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Wednesday, August 3, 2022

Covid vax intentions among parents of children ages 6 months - 4 years

 Aaron M. Scherer, PhD1; Courtney A. Gidengil, MD, MPH2,3; Amber M. Gedlinske, MPH1; et al

doi:10.1001/jamanetworkopen.2022.27437

Key Points

Question  What are parents’ intentions, concerns, and facilitators to COVID-19 vaccination for their children aged 6 months through 4 years?

Findings  In this cross-sectional study of 2031 US adults with children aged 6 months through 4 years, half indicated they intended to get their child a COVID-19 vaccine at some point, but only one-fifth intended to do so within 3 months of the child’s eligibility. The top concerns about and facilitators to COVID-19 vaccination for this age group related to COVID-19 vaccination safety and efficacy.

Meaning  These findings suggest that considerable efforts to increase parental COVID-19 vaccine confidence for children aged 6 months through 4 years may be needed to maximize COVID-19 vaccination for this age group.

Abstract

Importance  Children aged 6 months through 4 years have become eligible for COVID-19 vaccination, but little is known about parental intentions regarding, concerns about, or facilitators to COVID-19 vaccination for this age group.

Objectives  To evaluate parental intentions, concerns, and facilitators for COVID-19 vaccination for children aged 6 months through 4 years and to help inform the US Centers for Disease Control and Prevention Advisory Committee on Immunization Practices’ deliberations and recommendations for COVID-19 vaccination for children aged 6 months through 4 years.

Design, Setting, and Participants  This cross-sectional study fielded an online survey from February 2 to 10, 2022, among a nonprobability sample of US parents of children aged 6 months through 4 years who were recruited through Qualtrics using quota-based sampling for respondent gender, race and ethnicity, and child age group.

Main Outcomes and Measures  COVID-19 vaccination intentions, time to COVID-19 vaccination, COVID-19 vaccination concerns and facilitators, and trusted COVID-19 vaccination locations for children aged 6 months through 4 years.

Results  The final weighted sample of 2031 participants (73.5% participation rate) had more respondents who identified as male (985; weighted percentage, 54.8%) or White (696; weighted percentage, 66.2%), were aged 25 to 49 years (1628; weighted percentage, 85.6%), had at least a bachelor’s degree (711; weighted percentage, 40.0%), lived in a metropolitan area (1743; weighted percentage, 82.9%) or the South (961; weighted percentage, 43.4%), or received at least 1 dose of a COVID-19 vaccine (1205; weighted percentage, 59.8%). Half of respondents (645; weighted percentage, 45.6%) indicated that they “definitely” or “probably” will vaccinate their child aged 6 months through 4 years once they became eligible. However, only one-fifth (396; weighted percentage, 19.0%) indicated they would get a COVID-19 vaccine for their child in this age group within 3 months of them becoming eligible for vaccination. Vaccine safety and efficacy were parents’ top concerns, and receiving more information about safety and efficacy were the top facilitators to COVID-19 vaccination for this age group. A doctor’s office or clinic and local pharmacy were the most trusted COVID-19 vaccination locations for this age group.

Conclusions and Relevance  These results suggest that only a minority of parents of children in this age group are eager to vaccinate their children within the first few months of eligibility, with widespread concerns about COVID-19 vaccination for this age group. Thus, considerable efforts to increase parental COVID-19 vaccine confidence for children aged 6 months through 4 years may be needed to maximize COVID-19 vaccination for this age group in the United States.

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2794880?utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_term=080322

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'Dynamic travel restrictions can prevent rapid dispersion of new COVID-19 variants'

 A study of COVID-19 variant transmission into and across Canada shows that international travel restrictions were a key intervention for reducing or slowing spread, according to a report published today in eLife.

The results suggest that reducing the number of virus importations that can spark domestic outbreaks within a country through dynamic travel bans allows governments more time to prepare for a new variant -- by ramping up testing, contact tracing and vaccination programmes.

The COVID-19 pandemic has highlighted the importance of genomic epidemiology -- that is, genetic sequencing of SARS-CoV-2 samples from different regions and times -- to understand the origin and movement of virus variants internationally, especially variants of concern or interest. These methods have been used widely in the UK, US, Brazil, New Zealand and Europe, and have illustrated the variation in epidemic dynamics between countries that took different public health approaches to containing the virus.

"Large-scale SARS-CoV-2 genomic epidemiology analyses in Canada have so far been limited to a study on the early epidemic within Quebec," says lead author Angela McLaughlin, Research Assistant at the British Columbia Centre for Excellence in HIV/AIDS, and a PhD candidate in Bioinformatics, University of British Columbia, Canada. "We wanted to elaborate on this research with a national-scale analysis for the first and second COVID-19 waves. We also wanted to evaluate the impact of international travel restrictions in March 2020 on international importations of the virus and to understand why the virus persisted into 2021."

The team used available sequence data from Canadian COVID-19 cases and data on the prevalence of circulating variants in other countries to estimate the viruses' geographical origins. From this, they identified more than 2,260 introductions of new variants into Canada, including 680 sublineages -- viruses introduced from other countries that went on to circulate within the Canadian population. They also identified 1,582 singletons -- viruses introduced that did not appear to spread within the Canadian population.

Just as travel restrictions were introduced in April 2020, the importation rate reached its maximum (58.5 sublineages per week), including 31.8 from the US and 31.2 introduced solely into Quebec. Two weeks after travel restrictions took effect, the overall sublineage importation rate had dropped 3.4-fold and within four weeks had dropped 10.3-fold.

Despite these reductions, however, new virus variants continued to be introduced at a low level until August 2020 when there was a small spike in cases leading into the second wave. This suggests that wildtype sublineages introduced in the summer when prevalence and immunity were low contributed the highest proportion of COVID-19 cases in the second wave. In turn, this implies that even a low level of ongoing virus importations of similarly transmissible variants can contribute to viral persistence. By mid-October, travel restrictions were relaxed further, and importation rates rebounded quickly and contributed to the second wave.

By categorising transmission sources as within-province, between province, the US and other international sources, the team could see where the new virus importations were originating. They found that most first-wave virus introductions (January to July 2020) came from the US, followed by Russia, Italy, India, Spain and the UK, and were primarily imported into Quebec and Ontario. In the second wave (August 2020 to end February 2021), the origin of new sublineages was still dominated by the US, with increased relative contributions from India, the UK, Asia, Europe and Africa.

That the US was a large contributor of COVID-19 cases in 2020 was not unanticipated by the authors, given its high COVID-19 prevalence throughout 2020 and the long land border shared between the two countries. Even when international arrivals into Canada declined by 77.8% from 2019 to 2020, the number of truck drivers and crew members (air, ship and train) only declined by 24.8%, and accounted for almost half of all international arrivals after April 2020. Although essential key workers supporting the supply chain, these arrivals may have inadvertently facilitated additional importations from the US -- suggesting this is one area where better public health measures, such as contact tracing and rapid testing, could have helped prevent the movement of new variants.

"These analyses shed light on the natural epidemiological history of SARS-CoV-2 in the context of public health interventions and show how sublineage-based genomic surveillance can be used to identify gaps in a country's epidemic response," concludes senior author Jeffrey Joy, Research Scientist at the British Columbia Centre for Excellence in HIV/AIDS and Assistant Professor at the Department of Medicine, University of British Columbia. "Broad and longstanding restrictions against non-essential international travel is not necessarily an advisable policy in light of economic impacts. However, our analysis suggests that swift and stringent travel bans towards localities harbouring a high frequency of a new variant of concern, or an outbreak of an entirely new virus, not yet identified domestically, should be seriously considered to reduce the probability of seeding multiple, simultaneous outbreaks and overwhelming healthcare systems."


Story Source:

Materials provided by eLife. Note: Content may be edited for style and length.

Journal Reference:

  1. Angela McLaughlin, Vincent Montoya, Rachel L Miller, Gideon J Mordecai, Michael Worobey, Art FY Poon, Jeffrey B Joy. Genomic epidemiology of the first two waves of SARS-CoV-2 in Canada. eLife, 2022; 11 DOI: 10.7554/eLife.73896

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'RNA fishing' reveals new driver of melanoma malignancy and metastasis

 Researchers at the Centre for Genomic Regulation (CRG) have identified several proteins involved in the progression of melanoma, the deadliest form of skin cancer. One of the proteins -- PDIA6 -- was found to be particularly important for driving malignancy. Experiments with mice showed that melanoma cells with reduced levels of PDIA6 had an impaired ability to metastasize to the lung.

The researchers found that PDIA6 promoted melanoma malignancy by binding to RNA molecules inside the tumour's cell. The authors of the study, published in the journal Nucleic Acids Research with the support of "La Caixa" Foundation identified the region on the surface of PDIA6 that binds to RNA molecules. With further research, this information can help design new therapeutic compounds that prevent the spread of melanoma from one part of the body to another.

PDIA6 has been previously linked to the progression of lymphoma, breast and lung cancer. If further research finds that PDIA6 also binds to RNA in these other cancer types, it could lead to a therapeutic strategy that targets the same mechanism of action across different tumours.

The finding was made possible thanks to an 'RNA fishing' technique specifically designed to identify RNA-binding proteins. These are a class of proteins that carry out a variety of biological functions, an in cancer, confer resilience to cells by helping them adapt to changing environments and quickly respond to external threats, promoting cancer malignancy and resistance to therapy.

The technique, also known as RNA interactome capture, involves fishing out all messenger RNAs in a cell. Researchers then see which proteins are attached to them, which informs on the level and diversity of RNA-binding activities taking place inside the cells.

"RNA-binding proteins are of great therapeutic interest. The technique in this study can help us measure their activity, something not possible at such global scale with conventional methods. When used to compare tumour and non-tumour cells, the approach helps us identify which proteins might play important roles in cancer progression, and carrying out further experiments tells us how they work. We used this blueprint to uncover new vulnerabilities in melanoma, and we hope this can be repeated to find new therapeutic targets in other types of cancers too," explains Dr. Fátima Gebauer, researcher at the CRG and senior author of the study.

Out of the hundreds of RNA-binding proteins identified by the technique, the researchers selected 24 to carry out further analysis using varied criteria, for example because their RNA-binding activity had not been described or they were not previously linked to cancer progression. The researchers singled-out PDIA6 to further characterize its function, including transplantation experiments in mouse models. Future studies could delve into the roles of the other 23 proteins found.

"We are just scratching the surface of the potential of RNA-binding proteins as therapeutic targets. Identifying RNA-binding activities through functional methods, followed by detailed molecular understanding of their capacities, will pave the way for the design of inhibitors that may greatly improve personalized therapy for cancer," concludes Dr. Gebauer.

The work was carried out in collaboration with the University of Halle in Germany and the University of Oxford in the United Kingdom, with the support of the "la Caixa" foundation via a CaixaResearch Health grant. The project started in 2014 funded by "La Marató de TV3."

Story Source:

Materials provided by Center for Genomic Regulation. Note: Content may be edited for style and length.

Journal Reference:

  1. Neus Mestre-Farràs, Santiago Guerrero, Nadine Bley, Ezequiel Rivero, Olga Coll, Eva Borràs, Eduard Sabidó, Alberto Indacochea, Carlos Casillas-Serra, Aino I Järvelin, Baldomero Oliva, Alfredo Castello, Stefan Hüttelmaier, Fátima Gebauer. Melanoma RBPome identification reveals PDIA6 as an unconventional RNA-binding protein involved in metastasis. Nucleic Acids Research, 2022; DOI: 10.1093/nar/gkac605

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Cell, organ function in pigs restored after death

 Within minutes of the final heartbeat, a cascade of biochemical events triggered by a lack of blood flow, oxygen, and nutrients begins to destroy a body's cells and organs. But a team of Yale scientists has found that massive and permanent cellular failure doesn't have to happen so quickly.

Using a new technology they developed that delivers a specially designed cell-protective fluid to organs and tissues, the researchers restored blood circulation and other cellular functions in pigs a full hour after their deaths, they report in the Aug. 3 edition of the journal Nature.

The findings may help extend the health of human organs during surgery and expand availability of donor organs, the authors said.

"All cells do not die immediately, there is a more protracted series of events," said David Andrijevic, associate research scientist in neuroscience at Yale School of Medicine and co-lead author of the study. "It is a process in which you can intervene, stop, and restore some cellular function."

The research builds upon an earlier Yale-led project that restored circulation and certain cellular functions in the brain of a dead pig with technology dubbed BrainEx. Published in 2019, that study and the new one were led by the lab of Yale's Nenad Sestan, the Harvey and Kate Cushing Professor of Neuroscience and professor of comparative medicine, genetics, and psychiatry.

"If we were able to restore certain cellular functions in the dead brain, an organ known to be most susceptible to ischemia [inadequate blood supply], we hypothesized that something similar could also be achieved in other vital transplantable organs," Sestan said.

In the new study -- which involved senior author Sestan and colleagues Andrijevic, Zvonimir Vrselja, Taras Lysyy, and Shupei Zhang, all from Yale -- the researchers applied a modified version of BrainEx called OrganEx to the whole pig. The technology consists of a perfusion device similar to heart-lung machines -- which do the work of the heart and lungs during surgery -- and an experimental fluid containing compounds that can promote cellular health and suppress inflammation throughout the pig's body. Cardiac arrest was induced in anesthetized pigs, which were treated with OrganEx an hour after death.

Six hours after treatment with OrganEx, the scientists found that certain key cellular functions were active in many areas of the pigs' bodies -- including in the heart, liver, and kidneys -- and that some organ function had been restored. For instance, they found evidence of electrical activity in the heart, which retained the ability to contract.

"We were also able to restore circulation throughout the body, which amazed us," Sestan said.

Normally when the heart stops beating, organs begin to swell, collapsing blood vessels and blocking circulation, he said. Yet circulation was restored and organs in the deceased pigs that received OrganEx treatment appeared functional at the level of cells and tissue.

"Under the microscope, it was difficult to tell the difference between a healthy organ and one which had been treated with OrganEx technology after death," Vrselja said.

As in the 2019 experiment, the researchers also found that cellular activity in some areas of the brain had been restored, though no organized electrical activity that would indicate consciousness was detected during any part of the experiment.

The team was especially surprised to observe involuntary and spontaneous muscular movements in the head and neck areas when they evaluated the treated animals, which remained anesthetized through the entire six-hour experiment. These movements indicate the preservation of some motor functions, Sestan said.

The researchers stressed that additional studies are necessary to understand the apparently restored motor functions in the animals, and that rigorous ethical review from other scientists and bioethicists is required.

The experimental protocols for the latest study were approved by Yale's Institutional Animal Care and Use Committee and guided by an external advisory and ethics committee.

The OrganEx technology could eventually have several potential applications, the authors said. For instance, it could extend the life of organs in human patients and expand the availability of donor organs for transplant. It might also be able to help treat organs or tissue damaged by ischemia during heart attacks or strokes.

"There are numerous potential applications of this exciting new technology," said Stephen Latham, director of the Yale Interdisciplinary Center for Bioethics. "However, we need to maintain careful oversight of all future studies, particularly any that include perfusion of the brain."

The research was funded by the U.S. Department of Health & Human Services, National Institutes of Health, and National Institute of Mental Health.

This work was supported by the NIH grants MH117064, MH117064-01S1, R21DK128662, T32GM136651, F30HD106694, and Schmidt Futures.

Story Source:

Materials provided by Yale University. Original written by Bill Hathaway. Note: Content may be edited for style and length.

Journal Reference:

  1. Andrijevic, D., Vrselja, Z., Lysyy, T. et al. Cellular recovery after prolonged warm ischaemia of the whole body. Nature, 2022 DOI: 10.1038/s41586-022-05016-1

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Vitamin K prevents cell death: New function for long-known molecule

 A team of researchers located at Helmholtz Munich reports on a novel function of vitamin K, which is generally known for its importance in blood clotting. The researchers discovered that the fully reduced form of vitamin K acts as an antioxidant efficiently inhibiting ferroptotic cell death. Ferroptosis is a natural form of cell death in which cellular iron plays an important role and which is characterized by the oxidative destruction of cellular membranes. In addition, the team identified FSP1 as the warfarin-insensitive enzyme reducing vitamin K, the identity of which had been postulated but remained unknown for more than half a century.

During the last years, ferroptosis has been implicated as a driver of Alzheimer's disease and acute organ injuries among many other diseases. Thus, the present findings put forward the concept that vitamin K treatment might be a new powerful strategy to ameliorate these ferroptosis-related diseases.

Vitamin K is a potent ferroptosis suppressor

Since ferroptosis prevention is considered a highly promising approach for the therapy of many degenerative diseases, new mechanisms and compounds regulating ferroptosis are extensively being explored. To identify these new molecules, a team of researchers led by Dr. Eikan Mishima and Dr. Marcus Conrad, both from the Institute of Metabolism and Cell Death at Helmholtz Munich, along with collaborators from Tohoku University (Japan), University of Ottawa (Canada) and Technical University of Dresden (Germany), systematically studied a number of naturally occurring vitamins, as well as their derivatives. "Surprisingly, we identified that vitamin K, including phylloquinone (vitamin K1) and menaquinone-4 (vitamin K2), is able to efficiently rescue cells and tissues from undergoing ferroptosis" Dr. Eikan Mishima, first author of the study explained.

Unraveling the long sought-after vitamin K reducing enzyme FSP1

In 2019 a team of researchers around Dr. Marcus Conrad already identified an enzyme as a novel and strong inhibitor of ferroptosis: ferroptosis suppressor protein-1, short FSP1. The research team now found that the fully reduced form of vitamin K (i.e., vitamin K hydroquinone) acts as a strong lipophilic antioxidant and prevents ferroptosis by trapping oxygen radicals in lipid bilayers. In addition, they identified that FSP1 is the enzyme that efficiently reduces vitamin K to vitamin K hydroquinone, thereby driving a novel non-canonical vitamin K cycle. Since vitamin K is critically involved in blood clotting processes, the team further showed that FSP1 is responsible for the vitamin K-reduction pathway insensitive against warfarin, one of the most commonly prescribed anticoagulants.

Breakthrough in understanding vitamin K metabolism

Unraveling the identity of this enzyme solved the last riddle of vitamin K metabolism in blood clotting and elucidated the molecular mechanism of why vitamin K constitutes the antidote for overdosing of warfarin. "Our results therefore link the two worlds of ferroptosis research and vitamin K biology. They will serve as the stepping stone for the development of novel therapeutic strategies for diseases where ferroptosis has been implicated," Dr. Marcus Conrad highlighted. In addition, since ferroptosis most likely constitutes one of the oldest types of cell death, the researchers hypothesize that vitamin K might be one of the most ancient types of naturally occurring antioxidants. "Thus, new aspects of the role of vitamin K throughout the evolution of life are expected to be unveiled" Dr. Marcus Conrad explained.

Story Source:

Materials provided by Helmholtz Munich. Note: Content may be edited for style and length.

Journal Reference:

  1. Eikan Mishima, Junya Ito, Zijun Wu, Toshitaka Nakamura, Adam Wahida, Sebastian Doll, Wulf Tonnus, Palina Nepachalovich, Elke Eggenhofer, Maceler Aldrovandi, Bernhard Henkelmann, Ken-ichi Yamada, Jonas Wanninger, Omkar Zilka, Emiko Sato, Regina Feederle, Daniela Hass, Adriano Maida, André Santos Dias Mourão, Andreas Linkermann, Edward K. Geissler, Kiyotaka Nakagawa, Takaaki Abe, Maria Fedorova, Bettina Proneth, Derek A. Pratt, Marcus Conrad. A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature, Aug. 3, 2022 DOI: 10.1038/s41586-022-05022-3

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Key mechanism controlling skin regeneration IDd

 It's sunburn season. Many of us have experienced the pain and peeling that comes from unprotected time in the sun, but we may not focus on a remarkable and vital part of the process: the regeneration of skin as the damaged tissue is replaced with new.

Even without sunburn, the outer layer of skin, the epidermis, is constantly turning over to replace dead or damaged cells throughout our lifetime. This epidermal layer provides an essential barrier for the human body, reducing water loss and combating environmental threats. Scientists are working to identify the molecular mechanisms controlling skin epidermal regeneration, but much remains poorly understood.

Now a Northwestern University research team has identified a molecular switch, through a protein called CDK9, that plays an early and critical role in the skin stem cell differentiation process. This switch is "off" in the stem cells. When the switch is turned on, a specific group of genes is immediately activated to trigger downstream gene regulators, allowing the skin cells to progressively gain barrier function. The findings have relevance for improved understanding of cancer and wound healing, in addition to the fundamental understanding of skin regeneration.

"Skin stem cells need to continuously make decisions, to either make more copies of themselves -- a process known as self-renewal -- or to switch their fate towards differentiation. A delicate balance between these two decisions is crucial to maintain the integrity of skin and its barrier function," said Xiaomin Bao, a stem cell biologist at Northwestern who supervised the research. "We have discovered the switch bound to selected genomic regions inside the stem cells, ready to trigger the cell fate switch of initiating the stem cell's movement towards differentiation."

Bao is an assistant professor of molecular biosciences in the Weinberg College of Arts and Sciences and an assistant professor of dermatology at Northwestern University Feinberg School of Medicine. Her lab studies the fundamental biology of the process of skin stem cell differentiation.

The study was published recently by the journal Nature Communications.

Discovery of the switch

The integrity of skin epidermis relies on subsets of skin stem cells to continuously self-renew or differentiate, compensating for daily wear and tear. The differentiation process involves significant changes from more than 6,000 genes, ceasing stem cell proliferation while activating barrier-function genes.

Integrating genomics, genetics and pharmacological inhibition to human skin models, Bao and her team identified that the kinase activity switch of the protein CDK9 plays a key role in the decision of cells to initiate differentiation and progressively acquire the barrier function of the tissue. The kinase activity is off in the stem cell state, and the rapid-response genes directly controlled by the kinase are suppressed. When the kinase activity is on, the rapid-response genes are activated, which subsequently induce the downstream effectors, a group of transcription factors that can further drive the expression of barrier-function genes.

CDK9 (cyclin-dependent kinase 9) plays crucial roles in modulating gene expression at the step of "transcription," a process of copying specific DNA regions to RNA, before RNA can serve as templates for synthesizing new proteins. In the stem cell state, CDK9 is maintained in the "off" state when bound together with the proteins AFF1 and HEXIM1 on DNA, awaiting specific cellular signals such as the activation of protein kinase C signaling. Once the signaling is activated, this is sufficient to switch CDK9 from the inactive to the active state, allowing the rapid synthesis of RNA from the genomic regions directly bound by CDK9, the researchers found.

The switch is a quick one. "All the components are poised for action deep inside the stem cells," Bao said. When the stem cell receives specific external signals, the response inside the nucleus is very fast, with activated CDK9 quickly causing rapid-response genes such as ATF3 to be expressed within as short as one hour. The expression of ATF3 potently induces several downstream transcription factors to rewire the cell fate towards differentiation. This quick switch for gene activation is also built upon the pre-recruitment of RNA-synthesis machinery together with CDK9 to the rapid-response genes, before the signaling is activated.

"We are probing the unknown," Bao said. "Stem cell regulation is fundamental for sustaining the integrity of human tissue. We have found a key mechanism initiating the fate switch of skin stem cell towards differentiation, an integral process of regeneration. Learning more about the fundamental molecular mechanisms can help in the understanding of many different human diseases."


Story Source:

Materials provided by Northwestern University. Original written by Megan Fellman. Note: Content may be edited for style and length.

Journal Reference:

  1. Sarah M. Lloyd, Daniel B. Leon, Mari O. Brady, Deborah Rodriguez, Madison P. McReynolds, Junghun Kweon, Amy E. Neely, Laura A. Blumensaadt, Patric J. Ho, Xiaomin Bao. CDK9 activity switch associated with AFF1 and HEXIM1 controls differentiation initiation from epidermal progenitors. Nature Communications, 2022; 13 (1) DOI: 10.1038/s41467-022-32098-2

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New patent-pending method mass-produces antitumor cells to treat blood diseases and cancer

 A Purdue University chemical engineer has improved upon traditional methods to produce off-the-shelf human immune cells that show strong antitumor activity, according to a paper published in the peer-reviewed journal Cell Reports.

Xiaoping Bao, a Purdue University assistant professor from the Davidson School of Chemical Engineering, said CAR-neutrophils, or chimeric antigen receptor neutrophils, and engraftable HSCs, or hematopoietic stem cells, are effective types of therapies for blood diseases and cancer. Neutrophils are the most abundant white cell blood type and effectively cross physiological barriers to infiltrate solid tumors. HSCs are specific progenitor cells that will replenish all blood lineages, including neutrophils, throughout life.

"These cells are not readily available for broad clinical or research use because of the difficulty to expand ex vivo to a sufficient number required for infusion after isolation from donors," Bao said. "Primary neutrophils especially are resistant to genetic modification and have a short half-life."

Bao has developed a patent-pending method to mass-produce CAR-neutrophils from human pluripotent stem cells (hPSCs), that is, cells that self-renew and are able to become any type of human cell. The chimeric antigen receptor constructs were engineered to express on the surface of the hPSCs, which were directed into functional CAR-neutrophils through a novel, chemically defined protocol.

The method was created in collaboration with Qing Deng at Purdue's Department of Biological Sciences, Hal E. Broxmeyer, now deceased, at Indiana University School of Medicine, and Xiaojun Lian at the Pennsylvania State University.

"We developed a robust protocol for massive production of de novo neutrophils from human pluripotent stem cells," Bao said. "These hPSC-derived neutrophils displayed superior and specific antitumor activities against glioblastoma after engineering with chimeric antigen receptors."

Bao disclosed the innovation to the Purdue Research Foundation Office of Technology Commercialization, which has applied for an international patent under the Patent Cooperation Treaty system of the World Intellectual Property Organization. The innovation has been optioned to an Indiana-headquartered life sciences company.

"We will also work with Dr. Timothy Bentley, professor of neurology and neurosurgery,and his team at the Purdue College of Veterinary Medicine to run clinical trials in pet dogs with spontaneous glioma," Bao said.

This research project was partially supported by the Davidson School of Chemical Engineering and College of Engineering Startup Funds, Purdue Center for Cancer Research, Showalter Research Trust and federal grants from the National Science Foundation and National Institute of General Medical Sciences.

Story Source:

Materials provided by Purdue University. Original written by Steve Martin. Note: Content may be edited for style and length.

Journal Reference:

  1. Yun Chang, Ramizah Syahirah, Xuepeng Wang, Gyuhyung Jin, Sandra Torregrosa-Allen, Bennett D. Elzey, Sydney N. Hummel, Tianqi Wang, Can Li, Xiaojun Lian, Qing Deng, Hal E. Broxmeyer, Xiaoping Bao. Engineering chimeric antigen receptor neutrophils from human pluripotent stem cells for targeted cancer immunotherapy. Cell Reports, 2022; 40 (3): 111128 DOI: 10.1016/j.celrep.2022.111128

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