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Tag: Drug Resistance

  • Some mosquitoes like it hot

    Some mosquitoes like it hot

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    Newswise — Certain populations of mosquitoes are more heat tolerant and better equipped to survive heat waves than others, according to new research from Washington University in St. Louis.

    This is bad news in a world where vector-borne diseases are an increasingly global health concern. Most models that scientists use to estimate vector-borne disease risk currently assume that mosquito heat tolerances do not vary. As a result, these models may underestimate mosquitoes’ ability to spread diseases in a warming world.

    Researchers led by Katie M. Westby, a senior scientist at Tyson Research Center, Washington University’s environmental field station, conducted a new study that measured the critical thermal maximum (CTmax), an organism’s upper thermal tolerance limit, of eight populations of the globally invasive tiger mosquito, Aedes albopictus. The tiger mosquito is a known vector for many viruses including West Nile, chikungunya and dengue.

    “We found significant differences across populations for both adults and larvae, and these differences were more pronounced for adults,” Westby said. The new study is published Jan. 8 in Frontiers in Ecology and Evolution.

    Westby’s team sampled mosquitoes from eight different populations spanning four climate zones across the eastern United States, including mosquitoes from locations in New Orleans; St. Augustine, Fla.; Huntsville, Ala.; Stillwater, Okla.; St. Louis; Urbana, Ill.; College Park, Md.; and Allegheny County, Pa.

    The scientists collected eggs in the wild and raised larvae from the different geographic locations to adult stages in the lab, tending the mosquito populations separately as they continued to breed and grow. The scientists then used adults and larvae from subsequent generations of these captive-raised mosquitoes in trials to determine CTmax values, ramping up air and water temperatures at a rate of 1 degree Celsius per minute using established research protocols.

    The team then tested the relationship between climatic variables measured near each population source and the CTmax of adults and larvae. The scientists found significant differences among the mosquito populations.

    The differences did not appear to follow a simple latitudinal or temperature-dependent pattern, but there were some important trends. Mosquito populations from locations with higher precipitation had higher CTmax values. Overall, the results reveal that mean and maximum seasonal temperatures, relative humidity and annual precipitation may all be important climatic factors in determining CTmax.

    “Larvae had significantly higher thermal limits than adults, and this likely results from different selection pressures for terrestrial adults and aquatic larvae,” said Benjamin Orlinick, first author of the paper and a former undergraduate research fellow at Tyson Research Center. “It appears that adult Ae. albopictus are experiencing temperatures closer to their CTmax than larvae, possibly explaining why there are more differences among adult populations.”

    “The overall trend is for increased heat tolerance with increasing precipitation,” Westby said. “It could be that wetter climates allow mosquitoes to endure hotter temperatures due to decreases in desiccation, as humidity and temperature are known to interact and influence mosquito survival.”

    Little is known about how different vector populations, like those of this kind of mosquito, are adapted to their local climate, nor the potential for vectors to adapt to a rapidly changing climate. This study is one of the few to consider the upper limits of survivability in high temperatures — akin to heat waves — as opposed to the limits imposed by cold winters.

    “Standing genetic variation in heat tolerance is necessary for organisms to adapt to higher temperatures,” Westby said. “That’s why it was important for us to experimentally determine if this mosquito exhibits variation before we can begin to test how, or if, it will adapt to a warmer world.”

    Future research in the lab aims to determine the upper limits that mosquitoes will seek out hosts for blood meals in the field, where they spend the hottest parts of the day when temperatures get above those thresholds, and if they are already adapting to higher temperatures. “Determining this is key to understanding how climate change will impact disease transmission in the real world,” Westby said. “Mosquitoes in the wild experience fluctuating daily temperatures and humidity that we cannot fully replicate in the lab.”

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    Washington University in St. Louis

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  • Malnutrition linked to antibiotic resistance spike, study finds.

    Malnutrition linked to antibiotic resistance spike, study finds.

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    Newswise — University of B.C. researchers have uncovered startling connections between micronutrient deficiencies and the composition of gut microbiomes in early life that could help explain why resistance to antibiotics has been rising across the globe.

    The team investigated how deficiencies in crucial micronutrients such as vitamin A, B12, folate, iron, and zinc affected the community of bacteria, viruses, fungi and other microbes that live in the digestive system.

    They discovered that these deficiencies led to significant shifts in the gut microbiome of mice—most notably an alarming expansion of bacteria and fungi known to be opportunistic pathogens.

    Importantly, mice with micronutrient deficiencies also exhibited a higher enrichment of genes that have been linked to antibiotic resistance.

    “Micronutrient deficiency has been an overlooked factor in the conversation about global antibiotic resistance,” said Dr. Paula Littlejohn, a postdoctoral research fellow with UBC’s department of medical genetics and department of pediatrics, and the BC Children’s Hospital Research Institute. “This is a significant discovery, as it suggests that nutrient deficiencies can make the gut environment more conducive to the development of antibiotic resistance, which is a major global health concern.”

    Bacteria naturally possess these genes as a defence mechanism. Certain circumstances, such as antibiotic pressure or nutrient stress, cause an increase in these mechanisms. This poses a threat that could render many potent antibiotics ineffective and lead to a future where common infections could become deadly.

    Antibiotic resistance is often attributed to overuse and misuse of antibiotics, but the work of Dr. Littlejohn and her UBC colleagues suggests that the ‘hidden hunger’ of micronutrient deficiencies is another important factor.

    “Globally, around 340 million children under five suffer from multiple micronutrient deficiencies, which not only affect their growth but also significantly alter their gut microbiomes,” said Dr. Littlejohn. “Our findings are particularly concerning as these children are often prescribed antibiotics for malnutrition-related illnesses. Ironically, their gut microbiome may be primed for antibiotic resistance due to the underlying micronutrient deficiencies.”

    The study, published this week in Nature Microbiology, offers critical insights into the far-reaching consequences of micronutrient deficiencies in early life. It underscores the need for comprehensive strategies to address undernutrition and its ripple effects on health. Addressing micronutrient deficiencies is about more than overcoming malnutrition, it may also be a critical step in fighting the global scourge of antibiotic resistance.

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    University of British Columbia

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  • Metformin eases weight gain in youth on bipolar meds. Study finds.

    Metformin eases weight gain in youth on bipolar meds. Study finds.

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    Newswise — A new large-scale study led by researchers at the University of Cincinnati and Northwell Health, New York’s largest health care provider, found the drug metformin can help prevent or reduce weight gain in youth taking medication to treat bipolar disorder.

    The collaborative team presented its findings during a symposium at the American Academy of Child and Adolescent Psychiatry conference in New York City Oct. 27.

    Weight gain side effect

    Medications to treat bipolar disorder, known as second-generation antipsychotics (SGAs), are often effective at helping young patients’ mental health improve but can have significant side effects including elevated blood pressure and glucose, increased appetite and weight gain.

    “We, the clinicians naively justified that we’re improving your psychosis, so just deal with the weight gain,” said Victor Fornari, MD, a child/adolescent psychiatrist at Northwell Health. “But patients stopped taking their medicine because they said they didn’t want to gain weight.”

    UC’s Christina Klein, PhD, said in addition to patients not taking their medication, the weight gain side effects can lead to lifelong harmful health outcomes.

    “So you’re not just looking at the mental health, but you’re looking at the physical health of the whole person,” said Klein, a research scientist in UC’s Department of Psychiatry and Behavioral Neuroscience in the College of Medicine.

    Klein said a survey found patients want interventions to address the side effects as soon as possible, while doctors and caregivers prefer a wait and see approach. 

    Metformin, a medication typically used for Type 2 diabetes, is known to also prevent weight gain, but nearly all psychiatrists surveyed initially said they did not feel comfortable prescribing it, leading to the study testing metformin’s effect.

    Study design

    Klein said the study had a pragmatic design, meaning it had broad enrollment criteria and was conducted at a wide variety of clinics, even those without prior participation in research studies.

    “We wanted the regular person who was just going to their doctor,” Klein said. “It’s not this perfect patient where you have this disorder and nothing else, you’re only taking this medicine, you’re adherent to the medicine or you show up every time.”

    A total of 1,565 patients aged 8-19 with bipolar disorder taking SGAs were enrolled in the study, a “Herculean” accomplishment according to Fornari.

    “It was 60 sites across the country, and it was a large sample of patients to really demonstrate what’s going on,” he said. “I don’t know that anybody has done a study of this magnitude with almost 1,600 kids and their families.”

    Everyone enrolled in the trial received a lifestyle intervention with recommendations for healthy eating and exercise. Half of the youth were randomized to receive the healthy lifestyle intervention and were prescribed metformin. 

    “If patients weren’t doing well on the metformin, they could come off and stay in this study,” Klein said. “Really we’re just trying to meet the patients when and where they received services, seeing what happens to them over the course of two years.” 

    Prior to beginning the interventions, researchers collected information on youth living with bipolar disorders’ quality of life and adherence to taking their medication as prescribed. 

    While 87% of youth reported they took their medication regularly, a majority reported they were unhappy with their weight and/or had been sad, mad or frustrated about their weight. 

    Researchers also collected baseline metabolic data to determine if youth had metabolic syndrome, which Northwell’s Claudine Higdon, MD, said is a common consequence of taking SGAs that places youth at risk for diabetes and cardiovascular disease. The study found 33% of youth enrolled in the study had metabolic syndrome at the start. 

    “The key elements of metabolic syndrome are obesity, high blood pressure, elevated triglycerides and elevated glucose,” said Higdon, a child/adolescent psychiatrist. “It is important that clinicians monitor for metabolic syndrome when treating youth with second-generation antipsychotics.” 

    Study results

    UC’s Jeffrey Welge, PhD, said in the short-term six-month follow-up data, metformin had a modest but significant effect at preventing and in some cases reversing weight gain in the study’s patient population. The drug was also found to be safe, with some gastrointestinal distress symptoms being the only side effects reported.

    “It’s not a drug you take and weight falls off of you, but it tends to reduce that out of control appetite which we think then makes it easier for patients to adhere to a healthy diet and as they lose some weight maybe also make it easier for them to engage in more exercise,” said Welge, professor in UC’s Department of Psychiatry and Behavioral Neuroscience and Department of Environmental and Public Health Sciences. “So, the lifestyle is really what’s driving good outcomes, but metformin is in some cases putting the wind at their back to help with that.”

    “It’s safe, effective and very inexpensive. It’s an intervention that has the potential to have widespread applicability,” Fornari added. “It’s not a medicine that you need to have an endocrinologist or a pediatrician prescribe, and I think it really speaks to the fact that the psychiatrist needs to be caring for the entire person, the physical and the mental health of the patient.”

    While having an effect on weight gain, metformin was not found to have a significant effect on youth’s metabolic syndrome in the short term, Welge said. 

    “Further research is needed on effective interventions for metabolic syndrome,” Higdon said.

    Patient-centered partnership

    The study received funding from the Patient-Centered Outcomes Research Institute (PCORI), and included patient and caregiver advocate input throughout.

    “We really could not have done it without the support of youth living with bipolar disorders and their caregivers, and their continued recommendations on how to keep the trial patient-centered throughout the study,” Klein said. 

    Most research studies take about 15-17 years from being published to being widely applied in clinics across the country, so PCORI has additionally supported the research team with a dissemination grant so the knowledge can be spread more quickly.

    Klein said the team will conduct focus groups with youth living with bipolar disorders, as well as their caregivers and clinicians, to see how they want information to be presented to them. 

    UC’s Melissa DelBello, MD, served as the trial’s principal investigator

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    University of Cincinnati

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  • New antibiotic from ‘dark matter’ targets superbugs

    New antibiotic from ‘dark matter’ targets superbugs

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    Newswise — A new powerful antibiotic, isolated from bacteria that could not be studied before, seems capable to combat harmful bacteria and even multi-resistant ‘superbugs’. Named Clovibactin, the antibiotic appears to kill bacteria in an unusual way, making it more difficult for bacteria to develop any resistance against it. Researchers from Utrecht University, Bonn University (Germany), the German Center for Infection Research (DZIF), Northeastern University of Boston (USA), and the company NovoBiotic Pharmaceuticals (Cambridge, USA) now share the discovery of Clovibactin and its killing mechanism in the scientific journal Cell.

    Urgent need for new antibiotics

    Antimicrobial resistance is a major problem for human health and researchers worldwide are looking for new solutions. “We urgently need new antibiotics to combat bacteria that become increasingly resistant to most clinically used antibiotics,” says Dr. Markus Weingarth, a researcher from the Chemistry Department of Utrecht University.

    However, the discovery of new antibiotics is a challenge: few new antibiotics have been introduced into the clinics over the last decades, and then they often resemble older, already known antibiotics.

    “Clovibactin is different,” says Weingarth. “Since Clovibactin was isolated from bacteria that could not be grown before, pathogenic bacteria have not seen such an antibiotic before and had no time to develop resistance.”

    Antibiotic from bacterial dark matter

    Clovibactin was discovered by NovoBiotic Pharmaceuticals, a small US-based early-stage company, and microbiologist Prof. Kim Lewis from Northeastern University, Boston. Earlier, they developed a device that allows to grow ‘bacterial dark matter’, which are so-called unculturable bacteria. Intriguingly, 99% of all bacteria are ‘unculturable’ and could not be grown in laboratories previously, hence they could not be mined for novel antibiotics. Using the device, called iCHip, the US researchers discovered Clovibactin in a bacterium isolated from a sandy soil from North Carolina: E. terrae ssp. Carolina.

    In the joint Cell publication, NovoBiotic Pharmaceuticals shows that Clovibactin successfully attacks a broad spectrum of bacterial pathogens. It was also successfully used to treated mice infected with the superbug Staphylococcus aureus. 

    A broad target spectrum

    Clovibactin appears to have an unusual killing mechanism. It targets not just one, but three different precursor molecules that are all essential for the construction of the cell wall, an envelope-like structure that surrounds bacteria. This was discovered by the group of Prof. Tanja Schneider from the University of Bonn in Germany, one of the Cell paper’s co-authors.

    Schneider: “The multi-target attack mechanism of Clovibactin blocks bacterial cell wall synthesis simultaneously at different positions. This improves the drug’s activity and substantially increases its robustness to resistance development.”

    A cage-like structure

    How exactly Clovibactin blocks the synthesis of the bacterial cell wall was unraveled by the team of Dr. Markus Weingarth from Utrecht University. They used a special technique called solid-state nuclear magnetic resonance (NMR) that allows to study Clovibactin’s mechanism under similar conditions as in bacteria.

    “Clovibactin wraps around the pyrophosphate like a tightly sitting glove. Like a cage that encloses its target” says Weingarth. This is was gives Clovibactin its name, which is derived from Greek word “Klouvi”, which means cage. The remarkable aspect of Clovibactin’s mechanism is that it only binds to the immutable pyrophosphate that is common to cell wall precursors, but it ignores that variable sugar-peptide part of the targets. “As Clovibactin only binds to the immutable, conserved part of its targets, bacteria will have a much harder time developing any resistance against it. In fact, we did not observe any resistance to Clovibactin in our studies.”

    Fibrils capture the targets

    Clovibactin can do even more. Upon binding the target molecules, it self-assembles into large fibrils on the surface of bacterial membranes. These fibrils are stable for a long time and thereby ensure that the target molecules remain sequestered for as long as necessary to kill bacteria.

    “Since these fibrils only form on bacterial membranes and not on human membranes, they are presumably also the reason why Clovibactin selectively damages bacterial cells but is not toxic to human cells,” says Weingarth. “Clovibactin hence has potential for the design of improved therapeutics that kill bacterial pathogens without resistance development.”.

     

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    Utrecht University

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  • Scientists find ‘concerning’ flaw in malaria diagnostics

    Scientists find ‘concerning’ flaw in malaria diagnostics

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    Newswise — ITHACA, N.Y. — Current methods can vastly overestimate the rates that malaria parasites are multiplying in an infected person’s blood, which has important implications for determining how harmful they could be to a host, according to a new report.

    The findings also have consequences for understanding the evolution of traits that lead to drug resistance, how quickly a parasite might spread through a population, and for evaluating the effectiveness of new vaccines.

    The study, “Extraordinary Parasite Multiplication Rates in Human Malaria Infections,” appeared in the August issue of Trends in Parasitology.

    The researchers created a mathematical model of infection dynamics to identify that blood sampling biases and false inferences in previous computer models were leading to large overestimates.

    “The inability to accurately measure those rates is concerning,” said Megan Greischar, assistant professor of ecology and evolutionary biology in the College of Agriculture and Life Sciences, and corresponding author on the paper. Lauren Childs, associate professor of mathematics at Virginia Tech, is a coauthor.

    “We had a very simple model for how you infer multiplication rates that didn’t work, so now we know we need something more robust,” Greischar said. This study explains how the problems in accurately measuring multiplication rates arise, she said.

     Some candidate malaria vaccines act during a stage in the parasite’s life cycle when it replicates in the blood, so knowing its multiplication rates is key to evaluating a vaccine’s efficacy.

    Infected mosquitoes pass the malaria parasite into a human host during a blood meal. The parasites then multiply first in liver cells before moving into red blood cells. There, in synchrony with each other, parasites replicate inside the red blood cells and burst out into the blood, killing the cells. The daughter parasites then continue the next cycle and invade new red blood cells. This cycle repeats about every 48 hours.

    When it comes to measuring multiplication rates, clinicians take blood samples from infected patients and count the number of parasites observed. Timing is important, as young parasites that are early in their life cycle after bursting from red blood cells are easy to see. But as they age, later in the cycle, they become sticky, attach themselves to blood vessel walls and do not circulate. Since the cycle repeats again and again, the samples’ timing determines whether high or low numbers are observable in the blood.

    Sampling bias increases when samples are taken later in the cycle when observable parasites are low, versus early in the cycle when counts of young parasites are high.     

    Previous models used for estimating parasite multiplication rates tried to correct for this sampling bias by inferring how many parasites might exist later in a parasite brood’s life cycle, when they can’t be directly observed. This study suggests that those methods were insufficient to determine how fast parasites actually multiply.

     Previously published studies measured the maximum number of offspring produced by a human malaria parasite (Plasmodium falciparum) within a single 48-hour cycle of replication in artificial culture.

    “They should only be able to multiply at most 32-fold, which is quite large already,” meaning a single parasite could create 32 daughter parasites, at most, with a median of about 15 to 18, Greischar said.

    Using a mathematical model, combined with both modern and historical data from people infected with malaria, the researchers were able to identify that inferences made in previous models of parasite counts led to parasite multiplication rates that were orders of magnitude higher than what was possible.

    “We were seeing thousand-fold growth,” Greischar said. “That would mean that the parasites were making more than 1,000 parasites from a single red blood cell, repeatedly, which does not match with our understanding of the biology of these parasites.”

    Now that Greischar and Childs have identified the problem, next steps could include developing techniques to infer the hidden fraction of the parasite population in order to accurately calculate their multiplication rates.

    The study was funded by the College of Agriculture and Life Sciences and the National Science Foundation.

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    Cornell University

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  • Rapid Adaptation of Acinetobacter baumannii to Novel Environments

    Rapid Adaptation of Acinetobacter baumannii to Novel Environments

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    Newswise — FRANKFURT. Each year, over 670,000 people in Europe fall ill because of antibiotic-resistant pathogens, and 33,000 die from the infections. Especially feared are pathogens with resistances against multiple, or even all, known antibiotics. One of these is the bacterium Acinetobacter baumannii, feared today above all as the “hospital superbug”: According to estimates, up to five percent of all hospital-acquired and one tenth of all bacterial infections resulting in death can be attributed to this pathogen alone. This puts A. baumannii right at the top of a list of pathogens for which – according to the World Health Organization (WHO) – there is an urgent need to develop new therapies.

    Understanding which characteristics make A. baumannii a pathogen is one of the prerequisites for this. To this end, bioinformaticians led by Professor Ingo Ebersberger of Goethe University Frankfurt and the LOEWE Center for Translational Biodiversity Genomics (LOEWE-TBG) are comparing the genomes and the proteins encoded therein across a wide range of different Acinetobacter strains. Conclusions about which genes contribute to pathogenicity can be drawn above all from the differences between dangerous and harmless strains.

    Due to a lack of suitable methods, corresponding studies have so far concentrated on whether a gene is present in a bacterial strain or not. However, this neglects the fact that bacteria can acquire new characteristics by modifying existing genes and thus also the proteins encoded by them. That is why Ebersberger’s team has developed a bioinformatics method to track the modification of proteins along an evolutionary lineage and has now applied this method for the first time to Acinetobacter in collaboration with microbiologists from the Institute for Molecular Biosciences and the Institute of Medical Microbiology and Infection Control at Goethe University Frankfurt.

    In the process, the researchers concentrated on hair-like cell appendages, known as type IVa (T4A) pili, which are prevalent in bacteria and that they use to interact with their environment. The fact that they are present in harmless bacteria on the one hand and have even been identified as a key factor for the virulence of some pathogens on the other suggests that the T4A pili have repeatedly acquired new characteristics associated with pathogenicity during evolution.

    The research team could show that the protein ComC, which sits on the tip of the T4A pili and is essential for their function, shows conspicuous changes within the group of pathogenic Acinetobacter strains. Even different strains of A. baumannii have different variants of this protein. This leads bioinformatician Ebersberger to compare the T4A pili to a multifunctional garden tool, where the handle is always the same, but the attachments are interchangeable. “In this way, drastic functional modifications can be achieved over short evolutionary time spans,” Ebersberger is convinced. “We assume that bacterial strains that differ in terms of their T4A pili also interact differently with their environment. This might determine, for example, in which corner of the human body the pathogen settles.”

    The aim is to use this knowledge of the unexpectedly high diversity within the pathogen to improve the treatment of A. baumannii infections, as Ebersberger explains: “Building on our results, it might be possible to develop personalized therapies that are tailored to a specific strain of the pathogen.” However, the study by Ebersberger and his colleagues also reveals something else: Previous studies on the comparative genomics of A. baumannii have presumably only unveiled the tip of the iceberg. “Our approach has gone a long way towards resolving the search for possible components that characterize pathogens,” says Ebersberger.

    https://aktuelles.uni-frankfurt.de/english/how-the-hospital-pathogen-acinetobacter-baumannii-quickly-adapts-to-new-environmental-conditions/

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    Goethe-Universitat Frankfurt am Main

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  • UNC Researchers Receive NIH Grant to Study Drug-Resistant Malaria in Ethiopia

    UNC Researchers Receive NIH Grant to Study Drug-Resistant Malaria in Ethiopia

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    Newswise — CHAPEL HILL, NC – Ethiopia is Africa’s second most-populated country with an estimated 60% of its population at risk for malaria exposure. Plasmodium falciparum infection accounts for the majority of malaria deaths and approximately 70% of all cases. Artemisinin-based combination therapies (ACTs) have been critical to the success in reducing the global burden of falciparum malaria between 2000 and 2015. But the emergence and spread of artemisinin-resistant falciparum malaria has become a major threat to global elimination.

    “Ethiopia has made meaningful gains in the fight against malaria. However, the malaria parasite has a long history of evolving to survive, and it appears to be doing just that,” said Jonathan Parr, MD, MPH, assistant professor of medicine in infectious diseases at the UNC School of Medicine.

    The project “Epidemiology and Determinants of Emerging Artemisinin-Resistant Malaria in Ethiopia,” has been awarded 3.6 million in NIH R01 funding, building upon UNC-Chapel Hill’s strong partnership with the Ethiopian Public Health Institute (EPHI), the technical arm of the Ethiopia Federal Ministry of Health. The project also includes partners at Brown University, University of Notre Dame, and Imperial College London. Parr described the study as an exciting opportunity to use cutting-edge, multidisciplinary science in the fight against malaria.

    “We will be sequencing parasites from a network of sites across the country, conducting laboratory experiments, and performing predictive modeling to understand how dangerous new strains of malaria emerge and spread,” he said.

    Ashenafi Assefa, PhD, who trained as a UNC postdoctoral researcher in Dr. Parr’s group and has years of experience conducting translational malaria research, will lead study activities in Ethiopia, training personnel and running assays while overseeing protocol implementation and data collection. Assefa said the research outcomes will contribute to the advancement of scientific knowledge in the field.

    “This study is expected to generate critical evidence about the rise and expansion of drug-resistant parasites in the region,” said Assefa. “The results will be readily consumed by policymakers and advance malaria elimination efforts in Ethiopia and beyond.”

    Collaborating with EPHI, researchers will conduct surveys of people presenting to health facilities with falciparum malaria across Ethiopia to characterize resistant parasites. These results will be integrated into a point-of-care clinical tool for identifying individuals with drug-resistant falciparum malaria. The results will also guide the development of a model to predict the future spread of resistance mutations.

    Jon Juliano, MD, MSPH, heads the Infectious Disease Epidemiology and Ecology Lab at UNC, an interdisciplinary research collaboration that explores how pathogens interact with human hosts, with a focus on malaria.

    “We are entering a period of great concern about the effectiveness of antimalarial drugs in East Africa,” Juliano said. “The emergence of partial artemisinin resistance in multiple countries in the Rift Valley raises concerns about the long-term utility of these first line agents. This project represents a significant extension of studies to understand the emergence and spread of these mutations that the University of North Carolina is either leading or supporting in Rwanda, Uganda, Tanzania, the Democratic Republic of the Congo and now Ethiopia.”

    The UNC Institute for Global Health and Infectious Diseases (IGHID) at the UNC School of Medicine is an engine for global health research and pan-university collaboration, transforming health in North Carolina and around the world. IGHID facilitates research excellence while providing opportunities for investigators to nurture emerging scientists through training and service, to achieve positive patient care outcomes and practice.

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    University of North Carolina School of Medicine

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  • A New Strategy to Break Through Bacterial Barriers in Chronic Treatment-Resistant Wounds

    A New Strategy to Break Through Bacterial Barriers in Chronic Treatment-Resistant Wounds

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    Newswise — CHAPEL HILL, N.C. – Chronic wounds are open sores or injured tissue that fail to heal properly. These types of wounds are notoriously challenging to treat because of bacterial infections like Staphylococcus aureus, or S. aureus. Additionally, bacterial infections that are highly resistant to antibiotics, such as methicillin-resistant S. aureus (MRSA), are one of the main causes of life-threatening infections in hospital patients.

    To defend itself from our immune system and other threats, S. aureus can band together, creating a slick, slimy forcefield – or biofilm – around itself. The biofilm barrier is so thick that neither immune cells nor antibiotics can penetrate through and neutralize the harmful bacteria.

    Researchers at the UNC School of Medicine and the UNC-NC State Joint Department of Biomedical Engineering have developed a new method that combines palmitoleic acid, gentamicin, and non-invasive ultrasound to help improve drug delivery in chronic wounds that have been infected with S. aureus.

    Using their new strategy, researchers were able to reduce the challenging MRSA infection in the wounds of diabetic mice by 94%. They were able to completely sterilize the wounds in several of the mice, and the rest had significantly reduced bacterial burden. Their results were published in Cell Chemical Biology.

    “When bacteria are not completely cleared from chronic wounds, it puts the patient at high risk for the infection recurring or of developing a secondary infection,” said senior author Sarah Rowe-Conlon, PhD, a research associate professor in the Department of Microbiology and Immunology. “This therapeutic strategy has the potential to improve outcomes and reduce relapse of chronic wound infections in patients. We are excited about the potential of translating this to the clinic, and that’s what we’re exploring right now.”

    Biofilms act as a physical barrier to many classes of antibiotics. Virginie Papadopoulou, PhD, a research assistant professor in the UNC-NCSU Joint Department of Biomedical Engineering, was curious to know if non-invasive cavitation-enhanced ultrasound could create enough agitation to form open spaces in the biofilm to facilitate drug-delivery.

    Liquid droplets which can be activated by ultrasound, called phase change contrast agent (PCCA), are applied topically to the wound. An ultrasound transducer is focused on the wound and turned on, causing the liquid inside the droplets to expand and turn into microscopic gas-filled microbubbles, when then move rapidly.

    The oscillation of these microbubbles agitates the biofilm, both mechanically disrupting it as well as increasing fluid flow. Ultimately, the combination of the biofilm disruption and the increased permeation of the drugs through the biofilm allowed the drugs to come in and kill the bacterial biofilm with very high efficiency.

    “Microbubbles and phase change contrast agents act as local amplifiers of ultrasound energy, allowing us to precisely target wounds and areas of the body to achieve therapeutic outcomes not possible with standard ultrasound,” said Dayton, the William R. Kenan Jr. Distinguished Professor and Department Chair of the UNC-NCSU Joint Department of Biomedical Engineering. “We hope to be able to use similar technologies to locally delivery chemotherapeutics to stubborn tumors or drive new genetic material into damaged cells as well.”

    When the bacterial cells are trapped inside the biofilm, they are left with little access to nutrients and oxygen. To conserve their resources and energy, they transition into a dormant or sleepy state. The bacteria, which are known as persister cells in this state, are extremely resistant to antibiotics.

    Researchers chose gentamicin, a topical antibiotic typically ineffective against S. aureus due to widespread antibiotic resistance and poor activity against persister cells. The researchers also introduced a novel antibiotic adjuvant, palmitoleic acid, to their models.

    Palmitoleic acid, an unsaturated fatty acid, is a natural product of the human body that has strong antibacterial properties. The fatty acid embeds itself into the membrane of bacterial cells, and the authors discovered that it facilitates the antibiotic’s successful entry into S. aureus cells and is able to kill persister cells and reverse antibiotic resistance.

    Overall, the team is enthusiastic about the new topical, non-invasive approach because it may give scientists and doctors more tools to combat antibiotic resistance and to lessen the serious adverse effects of taking oral antibiotics.

    “Systemic antibiotics, such as oral or IV, work very well, but there’s often a large risk associated with them such as toxicity, wiping out gut microflora and C. difficile infection,” said Rowe-Conlon. “Using this system, we are able to make topical drugs work and they can be applied to the site of infection at very high concentrations, without the risks associated with systemic delivery.”

     

    About UNC School of Medicine

    The UNC School of Medicine (SOM) is the state’s largest medical school, graduating more than 180 new physicians each year. It is consistently ranked among the top medical schools in the US, including 5th overall for primary care by US News & World Report, and 6th for research among public universities. More than half of the school’s 1,700 faculty members served as principal investigators on active research awards in 2021. Two UNC SOM faculty members have earned Nobel Prize awards.

    About the Joint Department of Biomedical Engineering

    The Joint Department is ranked in the top 10 biomedical engineering programs in the US by the Blue Ridge Institute for Medical Research, top 20 biomedical engineering programs worldwide by the Shanghai Academic Ranking of World Universities, and is a top 5 institution for total bachelor’s degrees awarded in biomedical engineering (ASEE).

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    University of North Carolina School of Medicine

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  • Researchers track antimicrobial resistance in E. coli isolated from swine

    Researchers track antimicrobial resistance in E. coli isolated from swine

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    BYLINE: Ananya Sen

    Newswise — The spread of drug-resistant microbes has become a global health concern that threatens our ability to treat infections. The widespread use of antimicrobials in livestock, such as swine farms, exacerbates this problem. Therefore, we need surveillance systems to monitor these microbes to support the public health authorities. To this end, researchers at the University of Illinois Urbana-Champaign have tracked the antimicrobial resistance of Escherichia coli isolated from swine.

    Antimicrobials are essential for preventing and treating infections in humans and animals. According to the US Food and Drug Administration, 70% of all antibiotic sales in the US are used for livestock production. However, microbes change over time to combat these chemicals, eventually becoming resistant. As a result, infections become harder to treat. Concerningly, these resistant organisms can spread from farm animals to humans, creating a bigger health crisis.

    The researchers focused on E. coli since these bacteria are ubiquitous in the intestinal tract of humans and pigs, and they are good indicators to test whether meat and meat products have been contaminated. E. coli can also acquire and transfer resistance genes to other bacteria in the intestinal tract, making them ideal for monitoring programs of livestock and humans.

    “It is important to monitor the emergence of antimicrobial-resistant bacteria in the swine industry because in 2022 the US was the third largest producer and consumer of swine meat and products, after the European Union and China,” said Hamid Reza Sodagari, a postdoctoral research associate in the Varga lab. “Although it is a big problem, to the best of our knowledge this paper is the first surveillance study in the US that looks at antimicrobial resistance in E. coli from swine at slaughter.”

    The study used publicly available surveillance data of cecal samples, which were collected from the intestine after slaughter. The researchers focused on market swine and sows in the US between 2013 and 2019, and used the data compiled by the United States Department of Agriculture Food Safety Inspection Service under the National Antimicrobial Resistance Monitoring System for Enteric Bacteria program.

    “Federal agencies often don’t have the manpower to carry out such long-term and detailed analyses. Alternatively, for most researchers such studies are challenging because usually they track samples on a smaller scale. In this paper, however, we were able to look at more than 3,000 samples across several years,” said Csaba Varga, an assistant professor of epidemiology at the University of Illinois College of Veterinary Medicine and a faculty member in the “Infection Genomics for One Health” research theme within the campus’s Carl R. Woese Institute for Genomic Biology.

    Using different statistical methods, the researchers found that since 2013, the number of antimicrobials to which E. coli is resistant has either remained steady or increased over the years. In particular, the resistance to ceftriaxone, an important antimicrobial drug in both human and veterinary medicine, increased from 0.8% in 2013 to 7.7% in 2019. Even though these numbers are not high compared to the resistance to other antimicrobials, the increasing trend is concerning.

    “We don’t know why there is an increasing trend. It may be caused by mobile genetic elements, which can transfer antimicrobial resistance from one bacterium to another. We need to do further research at the molecular level to understand the reason for the increase,” Sodagari said.

    “We are not blaming anyone for this problem. Our study is meant to show that there is an issue and that surveillance systems are very important to show the changes in resistance,” Varga said. “By gathering this data, we hope that the public health authorities will be able to develop mitigation strategies.”

    The study “Evaluating Antimicrobial Resistance Trends in Commensal Escherichia coli Isolated from Cecal Samples of Swine at Slaughter in the United States, 2013-2019” was published in Microorganisms and can be found at 10.3390/microorganisms11041033.

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    University of Illinois Urbana-Champaign

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  • Novel Antibiotic Succeeds in Trial Against Hospital-Acquired Pneumonia

    Novel Antibiotic Succeeds in Trial Against Hospital-Acquired Pneumonia

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    Newswise — A Rutgers researcher leading a trial found that the novel combination antibiotic sulbactam-durlobactam combats dangerous pneumonia at least as well as the best currently approved treatment.

    The findings have led a unanimous expert committee to recommend that the Food and Drug Administration (FDA) approve the new drug, which could be available this summer to combat the often-fatal pneumonia strain known as carbapenem-resistant Acinetobacter baumannii–calcoaceticus complex (ABC), typically acquired in hospitals.

    “Antibiotic-resistant infections are a serious and persistent problem at healthcare facilities, and the [Centers for Disease Control] ranks ABC at the highest level on its threat list,” said Keith Kaye, chief of the Division of Allergy, Immunology and Infectious Disease at Robert Wood Johnson Medical School and first author of the trial report in The Lancet Infectious Diseases. “An estimated 8,500 hospital-acquired cases killed 700 patients and cost $280 million in 2019, so we greatly needed a breakthrough treatment like sulbactam-durlobactam.”

    The trial gave imipenem–cilastatin to 181 patients with laboratory-confirmed ABC and then randomized them to additional treatment with either sulbactam–durlobactam or the best existing treatment, an antibiotic called colistin. Mortality due to multiple causes after 28 days was 12 of 63 (19 percent) in the sulbactam–durlobactam group and 20 of 62 (32 percent) in the colistin group.

    The trial was large enough to prove that sulbactam-durlobactam prevents at least as many fatalities as colistin but not large enough to prove its superiority in this trial will persist in real-world use, though it may.

    The trial results did prove that sulbactam-durlobactam beats colistin in one crucial respect: tolerability. Kidney injury, serious adverse events and all treatment-related adverse events were significantly lower for patients who received sulbactam-durlobactam than for patients who received colistin.

    Another advantage of the novel antibiotic is dosing. All patients receive the same injectable dose of sulbactam–durlobactam. Doses of colistin in the study, on the other hand, varied with patient weight, so it’s considerably easier for providers to prescribe or administer the wrong amount.

    As its name implies, sulbactam-durlobactam combines two drugs. Sulbactam has been approved for use since 1986, but durlobactam is new and has yet to win approval. That could change soon, however. The FDA’s Antimicrobial Drugs Advisory Committee reviewed advance results of the new trial, along with earlier studies, and recommended on April 17 that the FDA approve the new combination for ABC treatment.

    FDA officials are free to reject such recommendations but almost always follow recommendations from advisory committees, which comprise independent experts on particular classes of disease and medication.

    “If all moves quickly, infected patients could begin receiving sulbactam-durlobactam as part of normal clinical care the second half of this year,” Kaye said. “Unfortunately, sulbactam-durlobactam isn’t the sort of wide-spectrum antibiotic that could prove effective in treating a wide variety of antibiotic-resistant infections, but it’s very good at treating this particularly dangerous one, and that’s a significant win.”

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    Rutgers University-New Brunswick

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  • Accelerated delivery of transcranial magnetic stimulation is safe and effective

    Accelerated delivery of transcranial magnetic stimulation is safe and effective

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    Newswise — May 12, 2023 — Accelerated schedules for repetitive transcranial magnetic stimulation (rTMS) can be offered to patients experiencing treatment-resistant major depressive disorder (MDD), a group of clinician–researchers and neuroscientists have concluded. The group cautions that such treatment should be proposed only after detailed discussion with patients about acceleration being an alternate form of rTMS scheduling, with documentation of informed consent.

    The recommendations are published in a special issue of Harvard Review of Psychiatry (HRP), “Interventional Neuropsychiatry and Neuromodulation: An Emerging Subspecialty in Brain Medicine.” HRP is published in the Lippincott portfolio by Wolters Kluwer.

    Repetitive TMS is a noninvasive therapy in which an electromagnet delivers repeated low-intensity pulses to stimulate the brain. It has been proven safe and effective in numerous clinical trials involving patients whose MDD does not respond to antidepressant medication. Conventionally, rTMS is given once daily 20 to 30 days over four to six weeks. That places great time demands on both patients and clinicians.

    Theta burst stimulation treats MDD

    The next step in development of rTMS is accelerated schedules in which patients undergo two or more sessions per day, each approximately 30 minutes long, separated by one hour or more. Although this change was just as effective in treating depression as once-daily rTMS, it created a different kind of impracticality and clinical inefficiency, according to Leo Chen, MBBS, MPsych, PhD, FRANZCP, of Monash University/Alfred Health in Melbourne, Australia, and colleagues. “These schedules required patients to attend treatment settings for long periods on each treatment day, limiting patient capacity at treatment clinics,” they note.

    The time burden can be alleviated, at least in part, with a novel approach called theta-burst stimulation (TBS). The most commonly used conventional rTMS protocol delivers electromagnetic pulses at a frequency of 10 Hz, whereas TBS refers to three pulses applied at 50 Hz (gamma frequency), repeated at 5 Hz (theta frequency) intervals. Two or more TBS sessions can be delivered within an hour.

    Dr. Chen and his colleagues recently published results from a multicenter randomized, controlled trial in which 10 days of TBS was compared head-to-head with a four week course of conventional rTMS. The two approaches were similar in antidepressant effect and safety. This was the largest study of accelerated TBS in depression to date.

    Standardization needed

    Accelerated delivery doesn’t necessarily mean accelerated response, the authors caution. Some retrospective studies have shown twice-daily rTMS induces antidepressant effects faster than once-daily administration, but the evidence is mixed. One barrier is that studies have varied widely in factors such as the stimulation target, frequency and intensity of stimulation, the duration of breaks between sessions, and the number of pulses applied per session and over a treatment course.

    Importantly, though, “accelerated rTMS’s antidepressant efficacy appears comparable to conventional, once-daily rTMS protocols,” Dr. Chen’s group writes. In addition, “studies show that accelerated rTMS protocols are well-tolerated and not associated with serious adverse effects.”

    “As with all therapies, the efficacy, safety, and tolerability of protocols that deviate from those investigated in clinical trials are unknown and should be cautioned against,” the researchers continue. “The durability and depression relapse patterns following accelerated rTMS remain a recognized knowledge gap.”

    Read [Accelerated Repetitive Transcranial Magnetic Stimulation to Treat Major Depression: The Past, Present, and Future]

    Wolters Kluwer provides trusted clinical technology and evidence-based solutions that engage clinicians, patients, researchers and students in effective decision-making and outcomes across healthcare. We support clinical effectiveness, learning and research, clinical surveillance and compliance, as well as data solutions. For more information about our solutions, visit https://www.wolterskluwer.com/en/health and follow us on LinkedIn and Twitter @WKHealth.

    ###

    About HRP

    Harvard Review of Psychiatry is the authoritative source for scholarly reviews and perspectives on a diverse range of important topics in psychiatry. Founded by the Harvard Medical School Department of Psychiatry, the journal is peer-reviewed and not industry sponsored. It is the property of President and Fellows of Harvard College and is affiliated with all of the Departments of Psychiatry at the Harvard teaching hospitals.

    Articles encompass all major issues in contemporary psychiatry, including (but not limited to) neuroscience, psychopharmacology, psychotherapy, history of psychiatry, and ethics. In addition to scholarly reviews, perspectives articles, and columns, the journal includes a Clinical Challenge section that presents a case followed by discussion and debate from a panel of experts.

    About Wolters Kluwer

    Wolters Kluwer (EURONEXT: WKL) is a global leader in professional information, software solutions, and services for the healthcare, tax and accounting, financial and corporate compliance, legal and regulatory, and corporate performance and ESG sectors. We help our customers make critical decisions every day by providing expert solutions that combine deep domain knowledge with specialized technology and services.

    Wolters Kluwer reported 2022 annual revenues of €5.5 billion. The group serves customers in over 180 countries, maintains operations in over 40 countries, and employs approximately 20,000 people worldwide. The company is headquartered in Alphen aan den Rijn, the Netherlands.

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    Wolters Kluwer Health: Lippincott

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  • First microbiome-targeting drug using CRISPR created by scientists

    First microbiome-targeting drug using CRISPR created by scientists

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    Newswise — Many people have experienced infections from E. coli, which are primarily seen as inconvenient and unpleasant. For some patients, like those with blood cancer, however, there is a risk that the bacteria will travel into the bloodstream. In those cases, an E. coli infection is too often fatal. The mortality rate is 15-20%.

    The predominant cure for such infections is the use of antibiotics that have detrimental effects on the patient’s microbiome, which play a key part in our physical and emotional well-being, and other side effects. Furthermore, growing problems with antibiotic resistance render such treatments less effective in treating infections.

    An international team of scientists has now engineered the first published CRISPR-based candidate (see fact box) for a drug that targets E. coli directly and leaves the microbiome intact. A new paper in Nature Biotechnology titled ‘Engineered phage with antibacterial CRISPR–Cas selectively reduce E. coli burden in mice’ describes the development of the drug candidate to a stage where it is ready for tests on humans.

    Through extensive use of synthetic biology, the team designed four bacterial viruses that use CRISPR technology to kill the unwanted bacteria precisely.

    “We believe that a narrow spectrum drug with these properties could be very useful to cancer patients, among others, who often get serious infections that are difficult to treat with current antibiotics,” says Morten Otto Alexander Sommer, a professor at DTU Biosustain, Co-founder of SNIPR Biome, and lead author of the paper.

    The work was carried out in collaboration with JAFRAL (Slovenia), JMI Laboratories (US), and Division of Infectuous Diseases at Weill Cornell Medicine (US).

    Engineering phages to target E. coli

    The team, primarily based at SNIPR Biome, screened a library of 162 naturally occurring phages (viruses that kill specific bacteria; see fact box). They found that eight of these phages showed promise in targeting E. coli. They then engineered the phages through gene editing to improve their ability to target E. coli.

    A cocktail of four of these phages, which they named SNIPR001, very effectively targeted bacteria in biofilms and reduced the number of E. coli in a manner that surpassed that of  naturally occurring phages. Further, they showed that the cocktail of phages was tolerated well in the gut of mice and mini pigs while reducing the emergence of E. coli. SNIPR001 is now in clinical development and has been granted a Fast-Track designation (expedited review) by the US Food and Drug Administration.

    FACT BOX: An overview of the SNIPR001 creation process:

    1. Naturally occurring phages are screened against a panel of E. coli strains.
    2. Phages with broad activity against E. coli are tail fibre engineered and/or armed with CRISPR–Cas systems containing sequences specific to E. coli, creating CAPs (Cas-armed phages).
    3. These CAPs are tested for host range, in vivo efficacy, and CMC specifications.

    SNIPR001 comprises four complementary CAPs and is a new precision antibiotic that selectively targets E.coli to prevent bacteremia in haematological cancer patients at risk of neutropenia (low levels of white blood cells).

    Blood cancer patients are first in line

    The reason this new development is exciting for blood cancer patients has to do with side effects stemming from their chemotherapy treatment. It causes the patient’s bone marrow to produce fewer blood cells and inflammation of the intestines. The latter increases the intestines’ permeability allowing bacteria from the gut to travel into the bloodstream. This combination of side effects leaves the patient vulnerable to infections from bacteria like E. coli. In such cases, the

    Today, patients at risk (i.e., with low levels of white blood cells) receive antibiotic treatments ahead of their chemotherapy, but in some cases, E. coli shows very high resistance to commonly used antibiotics. Also, the antibiotics themselves have several side effects that in some cases reduce the effect of the cancer treatments.

    “We need a wider variety of options available to treat these patients, preferably ones where we can specifically target the bacteria responsible to avoid side effects and that do not add to the problem of antibiotic resistance,” says Morten Otto Alexander Sommer.

    In recent years, researchers have been looking back towards using phages to treat infections because of the increase in antibiotic resistance. Before antibiotics were broadly available, phages were widely used and studied in countries that were then part of the Soviet Union. Still, there are few clinical trials, and the results haven’t been convincing, according to the paper.

    “Through emerging technologies like CRISPR, the use of phages in treating infections has become a viable pathway. As our results show, there is potential for enhancing naturally occurring phages through genetic engineering. It is my hope that this approach may also serve as a blueprint for new antimicrobials targeting resistant pathogens,” says Morten Otto Alexander Sommer.

    FACT BOX: CRISPR, phages, and phage therapy

    CRISPR technology is a way for scientists to edit DNA sequences in cells. It’s based on a defence mechanism bacteria naturally use to protect themselves. CRISPR technology uses a molecule called Cas9, which works like a pair of scissors to cut DNA at a specific spot.

    After the cut, the DNA can be fixed, or a new piece can be added. Scientists can use this tool to create genetically modified organisms, find new ways to treat genetic diseases, and learn more about how genes work.

    Phages are tiny viruses that can kill specific bacteria. They’re everywhere on Earth and help regulate bacterial populations and nutrient cycling. They infect and kill bacteria, and when the bacteria die, they release nutrients into the environment.

    Scientists use phages to treat bacterial infections, which is called phage therapy. They identify and isolate phages that can kill a specific bacterial strain and use them to fight infections caused by that strain.

    Phage therapy has some advantages to antibiotics, like targeting specific bacteria without side effects and potentially reducing antibiotic resistance.

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    Technical University of Denmark (DTU)

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  • Gut germs use strong substances to avoid antibiotics.

    Gut germs use strong substances to avoid antibiotics.

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    Newswise — The discovery shows why it can be so difficult to tackle drug-resistant bacteria, but does provide a possible avenue for tackling the problem. The super-polymer structures the bacteria use to transfer genes could also be exploited for precise drug delivery in future medicine.

    Gut bacteria form extracellular appendages called F-pili to connect to each other and transfer packets of DNA, called genes, that allow them to resist antibiotics. It was thought that the harsh conditions inside human and animal guts, including turbulence, heat, and acids, would break the F-pili, making transfer more difficult.

    However, new research by a team led by Imperial College London researchers has shown that the F-pili are actually stronger in these conditions, helping the bacteria transfer resistance genes more efficiently, and to clump into ‘biofilms’ – protective bacterial consortia – that help them fend off antibiotics.

    The results are published in Nature Communications.

    First author Jonasz Patkowski, from the Department of Life Sciences at Imperial, said: “The death toll from antimicrobial resistance is expected to match cancer by 2050, meaning we urgently need new strategies to combat this trend. Much of the spread of resistance is driven by bacteria swapping genes, so detailed understanding of this process could lead to new ways to interrupt it.”

    Not so fragile

    Different classes of bacteria use different types of pili to transfer genes in a process called conjugation. A classic experiment seemed to show that this process was fragile and could be interrupted by agitation, but this left a mystery: why do so many bacteria living in harsh conditions like guts use these systems if they are so fragile?

    The team therefore set out to test this assumption. By shaking E. coli bacteria while they used F-pili during conjugation, they discovered that agitation actually increased the efficiency of gene transfer between bacteria. They also observed that after transferring genes, the conjugated bacteria in shaken conditions clumped together more easily to form biofilms, which protect inner bacteria from the surrounding antibiotic molecules.

    To determine how the F-pili are able to do this, the team subjected them to a strength test by mounting a bacterium on a stage, connecting a glass bead using ‘molecular tweezers’ to the end of one of its F-pili, and pulling. The F-pili proved highly elastic, with spring-like properties that prevented them from breaking.

    They also tested the F-pili’s ability to withstand other common gut conditions, subjecting them to sodium hydroxide, urea, and excessively high temperatures of 100°C – all of which the F-pili survived.

    Molecular properties

    The team then went a step further, looking at the F-pili on a molecular level to see what gives them these incredible properties. They are primarily made up of F-pilin ‘subunits’ with interlinked phospholipid molecules.

    By modelling the F-pili without the phospholipids, the team showed how important these molecules are for the structure’s springiness and elastic strength. Repeating the pulling experiment revealed that the subunits quickly disassemble without the phospholipids supporting them, proving their novel role as a ‘molecular glue’ in long biopolymers.

    Lead researcher Dr Tiago Costa, from the Department of Life Sciences at Imperial, said: “Making F-pili is very costly to the bacteria in terms of resources and energy, so it’s no surprise they are worth the effort. We have shown how F-pili accelerate the spread of antibiotic resistance and biofilm formation in turbulent environments, but the challenge now is to find ways to combat this very efficient process.”

    While it would be advantageous to break F-pili in pathogenic bacteria, their properties could be helpful if we can engineer them for use in, for example, drug delivery. Patkowski explained: “It’s hard to find a tubular appendage with such strong properties. Bacteria use it to transfer genes, but if we could mimic these properties, we could use similar structures to precisely deliver drugs where they are needed in the body.”

    https://www.imperial.ac.uk/news/244513/gut-bacteria-superpolymers-dodge-antibiotics/

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    Imperial College London

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  • Capsule Wonder Drug Could Replace Insulin Injections for Diabetics

    Capsule Wonder Drug Could Replace Insulin Injections for Diabetics

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    Newswise — Scientists in Melbourne have designed a new type of oral capsule that could mean pain-free delivery of insulin and other protein drugs.

    Co-lead researcher Professor Charlotte Conn, a biophysical chemist from RMIT University, said protein drugs had proven challenging to deliver orally as the drugs degrade very quickly in the stomach – until now.

    “These types of drugs are typically administered with an injection – thousands of diabetics in Australia need insulin injections up to several times a day, which can be unpleasant for the patient and results in high healthcare costs,” said Conn, from RMIT’s School of Science.

    She said the new technology could also be used to deliver other protein drugs orally – including a new type of oral antibiotic developed by the RMIT team that can avoid resistance by dangerous superbugs.

    “Other protein drugs such as monoclonal antibodies have been developed to treat inflammatory conditions, cancer and other diseases with a projected market value of about $400 billion by 2030,” Conn said.

    An international patent application has been filed for RMIT’s technology.

    Strong pre-clinical results provide optimism for a new way to deliver insulin

    The team has tested the new oral capsule with insulin in a pre-clinical study and the results have been published in the international journal Biomaterials Advances.

    “We think the results are really exciting, and we’re doing a suite of pre-clinical testing so we can move to clinical trials as soon as possible,” Conn said.

    The research paper assessed the performance of the oral capsules with both fast-acting and slow-acting insulin.

    “When controlling the blood-sugar, you need a very fast response if you’re eating a meal. That’s known as fast-acting insulin,” Conn said.

    A slow-acting form acts over a much longer timeframe – up to a day or so – to keep the insulin in the body steady. Most diabetics take a combination of both types of insulin.

    “We had excellent absorption results for the slow-acting form – about 50% better than injection delivery for the same quantity of insulin,” Conn said.

    The capsule achieved good absorption results for fast-acting insulin, but the significant lag in the insulin taking effect compared with injection delivery would likely make it less practical.

    “Our results show there is real promise for using these oral capsules for slow-acting insulin, which diabetics could one day take in addition to having fast-acting insulin injections,” Conn said.

    “The oral capsules could potentially be designed to allow dosing over specific time periods, similar to injection delivery. We need to investigate this further, develop a way of doing so and undergo rigorous testing as part of future human trials.” 

    How does the team’s drug capsule work?

    Dr Jamie Strachan, the first author on the paper, said the capsule protected the drug inside so that it passed safely through the stomach to the small intestine.

    “The capsule has a special coating designed to not breakdown in the low pH environment of the stomach, before the higher pH levels in the small intestine trigger the capsule to dissolve,” said Strachan, from RMIT’s School of Science.

    “We package the insulin inside a fatty nanomaterial within the capsule that helps camouflage the insulin so that it can cross the intestinal walls.

    “It’s actually similar to how the Pfizer and the Moderna COVID vaccines work where the mRNA in those vaccines is also packaged within fats, helping to keep the drugs active and safe during delivery in the body.”

    These vaccines contain mRNA, which is similar to DNA, to safely carry the instructions for making a viral protein within the body, activating our immune system.

    A cheaper and more efficient way to deliver protein drugs

    Dr Céline Valéry, a pharmaceutical scientist from RMIT and study co-author, said they used the same amount of insulin in the oral capsules and in the injection delivery.

    “For many pre-clinical trials the oral formulations by necessity contain much higher levels of insulin to achieve the same response as the injection delivery. This is not a very cost-effective way to deliver protein drugs which tend to be expensive,” said Valéry, from RMIT’s School of Health and Biomedical Sciences.

    “It’s a great starting point but we need to do further trials to develop an alternative, pain-free method for the delivery of insulin and other protein drugs.”  

    ‘A promising new oral delivery mode for insulin using lipid-filled enteric-coated capsules,’ is published in Biomaterials Advances (DOI: 10.1016/j.bioadv.2023.213368).

    Jamie Strachan, Brendan Dyett, Stanley Chan, Brody McDonald, Ross Vlahos, Céline Valéry and Charlotte Conn are co-authors.

    MULTIMEDIA FOR MEDIA USE

    Here’s a link to images related to the story: https://cloudstor.aarnet.edu.au/plus/s/4gw6HYR8NokqnAL.

    There are photos of the oral capsule, along with a visual explanation from the scientists of what’s in the capsule and how it is prepared.

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    RMIT University

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  • Fungus/Fungal Disease Expert Can Comment on Outbreak at Healthcare Facilities

    Fungus/Fungal Disease Expert Can Comment on Outbreak at Healthcare Facilities

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    Darin Wiesner, a professor at Rutgers New Jersey Medical School who studies fungal disease, can comment on the surge of drug-resistant fungal infections at medical facilities across the US.

    The following quotes from Wiesner are available to journalists covering the issue.

    • Several aspects of C. auris should be concerning to immunocompromised patients, including the elderly and chronically ill, that receive care in a healthcare setting.
    • The fungus can access parts of an immunocompromised patient’s body that cause serious disease and make the treatment extremely difficult. C. auris is resistant to a few of the already small list of available antifungal medications.
    • At-risk populations congregate at healthcare facilities, C. auris tends to accumulate in areas that sick patients frequent, and the cycle repeats.
    • C. auris can grow on the skin and in nasal cavities of caregivers, as well as on surfaces of equipment and furniture at healthcare facilities.
    • Currently, there are only three classes of anti-fungal drugs. C. auris is completely resistant to one of them (azoles) and is evolving resistance to the others (polyenes and echinocandins). Like multi-drug resistant bacteria (e.g., MRSA), C. auris poses a serious risk of depleting treatment options and, consequently, increasing both the cost of treatment and the mortality of infected patients. Thankfully, developing new anti-fungal drugs is a very active area of investigation among academic researchers.

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    Rutgers University-New Brunswick

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  • Resistant bacteria are a global problem. Now researchers may have found the solution

    Resistant bacteria are a global problem. Now researchers may have found the solution

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    Newswise — Staphylococcus aureus. You may have had it in connection with a wound infection. In most cases, it will pass without treatment, while severe cases may require antibiotics, which kills the bacteria. This is the case for the majority of the population. In fact, many of us – though we feel perfectly fine – carry staphylococci in the nose, a good, moist environment in which the bacteria thrive.

    However, more and more staphylococci are becoming resistant to antibiotics (also known as multi resistant staphylococcus aureus or MRSA), and these infections can be difficult to treat.

    “Antibiotics resistance is an increasing problem, especially on a global scale. And when you have this relatively simple infection which suddenly cannot be treated with antibiotics, the situation can turn serious, sometimes life-threatening,” says Professor Niels Ødum from the LEO Foundation Skin Immunology Research Center at the University of Copenhagen.

    Therefore, all over the world, a lot of resources are being invested in fighting antibiotics resistance in staphylococcus aureus infections, and a new study among skin lymphoma patients has produced positive results. A new substance called endolysins has proven capable of killing both resistant and non-resistant staphylococcus aureus – without the need for antibiotics. But we will get back to that.

    The discovery is good news to patients with a weak immune system to whom a staphylococcus aureus infection can be serious and, at worst, fatal. But it also adds to the knowledge we have of other forms of treatment.

    “To people who are severely ill with e.g. skin lymphoma, staphylococci can be a huge, sometimes insoluble problem, as many are infected with a type of staphylococcus aureus that is resistant to antibiotics,” says Niels Ødum and adds:

    “That is why we are careful not to give antibiotics to everyone, because we do not want to have to deal with more resistant bacteria. Therefore, it is important that we find new ways of treating – and not the least to prevent – these infections.”

    New substance may be the answer

    In some patients, a staphylococcus aureus will cause the cancer to worsen. And even though antibiotics appear to work in some cases, it is not without its problems.

    “We can tell that giving high doses of antibiotics to patients with serious infections causes their health, skin and cancer symptoms to improve. But once we stop giving them antibiotics, the symptoms and staphylococci quickly return. Patients experience many adverse effects, and some risk getting resistant bacteria,” says Niels Ødum.

    Therefore, treating staphylococcus aureus can be tricky. At worst, cancer patients may die of an infection which doctors are unable to treat.

    And this is where endolysins enter the scene, as this new substance may be part of the solution to antibiotics resistance like MRSA.

    “This particular endolysin is a brand new, artificially produced enzyme that has been improved several times and designed as a new drug,” explains Postdoc Emil Pallesen, who is first author of the study. He adds:

    “The great thing about this enzyme is that it has been designed to penetrate the wall of staphylococcus aureus. This enables it to target and kill the harmful staphylococcus and leave harmless skin bacteria unharmed.”

    And that is what made the researchers decide to test the new substance; they expected it to be able to kill both resistant and non-resistant staphylococcus bacteria.

    “We have been testing the substance on skin samples from patients, and it does appear to kill staphylococcus aureus from patients. Endolysins do not care whether the bacterium is resistant to antibiotics or not, because it does not work in the same way as antibiotics,” says Niels Ødum and adds:

    “The really good news is that our lab tests have showed that endolysins do not just eradicate staphylococcus aureus; they also inhibit their ability to promote cancer growth.”

    The study, “Endolysin inhibits skin colonization by patient-derived Staphylococcus aureus and malignant T cell activation in cutaneous T cell lymphoma”, is published in the Journal of Investigative Dermatology.

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    University of Copenhagen, Faculty of Health and Medical Sciences

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  • New Class of Drugs Could Prevent Resistant COVID-19 Variants

    New Class of Drugs Could Prevent Resistant COVID-19 Variants

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    Newswise — The constant evolution of new COVID-19 variants makes it critical for clinicians to have multiple therapies in their arsenal for treating drug-resistant infections. Researchers have now discovered that a new class of oral drugs that acts directly on human cells can inhibit a diverse range of pathogenic SARS-CoV-2 strains.

    In their newly published study, the team found a novel mechanism through which the gene that expresses angiotensin converting enzyme-2 (ACE-2)—the cellular receptor to which SARS-CoV-2 binds so that it can enter and infect the cell—is turned on. They also found that a class of oral drugs currently in human clinical trials can block this pathway and potentially be a therapeutic for all SARS-CoV-2 variants, as well as any newly emerging SARS-like viruses. The team published its findings in Nature Genetics on March 8.

    Targeting these master regulatory complexes complements existing approaches and fills a need for a new drug class that can be exploited to help combat drug resistance and infection. -Craig Wilen, MD, PhD

    “Because of drug-resistant variants, we’re down to only one drug, Paxlovid, as far as our oral options,” says Craig Wilen, MD, PhD, associate professor of laboratory medicine and of immunobiology, and a member of Yale Cancer Center. “Targeting these master regulatory complexes complements existing approaches and fills a need for a new drug class that can be exploited to help combat drug resistance and infection.” Wilen and Cigall Kadoch, PhD, of Dana-Farber Cancer Institute, are co-senior authors of the study. The co-first authors are Jin Wei, PhD, postdoctoral scholar in the Wilen Lab, and Ajinkya Patil, MS, graduate student in the Kadoch Lab and the Program in Virology at Harvard Medical School.

    Researchers Identify Potential Anti-Viral Targets

    In a previous study published in 2021, Wilen’s team at Yale performed genetic screening to identify host factors that are essential for SARS-CoV-2 infection. One of the key players was the mammalian switch/sucrose non-fermentable (mSWI/SNF, also called BAF) chromatin remodeling complex, a group of over a dozen very conserved proteins that allow certain genes to turn on.

    “At that point, I’d never heard of it in the setting of virus infection, and we couldn’t understand why it was important for coronaviruses,” says Wilen. Thus, the group teamed up with experts on this complex, the Kadoch Lab at the Dana-Farber Cancer Institute and Harvard Medical School to find out how the protein complex acts to make cells susceptible to infection and if newly emerging drugs against these complexes could stunt viral infection.

    At the time they embarked on their collaborative work, the U.S. Food and Drug Administration had authorized six monoclonal antibody treatments for emergency use, yet none of these treatments work against the newest Omicron variants. This leaves clinicians with remdesivir, which can only be administered through an IV, limiting its use; molnupiravir, an oral drug that works similarly to remdesivir but only has 30 percent efficacy; and Paxlovid, an oral antiviral that works through inhibiting the viral protease. Paxlovid, Wilen says, is the mainstay of current treatment.

    “It’s a great drug that works well, but there has been some emerging drug resistance to it,” he says. “And currently, that is the only drug in our toolbox that we can give as an oral form.” The dwindling of effective treatments further highlights the critical need for a new class of drugs to add to the toolbox, and ideally, ones that are less susceptible to quick-acting resistance mechanisms.

    Blocking mSWI/SNF Protects Cells Against SARS-CoV-2

    First, the team discovered that disrupting mSWI/SNF complexes prevented viral entry into human cells. Because mSWI/SNF is known to regulate genes turning on and off, they then hypothesized that it might also play a role in activating the ACE-2 receptor. Next, they uncovered its mechanism: mSWI/SNF binds to another protein called HNF1A, a transcription factor, which directs it to the gene that encodes ACE-2. Upon disrupting mSWI/SNF complexes, the cell could no longer make ACE-2 and became resistant to infection by any virus that uses that receptor. This includes many coronaviruses.

    Small molecule inhibitors that target mSWI/SNF have already been developed by Kadoch-founded Foghorn Therapeutics and are in phase I clinical trials as a therapeutic for several cancers. Wilen and Kadoch found that this class of drugs was effective against multiple variants of SARS-CoV-2—including a remdesivir-resistant strain isolated from a Yale patient—without any adverse effects on the cell. “This is proof of principle that this can be a really important first- or second-line tool to combat drug resistance,” says Wilen.

    “Further, this speaks to the wide, multi-disease potential for pharmacologic modulation of chromatin remodeling complexes,” says Kadoch. “These molecular machines sit at the top of the pyramid in governing gene expression programs that go awry in many different human diseases—we are just at the tip of the iceberg in identifying and exploring their utility”.

    Wilen believes the drugs in these clinical trials can potentially be repurposed to inhibit both current and future coronaviruses. Furthermore, Wilen and Kadoch hope the work can provide insight into why certain people and specific cell types may be more susceptible to coronavirus than others. “Future work is needed to look at the underlying biology of why some people are asymptomatic while others experience severe infection and death,” Wilen says.

    COVID-19 will not be the last severe viral outbreak. Wilen’s lab studies coronaviruses circulating in wild bats, which he believes pose the highest risk for infecting humans and causing the next pandemic. Many of these viruses use ACE-2 as a receptor, which means that this new study may hold the key to slowing or stopping the next outbreak. “We’re going to have another pandemic, whether it’s in a few years or a decade. And we’re underprepared for it,” he says. “The best way to prepare is to have as many vaccines and drugs as possible ready to go so that we can combat the outbreak early with maximum effectiveness.”

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    Yale Cancer Center/Smilow Cancer Hospital

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  • Cancer: In Italy every year over 8000 patients candidate for liquid biopsy

    Cancer: In Italy every year over 8000 patients candidate for liquid biopsy

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    Newswise — Rome, 21 February 2023 – Almost 8,000 lung cancer patients are thought to qualify for a liquid biopsy each year in Italy in order to determine the best course of treatment. But in the not-too-distant future, the number of cancer patients for whom a simple blood test will choose the optimum course of treatment will grow dramatically. Blood sample enables continuous, real-time monitoring of the neoplasm’s development, much like in a video. An image of the tumour at the time of diagnosis can only be captured by a conventional biopsy, which is performed on tumour tissue. Also, even if it doesn’t currently reflect clinical practise, the difficulty is in using a blood test to make an early cancer diagnosis. The study, which is presented in the book “Liquid Biopsy: New Challenges in the Age of Immunotherapy and Precision Oncology,” by Antonio Russo, Ettore Capoluongo, Antonio Galvano, and Antonio Giordano, Ed. Elsevier, brings up truly innovative views on the use of liquid biopsy, which was presented today at a press conference in the Chamber of Deputies and has signatures from the top international experts.

    “Twenty years ago, in 2003, there were fewer than 50 publications in oncology that used the term “liquid biopsy,” but today there are more than 10,000, making it a real “hot topic,” states to Antonio Russo, COMU President, Full Professor of Medical Oncology at DICHIRONS – University of Palermo, and Treasurer of AIOM (Italian Association of Medical Oncology). The “Liquid Biopsy” manual serves as evidence of both the prominence of Sicily, specifically the University of Palermo, and the brilliance attained in this subject by Italian scholars across the globe.

    “Up to this point,“ continues Professor Russo, “the applications of liquid biopsy that have been shown effective in clinical practise involve advanced stage non-small cell lung cancer, for the assessment of the EGFR gene mutational status. In two clinical contexts, the method is suggested in these instances as a possible alternative for tumour tissue examination. 

    First of all, in patients who have just received a diagnosis and prior to beginning any kind of treatment, when the quantity or quality of tissue available is insufficient to perform the anticipated molecular analyses, when the molecular analysis of tissue has been found to be insufficient, or when it is impossible to obtain biopsy tissue due to the patient’s poor clinical conditions. It should be kept in mind that, even when used for histological diagnosis, the tissue sample is not acceptable for molecular characterization in roughly 30% of instances. In the second scenario, the liquid biopsy provides a very important contribution during the monitoring of patients with EGFR gene mutation, in progression after first-line treatment with targeted therapies, i.e. with first and second generation EGFR inhibitors. In these cases, blood sampling is very useful for searching for a specific resistance mutation and directing the change of cure, i.e. treatment with the third generation EGFR inhibitor. The latter, in light of the robust overall survival data, has now become a solid option on the front line and, given the high inhibitory activity, has made the use of liquid biopsy for the search for the resistance mutation secondary”.

    “The liquid biopsy has undoubted advantages over the traditional approach consisting of the analysis of tumor tissue – says Antonio Giordano, Director of the Sbarro Institute for Cancer Research and Molecular Medicine of Temple University in Philadelphia (USA) and Professor of Anatomy and Pathological Histology at the University of Sien, and Founder and President of the Sbarro Health Research Organization (SHRO). “It is minimally invasive, low-cost, has very fast reporting times and is practically free of complications, because it can be performed with a simple blood sample. Furthermore, it is characterized by a high level of acceptance by patients and can be repeated without problems, by performing serial sampling to highlight the onset of resistance to therapy in real time and, if necessary, modify the treatment.”

    “The liquid biopsy has undeniable advantages over the conventional method that involves the study of tumour tissue,” says Antonio Giordano, Director of the Sbarro Institute for Cancer Research and Molecular Medicine of Temple University in Philadelphia (USA) and Professor of Anatomy and Pathological Histology at the University of Siena, “It is less invasive, inexpensive, has extremely quick turnaround times, and is essentially complication-free because it can be carried out with a simple blood sample. Furthermore, serial sampling is used to highlight the development of therapy resistance in real time and, if necessary, change the treatment. It is characterised by a high level of patient acceptability and can be repeated without issues.

    Instead, very few patients opt to have a second tissue evaluation, in part because the general clinical circumstances often exclude it. Moreover, the tissue biopsy sample, particularly when it is obtained through fine-needle aspiration, may not necessarily be an accurate representation of the entire tumour. This is not the case with the liquid biopsy, which solves the issue of the heterogeneity of the tumour tissues by analysing the tumour DNA discharged into the circulation.”

    The predominant biopsy method currently utilised in clinical practise today is the examination of circulating tumour DNA, or ctDNA (circulating tumour DNA), which is a fraction of circulating free DNA (cell free DNA, or cfDNA), isolated from peripheral blood (particularly from plasma).

    “The chance of success is dependent on the quantity of ctDNA in the peripheral blood, which may impact the test’s sensitivity,” underlines Ettore Capoluongo, Full Professor of Clinical Biochemistry and Clinical Molecular Biology and SOC Director of Clinical Pathology and Genomics, Cannizzaro Hospital of Catania, “One drawback is that, depending on the volume and locations of the disease, the amount of ctDNA in the context of cfDNA is frequently limited, and this might result in “false negative” results on the liquid biopsy sample. The size and stage of the tumour are really connected to the concentration of ctDNA in plasma, with advanced-stage neoplasms releasing more ctDNA than early-stage ones. Exosomes, platelets, circulating tumour cells, circulating tumour RNA and microRNA, as well as other biological fluids like urine, saliva, ascitic fluid, and pleural could all be used in clinical practise in the future to provide additional information beyond that provided by the analysis of ctDNA isolated from plasma.” It is crucial that the measurement of these molecular tumour markers be as consistent as possible; for this reason, using liquid biopsy as part of the diagnostic process is the perfect scenario for clinic and laboratory collaboration.

    “Due to its capability to swiftly translate laboratory discoveries into clinical applications, the liquid biopsy must only be examined in laboratories that pass quality controls and serves as a key illustration of translational medicine,” explains Marcello Ciaccio, Full Professor of Clinical Biochemistry , Dean of the School of Medicine and Surgery of the University of Palermo, Past President and President-elect of SIBioC (Italian Society of Clinical Biochemistry and Clinical Molecular Biology), “which enables the simultaneous identification of all forms of genetic changes in several genes during a single liquid biopsy study. NGS is more cost-effective than a single gene method, according to cost analyses. This advantage becomes even clearer once a threshold of patients has been evaluated in order to fully realise the potential of NGS technologies, which enable the simultaneous profiling of several individuals while optimising costs and turnaround times. The subsequent step will be to make NGS approaches accessible and convenient to utilise. Building a real network is important to accomplish this goal.”

    “The liquid biopsy definitively establishes the importance of multidisciplinarity,” says Saverio Cinieri, National President of AIOM (Italian Association of Medical Oncology), “The Molecular Tumor Boards, interdisciplinary committees where various talents are combined to govern the clinical and decision-making processes of appropriateness, are responsible for selecting the material to be exposed to molecular analysis. Yet it’s important to make a distinction between regular clinical practise and research. Although if research efforts are in the right direction, it is not yet possible to diagnose cancer from a blood sample. Nowadays, the liquid biopsy plays a significant role as a predictor of response to therapy in lung cancer. An investigation based on a novel strategy, namely the methylation signatures of circulating free DNA, was presented at the most recent Congress of the European Society of Oncology. There were more than 6,000 participants who were over 50, appeared healthy, and had never been given a cancer diagnosis. In 1.4% of the participants, the test revealed changes in the methylation profile, which are common to more than 50 distinct forms of neoplasms. Among these individuals, the oncological diagnosis was confirmed in around 40% of the instances. Yet, in more than 60% of cases, no oncological illness diagnosis was made after the positive test results.”

    “The sensitivity of the liquid biopsy, in a context of early diagnosis, is therefore still conditioned by a high rate of false positives, the causes of which are being studied,” continues the AIOM President, “The emerging clinical applications of this procedure mainly concern colorectal, breast and advanced melanoma cancers. Indeed, there is solid and reproducible information regarding the characterization of RAS and BRAF genes for colorectal, PIK3CA for breast, BRAF and NRAS in melanoma. It is likely that plasma analysis for this type of alteration will soon be recommended in clinical practice”.

    “In order to personalise treatment, a very active area of study is the use of liquid biopsy in immunotherapy. This field has the potential to produce “dynamic” and reproducible biomarkers in the near future,” highlights Antonio Galvano, Associate Professor of Medical Oncology at the University of Palermo, “Only a fraction of patients today show a significant response or long-term benefit with immunotherapy drugs. Individual biological and immune factors affect the heterogeneity in the response. For this reason, the identification of predictive biomarkers of response or resistance to treatment, for example, with immune checkpoint inhibitors, assumes an important role. Numerous studies are underway with the aim of evaluating the potential use of cfDNA, ctDNA and soluble forms of immune checkpoints as predictive biomarkers of response. In recent years, our research group has published studies conducted mainly on lung, pancreatic and melanoma tumors in important international scientific journals. It is crucial to keep moving in this direction. “.

    “One of the roles of Patients’ Associations is to support the scientific community with regard to research progress, adopting a rigorous, but informative and easy to understand method,” continues Adriana Bonifacino, President of the IncontraDonna Foundation, “It is essential that patients are increasingly involved in trials, including those on liquid biopsy. The quality of life is becoming a central element in the evaluation of the innovativeness of treatments and the liquid biopsy fits into this context. Being able to monitor the evolution of the tumor in real time with a simple blood sample also represents an element of reassurance from a psychological point of view for the patient, as well as avoiding the invasiveness of traditional procedures on tumor tissue”.

    “The “Liquid Biopsy” book is distinguished by the special focus on educational aspects and by the inclusion of the so-called “expert comments,” authored by internationally known experts,”  concludes Professor Russo, “Our group of researchers from the University of Palermo has been conducting experiments on liquid biopsy since the early 2000s and is at the forefront in this sector, today with further studies on exosomes and on the determination of circulating immunocheckpoints. The exciting data from studies may also lead to changes in the parameters used to classify cancer stages. To the TNM system, where T describes the extent of the disease, N the status of the lymph nodes and M the possible presence of metastases, the B, such as blood, should be added, which provides information on circulating tumor DNA.”

     

     

    About the Sbarro Health Research Organization

    The Sbarro Health Research Organization (SHRO) is non-profit charity committed to funding excellence in basic genetic research to cure and diagnose cancer, cardiovascular diseases, diabetes and other chronic illnesses and to foster the training of young doctors in a spirit of professionalism and humanism. To learn more about the SHRO please visit www.shro.org

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    Sbarro Health Research Organization (SHRO)

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  • Results of the SORAYA study show conjugate therapy produced remissions in one-third of patients with drug-resistant ovarian cancer

    Results of the SORAYA study show conjugate therapy produced remissions in one-third of patients with drug-resistant ovarian cancer

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    Newswise — BOSTON – In an internationally conducted clinical trial lead by Dana-Farber involving patients with recurrent ovarian cancer that is resistant to platinum therapy, a novel conjugate therapy called mirvetuximab soravtansine resulted in substantially better responses than standard treatments.  Mirvetuximab soravtansine was granted accelerated approval by the U.S. Food and Drug Administration (FDA) in November 2022. The FDA approval was based on results of the SORAYA study which were published today in the Journal of Clinical Oncology and were previously reported at the Society for Gynecologic Oncology annual meeting in March 2022 and   the Annual American Society of Clinical Oncology meeting in June 2022.

    “The results of the SORAYA study supported the accelerated FDA approval of mirvetuximab for  patients with recurrent, platinum-resistant, folate receptor alpha-positive ovarian cancer,” Ursula A. Matulonis, MD, chief of the Division of Gynecologic Oncology  at Dana-Farber, lead author and co-principal investigator of the study. “The recent approval of this agent by the FDA makes it the first approved therapy for platinum resistant ovarian cancer since 2014, and the findings we report today in the Journal of Clinical Oncology underscore the benefit of mirvetuximab soravtansine for this patient population.”

    The study enrolled 106 patients with platinum-resistant high-grade serous ovarian cancer that highly expressed folate receptor alpha. The participants had been treated with up to three prior treatments for their ovarian cancer.

    The study results show that after a median follow-up of 13.4 months, 32.4% of participants had an objective anti-cancer response, including five who had a complete response, or the disappearance of all signs of cancer. The median duration of response was 6.9 months. Importantly, drug activity was observed irrespective of the number of previous lines of therapy received or PARP inhibitor exposure in patients having received prior bevacizumab. Mirvetuximab was well-tolerated by study participants. The most common adverse side effects associated with the treatment were blurred vision, keratopathy (a non-inflammatory condition of the eye), and nausea.

    The novel agent is one of a growing number of antibody-drug conjugates, or ADCs, which consist of a drug linked to an antibody that directly targets the cancer cell. Mirvetuximab connects an antibody targeting the folate receptor alpha molecule on high-grade serous ovarian cancers to a drug molecule called DM4 that disrupts microtubule formation. (Microtubules are major components of the cytoskeleton that give shape and structure to cells.) The folate receptor protein is far more abundant in some tumor cells than normal cells, making it an attractive target for cancer drugs.

    The study was sponsored by ImmunoGen.

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    Dana-Farber Cancer Institute

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  • Researchers receive grant to study how fungal pathogens become drug-resistant

    Researchers receive grant to study how fungal pathogens become drug-resistant

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    Newswise — A pair of Clemson University researchers are collaborating to discover why fungal pathogens become drug resistant.

    Genetics and Biochemistry Associate Professor Lukasz Kozubowski and Chemistry Professor Julia Brumaghim are studying how the fungal pathogen Cryptococcus neoformans develops resistance to azole compounds, a class of fungicides that are widely used in agriculture for crop protection and as a treatment for life-threatening human fungal infections. They received a $492,000 National Science Foundation grant for the work.

    Only three types of antifungal drugs exist, so drug resistance can severely limit treatment options.

    Most azole compounds work by inhibiting fungi rather than killing them, which makes the drugs safer for humans, said Kozubowski, co-principal investigator on the project. That’s because both humans and fungi are eukaryotic. Therefore, drugs designed to kill fungi may also harm their human hosts. Eukaryotes are single-celled or multicellular organisms whose cells contain a distinct, membrane-bound nucleus.

    Chance of drug resistance

    Conversely, while fungi-inhibiting drugs are safer for humans, their use also increases the chance of drug resistance.

    “We know resistance to azoles is a fact,” Kozubowski explained. “Apparently, the drugs can somehow stimulate the development of resistance. It is counterintuitive: You may think of a drug as killing or inhibiting the pathogen, but the drugs have some propensity to stimulate the development of resistance to the same drugs. So what they are supposed to kill, the drugs are actually stimulating the cells to develop a resistance to it.”

    It’s rare that a fungal cell isn’t killed or inhibited by antifungal treatment — and that adds a complication for the scientists.

    “The problem with resistance is that it’s quite an elusive target when it comes to understanding because essentially what we are after is an event that happens maybe one in a million times,” Kozubowski said. “You have a population of millions of cells, and unfortunately, if the drug doesn’t kill them all, there will always be that lucky cell, that one in a million, that develops something that causes resistance.”

    Drug resistance is also a problem with antibiotics, Kozubowski noted. 

    Emerging problem

    Fungal drug resistance is an emerging problem that is also growing in scope, adding to the urgency of the Clemson scientists’ work. “It’s not a last-year emerging, but in the past decades, we’ve been experiencing drug-resistant fungal infections. That’s true for bacterial infections as well,” Kozubowski said.

    Ultimately, he said the researchers’ goal is to better understand how drugs such as the azole compounds stimulate the mechanism of drug resistance. A top suspect: damaged DNA.

    Enter Brumaghim, the project’s principal investigator, who said she became interested in the project because her work focuses on how cellular DNA becomes damaged, which complements Kozubowski’s research.

    “I got involved in the project because I found out [Kozubowski] was working on how these compounds generate reactive oxygen species like the radical species that can damage DNA,” Brumaghim recalled. 

    Reactive oxygen species are unstable molecules that contain oxygen and easily react with other molecules in a cell. 

    “He said, ‘this is the mechanism, but we know nothing about how this could happen.’ And that’s what I do. We look at how metals generate these radical species that damage DNA,” Brumaghim said

    Then, the question facing Brumaghim and Kozubowski was, “what happens if you have more damage [to cellular DNA] than can be repaired,” Brumaghim said. “Then you get into trouble. If a cell cannot replicate its DNA sufficiently, it will die. It’s called ‘programmed cell death.’… The alternative to that is when you have mutations to the DNA, and the cell would be better off dying, but it doesn’t — that leads to cancer. Or with fungi, it leads to drug resistance — or that’s what we think.”Kozubowski described the interdepartmental collaboration as a “natural match.” 

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    Clemson University

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