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Tag: Lungs

  • AI analyzes lung ultrasound images to spot COVID-19

    AI analyzes lung ultrasound images to spot COVID-19

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    Artificial intelligence can spot COVID-19 in lung ultrasound images much like facial recognition software can spot a face in a crowd, new research shows.

    The findings boost AI-driven medical diagnostics and bring health care professionals closer to being able to quickly diagnose patients with COVID-19 and other pulmonary diseases with algorithms that comb through ultrasound images to identify signs of disease.

    The findings, newly published in Communications Medicine, culminate an effort that started early in the pandemic when clinicians needed tools to rapidly assess legions of patients in overwhelmed emergency rooms.

    We developed this automated detection tool to help doctors in emergency settings with high caseloads of patients who need to be diagnosed quickly and accurately, such as in the earlier stages of the pandemic. Potentially, we want to have wireless devices that patients can use at home to monitor progression of COVID-19, too.”


    Muyinatu Bell, senior author, the John C. Malone Associate Professor of Electrical and Computer Engineering, Biomedical Engineering, and Computer Science at Johns Hopkins University

    The tool also holds potential for developing wearables that track such illnesses as congestive heart failure, which can lead to fluid overload in patients’ lungs, not unlike COVID-19, said co-author Tiffany Fong, an assistant professor of emergency medicine at Johns Hopkins Medicine.

    “What we are doing here with AI tools is the next big frontier for point of care,” Fong said. “An ideal use case would be wearable ultrasound patches that monitor fluid buildup and let patients know when they need a medication adjustment or when they need to see a doctor.”

    The AI analyzes ultrasound lung images to spot features known as B-lines, which appear as bright, vertical abnormalities and indicate inflammation in patients with pulmonary complications. It combines computer-generated images with real ultrasounds of patients -; including some who sought care at Johns Hopkins.

    “We had to model the physics of ultrasound and acoustic wave propagation well enough in order to get believable simulated images,” Bell said. “Then we had to take it a step further to train our computer models to use these simulated data to reliably interpret real scans from patients with affected lungs.”

    Early in the pandemic, scientists struggled to use artificial intelligence to assess COVID-19 indicators in lung ultrasound images because of a lack of patient data and because they were only beginning to understand how the disease manifests in the body, Bell said.

    Her team developed software that can learn from a mix of real and simulated data and then discern abnormalities in ultrasound scans that indicate a person has contracted COVID-19. The tool is a deep neural network, a type of AI designed to behave like the interconnected neurons that enable the brain to recognize patterns, understand speech, and achieve other complex tasks.

    “Early in the pandemic, we didn’t have enough ultrasound images of COVID-19 patients to develop and test our algorithms, and as a result our deep neural networks never reached peak performance,” said first author Lingyi Zhao, who developed the software while a postdoctoral fellow in Bell’s lab and is now working at Novateur Research Solutions. “Now, we are proving that with computer-generated datasets we still can achieve a high degree of accuracy in evaluating and detecting these COVID-19 features.”

    Source:

    Journal reference:

    Zhao, L., et al. (2024). Detection of COVID-19 features in lung ultrasound images using deep neural networks. Communications Medicine. doi.org/10.1038/s43856-024-00463-5

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  • Second-hand vape smoke linked to more asthma symptoms in kids

    Second-hand vape smoke linked to more asthma symptoms in kids

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    In a recent study published in the journal Children, researchers retrospectively investigated the impacts of second-hand e-cigarette smoke exposure on childhood asthma, especially in home environments. They carried out a pilot, monocenter, observational study of 54 young asthma patients, half of whom experienced second-hand exposure (SHE) to second-hand aerosols (SHAs).

    Study: Association between Second-Hand Exposure to E-Cigarettes at Home and Exacerbations in Children with Asthma. Image Credit: Prostock-studio / ShutterstockStudy: Association between Second-Hand Exposure to E-Cigarettes at Home and Exacerbations in Children with Asthma. Image Credit: Prostock-studio / Shutterstock

    Despite finding no statistically significant association between electronic nicotine delivery systems (ENDSs) and asthma exacerbations (no difference in the number of patients requiring clinical intervention step-up), this study suggests that asthmatic children exposed to elevated levels of second-hand e-cigarette smoke may experience increases in their number of asthma symptomatic days. This highlights the need for heightened awareness, both amongst adolescents and their parents, of the psychological harms of the ‘safe’ vape.

    The ENDs pandemic and what this means for asthma patients

    Extensive research and medical reports highlight tobacco smoking as the single most preventable cause of global mortality and morbidity, with the habit associated with significant increases in the risks of numerous cancers, cardiovascular diseases (CVDs), respiratory ailments, and psychiatric disorders. Long-term global efforts have resulted in substantial reductions in tobacco use prevalence amongst adults and adolescents, representing one of the most noteworthy accomplishments of modern public health.

    Unfortunately, in recent years, tobacco smoking has been replaced by the use of electronic nicotine delivery systems (ENDSs). Commonly called ‘vapes,’ these devices are marketed as low- or no-risk alternatives to conventional smoking. While they are devoid of tar and a majority of the heavy metal components that make tobacco smoke harmful, recent research presents a growing body of evidence suggesting that ENDs are not as safe as we may think. Even non-smokers who take up vaping have been shown to develop adverse and often chronic respiratory symptoms, including bronchoconstriction and severe cough.

    Asthma is a respiratory condition characterized by difficulty breathing, chest pain, cough, and wheezing, which in severe cases may lead to life-threatening suffocation. Caused by the inflammation or narrowing of a patient’s airways or excessive mucus secretions along the respiratory tract, the condition is most common in young children. It presents the most common pediatric disease worldwide. Unfortunately, while a few studies have investigated the associations between e-cigarette exposure and asthma in adults and found that the former can exacerbate the latter, the impacts of second-hand exposure on pediatric asthma have hitherto remained unexplored.

    “Establishing evidence of adverse health effects caused by second-hand nicotine vaping exposure could represent a valid motivation for minimizing household exposure and imposing restrictions on vaping in public spaces.”

    About the study

    Aerosols produced by ENDs are known to contain volatile aldehydes and oxidant metals, some of which have been shown to produce adverse outcomes in adult patients’ lungs, both asthmatic and non-asthmatic. Unfortunately, the effects of these volatile organic compounds (VOCs) on children’s lungs remain unknown. The present study aims to fill this knowledge gap by retrospectively elucidating the associations between childhood ENDs exposure and asthma symptom progression.

    The observational study was carried out between January and May 2023 at “Gaetano Martino” Hospital, University of Messina, Italy, and comprised children or adolescents aged five to 17 with medically confirmed asthma. Data collection included demographics (age, sex, gender, and race), clinical (comorbidities), parents’ socioeconomic status, and the education levels of both parents and children. Additionally, ENDs exposure was recorded in terms of presence (yes/no) and frequency. All data was collected using a custom-designed questionnaire.

    The Asthma Control Test (ACT) and the children-Asthma Control Test (c-ACT were administered at the time of initial study enrolment. Patients were assigned to asthma or no-asthma cohorts (n = 27 per cohort), with analyses stratified to account for age – two age cohorts (5-11 [n = 65%] and 12-17 [n = 35%]). Continuous data variables were analyzed using descriptive statistics (expressed as means and standard deviations [SDs]), while ordinary variables were expressed as percentages. Fisher’s tests were used to compare cohorts qualitatively, while independent t-tests computed differences between continuous variables across cohorts.

    Study findings and conclusions

    The total sample size for the present study was 54, equally divided between children whose parents indulge in e-cigarette consumption at home and those whose parents do not. Of these, 39 were diagnosed with intermittent, nine with moderate, and six with severe asthma, respectively.

    While the dataset was too small to provide statistically significant differences between asthma and non-asthma cohorts, descriptive statistics reveal that ENDs had more profound impacts on younger children (Group A – 5 to 11 years) compared to their older counterparts (Group B – 12 to 17 years) with the former group needing six times more rescue therapy and 15% more therapeutic step-up than the former. These results are in concordance with the conventional assumption that younger children are at higher risk of asthma contraction due to their undeveloped immune systems and narrower respiratory passages.

    Despite not yielding statistically significant results, the proceeds of this study highlight the risk posed by household END usage to children. While not as harmful as conventional tobacco smoke, vaporization of e-liquids is known to release significant qualities of aldehydes, including formaldehyde, known for being respiratory irritants and carcinogens. Previous research comparing harmful aerosol concentrations in home environments raises cause for concern – ultrafine particulate matter produced by e-cigarettes matches. It sometimes exceeds that produced by an equivalent amount of tobacco smoke.

    “…our data highlight the importance of the prevention of the vaping epidemic and passive exposure to e-cigarettes, even among children and adolescents. Implementing educational programs to increase awareness about the risks of vaping among children and emphasizing the potential impact on respiratory health, especially for those with asthma, should be a priority. Launching targeted campaigns to inform parents about the dangers of vaping and its specific implications for children with asthma should be strengthened.”

    Journal reference:

    • Costantino, S., Torre, A., Foti Randazzese, S., Mollica, S. A., Motta, F., Busceti, D., Ferrante, F., Caminiti, L., Crisafulli, G., & Manti, S. (2024). Association between Second-Hand Exposure to E-Cigarettes at Home and Exacerbations in Children with Asthma. Children, 11(3), 356, DOI – 10.3390/children11030356,  https://www.mdpi.com/2227-9067/11/3/356

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  • Ultrasound technology shows promise in detecting thoracic surface vibrations

    Ultrasound technology shows promise in detecting thoracic surface vibrations

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    The thorax, the part of the body between the neck and abdomen, provides medical professionals with a valuable window into a patient’s respiratory health. By evaluating sound vibrations produced by the airflow induced within the lungs and bronchial tree during normal breathing as well as those produced by the larynx during vocalizations, doctors can identify potential disease-related abnormalities within the respiratory system.

    But, among other shortcomings, common respiratory assessments can be subjective and are only as good as the quality of the exam. While the advent of multipoint electronic stethoscopes has helped in terms of identifying abnormalities during normal breathing, there remains a dearth of technological devices that can help characterize surface vibrations produced by vocalizations.

    In AIP Advances, by AIP Publishing, a team of French researchers demonstrated the efficacy of ultrasound technology to detect low-amplitude movements produced by vocalizations at the surface of the chest. They also demonstrated the possibility of using the “airborne ultrasound surface motion camera” (AUSMC) to map these vibrations during short durations so as to illustrate their evolution.

    AUSMC is a new imaging technology that allows the observation of the human thorax surface vibrations due to respiratory and cardiac activities at high frame rates of typically 1,000 images per second. The technology shares the physical principle of conventional ultrasound Doppler imaging, but it does not require a probe to be applied on the skin.”


    Mathieu Couade, Author

    The researchers tested the AUSMC on 77 healthy volunteers to image the surface vibrations caused by natural vocalizations with the aim of reproducing the “vocal fremitus” – vocalization-induced vibrations on the surface of the body – as typically analyzed during physical examination of the thorax. Surface vibrations induced were detectable on all subjects, they reported.

    “The spatial distribution of vibrational energy was found to be asymmetric to the benefit of the right size of the chest, and frequency dependent in the anteroposterior axis,” said Couade. “As expected, the frequency distribution of vocalization does not overlap between men and women, with the latter being higher.”

    Ongoing clinical trials will use the AUSMC to focus on the identification of lung pathologies. But the researchers are hopeful that the technology, coupled with artificial intelligence algorithms, could usher in a new era of thorax examination in which vibration patterns can be isolated. This would offer a much better window on respiratory health and enable better diagnoses of respiratory diseases.

    Source:

    American Institute of Physics

    Journal reference:

    Wintzenrieth, F., et al. (2024) Airborne ultrasound for the contactless mapping of surface thoracic vibrations during human vocalizations: A pilot study. AIP Advances. doi.org/10.1063/5.0187945.

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  • Research uncovers mechanical explanation for instability in the lungs of ARDS patients

    Research uncovers mechanical explanation for instability in the lungs of ARDS patients

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    Researchers at the University of Minnesota Twin Cities may have discovered a mechanical explanation for instability observed in the lungs in cases of acute respiratory distress syndrome (ARDS), particularly in the aftermath of respiratory illnesses such as COVID-19 or pneumonia.

    The research was recently published in the Proceedings of the National Academy of Sciences (PNAS), a peer reviewed journal of the National Academy of Sciences.

    Currently, there is no known cure for ARDS, a life-threatening lung injury that allows fluid to leak into the lungs. The researchers in this study say that as many as two thirds of all patients that passed away from COVID-19 had ARDS. There is not a clear reason on why specific people with a severe respiratory illness may develop ARDS, while others may not, but researchers in this study were looking to find that answer.

    They identified the concentration of a lysolipid-;a byproduct of the immune response to viruses and bacteria-;that can have a major impact in adults suffering from ARDS. Increased concentration of this chemical eliminates the surfactant, a complex composed of fats and proteins generated in the lungs. The result is uneven lung inflation and, ultimately, respiratory distress in adults.

    “This study looked into the correlation of the concentration of the lysolipid in the lungs. Once that fluid reached a certain level, it started to cause severe impacts,” said University of Minnesota Department of Chemical Engineering and Materials Science Professor Joseph Zasadzinski and lead professor on the research. 

    Your average everyday person usually won’t need to think about this, but if a virus or infection is bothering your lung surfactant system and you end up in the hospital, then it could become top of mind very quickly.”


    Professor Joseph Zasadzinski, Department of Chemical Engineering and Materials Science, University of Minnesota

    There are a natural amount of these lysolipids that exist in the human body, and as long as those stay below a specific concentration, the average person can breathe normally. When someone has a bad infection, those lysolipids increase, which can lead to respiratory distress. Once a patient is headed in that direction, there are not many ways of reversing those symptoms. 

    “This research shows frequency dependence, or how quickly you open and close the lungs. This could help doctors try to tailor the treatment process for each specific patient,” said Clara Ciutara, a 2023 Ph.D. chemical engineering and materials science graduate and first author of the study.

    Previous research of neonatal respiratory distress syndrome (NRDS) in premature infants found that it could be treated by introducing replacement lung surfactant, but that was not the case in adults. It is the amount of lysolipid that determines the outcome of the surfactant in the lungs, not the breakdown of the existing lung surfactant. 

    The next step in the research will be to translate these ideas into a clinical environment and test to see if they can manipulate specific molecules to make them less active or stick to a specific place. This could help drop the concentration of the lysolipids to a threshold that may be able to reverse symptoms of ARDS and put people on the road to recovery.

    In addition to Zasadzinski and Ciutara, the research team included University of Minnesota Department of Chemical Engineering and Materials Science NIH postdoctoral fellow Steven V. Iasella, undergraduate student Boxun Huang, and former postdoctoral associate Sourav Barman.

    This work is supported by a grant from National Institutes of Health (NIH) Heart, Lung, and Blood Institute. All microscopy images were obtained at the University Imaging Center at the University of Minnesota.

    Source:

    Journal reference:

    Ciutara, C. O., et al. (2023). Evolution of interfacial mechanics of lung surfactant mimics progression of acute respiratory distress syndrome. Proceedings of the National Academy of Sciences. doi.org/10.1073/pnas.2309900120.

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  • Microplastics and nanoplastics could be harming your heart health

    Microplastics and nanoplastics could be harming your heart health

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    In a recent study published in The New England Journal of Medicine, researchers investigated whether micro- and nano-plastics (MNPs) are detectable in atherosclerotic plaques.

    Study: Microplastics and Nanoplastics in Atheromas and Cardiovascular Events. Image Credit: chayanuphol/Shutterstock.comStudy: Microplastics and Nanoplastics in Atheromas and Cardiovascular Events. Image Credit: chayanuphol/Shutterstock.com 

    Background

    Plastic production has been constantly increasing and is likely to continue until 2050. Plastics can degrade and form MNPs, inducing toxic effects.

    Studies have demonstrated the entry of MNPs into the body through skin exposure, inhalation, and ingestion, as well as their interactions with tissues/organs. Further, MNPs have been detected in the placenta, liver, lungs, urine, blood, and breast milk. Recent preclinical reports implicate MNPs as a cardiovascular risk factor.

    In vitro findings indicate that some MNPs promote inflammation, oxidative stress, and apoptosis in endothelial cells. Moreover, animal studies support the role of MNPs in myocardial fibrosis, endothelial dysfunction, and cardiac function impairment.

    However, their clinical relevance remains unknown. There is no evidence to suggest the infiltration of MNPs in human vascular lesions or associations between MNP burden and cardiovascular disease.

    About the study

    In the present study, researchers investigated the presence of MNPs in atherosclerotic plaques and the associations between MNP burden and cardiovascular disease.

    Consecutive patients aged 18–75 with asymptomatic carotid artery stenosis indicated for carotid endarterectomy were screened. Patients with valvular defects, secondary causes of hypertension, malignant neoplasms, or heart failure were excluded.

    Besides, patients who had complications in the postoperative period were also excluded. Baseline clinical examinations were performed, and health records were accessed for clinical, demographic, and intervention data.

    Fasting blood specimens were collected for biochemical analyses. Participants were followed up after carotid endarterectomy.

    Surgically excised atheromatous plaque specimens were obtained at atherectomy. MNP abundance was measured using pyrolysis–gas chromatography–mass spectrometry, and results were validated using electron microscopy (EM) and isotope analysis.

    The primary endpoint was a composite of non-fatal stroke, non-fatal myocardial infarction, or death. Patients were grouped based on the presence/absence of MNPs in plaques.

    Cox regression was performed to assess associations between the presence of MNPs in plaques and composite endpoint incidence.

    Analyses were adjusted for sex, age, body mass index (BMI), creatinine, low- and high-density lipoprotein cholesterol, total cholesterol, triglycerides, hypertension, diabetes, and prior cardiovascular events.

    Findings

    The team screened 312 patients; of these, 47 were lost to follow-up or had missing data, and eight had a stroke or died before discharge.

    Overall, 257 subjects were followed up for an average of 33.7 months. Polyethylene was detectable in the excised carotid plaque of 150 patients; thirty-one of these also had measurable levels of polyvinyl chloride in the plaque.

    The average levels of polyethylene and polyvinyl chloride in plaques were 21.7 μg/mg and 5.2 μg/mg, respectively.

    Patients with these MNPs were younger, male, smokers, had dyslipidemia, cardiovascular disease, diabetes, and higher levels of creatinine, and were less likely to have hypertension compared to those without MNPs.

    Ten random plaque samples with both polyvinyl chloride and polyethylene were analyzed using EM. Transmission EM (TEM) revealed particles (foreign origin) smaller than one μm with jagged edges within foamy macrophages.

    Besides, the same slices were observed with scanning EM (SEM), and spectral X-ray maps were generated from particles resembling those observed with TEM.

    The maps indicated decreased carbon and oxygen in plaque samples and increased chlorine. Given the probable non-biologic nature of chlorine, this might confirm polyvinyl chloride deposits.

    The researchers performed the isotope analysis on 26 random plaque samples as petroleum-derived plastics exhibit lower δ13C values, i.e., the ratio between carbon-13 and carbon-12, than human tissues.

    This analysis revealed two distinct patient clusters. One cluster included patients with higher δ13C values; the other cluster showed lower values, perhaps due to MNP contamination. Lower values were more evident in plaques with MNPs.

    The primary endpoint event occurred in 30 and eight patients with and without evidence of MNPs, respectively. Patients with MNPs in plaques had a higher risk of the primary endpoint events than those without MNPs.

    Conclusions

    In patients with high-grade asymptomatic carotid stenosis indicated for carotid endarterectomy, those with MNPs in plaques had a higher incidence of the composite endpoint than those without MNPs.

    Notably, the results do not prove causality; the association between MNPs in plaques and the primary endpoint might also entail risks from exposure to unmeasured, residual, or other confounding variables.

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  • Researchers take important step toward genetic therapy for hereditary conditions

    Researchers take important step toward genetic therapy for hereditary conditions

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    Researchers who work with tiny drug carriers known as lipid nanoparticles have developed a new type of material capable of reaching the lungs and the eyes, an important step toward genetic therapy for hereditary conditions like cystic fibrosis and inherited vision loss.

    Findings of the study led by Gaurav Sahay and Yulia Eygeris of the Oregon State University College of Pharmacy and Renee Ryals of Oregon Health & Science University were published today in the Proceedings of the National Academy of Sciences.

    Unlike other types of lipid nanoparticles that tend to accumulate in the liver, the ones in this study, based on the compound thiophene, are able to navigate their way to the tissues of the lungs and retina, where they deliver their therapeutic payload. The researchers refer to these new lipids as Thio-lipids.

    The collaboration demonstrated, by using animal models, the possibility of using Thio-lipids in lipid nanoparticles to deliver messenger RNA, the technology underpinning COVID-19 vaccines, to combat genetic blindness and pulmonary disease.

    These nanoparticles filled with fatty lipids can encapsulate genetic medicines like mRNA and CRISPR-Cas9 gene editors, which can be used to treat and even cure rare genetic diseases. Chemical structures of the lipids determine how potent are the lipid nanoparticles and which organ they can reach from the bloodstream.”


    Yulia Eygeris, senior research associate at OSU

    Lipids are organic compounds containing fatty tails and are found in many natural oils and waxes, and nanoparticles are tiny pieces of material ranging in size from one- to 100-billionths of a meter. Messenger RNA delivers instructions to cells for making a particular protein.

    With the coronavirus vaccines, the mRNA carried by the lipid nanoparticles instructs cells to make a harmless piece of the virus’ spike protein, which triggers an immune response from the body. 

    As a therapy for vision impairment resulting from inherited retinal degeneration, the mRNA would instruct cells in the retina – which don’t work right because of a genetic mutation – to manufacture the proteins needed for sight. Inherited retinal degeneration, commonly abbreviated to IRD, encompasses a group of disorders of varying severity and prevalence that affect one out of every few thousand people worldwide.

    An example of a genetic pulmonary condition is cystic fibrosis, a progressive disorder that results in persistent lung infection and affects 30,000 people in the U.S., with about 1,000 new cases identified every year.

    One faulty gene – the cystic fibrosis transmembrane conductance regulator, or CFTR – causes the disease, which is characterized by lung dehydration and mucus buildup that blocks the airway.

    The thiophene-based lipid nanoparticle study, which involved mice and non-human primates, stems from a $3.2 million grant to Sahay and Ryals from the National Eye Institute. The grant’s purpose is addressing limitations associated with the current primary means of delivery for gene editing: a type of virus known as adeno-associated virus, or AAV.

    “AAV has limited packaging capacity compared to lipid nanoparticles and it can prompt an immune system response,” said Sahay, a professor of pharmaceutical sciences. “It also doesn’t do fantastically well in continuing to express the enzymes the editing tool uses as molecular scissors to make cuts in the DNA to be edited.”

    Sahay calls the Thio-lipid findings “highly encouraging” but says more studies are needed, including research on the lipids’ long-term impact on retinal health.

    “But we think our results serve as a proof of concept and we will continue to explore Thio-lipids in potential treatments of pulmonary and retinal genetic diseases,” he said.

    Other OSU College of Pharmacy researchers contributing to the study were Mohit Gupta, Jeonghwan Kim, Antony Jozic, Milan Gautam, Jonas Renner, Dylan Nelson and Elissa Bloom.

    In addition to the National Eye Institute, funding and research support were provided by the Oregon National Primate Research Center and the Casey Eye Institute.

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  • Penn engineers develop targeted lung delivery system using lipid nanoparticles

    Penn engineers develop targeted lung delivery system using lipid nanoparticles

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    Penn Engineers have developed a new means of targeting the lungs with lipid nanoparticles (LNPs), the miniscule capsules used by the Moderna and Pfizer-BioNTech COVID-19 vaccines to deliver mRNA, opening the door to novel treatments for pulmonary diseases like cystic fibrosis. 

    In a paper in Nature Communications, Michael J. Mitchell, Associate Professor in the Department of Bioengineering, demonstrates a new method for efficiently determining which LNPs are likely to bind to the lungs, rather than the liver.

    The way the liver is designed. LNPs tend to filter into hepatic cells, and struggle to arrive anywhere else. Being able to target the lungs is potentially life-changing for someone with lung cancer or cystic fibrosis.”


    Michael J. Mitchell, Associate Professor, Department of Bioengineering, Penn

    Previous studies have shown that cationic lipids -; lipids that are positively charged -; are more likely to successfully deliver their contents to lung tissue. “However, the commercial cationic lipids are usually highly positively charged and toxic,” says Lulu Xue, a postdoctoral fellow in the Mitchell Lab and the paper’s first author. Since cell membranes are negatively charged, lipids with too strong a positive charge can literally rip apart target cells. 

    Typically, it would require hundreds of mice to individually test the members of a “library” of LNPs -; chemical variants with different structures and properties -; to find one with a low charge that has a higher likelihood of delivering a medicinal payload to the lungs.

    Instead, Xue, Mitchell and their collaborators used what is known as “barcoded DNA” (b-DNA) to tag each LNP with a unique strand of genetic material, so that they could inject a pool of LNPs into just a handful of animal models. Then, once the LNPs had propagated to different organs, the b-DNA could be scanned, like an item at the supermarket, to determine which LNPs wound up in the lungs. 

    After identifying an LNP that successfully penetrated lung cells, Xue, Mitchell and their collaborators administered the molecule to mice suffering from lung cancer: the treatment had a pronounced and positive effect, drastically reducing tumor size by delivering a strand of mRNA and gRNA that suppresses the growth of lung tumors.

    “This technology will help to accelerate the development of mRNA therapeutics beyond the liver,” says Xue, pointing to the speed, low cost and efficacy of the technique. 

    This study was conducted at the University of Pennsylvania School of Engineering and Applied science and supported by a US National Institutes of Health (NIH) Director’s New Innovator Award (DP2 TR002776), a Burroughs Wellcome Fund Career Award at the Scientific Interface (CASI), a US National Science Foundation CAREER Award (CBET-2145491) and an American Cancer Society Research Scholar Grant (RSG-22-122-01-ET).

    Other co-authors include Alex G. Hamilton, Rakan El-Mayta, Xuexiang Han, Ningqiang Gong, Junchao Xu, Christian G. Figueroa-Espada, Sarah J. Shepherd and Alvin J. Mukalel of Penn Engineering; Gan Zhao, Zebin Xiao and Andrew E. Vaughan of Penn Vet; Xinhong Xiong and Jiaxi Cui of Yangtze Delta Region Institute (Huzhou); Karin Wang of Temple University; and Mohamed-Gabriel Alameh and Drew Weissman of the Perelman School of Medicine at Penn.

    Source:

    University of Pennsylvania School of Engineering and Applied Science

    Journal reference:

    Xue, L., et al. (2024). High-throughput barcoding of nanoparticles identifies cationic, degradable lipid-like materials for mRNA delivery to the lungs in female preclinical models. Nature Communications. doi.org/10.1038/s41467-024-45422-9.

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  • Breakthrough blood test developed for early detection of sarcoidosis

    Breakthrough blood test developed for early detection of sarcoidosis

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    A research project led by Lobelia Samavati, M.D., professor of internal medicine and molecular medicine and genetics at the Wayne State University School of Medicine, and supported by the National Institutes of Health (NIH), has developed a tool to rapidly and inexpensively diagnose sarcoidosis, a chronic inflammatory disease marked by the growth of tiny lumps called granulomas in the lungs and other organs. The tool, which uses a simple blood test, could allow for selective use of more invasive diagnostic tests often used to identify the disease. The findings were published in the American Journal of Respiratory and Critical Care Medicine. 

    Currently, diagnosing sarcoidosis isn’t a straightforward process and requires tissue removal and testing with additional screenings to rule out other diseases, such as tuberculosis or lung cancer. Using a blood test will help diagnose faster, particularly in those organs that are more challenging to biopsy and with less harm to the patient.”


    James Kiley, Ph.D., Director of the NIH’s Division of Lung Diseases at the National Heart, Lung, and Blood Institute (NHLBI)

    Though the exact cause of sarcoidosis is unknown, researchers suspect it is an immune disorder triggered by a group of specific antigens, which are generally foreign substances that incite an immune response in the body. In the United States, an estimated 8-11 people per 100,000 are affected by sarcoidosis each year, according to previous research. 

    To identify antigens and determine which might be linked to sarcoidosis, scientists collected lung fluid samples and blood cells from patients with pulmonary sarcoidosis, then extracted the genetic material. Using a combination of molecular techniques, the researchers homed in on two newly described disease-specific antigen biomarkers that only bind to the antibodies of sarcoidosis positive patients. 

    They next designed a highly specific blood test, which only requires a small amount of blood, to determine if they could accurately detect sarcoidosis. To verify the test, researchers compared blood samples from 386 people, which included patients with sarcoidosis, patients with tuberculosis, patients with lung cancer and healthy individuals. The researchers confirmed that their test was able to differentiate patients who had sarcoidosis from those with other respiratory diseases. 

    “More testing needs to be completed before this screening method is ready for clinical use, but it’s possible that could be a reality within a few years,” said Samavati.

    “Dr. Samavati’s important work is an excellent example of how scientific research can have promising results that may lead to addressing major health challenges,” said Ezemenari M. Obasi, Ph.D., vice president for research at Wayne State University. “I look forward to the potential impact this research will have on the lives of those inflicted with sarcoidosis.”

    Source:

    Journal reference:

    Peng, C., et al. (2024). Discovery of Two Novel Immunoepitopes and Development of Peptide-based Sarcoidosis Immunoassay. American Journal of Respiratory and Critical Care Medicine. doi.org/10.1164/rccm.202306-1054oc

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  • Scientists uncover a new doorway for SARS-CoV-2 into human cells

    Scientists uncover a new doorway for SARS-CoV-2 into human cells

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    In a recent study published in the journal Proceedings of the National Academy of Sciences, researchers demonstrated that human transferrin receptor (TfR) mediates severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

    Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, presents influenza-like manifestations, including mild-to-severe pneumonia, acute respiratory distress syndrome, multiorgan failure, and fatal lung injury. Further, the etiology and pathogenesis of COVID-19 are not entirely understood and targeted therapies remain inadequate.

    The viral spike protein binds to the host receptor, angiotensin-converting enzyme 2 (ACE2), for cellular entry. Although SARS-CoV-2 preferentially infects cells in the respiratory tract, the virus has been detected in virtually all organs. Studies have revealed the presence of SARS-CoV-2 RNA in diverse cells lacking ACE2, suggesting that other receptors or co-receptors may mediate viral entry.

    Study: Human transferrin receptor can mediate SARS-CoV-2 infection. Image Credit: Kateryna Kon / ShutterstockStudy: Human transferrin receptor can mediate SARS-CoV-2 infection. Image Credit: Kateryna Kon / Shutterstock

    The study and findings

    In the present study, researchers identified TfR as an alternative receptor mediating the cellular entry of SARS-CoV-2. First, they used co-immunoprecipitation (Co-IP) to identify host proteins interacting with the viral spike in Calu-3 cells. This revealed 293 proteins, including 42 transmembrane proteins; two proteins were associated with entry (ACE2 and TfR). Next, the team evaluated TfR expression in the respiratory tract and liver in mice.

    TfR expression, both transcript and protein levels, was substantially higher in the lungs and trachea than in other tissues. Using immunohistochemical analysis, the researchers investigated the effects of SARS-CoV-2 on TfR expression in the lungs of humanized ACE2 (hACE2) mice and monkeys. This revealed a 1.5- and 1.8-fold increase in TfR expression in mice and monkeys, respectively.

    In addition, surface plasmon resonance revealed direct interactions between the viral spike and human TfR. Notably, the spike protein lacked interactions with Syrian hamster or mouse TfR. Docking analysis predicted two peptide sequences (QK8: QDSNWASK and SL8 SKVEKLTL) in TfR to be involved at the interface of TfR-spike interactions.

    Mutagenesis and Co-IP revealed that the A529 residue in TfR was essential for interactions with the spike. Further analysis indicated that physiological interactions between spike and TfR occurred at the cellular surface and during endocytosis. This was confirmed by electron microscopy using SARS-CoV-2 pseudoviral spike and HEK293/hACE2 and BHK-21/TfR cells.

    Next, the team evaluated the effects of soluble TfR, anti-TfR antibody, and SL8 and QK8 peptides on SARS-CoV-2 infection using reverse-transcription polymerase chain reaction (RT-PCR) and plaque assays. Results showed their inhibitory effects on SARS-CoV-2 in Vero E6 and Calu-3 cells. Cytotoxicity was not observed even at 1,000 nM.

    Confocal microscopy revealed that TfR was widespread on the surface of Calu-3 and Vero E6 cells, with the colocalization of TfR and SARS-CoV-2 at the surface and during endocytosis. Notably, treatment with the anti-TfR antibody inhibited the colocalization. Further, electron microscopy showed that viral particles were present in the cytosol and clathrin-coated pits in Vero E6 cells; likewise, treatment with anti-TfR antibody inhibited viral internalization.

    Next, ACE2 was knocked out (KO) from Calu-3 and Vero E6 cells and the cells were infected with SARS-CoV-2. This inhibited infection by 40% to 50%, suggesting that ACE2 might not be the only receptor mediating infection. In addition, TfR knockdown (KD) inhibited infection by 30%, whereas its overexpression (OE) promoted infection. TfR KO was not performed as it is lethal. TfR OE or KD did not impact ACE2 expression.

    Further, the team transfected C57 mice with adenovirus vector (Ad5) expressing hACE2 or humanized TfR (hTfR) and infected them with SARS-CoV-2. Viral load in the lungs in Ad5-hTfR and Ad5-hACE2 mice was significantly higher than in Ad5-empty mice. Finally, the researchers evaluated the effects of the anti-TfR antibody on infection in rhesus macaques. Anti-TfR antibody inhibited viral replication and reduced pneumonia.

    Viral load in the respiratory epithelium was also significantly lower between 3- and 7 days post-infection (dpi) compared to controls. Radiographs taken at 0 and 5 dpi revealed significantly less severe pulmonary infiltration in antibody-treated macaques relative to controls. Antibody-treated animals had no significant pulmonary lesions, while controls showed lung lesions of varying degrees.

    Conclusions

    Taken together, the study described the human TfR as a receptor for SARS-CoV-2. TfR can directly bind to the viral spike at an affinity comparable to that of ACE2. Notably, mouse TfR and the viral spike lacked interactions. Soluble TfR, SL8, and QK8 peptides and anti-TfR antibodies can inhibit infection. The team also illustrated the antiviral effects of the anti-TfR antibody in rhesus macaques. Overall, TfR could serve as an alternative infection pathway, facilitating viral entry through endocytosis.

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  • Study reveals BCG vaccine’s unexpected role in fighting influenza

    Study reveals BCG vaccine’s unexpected role in fighting influenza

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    As Canada’s flu season collides with record strep A cases and ongoing COVID-19 concerns, a new study is shedding light on our understanding of respiratory immune responses. Scholars from the Research Institute of the McGill University Health Centre (RI-MUHC) have discovered a surprising facet about a century-old vaccine for tuberculosis, Bacillus Calmette Guérin (BCG). The study, published in the journal Nature Immunology, uncovered a previously unknown mechanism that extends the vaccine’s shield to combat influenza A virus-;the most prevalent flu strain.

    The immune interactions involved here can ‘train’ the lungs, which are frequently exposed to infectious agents in the environment. If we can map out the protective immune pathways involved in the lungs, this will revolutionize our conceptual and clinical approaches in developing vaccines against infections, including emergent respiratory viruses.”


    Maziar Divangahi, lead author, pulmonary immunologist, senior scientist at the RI-MUHC, and Professor of Medicine at McGill University

    The discovery paves the way for future studies to assess whether BCG could be used to prevent other emergent viruses. Notably, research on the vaccine’s protection against COVID-19 has had promising results.

    Source:

    Journal reference:

    Tran, K. A., et al. (2024). BCG immunization induces CX3CR1hi effector memory T cells to provide cross-protection via IFN-γ-mediated trained immunity. Nature Immunology. doi.org/10.1038/s41590-023-01739-z.

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