Carbon Chemist

Tag: pH

  • Scientists transform skin cells into functional eggs in mice

    Scientists transform skin cells into functional eggs in mice

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    New research from Oregon Health & Science University describes the science behind a promising technique to treat infertility by turning a skin cell into an egg that is capable of producing viable embryos.

    Researchers at OHSU documented in vitro gametogenesis, or IVG, in a mouse model through the preliminary steps of a technique that relies upon transferring the nucleus of a skin cell into a donated egg whose nucleus has been removed. Experimenting in mice, researchers coaxed the skin cell’s nucleus into reducing its chromosomes by half, so that it could then be fertilized by a sperm cell to create a viable embryo.

    The study published today in the journal Science Advances.

    “The goal is to produce eggs for patients who don’t have their own eggs,” said senior author Shoukhrat Mitalipov, Ph.D., director of the OHSU Center for Embryonic Cell and Gene Therapy.

    The technique could be used by women of advanced maternal age or for those who are unable to produce viable eggs due to previous treatment for cancer or other causes. It also raises the possibility of men in same-sex relationships having children who are genetically related to both parents.

    Rather than attempting to differentiate induced pluripotent stem cells, or iPSCs, into sperm or egg cells, OHSU researchers are focused on a technique based on somatic cell nuclear transfer, in which a skin cell nucleus is transplanted into a donor egg stripped of its nucleus. In 1996, researchers famously used this technique to clone a sheep in Scotland named Dolly.

    In that case, researchers created a clone of one parent.

    In contrast, the OHSU study described the result of a technique that resulted in embryos with chromosomes contributed from both parents. The process involves three steps:

    • Researchers transplant the nucleus of a mouse skin cell into a mouse egg that is stripped of its own nucleus.

    • Prompted by cytoplasm -; liquid that fills cells -; within the donor egg, the implanted skin cell nucleus discards half of its chromosomes. The process is similar to meiosis, when cells divide to produce mature sperm or egg cells. This is the key step, resulting in a haploid egg with a single set of chromosomes.

    • Researchers then fertilize the new egg with sperm, a process called in vitro fertilization. This creates a diploid embryo with two sets of chromosomes -; which would ultimately result in healthy offspring with equal genetic contributions from both parents.

    OHSU researchers previously demonstrated the proof of concept in a study published in January 2022, but the new study goes further by meticulously sequencing the chromosomes.

    The researchers found that the skin cell’s nucleus segregated its chromosomes each time it was implanted in the donor egg. In rare cases, this happened perfectly, with one from each pair of matching egg and sperm chromosomes.

    “This publication basically shows how we achieved haploidy,” Mitalipov said. “In the next phase of this research, we will determine how we enhance that pairing so each chromosome-pair separates correctly.”

    Laboratories around the world are involved in a different technique of IVG that involves a time-intensive process of reprogramming skin cells to become iPSCs, and then differentiating them to become egg or sperm cells.

    We’re skipping that whole step of cell reprogramming. The advantage of our technique is that it avoids the long culture time it takes to reprogram the cell. Over several months, a lot of deleterious genetic and epigenetic changes can happen.”


    Paula Amato, Professor, Obstetrics and Gynecology, School of Medicine, Oregon Health & Science University

    Although researchers are also studying the technique in human eggs and early embryos, Amato said it will be years before the technique would be ready for clinical use.

    “This gives us a lot of insight,” she said. “But there is still a lot of work that needs to be done to understand how these chromosomes pair and how they faithfully divide to actually reproduce what happens in nature.”

    Source:

    Oregon Health & Science University

    Journal reference:

    Mikhalchenko, A., et al. (2024) Induction of somatic cell haploidy by premature cell division. Science Advances.  doi.org/10.1126/sciadv.adk9001.

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  • Biocompatible, bioresorbable sticker detects anastomotic leaks

    Biocompatible, bioresorbable sticker detects anastomotic leaks

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    Researchers led by Northwestern University and Washington University School of Medicine in St. Louis have developed a new, first-of-its-kind sticker that enables clinicians to monitor the health of patients’ organs and deep tissues with a simple ultrasound device.

    When attached to an organ, the soft, tiny sticker changes in shape in response to the body’s changing pH levels, which can serve as an early warning sign for post-surgery complications such as anastomotic leaks. Clinicians then can view these shape changes in real time through ultrasound imaging.

    Currently, no existing methods can reliably and non-invasively detect anastomotic leaks -; a life-threatening condition that occurs when gastrointestinal fluids escape the digestive system. By revealing the leakage of these fluids with high sensitivity and high specificity, the non-invasive sticker can enable earlier interventions than previously possible. Then, when the patient has fully recovered, the biocompatible, bioresorbable sticker simply dissolves away -; bypassing the need for surgical extraction.

    The study will be published on Friday (March 8) in the journal Science. The paper outlines evaluations across small and large animal models to validate three different types of stickers made of hydrogel materials tailored for the ability to detect anastomotic leaks from the stomach, the small intestine and the pancreas.

    “These leaks can arise from subtle perforations in the tissue, often as imperceptible gaps between two sides of a surgical incision,” said Northwestern’s John A. Rogers, who led device development with postdoctoral fellow Jiaqi Liu. “These types of defects cannot be seen directly with ultrasound imaging tools. They also escape detection by even the most sophisticated CT and MRI scans. We developed an engineering approach and a set of advanced materials to address this unmet need in patient monitoring. The technology has the potential to eliminate risks, reduce costs and expand accessibility to rapid, non-invasive assessments for improved patient outcomes.”

    “Right now, there is no good way whatsoever to detect these kinds of leaks,” said gastrointestinal surgeon Dr. Chet Hammill, who led the clinical evaluation and animal model studies at Washington University with collaborator Dr. Matthew MacEwan, an assistant professor of neurosurgery. “The majority of operations in the abdomen -; when you have to remove something and sew it back together -; carry a risk of leaking. We can’t fully prevent those complications, but maybe we can catch them earlier to minimize harm. Even if we could detect a leak 24- or 48-hours earlier, we could catch complications before the patient becomes really sick. This new technology has potential to completely change the way we monitor patients after surgery.”

    A bioelectronics pioneer, Rogers is the Louis Simpson and Kimberly Querrey Professor of Materials Science and Engineering, Biomedical Engineering and Neurological Surgery, with appointments at the McCormick School of Engineering and Northwestern University Feinberg School of Medicine. He also directs the Querrey Simpson Institute for Bioelectronics. At the time of the research, Hammill was an associate professor of surgery at Washington University. Rogers, Hammill and MacEwan co-led the research with Heling Wang, an associate professor at Tsinghua University in Beijing.

    The importance of being early

    All gastrointestinal surgeries carry the risk of anastomotic leaks. If the leak is not detected early enough, the patient has a 30% chance of spending up to six months in the hospital and a 20% chance of dying, according to Hammill. For patients recovering from pancreatic surgery, the risks are even higher. Hammill says a staggering 40-60% of patients suffer complications after pancreas-related surgeries.

    The biggest problem is there’s no way to predict who will develop such complications. And, by the time the patient is experiencing symptoms, they already are incredibly ill.

    “Patients might have some vague symptoms associated with the leak,” Hammill said. “But they have just gone through big surgery, so it’s hard to know if the symptoms are abnormal. If we can catch it early, then we can drain the fluid. If we catch it later, the patient can get sepsis and end up in the ICU. For patients with pancreatic cancer, they might only have six months to live as it is. Now, they are spending half that time in the hospital.”

    In search of improved outcomes for his patients, Hammill contacted Rogers, whose laboratory specializes in developing engineering solutions to address health challenges. Rogers’ team had already developed a suite of bioresorbable electronic devices to serve as temporary implants, including dissolving pacemakers, nerve stimulators and implantable painkillers.

    The bioresorbable systems piqued Hammill’s interest. The greatest odds of developing an anastomotic leak occur either three days or two weeks after surgery.

    “We like to monitor patients for complications for about 30 days,” Hammill said. “Having a device that lasts a month and then disappears sounded ideal.”

    Enhancing ultrasound

    Instead of developing new imaging systems, Rogers speculated that his team might be able to enhance current imaging methods -; allowing them to “see” features that otherwise would be invisible. Ultrasound technology already has many advantages: it’s inexpensive, readily available, does not require cumbersome equipment and does not expose patients to radiation or other risks.

    But, of course, there is a major drawback. Ultrasound technology -; which uses sound waves to determine the position, shape and structure of organs -; cannot reliably differentiate between various bodily fluids. Blood and gastric fluid, for example, appear the same.

    “The acoustic properties of the leaking fluids are very similar to those of naturally occurring biofluids and surrounding tissues,” Rogers said. “The clinical need, however, demands chemical specificity, beyond the scope of fundamental mechanisms that create contrast in ultrasound images.”

    Ultimately, Rogers’ team devised an approach to overcome this limitation by using tiny sensor devices designed to be readable by ultrasound imaging. Specifically, they created a small, tissue-adhesive sticker out of a flexible, chemically responsive, soft hydrogel material. Then, they embedded tiny, paper-thin metal disks into the thin layers of this hydrogel. When the sticker encounters acidic fluids, such as stomach acid, it swells. When the sticker encounters caustic fluids, such as pancreatic fluids, it contracts.

    Making the invisible visible

    As the hydrogel swells or shrinks in response to changing pH, the metal disks either move apart or closer together, respectively. Then, the ultrasound can view these subtle changes in placement.

    “Because the acoustic properties of the metal disks are much different than those of the surrounding tissue, they provide very strong contrast in ultrasound images,” Rogers said. “In this way, we can essentially ‘tag’ an organ for monitoring.” Because the need for monitoring extends only during a postsurgical recovery, Rogers team designed these stickers with bioresorbable materials. They simply disappear naturally and harmlessly in the body after they are no longer needed.

    Computational collaborator Yonggang Huang, the Jan and Marcia Achenbach Professorship in Mechanical Engineering and professor of civil and environmental engineering at McCormick, used acoustic and mechanical simulation techniques to help guide optimized choices in materials and device layouts to ensure high visibility in ultrasound images, even for stickers located at deep positions within the body.

    “CT and MRI scans just take a picture,” Hammill added. “The fluid might show up in a CT image, but there’s always fluid collections after surgery. We don’t know if it’s actually a leak or normal abdominal fluid. The information that we get from the new patch is much, much more valuable. If we can see that the pH is altered, then we know that something isn’t right.”

    Rogers team constructed stickers of varying sizes. The largest measures 12 millimeters in diameter, while the smallest is just 4 millimeters in diameter. Considering that the metal disks are each 1 millimeter or smaller, Rogers realized that it might be difficult for radiologists to assess the images manually. To overcome this challenge, his team also developed software that can automatically analyze the images to detect with high accuracy any relative movement of the disks.

    Improving quality of life

    To evaluate the efficacy of the new sticker, Hammill’s team tested it in both small and large animal models. In the studies, ultrasound imaging consistently detected changes in the shape-shifting sticker -; even when it was 10 centimeters deep inside of tissues. When exposed to fluids with abnormally high or low pH levels, the sticker altered its shape within minutes.

    Rogers and Hammill imagine that the device could be implanted at the end of a surgical procedure. Or, because it’s small and flexible, the device also fits (rolled up) inside a syringe, which clinicians can use to inject the tag into the body.

    “These tags are so small and thin and soft that surgeons can easily place collections of them at different locations,” Rogers said. “For example, if an incision extends by a few centimeters in length, an array of these tags can be placed along the length of the site to develop a map of pH for precisely locating the position of the leak.”

    “It’s obviously an early prototype, but I can envision the final product where, at the end of surgery, you just place these little patches for monitoring,” Hammill said. “It does its job and then completely disappears. This could have a huge impact on patients, their recovery time and, ultimately, their quality of life.”

    Next, Rogers and his team are exploring similar tags that could detect internal bleeding or temperature changes. “Detecting changes in pH is a good starting point,” Rogers said. “But this platform can extend to other types of applications by use of hydrogels that respond to other changes in local chemistry, or to temperature or other properties of clinical relevance.”

    Source:

     Northwestern University

    Journal reference:

    Liu, J., et al. (2024) Bioresorbable shape-adaptive structures for ultrasonic monitoring of deep-tissue homeostasis. Science. doi.org/10.1126/science.adk9880.

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  • Inherited genetic factors may predict elevated risk of new cancers among childhood cancer survivors

    Inherited genetic factors may predict elevated risk of new cancers among childhood cancer survivors

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    Common inherited genetic factors that predict cancer risk in the general population may also predict elevated risk of new cancers among childhood cancer survivors, according to a study led by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health. The findings, published March 7, 2024, in Nature Medicine, provide additional evidence that genetics may play an important role in the development of subsequent cancers in survivors of childhood cancer and suggest that common inherited variants could potentially inform screening and long-term follow-up of those at greatest risk. 

    Childhood cancer survivors are known to have a higher risk of developing a new cancer later in life due to adverse effects of cancer treatment or rare inherited genetic factors. In the new study, the researchers evaluated the combined effect of common variants with history of radiation treatment and found the resulting elevated cancer risk was greater than the sum of the individual associations for treatment and genetic factors alone. 

    Knowledge about a person’s genetic makeup could potentially be useful in managing their risk of subsequent cancers. The hope would be that, in the future, we can incorporate genetics along with treatment exposures and other risk factors to provide a more complete picture of a survivor’s risk of subsequent cancers to help guide their long-term follow-up care.” 


    Todd M. Gibson, Ph.D., lead investigator of NCI’s Division of Cancer Epidemiology and Genetics

    To assess the contribution of common inherited genetic variants to risk of subsequent cancer in people who survived childhood cancer, the research team used data from genome-wide association studies, or GWAS, that had been conducted in large populations of healthy individuals. Such studies have identified thousands of common inherited variants associated with risk of different cancers. The risk associated with a single common variant is typically small, but the effects of large numbers of variants can be bundled into a summary score, or polygenic risk score, that provides a more comprehensive estimate of someone’s genetic risk. 

    Although polygenic risk scores have shown promise for predicting cancer risk in the general population, it has not been known whether such scores are also associated with the risk of subsequent cancer among childhood cancer survivors. 

    To find out, the researchers looked at the association between polygenic risk scores and risk of basal cell carcinoma, female breast cancer, thyroid cancer, squamous cell carcinoma, melanoma, and colorectal cancer among 11,220 childhood cancer survivors from two large cohort studies. For all of these cancers except colorectal cancer, polygenic risk scores derived from GWAS in the general population were associated with the risk of these same cancers among childhood cancer survivors. 

    The researchers then looked at basal cell carcinoma, breast cancer, and thyroid cancer-;malignancies that occurred most often in the combined data set and that are strongly linked to radiation therapy-;to examine the joint effect of polygenic risk score and treatment history. They found that risk associated with the combination of higher-dose radiation exposure and higher polygenic risk score was greater than would be expected based on simply adding the risk associations of each individual risk factor. 

    For basal cell carcinoma, a high polygenic risk score was associated with 2.7-fold increased risk compared with a low polygenic risk score among survivors. History of higher radiation exposure to the skin was associated with a 12-fold increase in risk, compared with lower radiation exposure to the skin. However, survivors with high polygenic risk scores and higher doses of radiation to the skin had an 18.3-fold increased risk of basal cell carcinoma, compared with those with low polygenic risk scores who had received lower radiation doses to the skin.

    Moreover, by age 50, survivors with higher polygenic risk scores and higher radiation exposure had a greater cumulative incidence of basal cell carcinoma, breast cancer, or thyroid cancer than those with lower polygenic risk scores or lower radiation exposure. For example, among female survivors who had radiation to the chest, 33.9% of those with a high polygenic risk score had been diagnosed with breast cancer by age 50, compared with 21.4% of those with a low polygenic risk score.

    One limitation of the study is that the populations included in the analysis were predominantly of European ancestry, so additional studies are needed in diverse populations. Furthermore, polygenic risk scores are not yet used routinely in the clinic, although they may one day inform screening approaches or other clinical decisions. 

    “Although these results suggest that polygenic risk scores could play a role in improving guidelines for long-term follow-up of childhood cancer survivors exposed to radiation, right now they are not sufficient on their own to alter existing guidelines,” Dr. Gibson noted. 

    Source:

    NIH/National Cancer Institute

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  • A Journey into Women’s Brain Health Research

    A Journey into Women’s Brain Health Research

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    In this special International Women’s Day interview on the evolution of neurology with a special focus on women’s brain health, we dive into the work of Cheryl Carcel. With a unique perspective shaped by experiences in both low-middle-income and high-income countries, the conversation sheds light on the critical disparities in neurological care and outcomes between genders. 

    Please could you share with us the journey that led you to focus on neurology and, more specifically, on women’s brain health?

    As a medical student from a low-middle-income country (the Philippines), I was fascinated by neurology, where by taking a person’s medical history and performing physical examinations, it was possible to diagnose with good accuracy a person’s neurological disease. This is crucial in a country with few resources, such as diagnostic imaging.

    During my neurology training, I noticed that women were usually more disabled or likely  to die after a stroke, but I did not realize that this was a global issue. It wasn’t until I started my Ph.D. at the University of Sydney and analyzed some of the stroke clinical trials at The George Institute and found evidence that women indeed had worse outcomes including worse quality of life after stroke compared to men.

    These trials were run internationally, so not only was it happening in the Philippines, where I had first-hand experience with my patients, but also around the globe and even in high-income countries.

    In your research on sex and gender differences within neurology, what have been some of the most surprising or enlightening findings regarding how neurological disorders affect men and women differently?

    It still surprises me that in 2024, women and men still experience these differences. There are two things I want to highlight:

    We know about biological differences in women and men and that these may affect how we respond to diseases like stroke. For example, younger women are more likely to have a stroke than younger men, and this is probably due (to some extent) to hypertensive disorders of pregnancy and gestational hypertension.

    But the gender aspects are more difficult to explain because they may involve the role a woman plays in society – she may not immediately present to the hospital after a stroke (and thereby receive time-dependent life-saving medications) because she has caregiving responsibilities, or she may be older, living alone with no one to call the ambulance. Aside from the role women play in society, there may be differences in the way women and men are treated, or there may be implicit bias from healthcare professionals.

    Participants enrolled in stroke clinical trials are not often representative of the population experiencing the disease in the community. Women, people of color, and individuals from culturally and linguistically diverse backgrounds (CALD) are under-enrolled relative to their burden of disease in stroke. Treatment effect estimates of many medical therapies, including stroke, have been largely derived from trial evidence generated from a Caucasian male population, limiting the generalisability of the safety and efficacy evidence.

    Given the clear differences in how neurological conditions can manifest and impact men and women, how do you believe these insights should influence the development of treatments, patient care, and support systems in neurology?

    Work in this field (mine and many others) suggests that in order to overcome these differences, we need to consider the collection, analysis, and reporting of sex and gender health data and include more diverse populations in our clinical trials in order to provide reliable evidence on how safe and effective new medications and devices are for everyone. There has also been evidence to suggest that when women lead clinical trials, the trial population is more inclusive, and data is more likely to be disaggregated by sex.

    Image Credit: Tunatura/Shutterstock.com

    Image Credit: Tunatura/Shutterstock.com

    What are some of the most significant challenges you face in researching women’s brain health, and how do you propose the scientific community addresses these challenges to ensure more inclusive health outcomes?

    If you had asked me the same question 4 years ago, I would have said that the biggest challenge at that time was convincing the medical and research community that sex and gender differences in stroke/cardiovascular disease is a real problem.

    Now that all these mounting evidence cannot be ignored, the next challenge is to find strategies to narrow this health gap. One of the best ways of doing this is working with end-users—the people with lived experiences, health care professionals, advocacy groups, government, etc to find a solution that works for the people involved.

    You advocate for the disaggregation of data by sex in medical research. Can you explain how this approach has influenced your research outcomes and why it’s crucial for achieving gender equity in health care?

    Gender equality is one of the UN Sustainable Development Goals (Sustainable Development Goal 5). Clinically meaningful sex and gender differences in screening, risk factor prevalence, health-seeking behavior, treatment, and prognosis are increasingly recognized across a range of non-communicable diseases, which confer the greatest health burden.

    Why women and men’s experiences and treatment differ for the same diseases, and how this links to socially embedded gender structures, is under-appreciated in medical research and clinical practice. By disaggregating data by sex and, where possible, gender, we are not only doing good science (Prof Londa Schiebinger’s wise words Gendered Innovations | Stanford University), but we are expanding our knowledge of these differences into the health care system to improve clinical practice, medical research, health systems design, policy, and public health.

    Your trial in Nigeria and Peru focuses on essential acute stroke care in low-resource settings. How do you see this work contributing to a more inclusive approach to global health, especially concerning women’s health care in these regions?

    This trial is funded by the World Heart Federation, and our intention was two-fold: to improve acute stroke care in low-resource settings and to build research capacity in the area. The COVID pandemic has impacted this project, and it is currently on hold as we work through logistical issues. If this trial has a positive outcome, then having clear guidelines on essential acute stroke treatments has the potential to eliminate implicit and explicit gender bias.

    I am also working on another project that aims to improve the participation of women in stroke clinical trials. Ensuring that clinical trials include a balanced proportion of women and men and that key findings are interpreted separately by sex is crucial.

    When women are under-represented in trials, there is a threat that treatment is not safe or effective and introduces the potential for unequal access to treatments. Our ongoing efforts will develop and evaluate inclusive and innovative recruitment strategies to improve the representation of women in stroke trials, making stroke treatment more accessible to all people.

    As women, we need to be brave. Speak up and let your voice be heard and counted when you have something to say. You are important, and your voice matters.

    Based on your experience and research findings, what policies or actions do you believe are essential to advance the inclusion of women’s health needs in both national and international health agendas?

    An important program of work at The George Institute for Global Health in collaboration with the Australian Human Rights Institute at the University of New South Wales in Sydney is an Australia-wide Call to Action to embed sex and gender analysis into medical research. This work has led to the formation of The Sex and Gender Sensitive Research Call to Action Group, which includes 11 universities across Australia, the UK, and the United States committing to analysing and reporting health data by sex.

    A philanthropic group is currently funding a larger project aimed at translating the Call to Action paper. Some key wins of this project so far include mapping the key stakeholder organizations in Australia engaged in sex and gender research advocated for policy changes with the National Health and Medical Research Council and Medical Research Future Fund (the main health funding bodies in Australia) and through a co-design workshop with our group, the Association of Australian Medical Research Institutes (AAMRI), the peak body for medical research institutes across Australia, has produced a set of sex and gender policy recommendations for health and medical research.

    Through these policy changes in different stakeholder groups, we hope that we will achieve critical mass in Australia to make the collection, analysis, and reporting of sex and gender health data the norm and not just nice to do.

    This month, we will be launching Australia’s new National Centre for Sex and Gender Equity in Health and Medicine, which will bring together researchers, policymakers, healthcare professionals, and consumer stakeholders with an interest in addressing the effects of biological sex and gender identify on health outcomes, enabling greater learning, collaboration, and impact. This Centre is a partnership between The George Institute for Global Health, the Australian Human Rights Institute at UNSW Sydney and Deakin University.

    The center aims to develop effective strategies to prevent and treat the leading causes of death and disability for everyone; we need health and medical research that is inclusive and looks at how sex and gender affect different conditions. 

    Reflecting on this year’s theme for International Women’s Day, what does “Inspire Inclusion” mean to you personally and professionally, and how do you envision its implementation in the realm of brain health and beyond?

    This year, the UN’s theme is Count Her In: Invest in Women. Accelerate Progress. It talks a bit about economic empowerment but also provides equal opportunities to earn, learn, and lead. This is very relevant to our work on improving the participation of women in clinical trials. We want to be able to count women in by ensuring their health and medical data are captured; and are safe and effective.

    Where can readers find more information?

    About Cheryl Carcel

    A/Prof Cheryl Carcel is a neurologist and the Head of the Brain Health Program at The George Institute for Global Health in Sydney, Australia. She is a conjoint associate professor at University of New South Wales in Australia. She was selected as a World Heart Federation (WHF) Emerging Leader and a Stroke Society of Australasia Emerging Stroke Clinician and Scientist. Her most important life roles are being a mother of two young and active children and wife.

    Career highlights: 
    •    Recent promotion to Associate Professor at University of New South Wales and Head of the Brain Health Program at The George Institute.
    •    Appointed as acting director of the Centre for Sex and Gender Equity in Health and Medicine- a national centre in Australia that will address sex and gender inequities through world-class research that considers how sex and gender impact health and medicine.
    •    Invited to be one of the keynote speakers in the European Stroke Organisation’s Stroke Science Workshop last year. This is an important achievement as this workshop is a meeting on clinical and translational research aspects of stroke with a limited number of well-known stroke specialists as well as junior scientists. My invitation as a keynote speaker to this meeting signals that sex and gender differences should be considered front and centre in stroke. 

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  • Can postbiotics improve athletic performance and recovery?

    Can postbiotics improve athletic performance and recovery?

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    A recent systematic review published in Nutrients describes the utility of postbiotics in improving exercise performance and recovery.

    Study: It’s Dead! Can Postbiotics Really Help Performance and Recovery? A Systematic Review. Image Credit: Doucefleur / Shutterstock.com

    Probiotics vs. postbiotics

    Probiotics are live microorganisms that are associated with a wide variety of health benefits to the host when administered adequately. For example, probiotics can support gut health, improve mental health, prevent cardiometabolic diseases, improve sleep quality and duration, as well as reduce allergic reactions. Probiotics exert these health benefits through their effects on the immune system by reducing intestinal pH, maintaining intestinal barrier integrity, increasing gut microbial composition and diversity, reducing inflammation, and eliminating pathogens.

    Recently, the International Society of Sports and Nutrition has stated that probiotics might be beneficial for improving exercise performance and recovery, in addition to supporting the training and competition demands of athletes.

    In addition to probiotics, postbiotics have recently gained considerable attention in healthcare due to their potential ability to improve health. A significant advantage of using postbiotics for health purposes is their longer shelf-life and reduced susceptibility to degradation due to changes in ambient conditions.

    According to the International Scientific Association of Probiotics and Prebiotics (ISAPP), a postbiotic is defined as a preparation of inanimate microorganisms and/or their components that confers health benefits. Existing evidence indicates that postbiotics can exert positive health effects on gastrointestinal, dermatological, and respiratory diseases.

    Some of the different methods used to produce postbiotic preparations from live microorganisms include heat treatment, sonification, chemical treatment, and ultraviolet (UV) irradiation. Each method, as well as the processing condition, has a differential impact on the functionality of resulting postbiotics.

    About the study

    The authors systematically searched various electronic databases to identify studies that investigated the impact of postbiotic supplementation, specifically on exercise performance, recovery, as well as biomarkers related to muscle immune function, inflammation, and oxidative stress.

    Only peer-reviewed, randomized, double-blind, and placebo-controlled trials involving healthy adults were included in the systematic analysis. Postbiotic supplements used in these studies included paraprobiotics, Tyndallized probiotics, ghost biotics, heat-killed probiotics, inactivated probiotics, and nonviable probiotics. The different outcomes measured in these studies included exercise, exercise performance, and recovery.    

    Systematic review findings

    A total of 11 studies, including nine peer-reviewed papers and two conference abstracts, were included in the final review. These studies comprised a total of 477 participants and postbiotic supplementation periods ranging from 13 days to 12 weeks.

    Three studies directly compared the probiotic and postbiotic preparations of the same strains, including Lactiplantibaccilus plantarum TWK10, Lacticaseibacillus paracasei PS23, and Weizmannia coagulans GBI-30 6086.

    In one study investigating probiotic and postbiotic preparations of Weizmannia coagulans GBI-30 6086, none of the preparations were found to modulate the performance of healthy individuals participating in stressful lower-body exercises.

    Another comparative study showed that both probiotic and postbiotic preparations of Lacticaseibacillus paracasei PS23 can reduce the rate of muscle damage caused by maximal vertical jump, facilitate faster recovery, and improve fatigue as compared to placebo. However, only the postbiotic preparation was associated with a greater ability than the probiotic preparation to improve strength recovery.

    In one study investing probiotic and postbiotic preparations of Lactiplantibaccilus plantarum TWK10, both preparations similarly improved exercise performance. However, the probiotic preparation was superior than the postbiotic preparation in reducing glucose, lactate, and ammonia levels in response to exercise stimuli. This study also reported an increased inflammatory response to exercise in individuals supplemented with the postbiotic preparation.

    Another study investigating the effects of a postbiotic preparation of Weizmannia coagulans GBI-30 6086 reported enhanced lower body power and anti-inflammatory profiles in soldiers. Similarly, one study investigating a postbiotic preparation of Lactiplantibaccilus plantarum TWK10 revealed improvements in endurance performance, grip strength, and muscle mass in healthy exercising males.    

    Regarding other health benefits, one study investigating a postbiotic preparation of Lactobacillus gasseri OLL2809 observed preservation of natural killer cell activity and improvements in mood during strenuous exercise. Likewise, another study highlighted the ability of a postbiotic preparation of Lactococcus lactis JCM 5805 in improving antiviral responses and reducing the number of days with upper respiratory tract infection symptoms in athletes performing high-intensity training. Immunomodulatory and anti-inflammatory activities were also reported for the postbiotic preparation of Lacticaseibacillus paracasei MCC1849.   

    Significance

    Existing evidence suggests that postbiotics can be beneficial in improving mental health, reducing fatigue, and increasing the readiness of athletes across several weeks of exercise training. Thus, the current systematic review findings support the health and ergogenic benefits of postbiotic supplementation.

    Journal reference:

    • Kerksick, C. M., Moon, J. M., & Jager, R. (2024). It’s Dead! Can Postbiotics Really Help Performance and Recovery? A Systematic Review. Nutrients. doi:10.3390/nu16050720

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  • Harnessing repetitive DNA for early cancer detection

    Harnessing repetitive DNA for early cancer detection

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    People with cancer have different amounts of a type of repetitive DNA -; called Alu elements -; than people without cancer. Now, machine learning can measure that from a blood draw. Researchers at the Johns Hopkins Kimmel Cancer Center have used this finding to improve a test that detects cancer early, validating and reproducing the results by starting with a sample size tenfold larger than typical of such types of studies.

    The research was published Jan. 24 in the journal Science Translational Medicine.

    Alu elements are small: around 300 base pairs long out of 2 billion steps in a DNA ladder. But, changes in the proportion of Alu elements in people’s blood plasma occur regardless of where cancer originates, explains lead study author Christopher Douville, Ph.D., an assistant professor of oncology at Johns Hopkins.

    Blood testing holds great promise for the earlier detection of cancers before people exhibit any symptoms. However, analyzing results with machine learning “has not necessarily translated into long-term success for patients when minor fluctuations produce widely different predictions in these complex models. To have a long-term impact on patient care, physicians and patients must have confidence that models consistently and reproducibly classify cancer status. In our manuscript, we evaluated 1,686 individuals multiple times to assess whether our machine learning model consistently delivers the same answer.”


    Christopher Douville, Ph.D., assistant professor of oncology, Johns Hopkins

    Douville and colleagues developed a test to detect aneuploidy, chromosome copy number alterations found in cancers. The test measured aneuploidy through a blood test called liquid biopsy, which detects fragments of cancer cell DNA circulating in the bloodstream.

    However, Douville observed an unexplained signal that distinguished cancer from noncancer but could not be explained by chromosomes being gained or lost.

    The team decided to combine their previous test -; able to check 350,000 repetitive locations in DNA -; with an unbiased machine learning approach.

    Douville and colleagues collected samples from 3,105 people with solid cancers and 2,073 without. The study covered 11 cancer types and 7,615 blood samples. The repeats were used as replicates to see how well the model worked. They reached 98.9% specificity, which meant they could minimize false-positive test results. “This is crucial when screening asymptomatic patients, so people aren’t told incorrectly that they have cancer,” says Douville.

    In an independent validation cohort, adding Alu elements to the machine learning model caught 41% of cancer cases missed by eight existing biomarkers and the group’s previous test, making “a greater contribution,” authors wrote in the paper, “than aneuploidy or proteins.” The type of repetitive DNA contributing most to cancer detection was the largest subfamily of Alu elements, called AluS; the blood plasma of people with cancer had less of it than usual.

    The model was called A-PLUS (Alu Profile Learning Using Sequencing). The code is available online.

    Despite making up 11% of DNA from humans and other primates, Alu elements have been long touted as too difficult to use as a biomarker, Douville says. “They are small and repetitive -; technically difficult. But this research shows that counting repetitive lengths of DNA in blood plasma -; a motley crew of DNA fragments hailing from organs throughout the body -; is cost-effective and enhances early cancer detection,” Douville says. They envision their Alu-based cancer detection as a complement to the toolkit of other cancer tests available to clinicians. The next step is prioritizing which biomarkers seem the most promising and aggregating them together.

    Study co-authors included Kamel Lahouel, Albert Kuo, Haley Grant, Bracha Erlanger Avigdor, Samuel D. Curtis, Mahmoud Summers, Joshua D. Cohen, Yuxuan Wang, Austin Mattox, Jonathan Dudley, Lisa Dobbyn, Maria Popoli, Janine Ptak, Nadine Nehme, Natalie Silliman, Cherie Blair, Katharine Romans, Christopher Thoburn, Jennifer Gizzi, Michael Goggins, Ie-Ming Shih, Anne Marie Lennon, Ralph H. Hruban, Chetan Bettegowda, Kenneth W. Kinzler, Nickolas Papadopoulos, Bert Vogelstein and Cristian Tomasetti of the Johns Hopkins University School of Medicine and City of Hope.

    Additional authors were from the Department of Medicine and Department of Epidemiology at the University of Pittsburgh; the Department of Surgery at NYU Langone; and abroad in Vietnam (Pham Ngoc Thach University of Medicine and Saigon Precision Medicine Research Center) and Australia (the Walter and Eliza Hall Institute of Medical Research, the University of Melbourne, the University of Technology Sydney and the University of New South Wales).

    This study was supported by the NIH (grants U01CA271884, R21NS113016, RA37CA230400, U01CA230691, 5P50CA062924-22, Ovarian Cancer SPORE DRP 80057309), Oncology Core CA 06973, the Virginia and D.K. Ludwig Fund for Cancer Research, the John Templeton Foundation (62818), the Commonwealth Fund, the Thomas M. Hohman Memorial Cancer Research Fund, Alex’s Lemonade Stand Foundation, The Sol Goldman Sequencing Facility at Johns Hopkins, the Conrad R. Hilton Foundation, the Benjamin Baker Endowment (80049589), Swim Across America, Burroughs Wellcome Career Award for Medical Scientists, the Thomas M. Hohman Memorial Cancer Research Fund, and the NHMRC (Investigator Grant APP1194970).

    Under a license agreement between Exact Sciences Corp. and The Johns Hopkins University, Tomasetti and the university are entitled to royalty distributions. Tomasetti has patent applications for I.P. related to cancer early detection, is a member of the scientific advisory board of PrognomiQ Inc., an adviser for Haystack Oncology, and a paid consultant for the Rising Tide Foundation and Bayer AG. Vogelstein, Kinzler and Papadopoulos are founders of Thrive Earlier Detection, an Exact Sciences Company, and hold equity in and are consultants to CAGE Pharma. Kinzler, Papadopoulos and Douville are consultants to Thrive Earlier Detection. Vogelstein, Kinzler, Papadopoulos and Douville hold equity in Exact Sciences. Papadopoulos and Douville are consultants to Thrive Earlier Detection. Vogelstein, Kinzler, Cohen and Papadopoulos are founders of and own equity in Haystack Oncology and ManaT Bio. Kinzler and Papadopoulos are consultants to Neophore. Vogelstein is a consultant to and holds equity in Catalio Capital Management. Bettegowda is a consultant to Depuy-Synthes, Bionaut Labs, Haystack Oncology and Galectin Therapeutics, and is a co-founder of OrisDx. Bettegowda and Douville are co-founders of Belay Diagnostics.

    The companies named above, as well as other companies, have licensed previously described technologies related to the work described in this paper from The Johns Hopkins University. Vogelstein, Kinzler, Papadopoulos, Bettegowda and Douville are inventors of some of these technologies. Licenses to these technologies are or will be associated with equity or royalty payments to the inventors as well as to The Johns Hopkins University. Patent applications on the work described in this paper may be filed by The Johns Hopkins University. The terms of these arrangements are managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.

    Source:

    Journal reference:

    Douville, C., et al. (2024). Machine learning to detect the SINEs of cancer. Science Translational Medicine. doi.org/10.1126/scitranslmed.adi3883.

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  • The impact of quinoa bioactive compounds on gut health

    The impact of quinoa bioactive compounds on gut health

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    In a recent study published in Frontiers in Nutrition, researchers review the beneficial impacts of Chenopodium quinoa and its bioactive compounds, particularly its effects on intestinal microflora.

    Study: Progress in research on the effects of quinoa (Chenopodium quinoa) bioactive compounds and products on intestinal flora. Image Credit: Elena Schweitzer / Shutterstock.com

    What is quinoa?

    Quinoa is the common name of Chenopodium quinoa, a whole-grain crop belonging to the Amaranthaceae family. Quinoa is native to the South American Andes Mountains and can be found in three varieties differentiated by its white, black, or red color.

    Quinoa is becoming increasingly popular, especially among health- and fitness-conscious individuals, as it is a rich source of protein, fat, vitamins, minerals, fiber, and other bioactive compounds.

    Recent nutraceutical research using quinoa has discovered that its bioactive compounds can affect the body’s production of short-chain fatty acids (SCFAs) and alter intestinal pH, both of which are significant determinants of intestinal health. Intestinal microbiota health has profound effects on the risk and progression of chronic diseases, including cardiovascular diseases, neurological conditions, and cancers.

    Collating and discussing research on quinoa’s health and clinical benefits can better inform medical practitioners, health-conscious individuals, and future researchers of the optimal ways to utilize this natural, safe, and cost-effective plant.

    About the study

    The present study reviewed 85 scientific publications evaluating the biochemical composition of quinoa, its nutritional benefits, and the efficacy of its bioactives in improving intestinal health. The individual roles of quinoa-derived saponins, polyphenolic compounds, polysaccharides, and biopeptides in improving gut microbiota outcomes were also discussed.

    Saponins

    Saponins, which are also known as triterpene glycosides, are bitter plant-derived secondary metabolites with a broad spectrum of biologically relevant functions.

    Quinoa-derived saponins exhibit poor intestinal absorption and low bioavailability, thereby resulting in prolonged intestinal residence, which may allow these metabolites to be used by gut microbiota as a source of nutrition. Previous studies in rats have confirmed this interaction and shown that quinoa supplementation directly correlates with increasing gut microbial diversity.

    Metabolomic studies have found that saponins obtained from quinoa digestion can improve the metabolism of some vitamins and alter the ammonia cycle. However, caution must be taken when deciding upon supplementation dosages, as high concentrations of quinoa-derived saponins have been shown to be toxic in rat models.

    Polyphenolics

    Quinoa consists of many polyphenolic compounds. For example, as compared to placebo, red junglefowl treated with 1% quinoa quercetin exhibited reduced population sizes of opportunistic pathogens and increased populations of the beneficial bacterial phylum Firmicutes. When combined with supplementation of quinoa-derived cellulose, quercetin further increased the number of goblet cells, directly contributing to improved intestinal immunity.

    Quinoa polyphenols inhibit enzymes involved in the regulation of the digestive tract, thereby affecting the abundance of intestinal flora and improving the microenvironment of intestinal flora.”

    Polysaccharides

    Most quinoa-derived polysaccharides are prebiotics capable of increasing the proportion of beneficial probiotic Bifidobacteria and Collinsella bacteria. In combination with quinoa dietary fiber, quinia polysaccharides effectively modulate SCFA concentrations and reduce weight in high-fat diets (HFDs) characteristic in hyperlipidemia.

    Bioactive peptides

    In vivo studies using hypertensive rats (SHR) have shown that quinoa proteins contain numerous promising peptide precursors. While their mechanism of action remain unknown, these precursors have been shown to significantly reduce the blood pressure of SHR models, thus highlighting their application in cardiovascular research. These health benefits extend beyond blood pressure management, as some studies suggest the colorectal cancer applications of quinoa proteins.

    Quinoa proteins have also been found to be a naturally occurring source of angiotensin-converting enzyme (ACE) inhibitory peptides, an additional cardiovascular benefit.

    Flour containing quinoa protein can significantly enhance cecal microbial activity, the activities of α-glucosidase, β-glucosidase, and α-galactosidase, and the production of SCFAs in rats, while promoting a reduction in the pH of digesters, thereby indicating the favorable effects of these proteins on growth parameters and metabolism of intestinal flora.”

    Conclusions

    While research in the field remains in its infancy, a growing body of literature highlights the clinical and nutritional benefits of quinoa.

    The bioactive components of quinoa have been shown to promote the abundance of probiotic bacteria while simultaneously inhibiting pathogens. Furthermore, quinoa-derived bioactive compounds have been shown to reduce intestinal pH and increase the production of SCFAs.

    Journal reference:

    • Huang, H., Jia, C., Chen, X., et al. (2024). Progress in research on the effects of quinoa (Chenopodium quinoa) bioactive compounds and products on intestinal flora. Frontiers in Nutrition. doi:10.3389/fnut.2024.1308384

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  • Nerve overgrowth identified as cause of pain in recurring UTIs

    Nerve overgrowth identified as cause of pain in recurring UTIs

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    A perplexing problem for people with recurring urinary tract infections (UTIs) is persistent pain, even after antibiotics have successfully cleared the bacteria.

    Now Duke Health researchers have identified the likely cause – an overgrowth of nerve cells in the bladder.

    The finding, appearing March 1 in the journal Science Immunology, provides a potential new approach to managing symptoms of recurring UTIs that would more effectively target the problem and reduce unnecessary antibiotic usage.

    “Urinary tract infections account for almost 25% of infections in women,” said senior author Soman Abraham, Ph.D., professor in the departments of Pathology, Molecular Genetics and Microbiology, Integrative Immunobiology, and Cell Biology at Duke University School of Medicine.

    “Many are recurrent UTIs, with patients frequently complaining of chronic pelvic pain and urinary frequency, even after a round of antibiotics,” Abraham said. “Our study, for the first time, describes an underlying cause and identifies a potential new treatment strategy.”

    Abraham and colleagues collected bladder biopsies from recurrent UTI patients who were experiencing pain despite no culturable bacteria in their urine. Using biopsies from people without UTIs as a comparison, they found evidence that sensory nerves were highly activated in the UTI patients, explaining the persistent sense of pain and urinary frequency.

    Further studies in mice revealed the underlying events, with unique conditions in the bladder that prompt activated nerves in the lining to bloom and grow with each infection.

    “Typically, during every bout of UTI, epithelial cells laden with bacteria are sloughed off, and significant destruction of nearby nerve tissue occurs,” said Byron Hayes, lead author of the study and previously a postdoctoral fellow in Duke’s Department of Pathology. “These events trigger a rapid repair program in the damaged bladder involving massive regrowth of destroyed nerve cells.”

    This immune response, including repair activities, is led by mast cells – which are immune cells that fight infection and allergens. Mast cells release chemicals called nerve growth factor, which drive overgrowth and increase sensitivity of nerves. The result is pain and urgency.

    The researchers were able to address these symptoms by treating study mice with molecules that suppress production of the mast-cell generated nerve growth factor.

    This work helps illuminate a puzzling clinical condition that drives medical costs and affects the quality of life of millions of people, primarily women,” Abraham said. “Understanding the crosstalk between mast cells and nerves is an essential step toward effective treatments for people suffering repeat urinary tract infections.”


    Soman Abraham, Ph.D., Senior Author

    In addition to Abraham and Hayes, study authors include Hae Woong Choi, Abhay PS Rathore, Chunjing Bao, Jianling Shi, Yul Huh, Michael W Kim, Andrea Mencarelli, Pradeep Bist, Lai Guan Ng, Changming Shi, Joo Hwan Nho, Aram Kim, Hana Yoon, Donghoon Lim, Johanna L Hannan, J Todd Purves, Francis M Hughes Jr, and Ru-Rong Ji.

    The study received funding support from the National Institutes of Health (K12-DK100024, R01-DK121969, R01-DK121032, R01-GM144606), the National Research Foundation of Korea (2020R1C1C1003257), and a Korea University grant.

    Source:

    Duke University Medical Center

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  • SLU study examines the relationship between adversity, psychiatric and cognitive decline

    SLU study examines the relationship between adversity, psychiatric and cognitive decline

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    Saint Louis University associate professor of health management and policy in the College for Public Health and Social Justice, SangNam Ahn, Ph.D., recently published a paper in Journal of Clinical Psychology that examines the relationship between childhood adversity, and psychiatric decline as well as adult adversity and psychiatric and cognitive decline. His team discovered that just one instance of adversity in childhood can increase cases of mental illness later in life, and adverse events in adults can lead to a greater chance of both mental illness and cognitive decline later in life. 

    Life is very complicated, very dynamic. I really wanted to highlight the importance of looking into the lasting health effect of adversity, not only childhood but also adulthood adversity on health outcomes, especially physical health and psychiatric and cognitive health. There have been other studies before, but this is one of the first that looks into these issues comprehensively.” 


    SangNam Ahn, Ph.D., associate professor of health management and policy, Saint Louis University

    Ahn, along with his team of researchers, examined data from more nearly 3500 individuals over the course of 24 years. The group took the longitudinal data and evaluated it using a list of lifetime potential traumatic events.

    The research team included childhood adversity events such as moving due to financial difficulties, family requiring financial help, a parent experiencing unemployment, trouble with law enforcement before the age of 18, repeating school, physical abuse and parental abuse of drugs or alcohol. Adulthood adversity events included the death of a child, the death of a spouse, experiencing a natural disaster after age 17, firing a weapon in combat, a partner abusing drugs or alcohol, being a victim of a physical attack after age 17, a spouse or child battling a serious illness, receiving Medicaid or food stamps and experiencing unemployment. 

    The study determined that nearly 40 percent of all individuals experienced a form of childhood adversity, while that number climbed to nearly 80 percent for adulthood adversity. Those who experienced childhood adversity were also 17 percent more likely to experience adulthood adversity. Only 13 percent of individuals sampled reported two or more forms of childhood adversity, while 52 percent of adults experienced two or more forms of adult adversity. 

    In cases of either childhood adversity or adulthood adversity, researchers found individuals who experienced adversity were also more likely to experience anxiety and depression later in life, and in the case of adulthood adversity, were also more likely to experience cognitive decline later in life. 

    Individuals with one childhood adversity experience saw a five percent higher chance of suffering from anxiety, and those with two or more childhood adversity experiences had 26 percent and 10 percent higher chances of depression and anxiety, respectively. Individuals who experienced two adulthood adversities had a 24 percent higher chance of depression, while also experiencing a three percent cognitive decline later in life. 

    While most of the results were expected or unsurprising, one area that stood out to Ahn was education. Those individuals studied who reported higher levels of education saw a reduction in the number of adversity experiences. Ahn hopes to study this avenue more to learn how education may be able to mitigate or prevent these declines. 

    “Before including education, there was a significant association between childhood adversity and cognitive impairment,” Ahn said. “But when including education as a covariate, that significant association disappeared. Interesting. So there were important implications here. Education and attending school, people could be better off even if they were exposed to childhood adversity. They’re likely to learn positive coping mechanisms, which may help avoid relying on unhealthy coping mechanisms, such as smoking or excessive drinking or drug use.

    “Education is quite important in terms of health outcomes,” Ahn added. “If I am educated, I’m likely to get a better job, have a higher income, and live in areas with less crime. I’m likely to buy gym membership or regularly exercise. I’m likely to shop at Whole Foods and get proper nutrition. All of which help combat these adversities we hinted at in the study. So the education and health outcomes are already closely related, and that is what we saw in our study.”

    Ahn also encourages clinicians and everyday people alike to discuss their stress. Clinicians can learn more about their patients and have a better approach when it comes to their physical and mental health, while others could potentially relate to shared experiences. But through awareness and recognition, these adverse experiences could potentially have less serious, lasting effects. 

    “Public health is very interested in stress,” Ahn said. “But we’re still examining how daily stress impacts our long term health outcomes. So to see the effects here in the study, I want people to pay attention to their stress and proactively address it. Clinicians should have deep discussions with their patients about their stress and mental state. And those topics can be approached in other areas too, like the classroom or the dining room table. The more we are aware of stress and discuss our stress, the better we can handle any adversities we find in life.”

    Source:

    Journal reference:

    Ahn, S., et al. (2024). Lifetime adversity predicts depression, anxiety, and cognitive impairment in a nationally representative sample of older adults in the United States. Journal of Clinical Psychology. doi.org/10.1002/jclp.23642.

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  • Scientists discover a key mechanism used by human herpesvirus 8 to induce cancer

    Scientists discover a key mechanism used by human herpesvirus 8 to induce cancer

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    Cleveland Clinic researchers have discovered a key mechanism used by Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8), to induce cancer. The research points to effective new treatment options for KSHV-associated cancers, including Kaposi’s sarcoma, primary effusion lymphoma, and HHV8-associated multicentric Castleman disease.

    Our findings have significant implications: viruses cause between 10% to 20% of cancers worldwide, a number that is constantly increasing as new discoveries are made. Treating virus-induced cancers with standard cancer therapies can help shrink tumors that are already there, but it doesn’t fix the underlying problem of the virus. Understanding how pathogens transform a healthy cell into a cancer cell uncovers exploitable vulnerabilities and allows us to make and repurpose existing drugs that can effectively treat virus-associated malignancies.” 


    Jun Zhao, Ph.D., Cleveland Clinic Florida Research & Innovation Center

    The Nature Communications study, led by Dr. Zhao, reveals that KSHV manipulates two human enzymes called CDK6 and CAD to reshape the way human cells produce new nucleotides – the building blocks of DNA and RNA – and process glucose. The changes to how infected cells grow and how KSHV persists put cells at a much higher risk of forming tumors and play a crucial role in causing cancer. 

    The team showed the virus activates a specific pathway driving cell metabolism and proliferation. Inhibiting this process with existing FDA-approved breast cancer drugs reduced KSHV replication, blocked lymphoma progression and shrunk existing tumors in preclinical models. 

    Like other herpesviruses, KSHV often has no symptoms initially and remains in the body after primary infection. The virus stays dormant, suppressed by the immune system. However, KSHV can reactivate when immunity is weakened – as in older people, those with HIV/AIDS, and transplant recipients. In these high-risk groups, the now active virus can trigger aggressive cancers.

    KSHV-induced cancers are fast-acting, aggressive and difficult to treat. An estimated 10% of people in North America and Northern Europe have KSHV, but this ranges throughout the globe. More than 50% of individuals in parts of Northen Africa are estimated to have the virus. Experts estimate these rates are higher, as KSHV often goes undiagnosed because of lack of symptoms. These findings have implications that reach past KSHV; researchers can apply knowledge about KSHV to other cancer-associated viruses that might use the same process to cause cancer. 

    To understand the cells’ metabolic processes to uncover the virus’s vulnerabilities, Dr. Zhao collaborated with Michaela Gack, Ph.D., Scientific Director of the Florida Research & Innovation Center. 

    Rapidly replicating cancer cells reprogram metabolism to fuel growth. Meanwhile, most viruses cannot produce energy or necessary molecules on their own, so they rely on human cells to do the work for them. The team found that the virus takes over the host protein CDK6 and CAD, causing the infected cells to produce extra metabolites, which allows faster replication of the virus and an uncontrolled proliferation of the cells.

    The research team treated pre-clinical models with a CDK6-blocking drug, Palbociclib, an FDA-approved breast cancer medication, as well as a compound targeting CAD. They saw significant decreases in tumor size and increases in cancer survival rates: most tumors virtually disappeared after about a month of treatment, and remaining tumors shrank around 80%. Survival increased to 100% for selected lymphoma cell lines. 

    Dr. Zhao and his team are working to better understand the connections among KSHV, CDK6/CAD pathway, and cancer formation. With the knowledge they obtain, they plan to implement and refine their experimental drug combinations for clinical trials. 

    “Cellular metabolism could be hijacked by both viruses and cancers for pathogenesis,” said Dr. Zhao. “By investigating these metabolic rewiring mechanisms, we aim to find the Achilles’ heel of cancer-causing viruses and non-viral cancers. I’m excited to see what the future of this work holds.” 

    Source:

    Journal reference:

    Wan, Q., et al. (2024). Hijacking of nucleotide biosynthesis and deamidation-mediated glycolysis by an oncogenic herpesvirus. Nature Communications. doi.org/10.1038/s41467-024-45852-5.

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