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Microbiology

University of Louisville researchers receive $5.8 million to prevent immune system dysregulation

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Reviewed by Megan Craig, M.Sc.Jun 2 2023

Researchers at the University of Louisville have received $5.8 million in two grants from the National Institutes of Health to expand their work to better understand and prevent immune system dysregulation responsible for acute respiratory distress, the condition responsible for serious illness and death in some COVID-19 patients. A separate $306,000 NIH Small Business Innovation Research grant supports early testing of a compound developed at UofL as a potential treatment.

The three grants combined total $6.1 million.

During the pandemic, health care providers worked tirelessly to treat patients who became seriously ill with COVID-19. Some of those patients developed severe lung disease known as acute respiratory distress syndrome (ARDS) due to an excessive response of the immune system often called cytokine storm.

As they treated these critically ill patients, physicians and other providers at UofL Health shared their clinical insights and patient samples with researchers at UofL to discover the cause of the immune system overresponse.

At one time we had over 100 patients with COVID in the hospital. Once they were on a ventilator, mortality was about 50%. We were looking at this issue to see why some people would do well while some developed bad lung disease and did not do well or died.”

Jiapeng Huang, an anesthesiologist with UofL Health and professor and vice chair of the Department of Anesthesiology and Perioperative Medicine in the UofL School of Medicine

The UofL researchers, led by immunologist Jun Yan, discovered that a specific type of immune cells, low-density inflammatory neutrophils, became highly elevated in some COVID-19 patients whose condition became very severe. This elevation signaled a clinical crisis point and increased likelihood of death within a few days due to lung inflammation, blood clotting and stroke. Their findings were published in 2021 in JCI Insight.

With the new NIH funding, Yan is leading research to build on this discovery with deeper understanding of what causes a patient’s immune system to respond to an infection in this way and develop methods to predict, prevent or control the response.

“Through this fruitful collaboration, we now have acquired NIH funding for basic and translational studies and even progress toward commercialization of a potential therapy,” Yan said. “That’s why we do this research – eventually we want to benefit the patients.”

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Yan, chief of the UofL Division of Immunotherapy in the Department of Surgery, a professor of microbiology and immunology and a senior member of the Brown Cancer Center, will lead the new research, along with Huang and Silvia M. Uriarte, university scholar and professor in the Department of Oral Immunology and Infectious Diseases in the UofL School of Dentistry.

“COVID-19 continues to spotlight the impactful synergy between the clinical and research teams at the University of Louisville,” said Jason Smith, UofL Health chief medical officer. “Innovation is in the DNA of academic medicine. We collaborate to provide each patient the best options for prevention and treatment today, while developing the even better options for tomorrow.”

In addition to two research grants of $2.9 million each awarded directly to UofL, a $306,000 grant to a startup company will support early testing of a compound developed in the lab of UofL Professor of Medicine Kenneth McLeish that shows promise in preventing the dangerous cytokine storm while allowing the neutrophils to retain their ability to kill harmful bacteria and viruses. The compound, DGN-23, will be tested by UofL and Degranin Therapeutics, a startup operated by McLeish, Yan, Huang, Uriarte and Madhavi Rane, associate professor in the Department of Medicine.

“This is one more example of how UofL has led the charge in finding new and innovative ways to detect, contain and fight COVID-19 and other potential public health threats,” said Kevin Gardner, UofL’s executive vice president for research and innovation. “This team’s new research and technology could help keep people healthy and safe here and beyond.”

The knowledge gained through these studies may benefit not only COVID-19 patients, but those with other conditions in which immune dysregulation can occur, such as other types of viral and bacterial pneumonia and autoimmune diseases, and patients undergoing cancer immunotherapy and organ transplantation.

The grants

Grant 1 – $2.9 million, four-year grant to UofL. Investigators will study the new subset of neutrophils Yan identified to better understand how they contribute to acute respiratory distress and clotting. They also will determine whether a novel compound will prevent these complications. They will use lab techniques and studies with animal models that allow for manipulation of certain conditions that cannot be done in human subjects.

Grant 2 – $2.9 million, five-year grant to UofL. This work examines a more comprehensive landscape to characterize different subsets of neutrophils and measure their changes over the course of COVID-19 disease progression and how neutrophils contribute to immune dysfunction.

Grant 3 – $306,000, one-year grant to Degranin Therapeutics and UofL for early testing of DGN-23, a compound developed at UofL, to determine its effectiveness in preventing or reducing immune dysregulation.

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Source:

University of Louisville

Microbiology

Discontinuing oral antibiotics after breast reconstruction does not lead to an increase in infections

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Reviewed by Emily Henderson, B.Sc.Apr 27 2023

For breast cancer patients undergoing breast reconstruction after mastectomy, avoiding postoperative oral antibiotics does not reduce the risk of infections, reports a study in the May issue of Plastic and Reconstructive Surgery®, the official medical journal of the American Society of Plastic Surgeons (ASPS). The journal is published in the Lippincott portfolio by Wolters Kluwer.

Our experience suggests that discontinuing routine oral antibiotic treatment after implant-based breast reconstruction does not lead to an increase in surgical site infections, and will eliminate a small but significant risk of allergy and other antibiotic-related complications.”

Mark Sisco, MD, ASPS Member Surgeon, NorthShore University HealthSystem, Evanston, Ill

No increase in infections after policy change on preventive antibiotics

A growing number of breast cancer patients are undergoing breast reconstruction after mastectomy, particularly immediate reconstruction using implants. Surgical site infections (SSIs) occur in 10% to 25% of patients undergoing this procedure, leading to increased rates of hospital readmission, repeat surgery, and reconstructive failure.

Historically, plastic surgeons have given extended antibiotic prophylaxis (EAP) to reduce the risk of SSI. The use of postoperative oral antibiotics has continued despite a lack of evidence for its effectiveness, and amid rising concerns about antibiotic resistance. In 2016, the authors’ health system joined the growing trend toward ending routine EAP for post-mastectomy breast reconstruction.

To evaluate the impact of this practice change, Dr. Sisco and colleagues compared outcomes in two groups of patients: 654 women (1,004 breasts) receiving EAP and 423 women (683 breasts) not receiving postoperative oral antibiotics. Both groups received a single dose of intravenous antibiotic before surgery.

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After surgery, the overall infection rate was similar between groups: 7.9% with EAP and 9.1% without EAP. After adjustment for differences in patient characteristics, the risk of SSIs was not significantly different between groups. This was even though patients in the non-EAP were more likely to receive some newer techniques – including nipple-sparing mastectomy and pre-pectoral (“above the muscle”) implant placement – thought to carry an increased risk of complications.

‘Thousands of women nationwide’ may have adverse reactions to EAP

Meanwhile, patients receiving EAP had some “infrequent but not insignificant” adverse events, including a two percent rate of moderate to severe allergic reactions. At least four women in the EAP group developed infection with antibiotic-resistant Clostridium difficile (“C-diff”) bacteria. Neither of these complications occurred in patients who did not receive extended antibiotics.

There was also evidence that EAP affected the types of bacteria isolated from patients who developed infections, including a higher rate of gram-negative bacteria. Extended antibiotic use was associated with a “broader range of pathogens” and more frequent need for second-line intravenous antibiotics.

“Although the use of EAP does not appear to worsen clinical outcomes, marked differences in the microbiology of associated infections may make them more difficult to treat,” Dr. Sisco and coauthors write. Especially at a time when breast reconstruction rates are rapidly increasing, “Our findings suggest that thousands of women are having adverse reactions to EAP nationwide, and some of these are likely to be serious,” the researchers add.

While acknowledging some important limitations of their study, the authors note that a definitive randomized trial of ending routine EAP is unlikely to be performed. Dr. Sisco and colleagues conclude, “We hope that our experience will give surgeons additional evidence and courage to change their practice.”

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Source:

Wolters Kluwer

Journal reference:

Sisco, M., et al. (2022). Oral antibiotics do not prevent infection or implant loss after immediate prosthetic breast reconstruction: Evidence from 683 consecutive reconstructions without prophylaxis. Plastic & Reconstructive Surgery. doi.org/10.1097/prs.0000000000010073

Microbiology

Study offers a novel therapeutic option to combat antibiotic-resistant pneumonia

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Reviewed by Emily Henderson, B.Sc.Mar 29 2023

Increases in multidrug-resistance in the bacteria Streptococcus pneumoniae have made it the fourth-leading cause of death associated with antibiotic resistance.

In a study in PLOS Biology, researchers report a new target to fight against pneumonia due to infections by this opportunistic lung pathogen -; interference with the bacteria’s fermentation metabolism. This may offer a novel therapeutic option in the urgent need to discover new strategies to combat drug-resistant S. pneumoniae.

In a proof of principle, University of Alabama at Birmingham researchers showed that giving an existing drug -; one already approved by the United States Food and Drug Administration to treat methanol poisoning – in combination with the antibiotic erythromycin significantly reduced disease in mice infected with a virulent, multidrug-resistant S. pneumoniae. The combination therapy reduced bacterial burden in the lungs by 95 percent, and bacterial burdens in the spleen and heart by 100- and 700-fold, respectively. The FDA-approved drug alone, or erythromycin alone, had no effect.

Fomepizole, the FDA-approved drug, disrupts activity of the enzyme alcohol dehydrogenase in the bacteria. The mice were infected intratracheally with the multidrug-resistant clinical isolate S. pneumoniae serotype 35B strain 162–5678, which has high resistance to erythromycin. Notably, the S. pneumoniae 35B serotype has been reported as an emerging multidrug-resistant serotype in clinical settings. Eighteen hours after infection, the mice were given a single injection of erythromycin, with or without fomepizole.

Fomepizole, or other drugs that inhibit bacterial metabolism, have potential to dramatically increase the efficacy of erythromycin and other antibiotics, respectively, in vivo.”

Carlos Orihuela, Ph.D., professor and interim chair of the UAB Department of Microbiology

A broad foundation of basic research preceded this proof-of-principle experiment.

S. pneumoniae relies on fermentation and glycolysis to produce energy. During fermentation, pyruvate is converted to lactate, acetate and ethanol, and NADH is oxidized to regenerate NAD+, which is needed for glycolysis. Accordingly, maintenance of an available NAD+ pool, necessary for redox balance, is vital for sustained energy production, bacterial growth and survival.

Orihuela and UAB colleagues made S. pneumoniae mutants in five enzymes involved in fermentation and NAD+ production, and they found, in general, that the mutants had impaired metabolism. Two of the mutants, one for lactate dehydrogenase and one for alcohol dehydrogenase, had stark decreases in intracellular pool of ATP, the energy molecule of living cells. The other three mutants had significant, but more modest, decreases.

NAD+/NADH redox imbalances in the mutants generally interfered with production of S. pneumoniae virulence factors and colonization in the mouse nasopharynx. Some of the mutations influenced susceptibility to antibiotics, as tested with three antibiotics, including erythromycin, that interfere with protein synthesis, two antibiotics that disrupt cell wall synthesis and one antibiotic that targets DNA transcription.

Researchers found that treating a wildtype S. pneumoniae, which did not have mutations in alcohol dehydrogenase or the other enzymes, with fomepizole alone caused redox imbalances. In vitro tests showed that treatment of S. pneumoniae with fomepizole enhanced the susceptibility to antibiotics, including fourfold decreases in the minimal inhibitory concentrations of the antibiotics erythromycin and gentamicin.

“We also evaluated whether fomepizole treatment impacted the antibiotic susceptibility of other anaerobic gram-positive bacteria, including other streptococcal pathogens, including Streptococcus pyogenes, Streptococcus agalactiae and Enterococcus faecium, to erythromycin or gentamicin,” Orihuela said. “We observed from twofold to eightfold decreased minimal inhibitory concentration with fomepizole in most cases, including E. faecium.”

“Our results indicate that the blocking of NAD+ regeneration pathways during infection is a way to increase antibiotic susceptibility in drug-resistant gram-positive anaerobic pathogens,” Orihuela said. “This has clinical potential with regard to microbial eradication and treatment of disseminated infection.”

Globally, more than 3 million individuals are hospitalized due to pneumococcal disease annually, and hundreds of thousands die as a result.

Source:

University of Alabama at Birmingham

Journal reference:

Im, H., et al. (2023). Targeting NAD+ regeneration enhances antibiotic susceptibility of Streptococcus pneumoniae during invasive disease. PLOS Biology. doi.org/10.1371/journal.pbio.3002020.

Microbiology

Leaving lymph nodes intact until after immunotherapy could boost efficacy against solid tumors

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Reviewed by Emily Henderson, B.Sc.Mar 20 2023

Cancer treatment routinely involves taking out lymph nodes near the tumor in case they contain metastatic cancer cells. But new findings from a clinical trial by researchers at UC San Francisco and Gladstone Institutes shows that immunotherapy can activate tumor-fighting T cells in nearby lymph nodes.

The study, published March 16, 2023 in Cell, suggests that leaving lymph nodes intact until after immunotherapy could boost efficacy against solid tumors, only a small fraction of which currently respond to these newer types of treatments.

Most immunotherapies are aimed only at reinvigorating T cells in the tumor, where they often become exhausted battling the tumor’s cancer cells. But the new research shows that allowing the treatment to activate the immune response of the lymph nodes as well can play an important role in driving positive response to immunotherapy.

This work really changes our thinking about the importance of keeping lymph nodes in the body during treatment.”

Matt Spitzer, PhD, investigator for the Parker Institute for Cancer Immunotherapy and Gladstone-UCSF Institute of Genomic Immunology and senior author of the study

Lymph nodes are often removed because they are typically the first place metastatic cancer cells appear, and without surgery, it can be difficult to determine whether the nodes contain metastases.

“Immunotherapy is designed to jump start the immune response, but when we take out nearby lymph nodes before treatment, we’re essentially removing the key locations where T cells live and can be activated,” Spitzer said, noting that the evidence supporting the removal of lymph nodes is from older studies that predate the use of today’s immunotherapies.

Aim for the lymph nodes, not the tumor

Researchers have largely been working under the assumption that cancer immunotherapy works by stimulating the immune cells within the tumor, Spitzer said. But in a 2017 study in mice, Spitzer showed that immunotherapy drugs are actually activating the lymph nodes.

“That study changed our understanding of how these therapies might be working,” said Spitzer. Rather than the immunotherapy pumping up the T cells in the tumor, he said, T cells in the lymph nodes are likely the source for T cells circulating in the blood. Such circulating cells can then go into the tumor and kill off the cancer cells.

Having shown that intact lymph nodes can temper cancer’s hold in mice, Spitzer’s team wanted to know whether the same would prove true in human patients. They chose to design a trial for patients with head and neck cancers because of the high number of lymph nodes in those areas.

The trial enrolled 12 patients whose tumors hadn’t yet metastasized past the lymph nodes. Typically, such patients would undergo surgery to remove the tumor, followed by other treatments if recommended.

Instead, patients received a single cycle of an immunotherapy drug called atezolizumab (anti-PD-L1) that is produced by Genentech, a sponsor of the trial. A week or two later, Spitzer’s team measured how much the treatment activated the patients’ immune systems.

The treatment also included surgically removing each patient’s tumor and nearby lymph nodes after immunotherapy and analyzing how the immunotherapy affected them.

The team found that, after immunotherapy, the cancer-killing T cells in the lymph nodes began springing into action. They also found higher numbers of related immune cells in the patients’ blood.

Spitzer attributes some of the trial’s success to its design, which allowed the team to get a lot of information from a small number of patients by looking at the tissue before and after surgery and running detailed analyses.

“Being able to collect the tissue from surgery shortly after the patients had been given the drug was a really unique opportunity,” he said. “We were able to see, at the cellular level, what the drug was doing to the immune response.”

That kind of insight would be challenging to get from a more traditional trial in patients with later-stage disease, who would not typically benefit from undergoing surgery after immunotherapy.

Metastases inhibit immune response

Another benefit of the study design was that it allowed researchers to compare how the treatment affected lymph nodes with and without metastases, or a second cancer growth.

“No one had looked at metastatic lymph nodes in this way before,” said Spitzer. “We could see that the metastases impaired the immune response relative to what we saw in the healthy lymph nodes.”

It could be that the T cells in these metastatic nodes were less activated by the therapy, Spitzer said. If so, that could explain, in part, the poor performance of some immunotherapy treatments.

Still, the therapy prompted enough T-cell activity in the metastatic lymph nodes to consider leaving them in for a short period of time until treatment ends. “Removing lymph nodes with metastatic cancer cells is probably still important but taking them out before immunotherapy treatment may be throwing the baby out with the bathwater,” said Spitzer.

A subsequent goal of the current trial is to determine whether giving immunotherapy before surgery protects against the recurrence of tumors in the future. Researchers won’t know the answer to that until they’ve had a chance to monitor the participants for several years.

“My hope is that if we can activate a good immune response before the tumor is taken out, all those T cells will stay in the body and recognize cancer cells if they come back,” Spitzer said.

Next, the team plans to study better treatments for patients with metastatic lymph nodes, using drugs that would be more effective at reactivating their immune responses.

Source:

University of California – San Francisco

Journal reference:

Rahim, M. K., et al. (2023). Dynamic CD8+ T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes. Cell. doi.org/10.1016/j.cell.2023.02.021

Microbiology

Research identifies western diet-induced microbial and metabolic contributors to liver disease

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Reviewed by Emily Henderson, B.Sc.Mar 15 2023

New research from the University of Missouri School of Medicine has established a link between western diets high in fat and sugar and the development of non-alcoholic fatty liver disease, the leading cause of chronic liver disease.

The research, based in the Roy Blunt NextGen Precision Health Building at MU, has identified the western diet-induced microbial and metabolic contributors to liver disease, advancing our understanding of the gut-liver axis, and in turn the development of dietary and microbial interventions for this global health threat.

We’re just beginning to understand how food and gut microbiota interact to produce metabolites that contribute to the development of liver disease. However, the specific bacteria and metabolites, as well as the underlying mechanisms were not well understood until now. This research is unlocking the how and why.”

Guangfu Li, PhD, DVM, co-principal investigator, associate professor in the department of surgery and Department of Molecular Microbiology and Immunology

The gut and liver have a close anatomical and functional connection via the portal vein. Unhealthy diets change the gut microbiota, resulting in the production of pathogenic factors that impact the liver. By feeding mice foods high in fat and sugar, the research team discovered that the mice developed a gut bacteria called Blautia producta and a lipid that caused liver inflammation and fibrosis. That, in turn, caused the mice to develop non-alcoholic steatohepatitis or fatty liver disease, with similar features to the human disease.

“Fatty liver disease is a global health epidemic,” said Kevin Staveley-O’Carroll, MD, PhD, professor in the department of surgery, one of the lead researchers. “Not only is it becoming the leading cause of liver cancer and cirrhosis, but many patients I see with other cancers have fatty liver disease and don’t even know it. Often, this makes it impossible for them to undergo potentially curative surgery for their other cancers.”

As part of this study, the researchers tested treating the mice with an antibiotic cocktail administered via drinking water. They found that the antibiotic treatment reduced liver inflammation and lipid accumulation, resulting in a reduction in fatty liver disease. These results suggest that antibiotic-induced changes in the gut microbiota can suppress inflammatory responses and liver fibrosis.

Li, Staveley-O’Carroll and fellow co-principal investigator R. Scott Rector, PhD, Director of NextGen Precision Health Building and Interim Senior Associate Dean for Research -; are part of NextGen Precision Health, an initiative to expand collaboration in personalized health care and the translation of interdisciplinary research for the benefit of society. The team recently received a $1.2 million grant from the National Institutes of Health to fund this ongoing research into the link between gut bacteria and liver disease.

Source:

University of Missouri-Columbia

Journal reference:

Yang, M., et al. (2023). Western diet contributes to the pathogenesis of non-alcoholic steatohepatitis in male mice via remodeling gut microbiota and increasing production of 2-oleoylglycerol. Nature Communications. doi.org/10.1038/s41467-023-35861-1.

Microbiology

Study finds two substances capable of inhibiting proliferation of glioblastoma cells

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Reviewed by Emily Henderson, B.Sc.Mar 7 2023

Glioblastoma is a malignant tumor of the central nervous system (brain or spinal cord) and one of the deadliest types of cancer. Few drugs have proved effective at combating this uncontrolled growth of glial cells, which anyway constitute a large proportion of the brain tissue in mammals. The standard treatment is surgical removal of the tumor, followed by chemotherapy with temozolomide, radiation therapy, and then nitrosoureas (such as lomustine). Patient survival has improved moderately over the years, but the prognosis remains poor. These tumors are typically resistant to existing drugs and often grow back after surgery.

Promising results have now been reported in a study involving two substances found to inhibit proliferation of glioblastoma cells. An article on the study is published in the journal Scientific Reports.

The researchers conducted in vitro tests to evaluate the biological effects of 12 compounds obtained through total synthesis of apomorphine hydrochloride against glioblastoma cells. They found that two of these compounds – an isoquinoline derivative called A5 and an aporphine derivative called C1 – reduced the viability of glioblastoma cells, suppressed the formation of new tumor stem cells and boosted the effectiveness of temozolomide.

More research is needed to glean a better understanding of the action of these compounds on tumor cells and normal cells, but the results so far suggest a potential therapeutic application as novel cytotoxic agents to control glioblastomas.”

Dorival Mendes Rodrigues-Junior, first author of the article and postdoctoral researcher, University of Uppsala’s Department of Medical Biochemistry and Microbiology, Sweden

In designing the study, the researchers leveraged the apomorphine hydrochloride production process, in which each step in a sequence of chemical reactions creates compounds that are consumed in the next step. Previous research conducted by the group to evaluate the effectiveness of 14 of these compounds against head and neck squamous cell cancer had shown that A5 and C1 were promising, and they decided to conduct more tests. “Given the importance and urgency of identifying novel therapeutic substances that can be used to treat glioblastoma, we evaluated the same panel as in the previous study but now for this other type of tumor,” Rodrigues-Junior said.

The project on molecular markers of head and neck cancer was supported by FAPESP and also involved André Vettore, another author of the recently published article. Vettore is a professor in the Department of Biological Sciences at the Federal University of São Paulo (UNIFESP) in Diadema, Brazil.

“The findings of this study are interesting, but they’re only the first steps in a long journey. In vivo studies are still required to confirm the effects of A5 and C1 on glioblastoma cells and non-tumorigenic nerve cells,” Vettore said.

If the results of this future research are also promising, he added, it will be possible to move on to clinical trials to confirm the effectiveness of the compounds. “Once all these stages are completed, the compounds may finally be used to treat glioblastoma patients.”

Natural bioactive products

The study was conducted in vitro to evaluate the antitumor activity of 12 aromatic compounds obtained as intermediates in total synthesis of apomorphine, an alkaloid that interacts with the dopamine pathway and is widely used to control the motor alterations caused by Parkinson’s disease.

Alkaloids are a well-known class of natural products with multiple pharmacological properties and are studied for their anticonvulsant, antiplatelet aggregation, anti-HIV, dopaminergic, antispasmodic and anticancer effects.

FAPESP fosters studies of these substances via a project on bioactive natural products led at UNIFESP’s Department of Chemistry in Diadema by Cristiano Reminelli, second author of the Scientific Reports article. The other authors are Haifa Hassanie, Gustavo Henrique Goulart Trossini, Givago Prado Perecim, Laia Caja and Aristidis Moustakas.

Source:

São Paulo Research Foundation (FAPESP)

Journal reference:

Rodrigues-Junior, D.M., et al. (2023) Aporphine and isoquinoline derivatives block glioblastoma cell stemness and enhance temozolomide cytotoxicity. Scientific Reports. doi.org/10.1038/s41598-022-25534-2.

Microbiology

Cold snare polypectomy significantly reduces bleeding risk compared to hot snare polypectomy

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A randomized controlled trial (RCT) of more than 4,000 people found that the risk for delayed bleeding after polypectomy was significantly reduced among persons who received a cold snare polypectomy. The findings are published in Annals of Internal Medicine.

More than 16 million colonoscopies are performed annually in the U.S., and polypectomy during colonoscopy plays a pivotal role in preventing . Hot snare polypectomy (HSP) has been conventionally used to remove polyps but is associated with a higher risk of delayed bleeding, post-polypectomy syndrome, or perforation. Previous research on cold snare polypectomy (CSP) demonstrated that CSP was as effective as HSP but more efficient in removing small polyps, but its effect on reducing delayed bleeding has been shown only in high-risk patients.

Researchers from National Taiwan University Hospital conducted an RCT of 4,270 participants who were undergoing polypectomy in six centers in Taiwan. They report that only 8 out of 2,137 persons, or 0.4%, experienced delayed bleeding after CSP. In comparison, 31 out of 2,133 persons, or 1.5%, experienced delayed bleeding after HSP. They also report that only 0.2% of CSP group had emergency service visits compared with 0.6% of the HSP group. The authors show that CSP was also more efficient, with the study’s results showing that the time required for polypectomy is reduced by 26.9%.

According to the authors, the findings support the superior safety of CSP over HSP in managing colorectal sized 10 mm or smaller in the .

More information:
Li-Chun Chang et al, Cold Versus Hot Snare Polypectomy for Small Colorectal Polyps, Annals of Internal Medicine (2023). DOI: 10.7326/M22-2189

Journal information:
Annals of Internal Medicine

American College of Physicians

Science X Network

Microbiology

Screening patients for hidden reservoirs of bacteria could supplement infection-control efforts in hospitals

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Reviewed by Emily Henderson, B.Sc.Jan 12 2023

Hospitals have strict hygiene and sanitation protocols to protect patients from bacteria that rarely sicken healthy people but can be deadly for vulnerable patients already hospitalized with serious illnesses. Nearly 100,000 people die every year in U.S. hospitals of infections they develop after being admitted. But despite intense infection-control efforts, new strains of bacteria keep on emerging, seemingly out of nowhere, to sicken people in hospitals worldwide.

Researchers at Washington University School of Medicine in St. Louis have found evidence pointing to an unexpected source of such bacteria: the hospitalized patients themselves. Studying mice, the researchers discovered that urinary tract infections (UTIs) can arise after sterile tubes, called catheters, are inserted into the urinary tract, even when no bacteria are detectable in the bladder beforehand. Such tubes are commonly used in hospitals to empty the bladders of people undergoing surgery. In the mice, inserting the tubes activated dormant Acinetobacter baumannii (A. baumannii)bacteria hidden in bladder cells, triggering them to emerge, multiply and cause UTIs, the researchers said.

The findings, published Jan. 11 in Science Translational Medicine, suggest that screening patients for hidden reservoirs of dangerous bacteria could supplement infection-control efforts and help prevent deadly infections.

You could sterilize the whole hospital, and you would still have new strains of A. baumannii popping up. Cleaning is just not enough, and nobody really knows why. This study shows that patients may be unwittingly carrying the bacteria into the hospital themselves, and that has implications for infection control. If someone has a planned surgery and is going to be catheterized, we could try to determine whether the patient is carrying the bacteria and cure that person of it before the surgery. Ideally, that would reduce the chances of developing one of these life-threatening infections.”

Mario Feldman, PhD, co-senior author, professor of molecular microbiology

A. baumannii is a major threat to hospitalized people, causing many cases of UTIs in people with urinary catheters, pneumonia in people on ventilators, and bloodstream infections in people with central-line catheters into their veins. The bacteria are notoriously resistant to a broad range of antibiotics, so such infections are challenging to treat and easily can turn deadly.

Feldman teamed up with co-senior author Scott J. Hultgren, PhD, the Helen L. Stoever Professor of Molecular Microbiology and an expert on UTIs, to investigate why so many A. baumannii UTIs develop after people receive catheters.

Most UTIs among otherwise healthy people are caused by the bacterium Escherichia coli (E. coli). Research has shown that E. coli can hide out in bladder cells for months after a UTI seems to have been cured, and then re-emerge to cause another infection.

Feldman and Hultgren -; along with co-first authors Jennie E. Hazen, a graduate student, and Gisela Di Venanzio, PhD, an instructor in molecular microbiology -; investigated whether A. baumannii can hide inside cells like E. coli can. They studied mice with UTIs caused by A. baumannii. They used mice with weakened immune systems because, like people, healthy mice can fight off A. baumannii.

Once the infections had resolved and no bacteria were detected in the mice’s urine for two months, the researchers inserted catheters into the mice’s urinary tracts with a sterile technique. Within 24 hours, about half of the mice developed UTIs caused by the same strain of A. baumannii as the initial infection.

“The bacteria must have been there all along, hiding inside bladder cells until the catheter was introduced,” Hultgren said. “Catheterization induces inflammation, and inflammation causes the reservoir to activate, and the infection blooms.”

Since A. baumannii rarely causes symptoms in otherwise healthy people, many people who carry the bacteria may never know they’re infected, the researchers said. As part of this study, the researchers searched the scientific literature and discovered that about 2% of healthy people carry A. baumannii in their urine.

“I wouldn’t put much weight on the precise percentage, but I think we can say with certainty that some percentage of the population is walking around with A. baumannii,” Feldman said. “As long as they’re basically healthy, it doesn’t cause any problems, but once they’re hospitalized, it’s a different matter. This changes how we think about infection control. We can start considering how to check if patients already have Acinetobacter before they receive certain types of treatment; how we can get rid of it; and if other bacteria that cause deadly outbreaks in hospitals, such as Klebsiella, hide in the body in the same way. That’s what we’re working on figuring out now.”

Source:

Washington University School of Medicine

Journal reference:

Hazen, J.E., et al. (2023) Catheterization triggers resurgent infection seeded by host Acinetobacter baumannii reservoirs. Science Translational Medicine. doi.org/10.1126/scitranslmed.abn8134.

Microbiology

Study identifies Δ42PD-1 as novel therapeutic target for hepatocellular carcinoma immunotherapy

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Reviewed by Emily Henderson, B.Sc.Dec 15 2022

HKUMed researchers at AIDS Institute, Department of Microbiology and Department of Surgery, School of Clinical Medicine, and School of Biomedical Sciences discover the role of an isoformic programmed cell death protein 1 (PD-1), namely Δ42PD-1, in suppressing the function of killer T cells, which is a type of immune cells essential for killing cancer cells among hepatocellular carcinoma (HCC) patients. The study is a breakthrough because it demonstrates that Δ42PD-1 causes stronger functional loss of killer T cells, revealing a molecular mechanism underlying the failure of PD-1-targeted immune checkpoint blockade (ICB) therapy. Moreover, antibody drug targeting at Δ42PD-1 inhibits HCC progression in animal models, which is independent of the PD-1 pathway. The full research article is now published online in the journal of Gut, a top-tier academic journal.

Background

It is well known that HCC accounts for up to 92.3% of liver cancer cases in China. The 2018 Nobel Prize in Physiology or Medicine was awarded for the discovery of cancer ICB therapy by inhibition of negative immune regulation using PD-1-targeted antibody, such as Nivolumab. The ICB therapy has resulted in prolonged survival and even cure in some cancer patients. The ICB therapy, however, is not effective for about 80% of HCC patients. Understanding the mechanism of unsuccessful ICB, therefore, would be essential for discovering a novel therapeutic target to save more lives of HCC patients.

Research methods and findings

The research team found that human T cells, which express Δ42PD-1 but not PD-1, account for up to 71% of killer T cells in untreated HCC patients. Δ42PD-1 positive T cells are mainly found in tumor tissues, associated significantly with HCC poor prognosis. Moreover, Δ42PD-1 positive T cells have weaker killing function than PD-1 positive T cells. Treatment of HCC patients using Nivolumab, the PD-1-targeted ICB drug, even increases the number of Δ42PD-1 positive T cells, especially in patients with tumor progression. We demonstrated that Δ42PD-1 positive T cells inside tumors promote HCC growth through activating toll-like receptors-4-mediated inflammation. Instead of Nivolumab, anti-Δ42PD-1 antibody inhibits tumor growth in three HCC/humanized murine models through blocking of the Δ42PD-1-TLR4 axis, reducing the number of Δ42PD-1 positive T cells and increasing functional killer T cells inside tumor. These findings not only revealed a mechanism underlying the unsuccessful PD-1-targeted ICB therapy but also identify Δ42PD-1 as a novel therapeutic target for HCC immunotherapy.

Significance of the study

This important discovery has provided scientific evidence that Δ42PD-1 may serve as a novel drug target against HCC or other relevant cancers and may warrant the clinical development of a humanized Δ42PD-1-specific antibody for immunotherapy against HCC and related human cancers/diseases.

‘We were the first research group discovering the Δ42PD-1 protein in the world’, commented by Professor Chen Zhiwei, Director of AIDS Institute and Professor of the Department of Microbiology, School of Clinical Medicine, HKUMed, who led the study. ‘In this study, we not only further discover the dual activities of Δ42PD-1 on human T cells in both suppressing anti-tumor immune response and promoting tumorigenesis but also generate a potential anti-Δ42PD-1 antibody drug for HCC treatment’.

‘Besides immunotherapy against HCC, the anti-Δ42PD-1 antibody can also be used as a drug to prevent HCC recurrence without induction of graft rejection after liver transplantation’, added by Professor Nancy Man Kwan, Department of Surgery, School of Clinical Medicine, HKUMed.

About the research team

The collaborative research team was led by Professor Chen Zhiwei, Director of AIDS Institute and Professor of the Department of Microbiology, School of Clinical Medicine, HKUMed, together with Professor Nancy Man Kwan, Department of Surgery, School of Clinical Medicine, HKUMed and Dr Tan Zhiwu, research assistant professor at AIDS Institute and Department of Microbiology, School of Clinical Medicine, HKUMed. This collaborative team includes Chiu Mei-sum, Dr Zhou Dongyan, Yan Chi-wing, Kwan Ka-yi, Dr Wong Yik-chun, Li Xin, Dr Li Liu from AIDS Institute and Department of Microbiology, School of Clinical Medicine, HKUMed; Dr Yang Xinxiang, Dr Cheung Tan-to, Dr Wang Yuewen, Dr Zhu Jiye, Professor Lo Chung-mau, Department of Surgery, School of Clinical Medicine, HKUMed; Dr Yue Ming and Dr Song Youqiang from School of Biomedical Sciences, HKUMed; and Dr Anthony Chan Wing-hung, Dr Zhou Jingying, Professor To Ka-fai, Professor Alfred Cheng Sze-lok, Professor Stephen Lam Chan from the Chinese University of Hong Kong.

Source:

The University of Hong Kong

Journal reference:

Tan, Z., et al. (2022) Isoformic PD-1-mediated immunosuppression underlies resistance to PD-1 blockade in hepatocellular carcinoma patients. Gut. doi.org/10.1136/gutjnl-2022-327133.