Research from Queen Mary University of London has concluded that there is convincing evidence that type 2 diabetes is associated with an increased risk of Parkinson’s disease. The same study found that there was also evidence that type 2 diabetes may contribute to faster disease progression in patients who already have Parkinson’s.
Treating people with drugs already available for type 2 diabetes may reduce the risk and slow the progression of Parkinson’s. Screening for and early treatment of type 2 diabetes in patients with Parkinson’s may be advisable.
Previous systematic reviews and meta-analyses have produced conflicting results around the link between diabetes and the risk of Parkinson’s disease. This new study, published in the Movement Disorders Journal, used meta-analysis of observational data and meta-analysis of genetic data to evaluate the effect of type 2 diabetes on risk and progression of Parkinson’s disease.
Corresponding author Dr Alastair Noyce from Queen Mary University of London said: “This research brings together the results from many other studies to provide convincing evidence that type 2 diabetes likely affects not only Parkinson’s risk, but also Parkinson’s progression. There are many treatment strategies for type 2 diabetes, including prevention strategies, which may be re-purposed for the treatment of Parkinson’s.”
The Preventive Neurology Unit is funded by Barts Charity. Funding for co-authors came from the Michael J. Fox Foundation, the Canadian Consortium on Neurodegeneration in Aging (CCNA), the Canada First Research Excellence Fund (CFREF), Parkinson Canada, and the Intramural Research Program of the NIH, National Institute on Aging.
Research paper: ‘Type 2 diabetes as a determinant of Parkinson’s disease risk and progression’. Harneek Chohan, Konstantin Senkevich, Radhika K Patel, Jonathan P Bestwick, Benjamin M Jacobs, Sara Bandres Ciga, Ziv Gan-Or, Alastair J Noyce. Movement Disorders Journal, 2021. https://movementdisorders.onlinelibrary.wiley.com/doi/abs/10.1002/mds.28551
A new type of CAR T-cell therapy more than triples the expected length of remission for multiple myeloma patients who have relapsed several times, according to an international clinical trial with UT Southwestern as the lead enrolling site.
Results of the trial, published recently in the New England Journal of Medicine, were significantly better than those seen with other therapies available to heavily relapsed and refractory myeloma patients who had already received the three main classes of treatment. Nearly three-quarters of the patients had at least a partial response to the therapy. About a third achieved a complete remission, with the disappearance of all traces of cancer.
Median time without the disease worsening was 8.8 months with this new treatment, but Larry D. Anderson Jr., M.D., Ph.D., associate professor of internal medicine and co-first author of the journal article, points out that patients who received the trial’s maximum dose of engineered T-cells experienced longer remissions, bringing the average to more than 12 months. Previously, similar patients treated with currently available therapies following multiple relapses have only had an average of three to four months of remission before their disease returned.
“We have patients that are over two years out from their single infusion of CAR T-cells and still in remission despite having no other treatment options when they were enrolled in this trial,” says Anderson, a member of the Harold C. Simmons Comprehensive Cancer Center who cares exclusively for patients with plasma cell disorders, mostly myeloma patients. “The results mark a true breakthrough with unprecedented depth and duration of remissions from what we hope will be the first cellular therapy option to become available for myeloma patients. Even though we don’t yet know if some of these patients may be cured, and many relapse within one to two years, it can at least buy many patients time until other treatment options become available. Most patients also have good quality of life with relatively low risk of severe CAR T-cell-related side effects.”
Multiple myeloma, the second most common blood cancer, is a cancer of plasma cells, a white blood cell important in the immune system. The disease’s attack on bone marrow puts patients at risk of life-threatening infections. It is diagnosed in more than 32,000 people a year, and African Americans are twice as likely as the general population to be diagnosed with this disease.
Three main classes of treatment are available now for multiple myeloma: drugs called proteasome inhibitors, drugs to modulate the immune system, and antibody treatments. Among more than a dozen new therapies for myeloma approved by the Food and Drug Administration over the past decade, most offer only a few months of remission for patients with multiple relapses. Until now, most treatments induce responses in only a third of patients, and complete remissions are rare.
Larry D. Anderson Jr., UT Southwestern Medical Center
The phase 2 trial involved 128 patients, ages 18 and older, who previously had been given regimens from the three main classes of treatment. The patients received a median of six previous antimyeloma regimens; 120 formerly had undergone stem cell transplantation.
The clinical trial included nine sites in the U.S., one in Canada, and 10 sites in five European countries. Several patients traveled from as far away as Michigan and Minnesota to UT Southwestern’s Dallas campus to be part of the trial.
Study participants had their T-cells engineered to target a molecule called B-cell maturation antigen, or BCMA, which is only found in plasma cells and myeloma cells. This new T-cell therapy for myeloma patients is called idecabtagene vicleucel, or ide-cel. It is also known as bb2121.
The infusions of the engineered cells started a two-week hospitalization period during which doctors watched for possible side effects such as anemia; neutropenia, a drop in a type of white blood cells; and thrombocytopenia, a drop in blood platelets. Although low blood counts were common, they were manageable, and other severe side effects were uncommon.
“One of the nice things we saw in this study was that the rates of severe CAR T-cell-related toxicities – called neurotoxicity and cytokine release syndrome – were very low in multiple myeloma compared to what we have seen with lymphoma CAR T-cell infusions,” Anderson says. “The majority of people had some side effects, but most were low level and manageable, and I would say this therapy is often much better tolerated than a stem cell transplant, which most of these patients had already gone through.”
Pioneered in the late 1980s, CAR T-cell therapy is a promising and still emerging treatment for blood cancers. CAR, which stands for chimeric antigen receptor, takes part of its name from the chimera, the mythical animal with the tail of a serpent and head of a lion. In modern medicine’s version of the chimera, the head is an antibody, and the tail is a T-cell receptor. CAR T-cell therapy involves harvesting a patient’s own T-cells by withdrawing blood, reengineering them in a lab to have this cancer-fighting chimera, and then growing hundreds of millions of them to put back into the patient by infusion.
CAR T-cell therapy is currently approved for use only in lymphoma and leukemia. Several different CAR T-cell treatments for myeloma are in clinical trials, but this CAR T-cell treatment is the first to complete and publish data from an FDA registration trial. Based on these results, the pharmaceutical companies Bristol Myers Squibb and bluebird bio are seeking FDA approval of ide-cel as a standard therapy for relapsed myeloma with a decision expected by the end of March.
The trial was funded by bluebird bio and Celgene, a Bristol Myers Squibb company. Anderson is a consultant who serves on an advisory board for Celgene and has other consulting activities disclosed in the manuscript.
Reference: Nikhil C. Munshi, Larry D. Anderson, Jr., Nina Shah, Deepu Madduri et al., “Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma”, February 25, 2021, N Engl J Med 2021; 384:705-716 DOI: 10.1056/NEJMoa2024850
It focuses on an iconic and relatively young star, Vega, which is part of the constellation Lyra and has a mass twice that of our own sun. This celestial body sits just 25 light-years, or about 150 trillion miles, from Earth—pretty close, astronomically speaking.
Scientists can also see Vega with telescopes even when it’s light out, which makes it a prime candidate for research, said study coauthor Samuel Quinn.
“It’s bright enough that you can observe it at twilight when other stars are getting washed out by sunlight,” said Quinn, an astronomer at the Harvard and Smithsonian Center for Astrophysics (CfA).
Artist impression of the planet in orbit around the white starTop: Artist’s depiction of a planet named KELT-9b, currently the hottest known exoplanet, which may resemble a candidate world in orbit around Vega; bottom: Historical illustration dating back to the early 1800s of the constellation Lyra, depicted right as a golden lyre. (Credits: NASA/JPL-Caltech; Public domain image via Wikimedia Commons)
Despite the star’s fame, researchers have yet to find a single planet in orbit around Vega. That might be about to change: Drawing on a decade of observations from the ground, Hurt, Quinn and their colleagues unearthed a curious signal that could be the star’s first-known world.
If the team’s findings bear out, the alien planet would orbit so close to Vega that its years would last less than two-and-a-half Earth days. (Mercury, in contrast, takes 88 days to circle the sun). This candidate planet could also rank as the second hottest world known to science—with surface temperatures averaging a searing 5,390 degrees Fahrenheit.
Hurt said the group’s research also helps to narrow down where other, exotic worlds might be hiding in Vega’s neighborhood.
“This is a massive system, much larger than our own solar system,” Hurt said. “There could be other planets throughout that system. It’s just a matter of whether we can detect them.”
Youthful energy
Quinn would like to try. Scientists have discovered more than 4,000 exoplanets, or planets beyond Earth’s solar system, to date. Few of those, however, circle stars that are as bright or as close to Earth as Vega. That means that, if there are planets around the star, scientists could get a really detailed look at them.
“It would be really exciting to find a planet around Vega because it offers possibilities for future characterization in ways that planets around fainter stars wouldn’t,” Quinn said.
There’s just one catch: Vega is what scientists call an A-type star, the name for objects that tend to be bigger, younger and much faster-spinning than our own sun. Vega, for example, rotates around its axis once every 16 hours—much faster than the sun with a rotational period that clocks in at 27 Earth days. Such a lightning-fast pace, Quinn said, can make it difficult for scientists to collect precise data on the star’s motion and, by extension, any planets in orbit around it.
To take on that game of celestial hide-and-seek, he and colleagues pored through roughly 10 years of data on Vega collected by the Fred Lawrence Whipple Observatory in Arizona. In particular, the team was looking for a tell-tale signal of an alien planet—a slight jiggle in the star’s velocity.
“If you have a planet around a star, it can tug on the star, causing it to wobble back and forth,” Quinn said.
Hot and puffy
The search may have paid off, said Hurt, who began the study as a summer research fellow working for Quinn at the CfA. The team discovered a signal that indicates that Vega might host what astronomers call a “hot Neptune” or maybe a “hot Jupiter.”
“It would be at least the size of Neptune, potentially as big as Jupiter and would be closer to Vega than Mercury is to the sun,” Hurt said.
That close to Vega, he added, the candidate world might puff up like a balloon, and even iron would melt into gas in its atmosphere.
The researchers have a lot more work to do before they can definitively say that they’ve discovered this sizzling planet. Hurt noted that the easiest way to look for it might be to scan the stellar system directly to look for light emitted from the hot, bright planet.
For now, the student is excited to see his hard work reflected in the constellations: “Whenever I get to go outside and look at the night sky and see Vega, I say ‘hey, I know that star.”
Other coauthors on the new study include David Latham, Gilbert Esquerdo, Michael Calkins, Perry Berlind, Christian Latham and George Zhou at the CfA; Andrew Vandeburg at the University of Wisconsin-Madison; and Ruth Angus at the American Museum of Natural History
Featured image: Vega is the fifth brightest star, excluding the sun, that can be seen from Earth. (Credit: CC image by Stephen Rahn via Wikimedia Commons)
Reference: Spencer A. Hurt, Samuel N. Quinn et al., “A Decade of Radial-velocity Monitoring of Vega and New Limits on the Presence of Planets”, Astronomical Journal, 161(4), 2021. https://iopscience.iop.org/article/10.3847/1538-3881/abdec8
Study at University of Cologne shows that the exchange of genes drives functional changes in bacteria very rapidly / Publication in PNAS
Bacteria integrate genetic material from other bacterial strains more easily than previously thought, which can lead to improved fitness and accelerated evolution. This is shown in a recent study by biophysicists at the University of Cologne. The team analysed genome transfer between bacteria of different lineages. The study was published in the journal PNAS.
In the experiment, the team brought one strain of bacteria into contact with DNA fragments from another strain. The uptake of foreign genetic material is known as horizontal gene transfer — in contrast to vertical gene transfer, by which genes are inherited from a parent cell of the same lineage. The results show that laboratory evolution through horizontal gene transfer can rapidly produce hybrid organisms of different lineages with extensive genomic and functional changes. “It is a bit like interbreeding modern humans and Neandertals’”, says Dr. Fernanda Pinheiro of the Institute of Biological Physics at the University of Cologne and author of the study. The bacteria readily integrated foreign DNA at many sites in the genome. Within 200 generations, the research team observed the exchange of up to 14 percent of the bacterium’s core genes.
Horizontal gene transfer is an important factor in bacterial evolution that can operate across species boundaries. “Yet we know little about the rate and genomic targets of cross-strain gene transfer. Also, little is known so far about the effects on the physiology and fitness of the recipient organism”, says Pinheiro. From a scientific perspective, hybrid creatures whose parents belong to different species raise fundamental evolutionary biology questions: What combinations of traits yield viable organisms? What are the limits of evolutionary processes when more than one species is involved in reproduction? “Our study makes an important contribution here,” Pinheiro adds.
Is the uptake of genes random or does it follow a definite pattern? As the researchers observed, some functional units of the foreign genome were repeatedly imported and the resulting hybrid bacteria had higher growth rates. “This implies that cross-lineage gene exchange drives evolution very efficiently,” Pinheiro says. Integrating foreign genes through horizontal gene transfer produces new combinations of genes yet preserves essential structures that make a cell viable. Thus, the study opens new perspectives for future work: to combine transfer evolution experiments and synthetic biology methods to engineer functional innovations.
Reference: Jeffrey J. Power, Fernanda Pinheiro, Simone Pompei, Viera Kovacova, Melih Yüksel, Isabel Rathmann, Mona Förster, Michael Lässig, Berenike Maier, “Adaptive evolution of hybrid bacteria by horizontal gene transfer”, Proceedings of the National Academy of Sciences Mar 2021, 118 (10) e2007873118; DOI: 10.1073/pnas.2007873118
Today’s humans share genes with oceanic creatures missing heads
The earliest multicellular organisms may have lacked heads, legs, or arms, but pieces of them remain inside of us today, new research shows.
According to a UC Riverside study, 555-million-year-old oceanic creatures from the Ediacaran period share genes with today’s animals, including humans.
“None of them had heads or skeletons. Many of them probably looked like three-dimensional bathmats on the sea floor, round discs that stuck up,” said Mary Droser, a geology professor at UCR. “These animals are so weird and so different, it’s difficult to assign them to modern categories of living organisms just by looking at them, and it’s not like we can extract their DNA — we can’t.”
Fossil of Dickinsonia, an Ediacaran-era animal. (Mary Droser/UCR)
However, well-preserved fossil records have allowed Droser and the study’s first author, recent UCR doctoral graduate Scott Evans, to link the animals’ appearance and likely behaviors to genetic analysis of currently living things. Their research on these links has been recently published in the journal Proceedings of the Royal Society B.
For their analysis, the researchers considered four animals representative of the more than 40 recognized species that have been identified from the Ediacaran era. These creatures ranged in size from a few millimeters to nearly a meter in length.
Kimberella were teardrop-shaped creatures with one broad, rounded end and one narrow end that likely scraped the sea floor for food with a proboscis. Further, they could move around using a “muscular foot” like snails today. The study included flat, oval-shaped Dickinsonia with a series of raised bands on their surface, and Tribrachidium, who spent their lives immobilized at the bottom of the sea.
Also analyzed were Ikaria, animals recently discovered by a team including Evans and Droser. They were about the size and shape of a grain of rice, and represent the first bilaterians — organisms with a front, back, and openings at either end connected by a gut. Evans said it’s likely Ikaria had mouths, though those weren’t preserved in the fossil records, and they crawled through organic matter “eating as they went.”
All four of the animals were multicellular, with cells of different types. Most had symmetry on their left and right sides, as well as noncentralized nervous systems and musculature.
Additionally, they seem to have been able to repair damaged body parts through a process known as apoptosis. The same genes involved are key elements of human immune systems, which helps to eliminate virus-infected and pre-cancerous cells.
These animals likely had the genetic parts responsible for heads and the sensory organs usually found there. However, the complexity of interaction between these genes that would give rise to such features hadn’t yet been achieved.
“The fact that we can say these genes were operating in something that’s been extinct for half a billion years is fascinating to me,” Evans said.
The work was supported by a NASA Exobiology grant, and a Peter Buck postdoctoral fellowship.
Going forward, the team is planning to investigate muscle development and functional studies to further understand early animal evolution.
“Our work is a way to put these animals on the tree of life, in some respects,” Droser said. “And show they’re genetically linked to modern animals, and to us.”
Reference: Scott D. Evans, Mary L. Droser and Douglas H. Erwin, “Developmental processes in Ediacara macrofossils”, Proceedings of the Royal Society B, Published: 24 February 2021. https://doi.org/10.1098/rspb.2020.3055
Recently, research group, led by Prof. FU Yao and associate research fellow LU Xi From Hefei National Laboratory for Physical Sciences at the Microscale and School of Chemistry and Materials Science of the University of Science and Technology of China (USTC), has made significant achievements in the field of synthesis of chiral amines. They developed a mild and general nickel-catalysed asymmetric reductive hydroalkylation and realized the modular synthesis of chiral aliphatic amines.
Results were published in Nature Communications on Feb. 26, 2021.
Chiral amines are important chiral auxiliaries and key synthetic intermediates of pharmaceuticals and natural products. It is an important direction to develop efficient and convenient synthesis of chiral amines in organic synthetic chemistry. However, conventional catalytic synthesis methods, such as imine and enamine hydrogenation, imine alkylation, olefin hydroamination and others, have limited substrate structure in the synthesis of dialkyl substituted chiral aliphatic amines.
The research group proposed the concept of olefin reductive coupling and developed a cheap nickel catalytic system to realize carbon carbon coupling under mild conditions by replacing equivalent metal reagents with olefins.
In this work, they combined saturated carbon couple, and successfully realized the asymmetric hydroalkylation of enamides catalyzed by Ni MH. In addition, the asymmetric hydroalkylation of enamide with α-borate halide can be realized to prepare β-aminoborate with two chiral centers. Tandem conversion of organic boron compounds will contribute to the development of amine chiral molecules with complex structures.
This work is a complement and breakthrough for the structural limitations of conventional chiral amine synthesis strategies.
A new substance could improve the treatment of persistent cancers. Researchers at Martin Luther University Halle-Wittenberg (MLU) and the University of Greifswald have developed a new inhibitor that makes drug-resistant tumour cells respond again to chemotherapy. The new substance blocks a protein in the cancer cells that normally transports the cancer drugs back out of the cells. The results were published in the scientific journal “Molecules”.
In addition to radiation therapy, cytotoxic agents, also known as chemotherapy, are frequently used to treat cancer. They prevent cells from dividing and thus cancer cells are unable to multiply unchecked. “Cytotoxic agents remain a very important form of treatment because they have a general effect, in other words, they work on different types of cancer,” explains Dr Andreas Hilgeroth, a professor of pharmacy at MLU. However, some tumours are resistant to chemotherapy. They possess certain proteins that transport the drugs back out of the cancer cell.
Hilgeroth’s research group has now developed a new class of substances that inhibits one of these transport proteins: the multi-drug resistant protein 4 (MRP4). “It plays a particular role in leukaemia,” says Professor Christoph Ritter from the Institute of Pharmacy at the University of Greifswald. The protein transports chemical messengers that appear to contribute to the development of that type of cancer. Ritter supported the team in the efficacy studies on special, drug-resistant cancer cell lines. The researchers were able to show that the cells treated with the new inhibitor transported fewer of the dye-labelled messengers and that the cytotoxic agents began having an effect again. “One of the substances showed particularly promising results,” says Ritter, adding, it inhibited the protein much better than the best inhibitor known to date.
The new substances could have two simultaneously positive effects: “preventing the transport of cancer-promoting messengers and ensuring that the chemotherapy starts working again,” explains Hilgeroth. If they prove to be successful in further tests, however, they will only be administrable in patients who have tumours containing the MRP4 transport protein. However, a pre-screening that uses markers to identify the type and characteristics of a specific cancer is already part of standard treatment. “There is an increasing focus on individualised medicine, especially in cancer therapy,” says Hilgeroth. Drugs are used that are tailored to the type and characteristics of the cancer. A different inhibitor would then be used on a different transport protein.
The efficacy must now be confirmed in further preclinical trials. Researchers will try to establish how well the newly developed drugs specifically inhibit MRP4 in order to reduce side effects. If the substances are a success, several years of clinical trials will follow to confirm their efficacy in patients.
About the study: Henry Döring, David Kreutzer, Christoph Ritter, Andreas Hilgeroth. Discovery of Novel Symmetrical 1,4-Dihydropyridines as Inhibitors of Multidrug-Resistant Protein (MRP4) Efflux Pump for Anticancer Therapy. Molecules (2020). doi: 10.3390/molecules26010018
Native to the southeastern United States, a weedy grass has spread northward to Canada and also made its way to Australia and Japan. Andropogon virginicus grows densely packed and up to seven feet tall, disrupting growth patterns of other plants and competing for resources. When burned, it grows back stronger. There is no way to effectively remove the weed once it has invaded. But there might be a way to use it to human advantage.
An international team of researchers has found that A. virginicus extracts appear to be effective against several human diseases, including diabetes and cancer. The results were published on Dec. 31, 2020, in a special issue of Plants, titled “Biological Activities of Plant Extracts.”
“A. virginicus is an invasive weed that seriously threatens agricultural production and economics worldwide,” said paper author Tran Dang Xuan, associate professor in the Transdisciplinary Science and Engineering Program in the Graduate School of Advanced Science and Engineering at Hiroshima University. “However, no solution efficiently utilizing and tackling this plant has been found yet. In this paper, we highlight the potential application of A. virginicus extracts in future medicinal production and therapeutics of chronic diseases such as type 2 diabetes and blood cancer, which can deal with both crop protection and human health concerns.”
Researchers found high levels of flavonoids in the samples they extracted from the weed. These plant chemicals have significant antioxidant and anti-inflammatory properties, according to Xuan. When tested against a variety of cell lines, the extracted plant chemicals bonded to free radicals, preventing damage to the cells. At skin level, this helps prevent age spots by inhibiting a protein called tyrosinase. Among other, deeper healthful actions, this bonding also helps prevent knock-on cellular actions that can lead to type 2 diabetes.
The team also specifically applied the extracted chemicals to a line of chronic myelogenous leukemia, a rare blood cancer. The extract appeared to kill off the cancer cells.
Xuan said the researchers plan to establish a comprehensive process to isolate and purify the compounds responsible for known biological properties, as well as work to identify new uses. They will further test the therapeutical effects of the compounds, with the eventual goal of preparing functional pharmaceuticals for human use.
“Although A. virginicus has been considered a harmful invasive species without economic value, its extracts are promising sources of antioxidant, anti-diabetic, anti-tyrosinase, and antitumor agents,” Xuan said.
Co-authors include La Hoang Anh, Nguyen Van Quan and Yu Iuchi, Transdisciplinary Science and Engineering Program in the Graduate School of Advanced Science and Engineering at Hiroshima University, Japan; Vu Quang Lam and Akiyoshi Takami, Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, Japan; and Rolf Teschke, Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Teaching Hospital of the Medical Faculty, Goethe University Frankfurt, Germany.
Findings from the study suggest that night shift workers are at increased risk of developing cancer because night shifts disrupt natural 24-hour rhythms in the activity of certain cancer-related genes.
New clues as to why night shift workers are at increased risk of developing certain types of cancer are presented in a new study conducted at Washington State University Health Sciences Spokane.
Published online in the Journal of Pineal Research, the study involved a controlled laboratory experiment that used healthy volunteers who were on simulated night shift or day shift schedules. Findings from the study suggest that night shifts disrupt natural 24-hour rhythms in the activity of certain cancer-related genes, making night shift workers more vulnerable to damage to their DNA while at the same time causing the body’s DNA repair mechanisms to be mistimed to deal with that damage.
Though more research still needs to be done, these discoveries could someday be used to help prevent and treat cancer in night shift workers.
“There has been mounting evidence that cancer is more prevalent in night shift workers, which led the World Health Organization’s International Agency for Research on Cancer to classify night shift work as a probable carcinogenic,” said co-corresponding author Shobhan Gaddameedhi, an associate professor formerly with the WSU College of Pharmacy and Pharmaceutical Sciences and now with North Carolina State University’s Biological Sciences Department and Center for Human Health and the Environment. “However, it has been unclear why night shift work elevates cancer risk, which our study sought to address.”
Studying the rhythms in cancer-related genes
As part of a partnership between the WSU Sleep and Performance Research Center and the U.S. Department of Energy’s Pacific Northwest National Laboratory (PNNL), Gaddameedhi and other WSU scientists worked with bioinformatics experts at PNNL to study the potential involvement of the biological clock, the body’s built-in mechanism that keeps us on a 24-hour night and day cycle. Though there is a central biological clock in the brain, nearly every cell in the body also has its own built-in clock. This cellular clock involves genes known as clock genes that are rhythmic in their expression, meaning their activity levels vary with the time of day or night. The researchers hypothesized that the expression of genes associated with cancer might be rhythmic, too, and that night shift work might disrupt the rhythmicity of these genes.
To test this, they conducted a simulated shift work experiment that had 14 participants spend seven days inside the sleep laboratory at WSU Health Sciences Spokane. Half of them completed a three-day simulated night shift schedule, while the other half were on a three-day simulated day shift schedule. After completing their simulated shifts, all participants were kept in a constant routine protocol that is used to study humans’ internally generated biological rhythms independent of any external influences. As part of the protocol, they were kept awake for 24 hours in a semi-reclined posture under constant light exposure and room temperature and were given identical snacks every hour. Every three hours a blood sample was drawn.
Analyses of white blood cells taken from the blood samples showed that the rhythms of many of the cancer-related genes were different in the night shift condition compared to the day shift condition. Notably, genes related to DNA repair that showed distinct rhythms in the day shift condition lost their rhythmicity in the night shift condition.
The researchers then looked at what the consequences of the changes in the expression of cancer-related genes might be. They found that white blood cells isolated from the blood of night shift participants showed more evidence of DNA damage than those of day shift participants. What’s more, after the researchers exposed isolated white blood cells to ionizing radiation at two different times of day, cells that were radiated in the evening showed increased DNA damage in the night shift condition as compared to the day shift condition. This meant that white blood cells from night shift participants were more vulnerable to external damage from radiation, a known risk factor for DNA damage and cancer.
“Taken together, these findings suggest that night shift schedules throw off the timing of expression of cancer-related genes in a way that reduces the effectiveness of the body’s DNA repair processes when they are most needed,” said co-corresponding author Jason McDermott, a computational scientist with the Pacific Northwest National Laboratory’s Biological Sciences Division.
Potential for improved prevention, treatment
The researchers’ next step is to conduct the same experiment with real-world shift workers who have been consistently on day or night shifts for many years to determine whether in night workers the unrepaired DNA damage builds up over time, which could ultimately increase the risk of cancer. If what happens in real-world shift workers is consistent with the current findings, this work could eventually be used to develop prevention strategies and drugs that could address the mistiming of DNA repair processes. It could also be the basis for strategies to optimize the timing of cancer therapy so that treatment is administered when effectiveness is greatest and side effects are minimal, a procedure called chronotherapy that would need to be fine-tuned to the internal rhythms of night workers.
“Night shift workers face considerable health disparities, ranging from increased risks of metabolic and cardiovascular disease to mental health disorders and cancer,” said co-senior author Hans Van Dongen, a professor in the WSU Elson S. Floyd College of Medicine and director of the WSU Sleep and Performance Research Center. “It is high time that we find diagnosis and treatment solutions for this underserved group of essential workers so that the medical community can address their unique health challenges.”
In addition to Van Dongen, Gaddameedhi, and McDermott, study authors included Bala Koritala, Kenneth Porter, Osama Arshad, Rajendra Gajula, Hugh Mitchell, Tarana Arman, Mugimane Manjanatha, and Justin Teeguarden.
Reference: Koritala, B.S., Porter, K.I., Arshad, O.A., Gajula, R.P., Mitchell, H.D., Arman, T., Manjanatha, M.G., Teeguarden, J., Van Dongen, H.P., McDermott, J.E. and Gaddameedhi, S. (2021), Night shift schedule causes circadian dysregulation of DNA repair genes and elevated DNA damage in humans. J Pineal Res. Accepted Author Manuscript e12726. https://onlinelibrary.wiley.com/doi/10.1111/jpi.12726https://doi.org/10.1111/jpi.12726
