioned by President Muhammadu Buhari.
The Discovery RT, a simulation CT machine, is the first of such technology to be installed in the country. It enables physicians to study the body in detail allowing them to determine the exact location, shape, and size of the tumor to be treated. As part of the partnership, GE Healthcare will also provide servicing of the equipment and deliver hands-on training for the hospital’s radiology staff on the new technology.
Nigeria currently has eight public and one private comprehensive cancer care centers to serve its growing population of over 180 million people. Many of the public cancer centers have radiotherapy machines that are outdated, making access to radiation therapy more difficult for cancer patients. The new Radiotherapy Centre will increase access to quality services for the patients across Lagos state. This will help early detection and treatment of cancer, which improves chances of its being cured.
“For many years, GE Healthcare has developed tools that help improve the care of patients through advanced technologies that facilitate the diagnosis as well as help the fight against diseases such as cancer. We are happy to collaborate with NSIA in this landmark achievement for Nigeria in progressing the availability of world-class radiotherapy for cancer patients in the region. This will help improve the overall results in the fight against cancer, as well as in improving the quality of life”, said Eyong Ebai, General Manager for West Central and French Sub-Sahara Africa at GE Healthcare.
The World Health Organization (WHO) projects that by 2030, between 10 and 11 million cancers will be diagnosed in low and middle-income countries.
The world now has more young people than ever before – of the 7.2 billion people worldwide, over 3 billion are younger than 25 years, making up 42% of the world population. Around 1.2 billion of these young people are adolescents aged between 10 and 19 years.
Adolescence is a critical time of life. It is a time when people become independent individuals, forge new relationships, develop social skills and learn behaviours that will last the rest of their lives. It can also be one of the most challenging periods. In this turbocharged neurological, physical, and emotional transition from childhood to adulthood, young people face a range of health risks. They are often exposed to harmful products such as tobacco, alcohol and drugs, they face greater risks of violence (including homicide) and road traffic injuries than in childhood, and can experience devastating mental health issues such as depression, anxiety, self-harm, substance abuse and addiction to video games, as well as eating disorders and suicide. Young people can also face sexual health issues such as sexually transmitted diseases or teenage pregnancy.
Many of these issues are linked to wider societal determinants and social norms. For example, pressures to conform to ideals about body image, normalization of recreational drinking in media, social exclusion, challenges in accessing support services, coupled with rapid physiological and neurological changes and the urge for exploration and experimentation, can make it hard to cope with the varied challenges that today’s youth will almost certainly encounter.
Depending on where they live in the world, young people may face an even wider range of threats to their health, including racial or gender discrimination or violence, human rights violations, conflict or social disruption from natural disasters, being overweight or obese, female genital mutilation (FGM), forced child marriages or sexual exploitation and abuse.
The numbers are striking: about 3000 adolescents die every day; in 2016, more than 1.1 million adolescents aged 10-19 lost their lives, mainly to preventable causes such as road injuries, complications of pregnancy or giving birth, or because of HIV/AIDS.
A team from the George Washington University (GW) Cancer Center has been approved for a $300,000 funding award through the Eugene Washington PCORI Engagement Awards (Engagement Awards) program, an initiative of the Patient-Centered Outcomes Research Institute (PCORI).
The funds will support dissemination of patient-driven standards for quality cancer survivorship care.
Mandi Pratt-Chapman, MA, associate center director for patient-centered initiatives and health equity at the GW Cancer Center and principal investigator for the award will lead the engagement project.
The project, “Disseminating Patient-Driven Standards for Quality Cancer Survivorship Care” will focus on engaging well-established relationships with comprehensive cancer control coalitions to disseminate and facilitate implementation of the Survivorship Care Quality Index (SCQI) into practice among oncology and primary care providers at both a national level and targeted states.
The SCQI is designed to help health care providers develop, assess and track patient-centered, high quality survivorship care and was developed through a previous PCORI award. The SCQI provides a holistic inventory of quality care services that help providers optimize the limited time available in a clinical encounter.
“I’m very excited about this opportunity to provide a framework and tools for cancer centers to improve the quality of survivorship care,” said Pratt-Chapman, who served as co-principal investigator on the original project that resulted in the SCQI. “By providing organizations with evidence-based recommendations and practical tools for putting those recommendations into practice, we hope to ultimately improve care for the 15.5 million cancer survivors across the United States.”
The insights of the SCQI are designed to be useful to both oncology and primary care providers in a variety of diverse settings. As a part of this work, the GW Cancer Center will work with a Community Advisory Board to create resources to support improvements in quality care including toolkits, tip sheets and resource guides for providers as well as training through an online learning module and in-person workshops in collaboration with comprehensive cancer control coalitions.
“Disseminating Patient-Driven Standards for Quality Cancer Survivorship Care” is part of a portfolio of projects that PCORI has funded to help develop a community of patients and other stakeholders equipped to participate as partners in comparative clinical effectiveness research (CER) and disseminate PCORI-funded study results. Through the Engagement Award Program, PCORI is creating an expansive network of individuals, communities and organizations interested in and able to participate in, share, and use patient-centered CER.
PCORI is an independent, non-profit organization authorized by Congress in 2010 to fund comparative effectiveness research that will provide patients, their caregivers and clinicians with the evidence needed to make better-informed health and health care decisions. PCORI is committed to seeking input from a broad range of stakeholders to guide its work.
About the GW Cancer Center
The George Washington University (GW) Cancer Center is a collaboration of the George Washington University, the GW Hospital and the GW Medical Faculty Associates to expand GW’s efforts in the fight against cancer. The GW Cancer Center also incorporates all existing cancer-related activities at GW, with a vision to create a cancer-free world through groundbreaking research, innovative education and equitable care for all.
NIH scientists use epigenetics to help predict disease development.
If a woman’s biologic age is older than her chronologic age, she has an increased risk of developing breast cancer. NIEHS
Biologic age, a DNA-based estimate of a person’s age, is associated with future development of breast cancer, according to scientists at the National Institutes of Health.
Biologic age was determined by measuring DNA methylation, a chemical modification to DNA that is part of the normal aging process. The study showed for every five years a woman’s biologic age was older than her chronologic or actual age, known as age acceleration, she had a 15 percent increase in her chance of developing breast cancer. The study was published online Feb. 22 in the Journal of the National Cancer Institute.
Scientists from the National Institute of Environmental Health Sciences (NIEHS), part of NIH, speculate that biologic age may be tied to environmental exposures. If so, it may be a useful indicator of disease risk. They used three different measures, called epigenetic clocks, to estimate biologic age. These clocks measure methylation found at specific locations in DNA. Researchers use these clocks to estimate biologic age, which can then be compared to chronologic age.
The researchers used DNA from blood samples provided by women enrolled in the NIEHS-ledSister Study, a group of more than 50,000 women in the U.S. and Puerto Rico. The study was specifically designed to identify environmental and genetic risk factors for breast cancer. The research team measured methylation in a subset of 2,764 women, all of whom were cancer-free at the time of blood collection.
“We found that if your biologic age is older than your chronologic age, your breast cancer risk is increased. The converse was also true. If your biologic age is younger than your chronologic age, you may have decreased risk of developing breast cancer,” said corresponding author Jack Taylor, M.D., Ph.D., head of the NIEHS Molecular and Genetic Epidemiology Group. “However, we don’t yet know how exposures and lifestyle factors may affect biologic age or whether this process can be reversed.”
Lead author Jacob Kresovich, Ph.D., a postdoctoral fellow in the Taylor group, had read studies that used epigenetic clocks to predict age-related mortality. Since age is the leading risk factor for breast cancer, he hypothesized that age acceleration may be associated with higher breast cancer risk.
“If you look at a group of people who are all the same age, some may be perfectly healthy while others are not,” Kresovich said. “That variability in health may be better captured by biologic age than chronologic age.”
Kresovich suggests that using DNA methylation to measure biologic age may help scientists better understand who is at risk for developing cancer and other age-related diseases. This research is an example of epigenetics, a field that studies how biochemical processes turn individual genes on or off, without affecting the DNA sequence.
The Taylor group plans to continue using epigenetic data, along with information on genetics, environment, and lifestyle to better understand how these factors interact and contribute to disease risks.
This press release describes a basic research finding. Basic research increases our understanding of human behavior and biology, which is foundational to advancing new and better ways to prevent, diagnose, and treat disease. Science is an unpredictable and incremental process— each research advance builds on past discoveries, often in unexpected ways. Most clinical advances would not be possible without the knowledge of fundamental basic research.
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The National Institute of Environmental Health Sciences (NIEHS): NIEHS supports research to understand the effects of the environment on human health and is part of the National Institutes of Health.
The National Institutes of Health (NIH):NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases.
Children with Both Conditions have Abnormal Skin Near Eczema Lesions, NIH-Funded Research Finds
A researcher demonstrates the minimally invasive collection of skin samples using small, clear tape strips. Credit: National Jewish Health
Atopic dermatitis, a common inflammatory skin condition also known as allergic eczema, affects nearly 20 percent of children, 30 percent of whom develop food allergies.
Scientists have now found that children with both atopic dermatitis and food allergy have structural and molecular differences in the top layers of healthy-looking skin near the eczema lesions, whereas children with atopic dermatitis alone do not.
Defining these differences may help identify children at elevated risk for developing food allergies, according to research published online today in Science Translational Medicine. The research was supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.
“Children and families affected by food allergies must constantly guard against an accidental exposure to foods that could cause life-threatening allergic reactions,” said NIAID Director Anthony S. Fauci, M.D. “Eczema is a risk factor for developing food allergies, and thus early intervention to protect the skin may be one key to preventing food allergy.” Children with atopic dermatitis develop patches of dry, itchy, scaly skin caused by allergic inflammation. Atopic dermatitis symptoms range from minor itchiness to extreme discomfort that can disrupt a child’s sleep and can lead to recurrent infections in scratched, broken skin.
A drawing of skin and a hair follicle. In this study, scientists analyzed the outermost layer of the skin, the stratum cornea, highlighted here in yellow.Credit: NIAMS, NIH
The study, led by Donald Y.M. Leung, M.D., Ph.D., of National Jewish Health in Denver, examined the top layers of the skin, known as the stratum corneum, in areas with eczema lesions and in adjacent normal-looking skin. The study enrolled 62 children aged 4 to 17 who either had atopic dermatitis and peanut allergy, atopic dermatitis and no evidence of any food allergy, or neither condition. Investigators collected skin samples by applying and removing small, sterile strips of tape to the same area of skin. With each removal, a microscopic sublayer of the first layer of skin tissue was collected and preserved for analysis. This technique allowed researchers to determine the skin’s composition of cells, proteins and fats, as well as its microbial communities, gene expression within skin cells and water loss through the skin barrier.
Researchers found that the skin rash of children with both atopic dermatitis and food allergy was indistinguishable from the skin rash of children with atopic dermatitis alone. However, they found significant differences in the structure and molecular composition of the top layer of non-lesional, healthy-appearing skin between children with atopic dermatitis and food allergy compared with children with atopic dermatitis alone. Non-lesional skin from children with atopic dermatitis and food allergy was more prone to water loss, had an abundance of the bacteria Staphylococcus aureus, and had gene expression typical of an immature skin barrier. These abnormalities also were seen in skin with active atopic dermatitis lesions, suggesting that skin abnormalities extend beyond the visible lesions in children with atopic dermatitis and food allergy but not in those with atopic dermatitis alone.
“Our team sought to understand how healthy-looking skin might be different in children who develop both atopic dermatitis and food allergy compared to children with atopic dermatitis alone,” said Dr. Leung. “Interestingly, we found those differences not within the skin rash but in samples of seemingly unaffected skin inches away. These insights may help us not only better understand atopic dermatitis, but also identify children most at risk for developing food allergies before they develop overt skin rash and, eventually, fine tune prevention strategies so fewer children are affected.”
Allergy experts consider atopic dermatitis to be an early step in the so-called “atopic march,” a common clinical progression found in some children in which atopic dermatitis progresses to food allergies and, sometimes, to respiratory allergies and allergic asthma. Many immunologists hypothesize that food allergens may reach immune cells more easily through a dysfunctional skin barrier affected by atopic dermatitis, thereby setting off biological processes that result in food allergies.
Reference: D Leung et al. Non-lesional skin surface distinguishes atopic dermatitis with food allergy as unique endotype. Science Translational Medicine DOI: 10.1126/scitranslmed.aav2685 (2019).
