Posted on NIH. 2 September, 2020
The National Institutes of Health (NIH) is our nation’s medical research agency and strives to make scientific discoveries that improve health and save lives. Founded in 1870, the NIH conducts its own scientific research through its Intramural Research Program (IRP), which supports approximately 1,200 principal investigators and more than 4,000 postdoctoral fellows conducting basic, translational and clinical research. In this blog, we will highlight recent ground-breaking NIH research.
In recent years, the incidence of non-small cell lung cancer (NSCLC) in the United States has progressively decreased with significant declines in mortality rates resulting from advanced stages of the disease. Reduced tobacco consumption and recent advances in treatment have contributed to this recent improvement in lung cancer related conditions.
In a study led by researchers at the National Cancer Institute (NCI), it was determined that nationwide mortality rates in the US that NSCLC, the most common category of lung cancer, are declining faster than its incidence. Dr. Douglas R. Lowy, NCI deputy director and co-author of this study, indicates this is an advance that correlates with the U.S. Food and Drug Administration approval of several targeted therapies for this cancer in recent years. “Until now, however, we have not known whether newer treatments might contribute to some of the recent improvement.”
NCI researchers evaluated data for NSCLC, which accounts for 76% of lung cancer in the U.S., and small-cell lung cancer (SCLC), which accounts for 13%. During the last ten years, novel treatments for NSCLC have become available, including those that have the ability to target genetic changes seen in NSCLC tumors as well as immune checkpoint inhibitors that assist the immune system in attacking NSCLC. However, fewer advancements have been made in the treatment of SCLS.
In this current study, the researchers observed an overall decrease in the mortality rate of NSCLS at a faster rate than the relative decrease of incidence of NSCLS in recent years. Among men, deaths from NSCLC decreased 3.2% annually from 2006 to 2013 and 6.3% annually from 2013 to 2016, whereas incidence decreased 1.9% annually during 2001 to 2008 and 3.1% annually from 2008 to 2016. The two-year survival rate for patients with NSCLC improved from 26% for patients diagnosed in 2001 to 35% for those diagnosed in 2014.
The original hypothesis that lung cancer screening was responsible for the decreases in NSCLC mortality was disproved as screening rates remained low and stable and cannot account for the decline in mortality. Instead, the study determined that reductions in smoking in conjunction with advances in treatment both contributed to the rapid decline in deaths and incidence of NSCLC.
In comparison, decreases in SCLC related deaths corresponded with the decrease in incidence, and the two-year survival remained largely unchanged. Overall, SCLC deaths declined 4.3% annually with a decline of incidence at 3.6% annually. Therefore, the reduction in mortality resulting from primarily reflects declines in incidence which is large due largely to the reduction in tobacco usage in the US.
Beginning in 2012, the National Comprehensive Cancer Network (NCNN) advised that all patients with nonsquamous NSCLC patients undergo genetic testing for EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma kinase) mutations. At least eight mutations in the EGFR gene and ALK gene rearrangements have been associated with lung cancer and are therefore targets for new drug therapies in the treatment of NSCLC. Because immune checkpoint inhibitors were not in widespread use over the period of the analysis, the authors suspect that most of the survival benefit was attributable to effective EGFR or ALK inhibitors or other advances in therapy. The effect of immune checkpoint inhibitors on NSCLC survival is significant which suggests that this is another viable target for the treatment of NSCLC.
“The survival benefit for patients with non-small cell lung cancer treated with targeted therapies has been demonstrated in clinical trials, but this study highlights the impact of these treatments at the population level,” said Dr. Nadia Howlader of NCI’s Division of Cancer Control and Population Sciences, who led the study. “We can now see the impact of advances in lung cancer treatment on survival.”
Biowulf Lends Massive Computing Power to NIH Research Efforts
Biomedical research relies heavily on high-performance computing (HPC) to manage and analyze enormous amounts of scientific data. Biowulf, NIH’s state-of-the art supercomputer enables IRP (Intramural Research Program) investigators to analyze massive datasets and attempt research projects whose sheer scale would make them otherwise impossible. As of December 2019, Biowulf continues to be ranked in the top 500 most powerful supercomputers in the world by the TOP500 project. With the global effort underway to develop a vaccine in the fight against COVID-19, the NIH community is contributing to this unprecedented effort with a supercomputing tool solely dedicated to biomedical research.
Biowulf, which is managed and supported by the NIH’s Center for Information Technology (CIT), enables IRP researchers to process massive quantities of data with the haste that a global pandemic demands. Between March 23 and August 3, IRP researchers studying COVID-19 used more than 10.2 million CPU hours to process more than 275,000 separate tasks for genomic analysis, image processing, and statistical calculations utilizing Biowulf.
NIH scientists who are conducting coronavirus-related research are granted ‘priority access’ to the institution’s supercomputing resources. Even a computer as powerful as Biowulf has a limit as to how many tasks can be handled at any one time. When a scientist submits a task to be processed on Biowulf, the request is put into a queue. A program scheduler then determines when the task will be performed based on a number of factors. “What we’ve done with COVID-19 priority access is we put those projects at the top of the queue,” Steve Bailey, Director of high performance computing at CIT explains. “If someone is doing COVID-19 research, they jump to the front of the line.”
The emergence of innovative technologies such artificial intelligence, machine learning and advanced robotics systems have enabled researchers to screen and analyze large number of compounds much more quickly than traditional scientific methods. The supercomputing power of Biowulf now allows IRP scientists to simulate how various drugs, natural compounds, and synthetic molecules might interact with proteins on the surface of the coronavirus. Through the use of ‘in-silico’ drug screening methods, a computer can simulate molecular interactions. The computer models hundreds of random scenarios in which compounds come into contact at different places and calculates the energy of the molecular bonds that would form between the compounds in each scenario. If this ‘energy of interaction’ is low enough, the software determines the interaction as likely to occur in real life, however if that energy is too high, the computer rules it out because the bonds would be unstable or unlikely to form at all. Simulating molecular interactions in this way allows researchers to very quickly evaluate the ability of many different drug candidates to bind to a certain molecule, such as a specific viral protein that is associated with the coronavirus.
IRP Senior associate scientist Dr. Nadya Tarasova, along with her team of researchers are using Biowulf to screen thousands of FDA-approved drugs and natural compounds, in addition to more than two billion synthetic molecules for their ability to bind to various proteins on the surface of the coronavirus. Biowulf only requires about 30 seconds to test each compound and can process multiple simulations simultaneously, making it possible for Dr. Tarasova’s team to evaluate nearly 10 million compounds in a single day.
“We use these virtual screens for drug discovery not only because they are much more economical than actual high-throughput screens, but also because they allow exploration of a much higher diversity of compounds, thus increasing the chances of success,” says Dr. Tarasova.
Her team’s work on Biowulf has identified more than 200 molecules as having the potential to bind to coronavirus proteins, and have confirmed the computer modeled predictions for roughly half of them, which include several drugs that are FDA approved for other uses.
The identification of potential therapeutics using computer simulations critically depends on having detailed information about the structure of the coronavirus and the proteins responsible for its ability to cause infection. As such, several groups of IRP researchers are using Biowulf to determine the detailed structure of the virus at the molecular level as well as it’s interaction with various proteins.
A team of IRP researchers led by IRP senior investigator Dr. Peter Kwong are using Biowulf to process images obtained by cryo-electron microscopy. Dr. Kwong’s group is generating atomic level visualizations of the spike protein as well as the attachment of the coronavirus to the human ACE2 receptor, the gateway by which the virus infiltrates cells.
Meanwhile, a team of researchers led by IRP senior investigator Dr. William Copeland and Dr. Mario Borgnia, director of the Molecular Microscopy Consortium at the NIH’s National Institute of Environmental Health Sciences (NIEHS), are conducting research that is focused on investigating the outer portion of the coronavirus’ spike protein, known as the ectodomain, which initiates contact with cells. Understanding more about this specific part of the spike protein will provide useful information about the mechanism that the virus uses to infect cells and whether lab-produced antibodies have the ability bind to and inhibit it.
Researchers led by senior investigator Dr. Markus Hafner are studying the structural details of the coronavirus’ RNA, which produces the proteins that allow it to function and infect cells. One of the primary differences between the RNA genome of the virus that causes COVID-19 and that of other coronaviruses is a short of 12 base pairs, out a genome of approximately 30,000 base pairs in total, that affect the virus’ spike protein. Dr. Amir Manzourolajdad, a research fellow in Dr. Hafner’s lab, theorizes that this minor genetic difference, and others like it, could alter the structure of the virus’ RNA in a way that changes how those genetic blueprints are copied and utilized to manufacture viral proteins. Therefore, developing a detailed structural model of the coronavirus’ RNA could provide further insight into the life cycle of the virus and why it is so highly infectious.
“Access to a supercomputer like Biowulf makes all these analyses possible,” Dr. Manzourolajdad says. “This is a virus with a long genome, so running these analyses can take anywhere from a few hours up to a week, as well as large amounts of memory. They would be impossible without a supercomputer.”
The current global COVID-19 pandemic necessitates the need for accelerating the pace of scientific research aimed at developing a vaccine and ultimately a cure for this widespread disease. Cutting-edge technology like the supercomputing power of Biowulf is enabling scientists to speed the progress of their research and develop a clear understanding of the coronavirus and its associated mechanisms of infection to drive towards an end to this disease.
Opioids are a class of drugs often prescribed for the management of pain. However, repetitive use of opioids can lead to dependency and addiction. When used during pregnancy, opioids have the potential to cross the placenta and enter the fetal central nervous system, leading to complications during pregnancy or possible miscarriage.
In a recent study by the National Institutes of Health (NIH), researchers determined that opioid use may contribute to a lower chance of conception and may also be associated with an increased probably of pregnancy loss. Much of the research was focused upon the effects of drug dependency resulting from prescription opioid use. Little information exists on non-habitual, periodic opioid use around the time of conception and early in pregnancy.
The research team analyzed data from the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial, which investigated the usage of low-dose aspirin as a treatment for the prevention of pregnancy loss. The group of participants were women, ranging from 18 to 40 years of age, who had a history of one or two pregnancy losses. The study group was followed for six monthly cycles if they did not get pregnant and throughout the pregnancy if they did. The women provided urine samples during the study, which were analyzed for various prescription opioids.
Of the 1,228 women in the study, 226 (18%) had used opioids while trying to conceive and 33 (5%) of 685 women who became pregnant had used opioids during early stages of their pregnancy. None of the women in the study tested positive for methadone or buprenorphine, which are typically used in the treatment of opioid dependency.
The use of opioids prior to conception was associated with a 29% lower chance of achieving pregnancy during a given monthly cycle, compared to women who had not used opioids. Among the women who became pregnant, those who used opioids around the time of conception were 1.5 times as likely to have a miscarriage as women who had not. Women who used opioids during the first four weeks of pregnancy were more than twice as likely to result in a miscarriage. Women who used opioids in weeks four through eight of pregnancy were 2.5 times as likely to have a miscarriage.
“Our findings indicate that women who are pregnant or planning a pregnancy should, along with their physicians, consider the potential effects opioids may have on their ability to conceive or sustain a pregnancy,” said Dr. Kerry Flannagan, primary author of the study and a postdoctoral researcher in the Division of Intramural Population Health Research at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development
The authors called for additional research on how opioid use affects fertility and the early stages of pregnancy. They added that until more is known, patients and physicians should evaluate the potential risks and benefits of opioids for pain management among women who are pregnant or may become pregnant, including those undergoing assisted reproduction procedures.
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