Muscle proteins whose quantity is reduced in type 2 diabetes

 Globally, more than 400 million people have diabetes, most of them suffering from type 2 diabetes.

Before the onset of actual type 2 diabetes, people are often diagnosed with abnormalities in glucose metabolism that are milder than those associated with diabetes. The term used to indicate such cases is prediabetes. Roughly 5-10% of people with prediabetes develop type 2 diabetes within a year-long follow-up.

Insulin resistance in muscle tissue is one of the earliest metabolic abnormalities detected in individuals who are developing type 2 diabetes, and the phenomenon is already seen in prediabetes.

In a collaborative study, researchers from the University of Helsinki, the Helsinki University Hospital and the Minerva Foundation Institute for Medical Research investigated the link between skeletal muscle proteome and type 2 diabetes.

In the study, the protein composition of the thigh muscle was surveyed in men whose glucose tolerance varied from normal to that associated with prediabetes and type 2 diabetes. A total of 148 muscle samples were analysed.

The results were published in the iScience journal.

"Our study is the broadest report on human muscle proteomes so far. The findings confirm earlier observations that have exposed abnormalities in muscle mitochondria in connection with type 2 diabetes," says Docent Heikki Koistinen from the University of Helsinki, Helsinki University Hospital and Minerva Foundation Institute for Medical Research, who headed the study.

Protein concentration already decreases in prediabetes

The researchers utilised mass spectrometry, enabling them to identify over 2,000 muscle proteins.

According to the findings, the quantity of dozens of proteins had already changed in prediabetic study subjects.

The greatest changes were observed in connection with type 2 diabetes, where the quantity of more than 400 proteins had primarily dropped. Most of these proteins were associated with mitochondrial energy metabolism.

In fact, the results highlight the significance of mitochondria when prediabetes is progressing toward type 2 diabetes.

"We found that the levels of mitochondrial muscle proteins are clearly reduced already in prediabetes," Koistinen notes.

The researchers also observed abnormalities, both in conjunction with prediabetes and type 2 diabetes, in the concentration of a range of phosphoproteins, which affect metabolism and muscle function.

Regular physical activity as targeted therapy

The researchers believe their new observations have multiple uses, including in the search for new drug targets.

"Still, there already exists an excellent and economical targeted therapy, since regular physical activity increases the number of muscle mitochondria and improves metabolism diversely," Koistinen points out.

Physical activity is also key when reducing the risk of developing diabetes.

"You can halve the risk of developing diabetes by losing weight, increasing physical activity and observing a healthy diet," Koistinen says.

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Materials provided by University of Helsinki. Note: Content may be edited for style and length.

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Journal Reference:

1. Tiina Öhman, Jaakko Teppo, Neeta Datta, Selina Mäkinen, Markku Varjosalo, Heikki A. Koistinen. Skeletal muscle proteomes reveal downregulation of mitochondrial proteins in transition from prediabetes into type 2 diabetes. iScience, 2021; 24 (7): 102712 DOI: 10.1016/j.isci.2021.102712

https://www.sciencedaily.com/releases/2021/06/210629134307.htm

How a COVID-19 infection changes blood cells in the long run

 Using real-time deformability cytometry, researchers at the Max-Planck-Zentrum für Physik und Medizin in Erlangen were able to show for the first time: Covid-19 significantly changes the size and stiffness of red and white blood cells -- sometimes over months. These results may help to explain why some affected people continue to complain of symptoms long after an infection (long Covid).

Shortness of breath, fatigue and headaches: some patients still struggle with the long-term effects of a severe infection by the SARS-CoV-2 coronavirus after six months or more. This post Covid-19 syndrome, also called long covid, is still not properly understood. What is clear is that -- during the course of the disease -- often blood circulation is impaired, dangerous vascular occlusions can occur and oxygen transport in is limited. These are all phenomena in which the blood cells and their physical properties play a key role.

To investigate this aspect, a team of scientists led by Markéta Kubánková, Jochen Guck, and Martin Kräter from the Max-Planck-Zentrum für Physik und Medizin, the Max Planck Institute for the Science of Light (MPL), the Friedrich Alexander University Erlangen-Nuremberg and the German Centre for Immunotherapy measured the mechanical states of red and white blood cells. "We were able to detect clear and long-lasting changes in the cells -- both during an acute infection and even afterwards," reports Professor Guck, currently managing director of MPL. The research group has now published their results in Biophysical Journal.

To analyse the blood cells, they used a self-developed method called real-time deformability cytometry (RT-DC), which has recently been recognized with the prestigious Medical Valley Award. In this method, the researchers send the blood cells through a narrow channel at high speed. In the process, the leukocytes and erythrocytes are stretched. A high-speed camera records each of them through a microscope, and custom software determines which cell types are present, and how big and deformed they are. Up to 1000 blood cells can be analysed per second. The advantage of the method: It is fast and the cells do not have to be labelled in a laborious procedure.

The method could help as an early warning system to detect future pandemics by unknown viruses

The biophysicists from Erlangen examined more than four million blood cells from 17 patients acutely ill with Covid-19, from 14 people who had recovered and 24 healthy people as a comparison group. They found that, for example, the size and deformability of the red blood cells of patients with the disease deviated strongly from those of healthy people. This indicates damage to these cells and could explain the increased risk of vascular occlusion and embolisms in the lungs. In addition, the oxygen supply, which is one of the main tasks of the erythrocytes, may be impaired in infected persons. Lymphocytes (one type of white blood cell responsible for the acquired immune defense) were in turn significantly softer in Covid-19 patients, which typically indicates a strong immune reaction. The researchers made similar observations for neutrophil granulocytes, another group of white blood cells involved in the innate immune response. These cells even remained drastically altered seven months after the acute infection.

"We suspect that the cytoskeleton of immune cells, which is largely responsible for cell function, has changed," explains Markéta Kubánková, first author of the research article. In her view, real-time deformability cytometry has the potential to be used routinely in the diagnosis of Covid-19 -- and even to serve as an early warning system against future pandemics caused by as yet unknown viruses.

Story Source:

Materials provided by Max-Planck-Gesellschaft. Note: Content may be edited for style and length.

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Journal Reference:

1. Markéta Kubánková, Bettina Hohberger, Jakob Hoffmanns, Julia Fürst, Martin Herrmann, Jochen Guck, Martin Kräter. Physical phenotype of blood cells is altered in COVID-19. Biophysical Journal, 2021; DOI: 10.1016/j.bpj.2021.05.025

https://www.sciencedaily.com/releases/2021/06/210629144312.htm

Mechanisms of increased infectivity, antibody resistance of SARS-CoV-2 variants

 Combining structural biology and computation, a Duke-led team of researchers has identified how multiple mutations on the SARS-CoV-2 spike protein independently create variants that are more transmissible and potentially resistant to antibodies.

By acquiring mutations on the spike protein, one such variant gained the ability to leap from humans to minks and back to humans. Other variants -- including Alpha, which first appeared in the United Kingdom, Beta, which appeared in South Africa, and Gamma, first identified in Brazil -- independently developed spike mutations that enhanced their ability to spread rapidly in human populations and resist some antibodies.

The researchers published their findings in Science.

"The spike on the surface of the virus helps SARS-CoV-2 enter into host cells," said senior author Priyamvada Acharya, Ph.D., director of the Division of Structural Biology at the Duke Human Vaccine Institute.

"Changes on the spike protein determine transmissibility of the virus -- how far and quickly it spreads," Acharya said. "Some variations of the SARS-CoV-2 spike are occurring at different times and different places throughout the world, but have similar results, and it's important to understand the mechanics of these spike mutations as we work to fight this pandemic."

Acharya and colleagues -- including first author Sophie Gobeil, Ph.D., and co-corresponding author Rory Henderson, Ph.D., -- developed structural models to identify changes in the virus's spike protein. Cryo-electron microscopy allowed atomic level visualization, while binding assays enabled the team to create mimics of the live virus that directly correlated with its function in host cells. From there, the team used computational analysis to build models that showed the structural mechanisms at work.

"By building a skeleton of the spike, we could see how the spike is moving, and how this movement changes with mutations," Henderson said. "The different variant spikes are not moving the same way, but they accomplish the same task. "The different variant spikes are not moving the same way, but they accomplish the same task. The variants first appearing in South Africa and Brazil use one mechanism, while the UK and the mink variants use another mechanism."

All the variants showed increased ability to bind to the host, notably via the ACE2 receptor. The changes also created viruses that were less susceptible to antibodies, raising concerns that continued accumulation of spike mutations may reduce the efficiency of current vaccines.

Gobeil said the research illuminated the complexity of the virus: "It's amazing how many different ways the virus comes up with to be more infectious and invasive," she said. "Nature is clever."

In addition to Gobeil, Acharya and Henderson, study authors include Katarzyna Janowska, Shana McDowell, Katayoun Mansouri, Robert Parks, Victoria Stalls, Megan F. Kopp, Kartik Manne, Dapeng Li, Kevin Wiehe, Kevin O. Saunders, Robert J. Edwards, Bette Korber and Barton F. Haynes.

The study received support from the National Institutes of Health (R01 AI145687, AI142596) and the State of North Carolina through the CARES Act.

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Materials provided by Duke University Medical Center. Note: Content may be edited for style and length.

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Journal Reference:

1. Sophie M.-C. Gobeil, Katarzyna Janowska, Shana Mcdowell, Katayoun Mansouri, Robert Parks, Victoria Stalls, Megan F. Kopp, Kartik Manne, Dapeng Li, Kevin Wiehe, Kevin O. Saunders, Robert J. Edwards, Bette Korber, Barton F. Haynes, Rory Henderson, Priyamvada Acharya. Effect of natural mutations of SARS-CoV-2 on spike structure, conformation, and antigenicity. Science, June 24, 2021; DOI: 10.1126/science.abi6226

https://www.sciencedaily.com/releases/2021/06/210629144317.htm

Promising new pathway to treating type 2 diabetes

 This year marks the 100th anniversary of the discovery of insulin, a scientific breakthrough that transformed Type 1 diabetes, once known as juvenile diabetes or insulin-dependent diabetes, from a terminal disease into a manageable condition.

Today, Type 2 diabetes is 24 times more prevalent than Type 1. The rise in rates of obesity and incidence of Type 2 diabetes are related and require new approaches, according to University of Arizona researchers, who believe the liver may hold the key to innovative new treatments.

"All current therapeutics for Type 2 diabetes primarily aim to decrease blood glucose. So, they are treating a symptom, much like treating the flu by decreasing the fever," said Benjamin Renquist, an associate professor in the UArizona College of Agriculture and Life Sciences and BIO5 Institute member. "We need another breakthrough."

In two newly published papers in Cell Reports, Renquist, along with researchers from Washington University in St. Louis, the University of Pennsylvania and Northwestern University, outline a new target for Type 2 diabetes treatment.

Renquist, whose research lab aims to address obesity-related diseases, has spent the last nine years working to better understand the correlation between obesity, fatty liver disease and diabetes, particularly how the liver affects insulin sensitivity.

"Obesity is known to be a cause of Type 2 diabetes and, for a long time, we have known that the amount of fat in the liver increases with obesity," Renquist said. "As fat increases in the liver, the incidence of diabetes increases."

This suggested that fat in the liver might be causing Type 2 Diabetes, but how fat in the liver could cause the body to become resistant to insulin or cause the pancreas to over-secrete insulin remained a mystery, Renquist said.

Renquist and his collaborators focused on fatty liver, measuring neurotransmitters released from the liver in animal models of obesity, to better understand how the liver communicates with the brain to influence metabolic changes seen in obesity and diabetes.

"We found that fat in the liver increased the release of the inhibitory neurotransmitter Gamma-aminobutyric acid, or GABA," Renquist said. "We then identified the pathway by which GABA synthesis was occurring and the key enzyme that is responsible for liver GABA production -- GABA transaminase."

A naturally occurring amino acid, GABA is the primary inhibitory neurotransmitter in the central nervous system, meaning it decreases nerve activity.

Nerves provide a conduit by which the brain and the rest of the body communicate. That communication is not only from the brain to other tissues, but also from tissues back to the brain, Renquist explained.

"When the liver produces GABA, it decreases activity of those nerves that run from the liver to the brain. Thus, fatty liver, by producing GABA, is decreasing firing activity to the brain," Renquist said. "That decrease in firing is sensed by the central nervous system, which changes outgoing signals that affect glucose homeostasis."

To determine if increased liver GABA synthesis was causing insulin resistance, graduate students in Renquist's lab, Caroline Geisler and Susma Ghimire, pharmacologically inhibited liver GABA transaminase in animal models of Type 2 diabetes.

"Inhibition of excess liver GABA production restored insulin sensitivity within days," said Geisler, now a postdoctoral researcher at the University of Pennsylvania and lead author on the papers. "Longer term inhibition of GABA-transaminase resulted in decreased food intake and weight loss."

Researchers wanted to ensure the findings would translate to humans. Kendra Miller, a research technician in Renquist's lab, identified variations in the genome near GABA transaminase that were associated with Type 2 diabetes. Collaborating with investigators at Washington University, the researchers showed that in people with insulin resistance, the liver more highly expressed genes involved in GABA production and release.

The findings are the foundation of an Arizona Biomedical Research Commission-funded clinical trial currently underway at Washington University School of Medicine in St. Louis with collaborator Samuel Klein, co-author on the study and a Washington University professor of medicine and nutritional science. The trial will investigate the use of a commercially available Food and Drug Administration-approved inhibitor of GABA transaminase to improve insulin sensitivity in people who are obese.

"A novel pharmacological target is just the first step in application; we are years away from anything reaching the neighborhood pharmacy," Renquist said. "The magnitude of the obesity crisis makes these promising findings an important first step that we hope will eventually impact the health of our family, friends and community."

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Story Source:

Materials provided by University of Arizona. Original written by Rosemary Brandt. Note: Content may be edited for style and length.

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Journal Reference:

1. Caroline E. Geisler, Susma Ghimire, Stephanie M. Bruggink, Kendra E. Miller, Savanna N. Weninger, Jason M. Kronenfeld, Jun Yoshino, Samuel Klein, Frank A. Duca, Benjamin J. Renquist. A critical role of hepatic GABA in the metabolic dysfunction and hyperphagia of obesity. Cell Reports, 2021; 35 (13): 109301 DOI: 10.1016/j.celrep.2021.109301

https://www.sciencedaily.com/releases/2021/06/210629191737.htm

Embryo freezing for IVF appears linked to blood pressure problems in pregnancy

 A large cohort study drawn from the national IVF registry of France, which included almost 70,000 pregnancies delivered after 22 weeks gestation between 2013 and 2018, has found a higher risk of pre-eclampsia and hypertension in pregnancies derived from frozen-thawed embryos. This risk was found significantly greater in those treatments in which the uterus was prepared for implantation with hormone replacement therapies. The results confirm with real-life data what has been observed in sub-groups of patients in other studies.

The results are presented today by Dr Sylvie Epelboin from the Hôpital Bichat-Claude Bernard, Paris, at the online annual meeting of ESHRE. The study was performed on behalf of the Mother & child health after ART network, of the French Biomedecine Agency. She said that the results highlight two important considerations in IVF: the potentially harmful effects on vascular pathologies of high and prolonged doses of hormone replacement therapies used to prepare the uterus for the implantation of frozen-thawed embryos; and the protective effect of a corpus luteum (1), which is present in natural or stimulated cycles for embryo transfer. The hormone replacement therapy given to prepare the uterus for embryo transfer, explained Dr Epelboin, suppresses ovulation and therefore the formation of the corpus luteum.

The risk of pre-eclampsia and other pregnancy-related disorders of pregnancy has been raised in a growing number of studies of freezing in IVF.(2) However, the overall risks of maternal morbidity are known to be generally lower in pregnancies resulting from frozen embryo transfer than in those from fresh transfers -- except in relation to the risk of pre-eclampsia. While some studies have observed such risks in frozen embryo transfers, few studies, said Dr Epelboin, have compared these "maternal vascular morbidities with the two hormonal environments that preside over the early stages of embryonic development."

This study divided the cohort of pregnancies from IVF and ICSI in the French national database into three groups of singletons for comparison: those derived from frozen embryo transfer in a natural "ovulatory" cycle (whether stimulated or not) (n = 9,500); those from frozen embryo transfer with hormone replacement therapy (n = 10,373); and conventional fresh transfers (n = 48,152).

Results showed a higher rate of pre-eclampsia with frozen embryos transferred in the artificial (ie, prepared with hormone therapy) frozen cycle (5.3%) than in an ovulatory cycle (2.3%) or in fresh cycles (2.4%). The rates were found similarly distinct in pregnancy-induced hypertension (4.7% vs 3.4% vs 3.3%). These differences were statistically significant, even after adjusting for maternal characteristics (age, parity, tobacco, obesity, history of diabetes, hypertension, endometriosis, polycystic ovaries, premature ovarian failure) to avoid bias.

Dr Epelboin and colleagues concluded that the study demonstrates that preparation of the uterus with hormones in an artificial cycle is significantly associated with a higher risk of vascular disorders than from cycles with preserved ovulation and fresh embryo transfers.

The use of frozen embryos has increased in IVF in recent years. Success rates in frozen-thawed embryo transfers are reported to be as or more successful than with fresh embryos and, because frozen transfers appear to reduce the risk of hyperstimulation, it also has safety advantages; the blood pressure risks observed in this study and others do not appear to outweigh these benefits, said Dr Epelboin.

Moreover, because results obtained in an ovulatory cycle appear not to affect the chance of pregnancy, preservation of the ovulatory cycle could be advocated as first-line preparation in frozen embryo transfers whenever the choice is possible.

Presentation 0-182 Wednesday 30 June Higher risk of preeclampsia and pregnancy-induced hypertension with artificial cycle for Frozen-thawed Embryo Transfer compared to ovulatory cycle or fresh transfer following In Vitro Fertilization

1. The corpus luteum in pregnancy

   The corpus luteum is a naturally developing cluster of cells which form in the ovary during early pregnancy and pump out a pulse of progesterone, a fertility hormone. Progesterone supports the lining of the uterus (endometrium) during pregnancy and improves blood flow.

2. Embryo freezing and the risk of pre-eclampsia in pregnancy
   • This is the first large-scale study to identify an association between a hormonally prepared uterus (artificial cycle) and a significantly raised risk of pre-eclampsia in pregnancies following the transfer of a frozen-thawed embryo. Several (but not all) randomised trials of freezing embryos generated from an initial egg collection ("freeze-all") have observed such trends as a secondary endpoint. A substantial review of the literature published in 2018 (Maheshewari et al, Hum Reprod Update 2018) concluded that the evidence in favour of embryo freezing was "reassuring" while adding "a need for caution" from the increased risk of hypertension in pregnancy. Generally, embryo freezing allows several transfers from an initial egg collection treatment (and thereby encourages single embryo transfer and the avoidance of multiple pregnancies) and in freeze-all protocols avoids transfer in the same cycle in which the ovaries were stimulated.

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Materials provided by European Society of Human Reproduction and Embryology. Note: Content may be edited for style and length.

https://www.sciencedaily.com/releases/2021/06/210630115355.htm

5-minute breathing workout lowers blood pressure as much as exercise, drugs

 Working out just five minutes daily via a practice described as "strength training for your breathing muscles" lowers blood pressure and improves some measures of vascular health as well as, or even more than, aerobic exercise or medication, new CU Boulder research shows.

The study, published June 29 in the Journal of the American Heart Association, provides the strongest evidence yet that the ultra-time-efficient maneuver known as High-Resistance Inspiratory Muscle Strength Training (IMST) could play a key role in helping aging adults fend off cardiovascular disease -- the nation's leading killer.

In the United States alone, 65% of adults over age 50 have above-normal blood pressure -- putting them at greater risk of heart attack or stroke. Yet fewer than 40% meet recommended aerobic exercise guidelines.

"There are a lot of lifestyle strategies that we know can help people maintain cardiovascular health as they age. But the reality is, they take a lot of time and effort and can be expensive and hard for some people to access," said lead author Daniel Craighead, an assistant research professor in the Department of Integrative Physiology. "IMST can be done in five minutes in your own home while you watch TV."

Developed in the 1980s as a way to help critically ill respiratory disease patients strengthen their diaphragm and other inspiratory (breathing) muscles, IMST involves inhaling vigorously through a hand-held device which provides resistance. Imagine sucking hard through a tube that sucks back.

Initially, when prescribing it for breathing disorders, doctors recommended a 30-minute-per-day regimen at low resistance. But in recent years, Craighead and colleagues have been testing whether a more time-efficient protocol -- 30 inhalations per day at high resistance, six days per week -- could also reap cardiovascular, cognitive and sports performance improvements.

For the new study, they recruited 36 otherwise healthy adults ages 50 to 79 with above normal systolic blood pressure (120 millimeters of mercury or higher). Half did High-Resistance IMST for six weeks and half did a placebo protocol in which the resistance was much lower.

After six weeks, the IMST group saw their systolic blood pressure (the top number) dip nine points on average, a reduction which generally exceeds that achieved by walking 30 minutes a day five days a week. That decline is also equal to the effects of some blood pressure-lowering drug regimens.

Even six weeks after they quit doing IMST, the IMST group maintained most of that improvement.

"We found that not only is it more time-efficient than traditional exercise programs, the benefits may be longer lasting," Craighead said.

The treatment group also saw a 45% improvement in vascular endothelial function, or the ability for arteries to expand upon stimulation, and a significant increase in levels of nitric oxide, a molecule key for dilating arteries and preventing plaque buildup. Nitric oxide levels naturally decline with age.

Markers of inflammation and oxidative stress, which can also boost heart attack risk, were significantly lower after people did IMST.

And, remarkably, those in the IMST group completed 95% of the sessions.

"We have identified a novel form of therapy that lowers blood pressure without giving people pharmacological compounds and with much higher adherence than aerobic exercise," said senior author Doug Seals, a Distinguished Professor of Integrative Physiology. "That's noteworthy."

The practice may be particularly helpful for postmenopausal women.

In previous research, Seals' lab showed that postmenopausal women who are not taking supplemental estrogen don't reap as much benefit from aerobic exercise programs as men do when it comes to vascular endothelial function. IMST, the new study showed, improved it just as much in these women as in men.

"If aerobic exercise won't improve this key measure of cardiovascular health for postmenopausal women, they need another lifestyle intervention that will," said Craighead. "This could be it."

Preliminary results suggest MST also improved some measures of brain function and physical fitness. And previous studies from other researchers have shown it can be useful for improving sports performance.

"If you're running a marathon, your respiratory muscles get tired and begin to steal blood from your skeletal muscles," said Craighead, who uses IMST in his own marathon training. "The idea is that if you build up endurance of those respiratory muscles, that won't happen and your legs won't get as fatigued."

Seals said they're uncertain exactly how a maneuver to strengthen breathing muscles ends up lowering blood pressure, but they suspect it prompts the cells lining blood vessels to produce more nitric oxide, enabling them to relax.

The National Institutes of Health recently awarded Seals $4 million to launch a larger follow-up study of about 100 people, comparing a 12-week IMST protocol head-to-head with an aerobic exercise program.

Meanwhile, the research group is developing a smartphone app to enable people to do the protocol at home using already commercially available devices.

Those considering IMST should consult with their doctor first. But thus far, IMST has proven remarkably safe, they said.

"It's easy to do, it doesn't take long, and we think it has a lot of potential to help a lot of people," said Craighead.

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Story Source:

Materials provided by University of Colorado at Boulder. Original written by Lisa Marshall. Note: Content may be edited for style and length.

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Journal Reference:

1. Daniel H. Craighead, Thomas C. Heinbockel, Kaitlin A. Freeberg, Matthew J. Rossman, Rachel A. Jackman, Lindsey R. Jankowski, Makinzie N. Hamilton, Brian P. Ziemba, Julie A. Reisz, Angelo D’Alessandro, L. Madden Brewster, Christopher A. DeSouza, Zhiying You, Michel Chonchol, E. Fiona Bailey, Douglas R. Seals. Time‐Efficient Inspiratory Muscle Strength Training Lowers Blood Pressure and Improves Endothelial Function, NO Bioavailability, and Oxidative Stress in Midlife/Older Adults With Above‐Normal Blood Pressure. Journal of the American Heart Association, 2021; DOI: 10.1161/JAHA.121.020980

https://www.sciencedaily.com/releases/2021/06/210630135033.htm

Machine learning helps in predicting when immunotherapy will be effective

 When it comes to defense, the body relies on attack thanks to the lymphatic and immune systems. The immune system is like the body's own personal police force as it hunts down and eliminates pathogenic villains.

"The body's immune system is very good at identifying cells that are acting strangely. These include cells that could develop into tumors or cancer in the future," says Federica Eduati from the department of Biomedical Engineering at TU/e. "Once detected, the immune system strikes and kills the cells."

Stopping the attack

But it's not always so straightforward as tumor cells can develop ways to hide themselves from the immune system.

"Unfortunately, tumor cells can block the natural immune response. Proteins on the surface of a tumor cell can turn off the immune cells and effectively put them in sleep mode," says Oscar Lapuente-Santana, PhD researcher in the Computational Biology group.

Fortunately, there is a way to wake up the immune cells and restore their antitumor immunity, and it's based on immunotherapy.

Introducing immunotherapy

Immunotherapy is a cancer treatment that assists the immune system in its fight against cancer cells. One type of immunotherapy involves immune checkpoint blockers (ICB), which are drugs that tell the immune cells to ignore the shutdown orders coming from cancer cells.

The discovery of ICB has been revolutionary for cancer treatment, with James P. Allison and Tasuku Honjo jointly awarded the 2018 Nobel Prize in Physiology or Medicine for their work on ICB.

Although ICB has been successfully used to treat plenty of patients and different cancer types, only one-third of patients respond to the treatment.

"ICB has had a big impact, but it could be bigger if we could figure out quickly which patients are most likely to respond to the treatment," says Eduati. "And it would also be great if we could understand why other patients are not responding to ICB."

To solve this problem, Lapuente-Santana and Eduati, along with colleagues Maisa van Genderen (TU/e), Peter Hilbers (TU/e) and Francesca Finotello (Medical University of Innsbruck), turned to machine learning to predict how patients might respond to ICB. Their work has just been published in the journal Patterns.

Searching the tumor microenvironment

To predict whether a patient will respond to ICB, the researchers first needed to find particular biomarkers in tumor samples from the patients.

"Tumors contain more than just tumour cells, they also contain several different types of immune cells and fibroblasts, which can have a pro- or anti-tumour role, and they communicatie with each other," explains Lapuente-Santana. "We needed to find out how complex regulatory mechanisms in the tumor microenvironment affect response to ICB. We turned to RNA-sequencing datasets to provide a high-level representation of several aspects of the tumor microenvironment."

To find the right mechanisms that could serve as biomarkers to predict patients' response to ICB, the team searched the microenvironment of tumors using computational algorithms and datasets from previous clinical patient care.

"RNA-sequencing datasets are publicly available, but the information about which patients responded to ICB therapy is only available for a small subset of patients and cancer types," says Eduati. "So, we used a trick to solve the data problem."

The trick

For their trick, instead of looking for the actual biological response to ICB treatment, the researchers picked out several substitute immune responses from the same datasets. Despite not being the primary response to ICB, together they could be used as an indicator of the effectiveness of ICB.

Thanks to this approach, the team could use a large public dataset with thousands of patient samples to robustly train machine learning models.

"A significant challenge with this work was the proper training of the machine learning models. By looking at substitute immune responses during the training process, we were able to solve this," says Lapuente-Santana.

With the machine learning models in place, the researchers then tested the accuracy of the model on different datasets where the actual response to ICB treatment was known. "We found that overall, our machine learning model outperforms biomarkers currently used in clinical settings to assess ICB treatments," says Eduati.

But why are Eduati, Lapuente-Santana, and their colleagues turning to mathematical models to solve a medical treatment problem? Will this replace the doctor? "Mathematical models can provide a big picture of how individual molecules and cells are interconnected, while at the same time approximate the behavior of tumors in a particular patient. In clinical settings, this means that immunotherapy treatment with ICB can be personalized to a patient. It's important to remember that the models can help doctors with their decisions on the best treatment, they won't replace them." says Eduati.

In addition, the model also helps in understanding which biological mechanisms are important for the biological response. Understanding and identifying the mechanisms that mediate ICB response can guide how best to combine ICB with other treatments to improve its clinical efficacy. However, this will first require experimental validation of the identified mechanisms before translating these results to clinical settings.

Dare to DREAM

The machine learning approach presented in the paper was also used by some of the researchers to take part in a DREAM challenge called "Anti-PD1 Response Prediction DREAM Challenge."

DREAM is an organization dedicated to running crowd-sourced challenges involving algorithms in biomedicine. "We came first in one of the sub-challenges and competed under the name cSysImmunoOnco team," adds Eduati.

Our immune system might be an efficient detective and disease hunter, but every now and then it needs a helping hand to eradicate elusive villains like cancer cells. Immunotherapy using immune checkpoint blockers is one such approach, but it doesn't work for everyone.

Lapuente-Santana, Eduati, and colleagues have certainly dared to dream, and their work could prove pivotal in quickly identifying those who could be successfully treated with ICB in the future.

Thanks to machine learning, the researchers hope to rapidly deliver proper and effective cancer treatments to specific patients.

And for some cancer cells, it means that there could be no place to run, and no place to hide.

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Materials provided by Eindhoven University of Technology. Note: Content may be edited for style and length.

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Journal Reference:

1. Óscar Lapuente-Santana, Maisa van Genderen, Peter A.J. Hilbers, Francesca Finotello, Federica Eduati. Interpretable systems biomarkers predict response to immune-checkpoint inhibitors. Patterns, 2021; 100293 DOI: 10.1016/j.patter.2021.100293

https://www.sciencedaily.com/releases/2021/06/210630135027.htm