Tag Archives: Cancer

Microbiology

Candida auris infection without epidemiologic links to a prior outbreak

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Dr. Priyom Bose, Ph.D.By Dr. Priyom Bose, Ph.D.Mar 23 2023Reviewed by Danielle Ellis, B.Sc.

The Centers for Disease Control and Prevention (CDC) has classified Candida auris (C. auris) as an urgent public threat due to its role in elevating mortality, its ability to persist in hospital environments, and the high possibility of developing pan-drug resistance.

Notably, a recent study published in the journal Open Forum Infectious Diseases has pointed out that surfaces near patients with C. auris quickly become re-contaminated after cleaning.

Existing research has not adequately elucidated the environmental reservoirs of C. auris. Further, few studies have reported epidemiologic links associated with C. auris infection. 

Study: The Emergence and Persistence of Candida auris in Western New York with no Epidemiologic Links: A Failure of Stewardship?. Image Credit: Kateryna Kon / ShutterstockStudy: The Emergence and Persistence of Candida auris in Western New York with no Epidemiologic Links: A Failure of Stewardship? Image Credit: Kateryna Kon / Shutterstock

Background

C. auris is a species of fungus that grows as yeast. It is one of the few species of the genus Candida which cause candidiasis in humans. In the past, C. auris infection was primarily found in cancer patients or those subjected to feeding tubes.

In the United States (US), the emergence of C. auris was traced to New York, and surveillance for this fungal infection was focused mainly on New York City to detect outbreaks. Recently, scientists investigated the association between genomic epidemiology and C. auris infection in Western New York.

A Case Study

The study describes the emergence of C. auris in a patient hospitalized at a small community hospital in Genesee County, New York (NY). In January 2022, C. auris was isolated from the urine culture of a 68-year-old male on the 51st day of hospitalization.

This patient had no known epidemiological connections outside his immediate community. Before his hospitalization, he was not exposed to other patients or family members associated with C. auris infection.

This patient had no history of organ transplantation, decubitus ulcers, hemodialysis, feeding tubes, or nursing home stays. He had an active lifestyle with a history of mild vascular dementia. He was hospitalized due to pneumonia and was prescribed azithromycin treatment.

Post hospitalization, he tested positive for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and was treated with dexamethasone (6 mg) daily for 10 days and remdesivir (200 mg) once, followed by 100 mg daily for five days.

Since the patient’s chest radiograph showed left lobar consolidation, he was further treated with empiric ceftriaxone and azithromycin. As the respiratory symptoms deteriorated, he received non-invasive positive pressure ventilation, with subsequent endotracheal intubation for eight days. He was successfully extubated. He developed a fever and received antimicrobial therapy for 73 days. The patient had a urinary catheter and a peripherally inserted central line in his arm for 35 days. 

Microbiology culture test and serum procalcitonin levels remained negative and within normal levels. On the 22nd day of hospitalization, Candida albicans were isolated from respiratory samples. On the 51st day, the urine culture revealed the presence of azole-resistant C. auris.

The isolated C. auris (MRSN101498) was forwarded to the Multidrug-resistant organism Repository and Surveillance Network (MRSN), where genomic sequencing was performed. After the patient was discharged, the hospital room was cleaned using hydrogen peroxide and peracetic acid, followed by ultraviolet-C light. Other patients who shared rooms with the patient with C. auris were tested for infection.

Study Outcomes

C. auris was not detected in the Western NY community hospital in the past year. Physicians stated that the patient received excessive antibiotic treatment for a prolonged period. Genomic studies revealed that the MRSN101498 genome sequence was closely related to the 2013 Indian strain with minor genomic differences. Interestingly, the K143R mutation in ERG11 was found in MRSN101498, which is associated with triazole resistance in Candida albicans.

Whole genome single nucleotide polymorphism (SNP) analysis also highlighted that MRSN101498 was strongly genetically related to four other isolates, with marginal differences.

These isolates were linked to an outbreak in March 2017 in a hospital 47 miles northeast of Rochester, NY. Based on the current findings, it is highly likely that isolates from Western NY share a recent common ancestor.

Study Importance

This case study is important for several reasons, including the absence of epidemiologic links to C.auris infection. Since reports from rural sectors are rare, this study addresses a vital surveillance ‘blind spot.’ 

However, the current study failed to identify the potential reservoirs of MRSN101498 in Western NY. Sporicidal disinfectants were inefficient for both Clostridioides difficile and C. auris. However, terminal cleaning protocols that included UV irradiation and sporicidal cleaning agents were able to eradicate C. auris effectively.

The current study highlights the role of excessive antibiotic exposure in the emergence of C. auris. It also indicates the challenges in eliminating fungi from hospital settings. The authors recommend proper antibiotic treatment and cleaning procedures for drug-resistant pathogens.

Journal reference:
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

Host immune system forms small lesions in the intestines in response to bacterial infection

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Reviewed by Emily Henderson, B.Sc.Mar 14 2023

Yersinia bacteria cause a variety of human and animal diseases, the most notorious being the plague, caused by Yersinia pestis. A relative, Yersinia pseudotuberculosis, causes gastrointestinal illness and is less deadly but naturally infects both mice and humans, making it a useful model for studying its interactions with the immune system.

These two pathogens, as well as a third close cousin, Y. enterocolitica, which affects swine and can cause food-borne illness if people consume infected meat, have many traits in common, particularly their knack for interfering with the immune system’s ability to respond to infection.

The plague pathogen is blood-borne and transmitted by infected fleas. Infection with the other two depends on ingestion. Yet the focus of much of the work in the field had been on interactions of Yersinia with lymphoid tissues, rather than the intestine. A new study of Y. pseudotuberculosis led by a team from Penn’s School of Veterinary Medicine and published in Nature Microbiology demonstrates that, in response to infection, the host immune system forms small, walled-off lesions in the intestines called granulomas. It’s the first time these organized collections of immune cells have been found in the intestines in response to Yersinia infections.

The team went on to show that monocytes, a type of immune cell, sustain these granulomas. Without them, the granulomas deteriorated, allowing the mice to be overtaken by Yersinia.

“Our data reveal a previously unappreciated site where Yersinia can colonize and the immune system is engaged,” says Igor Brodsky, senior author on the work and a professor and chair of pathobiology at Penn Vet. “These granulomas form in order to control the bacterial infection in the intestines. And we show that if they don’t form or fail to be maintained, the bacteria are able to overcome the control of the immune system and cause greater systemic infection.”

The findings have implications for developing new therapies that leverage the host immune system, Brodsky says. A drug that harnessed the power of immune cells to not only keep Yersinia in check but to overcome its defenses, they say, could potentially eliminate the pathogen altogether.

A novel battlefield

Y. pestis, Y. pseudotuberculosis, and Y. enterocolitica share a keen ability to evade immune detection.

“In all three Yersinia infections, a hallmark is that they colonize lymphoid tissues and are able to escape immune control and replicate, cause disease, and spread,” Brodsky says.

Earlier studies had shown that Yersinia prompted the formation of granulomas in the lymph nodes and spleen but had never observed them in the intestines until Daniel Sorobetea, a research fellow in Brodsky’s group, took a closer look at the intestines of mice infected with Y. pseudotuberculosis.

“Because it’s an orally acquired pathogen, we were interested in how the bacteria behaved in the intestines,” Brodsky says. “Daniel made this initial observation that, following Yersinia pseudotuberculosis infection, there were macroscopically visible lesions all along the length of the gut that had never been described before.”

The research team, including Sorobetea and later Rina Matsuda, a doctoral student in the lab, saw that these same lesions were present when mice were infected with Y. enterocolitica, forming within five days after an infection.

A biopsy of the intestinal tissues confirmed that the lesions were a type of granuloma, known as a pyogranuloma, composed of a variety of immune cells, including monocytes and neutrophils, another type of white blood cell that is part of the body’s front line in fighting bacteria and viruses.

Granulomas form in other diseases that involve chronic infection, including tuberculosis, for which Y. pseudotuberculosis is named. Somewhat paradoxically, these granulomas-;while key in controlling infection by walling off the infectious agent-;also sustain a population of the pathogen within those walls.

The team wanted to understand how these granulomas were both formed and maintained, working with mice lacking monocytes as well as animals treated with an antibody that depletes monocytes. In the animals lacking monocytes “these granulomas, with their distinct architecture, wouldn’t form,” Brodsky says.

Instead, a more disorganized and necrotic abscess developed, neutrophils failed to be activated, and the mice were less able to control the invading bacteria. These animals experienced higher levels of bacteria in their intestines and succumbed to their infections.

Groundwork for the future

The researchers believe the monocytes are responsible for recruiting neutrophils to the site of infection and thus launching the formation of the granuloma, helping to control the bacteria. This leading role for monocytes may exist beyond the intestines, the researchers believe.

We hypothesize that it’s a general role for the monocytes in other tissues as well.”

Igor Brodsky, senior author

But the discoveries also point to the intestines as a key site of engagement between the immune system and Yersinia.

“Previous to this study we knew of Peyer’s patches to be the primary site where the body interacts with the outside environment through the mucosal tissue of the intestines,” says Brodsky. Peyer’s patches are small areas of lymphoid tissue present in the intestines that serve to regulate the microbiome and fend off infection.

In future work, Brodsky and colleagues hope to continue to piece together the mechanism by which monocytes and neutrophils contain the bacteria, an effort they’re pursing in collaboration with Sunny Shin’s lab in the Perelman School of Medicine’s microbiology department.

A deeper understanding of the molecular pathways that regulate this immune response could one day offer inroads into host-directed immune therapies, by which a drug could tip the scales in favor of the host immune system, unleashing its might to fully eradicate the bacteria rather than simply corralling them in granulomas.

“These therapies have caused an explosion of excitement in the cancer field,” Brodsky says, “the idea of reinvigorating the immune system. Conceptually we can also think about how to coax the immune system to be reinvigorated to attack pathogens in these settings of chronic infection as well.”

Source:

University of Pennsylvania

Journal reference:

Sorobetea, D., et al. (2023). Inflammatory monocytes promote granuloma control of Yersinia infection. Nature Microbiology. doi.org/10.1038/s41564-023-01338-6.

Microbiology

Healthy gut bacteria can travel to other parts of the body and boost antitumor immunity

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Reviewed by Emily Henderson, B.Sc.Mar 9 2023

Researchers at UT Southwestern Medical Center have discovered how healthy bacteria can escape the intestine, travel to lymph nodes and cancerous tumors elsewhere in the body, and boost the effectiveness of certain immunotherapy drugs. The findings, published in Science Immunology, shed light on why antibiotics can weaken the effect of immunotherapies and could lead to new cancer treatments.

Scientists have been stumped as to how bacteria inside your gut can have an impact on a cancer in your lungs, breasts, or skin. Now we understand that mechanism much better and, in the future, hope to use this knowledge to better fight cancer.”

Andrew Y. Koh, M.D., Associate Professor of Pediatrics, Microbiology, and in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern

Previous studies, including one led by Dr. Koh at UT Southwestern, have shown an association between the composition of gut microbiomes – the microorganisms found inside the digestive tract – and the effectiveness of cancer treatments that target the immune system, including pembrolizumab (Keytruda) and ipilimumab (Yervoy). However, researchers have reached conflicting conclusions about the ideal balance of microorganisms to optimize therapy, with studies pointing to different beneficial bacteria.

Dr. Koh and colleagues used mice with melanoma tumors to probe how the drugs, called immune checkpoint inhibitors, affected the movement of gut microbes through the body. They found that immune checkpoint inhibitors, which boost the activity of the immune system against tumors, also cause inflammation in the digestive system that leads to remodeling of lymph nodes in the gut.

Due to these changes, bacteria can leave the intestines and travel to lymph nodes near the tumor and the tumor itself, the researchers found. Here, the microbes activate a set of immune cells that act to kill tumor cells.

“Immune checkpoint inhibitors work by releasing the brakes on the immune system to target cancer,” said Dr. Koh, who is also Director of the Cellular and ImmunoTherapeutics Program at UTSW and Children’s Health. “What we think is that these microorganisms and the immune cells they’re activating are essentially pressing on the accelerator of the immune system at the same time.”

The findings suggest that a course of antibiotics, which can eliminate most gut microbes, is detrimental to immune checkpoint inhibitors because the bacteria can no longer play this role of immune accelerant. It also helps explain why researchers have found many types of bacteria in patient microbiomes that seem to be beneficial for treatment.

“As long as a subset of beneficial bacteria can translocate from the gut to the lymph node or tumor, it may not matter exactly which bacteria it is,” said Dr. Koh.

Dr. Koh’s team is now working toward the development of bacterial-based treatments to boost the efficacy of immune checkpoint inhibitors.

Other UTSW researchers who contributed to the study include first author and UTSW graduate student Yongbin Choi, Lora Hooper, Jake Lichterman, Laura Coughlin, Nicole Poulides, Wenling Li, Priscilla Del Valle, Suzette Palmer, Shuheng Gan, Jiwoong Kim, Xiaowei Zhan, Yajing Gao, and Bret Evers.

Dr. Hooper, a Howard Hughes Medical Institute Investigator, holds the Jonathan W. Uhr, M.D. Distinguished Chair in Immunology and is a Nancy Cain and Jeffrey A. Marcus Scholar in Medical Research, in honor of Dr. Bill S. Vowell.

The research was supported by funding from the National Institutes of Health (R01 CA231303, K24 AI123163, R01 DK070855), the Crow Family Fund, the UT Southwestern Medical Center and Children’s Health Cellular and ImmunoTherapeutics Program, National Research Service Award-Integrative Immunology Training Grant (5T32AI005284-43), The Welch Foundation (I-1874), and the Howard Hughes Medical Institute.

Source:

UT Southwestern Medical Center

Journal reference:

Choi, Y., et al. (2023) Immune checkpoint blockade induces gut microbiota translocation that augments extraintestinal antitumor immunity. Science Immunology. doi.org/10.1126/sciimmunol.abo2003.

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

Adult T-cell leukemia/lymphoma (ATLL) is a rare type of cancer that impacts T cells, a crucial immune cell …

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Adult T-cell leukemia/lymphoma (ATLL) is a rare type of cancer that impacts T cells, a crucial immune cell that plays an important role in fighting infection. ATLL tends to be aggressive, and can manifest in the blood as leukemia, in the lymph nodes as lymphoma, or other tissues like the skin. ATLL has been associated with human T-cell lymphotropic virus type 1 (HTLV-1) infections, although fewer than five percent of people with this virus end up developing ATLL. Right now, clinicians cannot predict which people with HTLV-1 infections will get ATLL. While some types of ATLL tumors can be surgically removed, survival prospects for these patients is not good.

Image credit: Pixabay

A recent article published in Genes & Cancer noted that even though a monoclonal antibody that can treat ATLL called mogamulizumab has recently been approved, the survival rate is still poor.

Viruses are known to change gene expression in host cells, and HTLV-1 is no different. Previous work reported in PLOS Pathogens showed that when HTLV-1 infects cells, it causes a huge number of genetic and epigenetic changes with viral proteins it generates called Tax and HBZ. These many genetic changes could be interfering with chemotherapeutics and may render them less effective, suggested researcher Tatsuro Jo of the Nagasaki Genbaku Hospital.

In the HTLV-1 genome, there is an opportunity, however. Its genome is completely different from the human genome, so the viral proteins generated during HTLV-1 infection are excellent therapeutic targets. ATLL survivors have been found to carry cytotoxic T lymphocytes that work against the HTLV-1 Tax protein. People who survive ATLL over the long term may have been able to activate strong antitumor mechanisms.

Jo added that some people who have lived for a long time after an ATLL diagnosis, and prior to the approval of mogamulizumab, had also developed herpesvirus infections. It’s been suggested that herpes infections can trigger powerful cellular immunity mechanisms.

“Although contracting herpes simplex or herpes zoster is unpleasant, the mechanism by which these herpesvirus infections can produce a therapeutic effect on refractory ATLL via the activation of the host’s cellular immunity is extremely interesting and worth further study,” said Jo.

Sources: Impact Journals LLC, Genes & Cancer


Carmen Leitch

Microbiology

Simple blood tests for telomeric protein could provide a valuable screen for certain cancers

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Reviewed by Emily Henderson, B.Sc.Feb 21 2023

Once thought incapable of encoding proteins due to their simple monotonous repetitions of DNA, tiny telomeres at the tips of our chromosomes seem to hold a potent biological function that’s potentially relevant to our understanding of cancer and aging.

Reporting in the Proceedings of the National Academy of Science, UNC School of Medicine researchers Taghreed Al-Turki, PhD, and Jack Griffith, PhD, made the stunning discovery that telomeres contain genetic information to produce two small proteins, one of which they found is elevated in some human cancer cells, as well as cells from patients suffering from telomere-related defects.

Based on our research, we think simple blood tests for these proteins could provide a valuable screen for certain cancers and other human diseases. These tests also could provide a measure of ‘telomere health,’ because we know telomeres shorten with age.”

Jack Griffith, PhD, the Kenan Distinguished Professor of Microbiology and Immunology and Member of the UNC Lineberger Comprehensive Cancer Center

Telomeres contain a unique DNA sequence consisting of endless repeats of TTAGGG bases that somehow inhibit chromosomes from sticking to each other. Two decades ago, the Griffith laboratory showed that the end of a telomere’s DNA loops back on itself to form a tiny circle, thus hiding the end and blocking chromosome-to-chromosome fusions. When cells divide, telomeres shorten, eventually becoming so short that the cell can no longer divide properly, leading to cell death.

Scientist first identified telomeres about 80 years ago, and because of their monotonous sequence, the established dogma in the field held that telomeres could not encode for any proteins, let alone ones with potent biological function.

In 2011 a group in Florida working on an inherited form of ALS reported that the culprit was an RNA molecule containing a six-base repeat which by a novel mechanism could generate a series of toxic proteins consisting of two amino acids repeating one after the other. Al-Turki and Griffith note in their paper a striking similarity of this RNA to the RNA generated from human telomeres, and they hypothesized that the same novel mechanism might be in play.

They conducted experiments – as described in the PNAS paper – to show how telomeric DNA can instruct the cell to produce signaling proteins they termed VR (valine-arginine) and GL (glycine-leucine). Signaling proteins are essentially chemicals that trigger a chain reaction of other proteins inside cells that then lead to a biological function important for health or disease.

Al-Turki and Griffith then chemically synthesized VR and GL to examine their properties using powerful electron and confocal microscopes along with state-of-the-art biological methods, revealing that the VR protein is present in elevated amounts in some human cancer cells, as well as cells from patients suffering from diseases resulting from defective telomeres.

“We think it’s possible that as we age, the amount of VR and GL in our blood will steadily rise, potentially providing a new biomarker for biological age as contrasted to chronological age,” said Al-Turki, a postdoctoral researcher in the Griffith lab. “We think inflammation may also trigger the production of these proteins.”

Griffith noted, “When you go against current thinking, you are usually wrong because you are bucking many people who’ve worked so diligently in their fields. But occasionally scientists have failed to put observations from two very distant fields together and that’s what we did. Discovering that telomeres encode two novel signaling proteins will change our understanding of cancer, aging, and how cells communicate with other cells.

“Many questions remain to be answered, but our biggest priority now is developing a simple blood test for these proteins. This could inform us of our biological age and also provide warnings of issues, such as cancer or inflammation.”

Source:

University of North Carolina Health Care

Journal reference:

Al-Turki, T., et al. (2023) Mammalian Telomeric RNA (TERRA) can be translated to produce valine-arginine and glycine-leucine dipeptide repeat proteins. PNAS. doi.org/10.1073/pnas.2221529120.

Microbiology

UTHSC researchers secure $308,000 grant from Department of Defense for dementia study

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Reviewed by Emily Henderson, B.Sc.Feb 19 2023

Repeated traumatic brain injuries (TBI) in soldiers and military personnel can cause behavioral, neurological, and cognitive effects and lead to dementia. There is currently no treatment for that type of dementia, but a $308,000 grant from the United States Department of Defense aims to help researchers at the University of Tennessee Health Science Center find one.

TBI can lead to the development of frontotemporal degeneration (FTD), a progressive process marked by atrophy of the frontal and temporal lobes. FTD is one of the most common causes of dementia in people under the age of 65.

Principal investigator Mohammad Moshahid Khan, PhD, associate professor in the Department of Neurology, and co-investigator Tayebeh Pourmotabbed, PhD, professor in the Department of Microbiology, Immunology, and Biochemistry, are working on a project to find the first therapeutic intervention to prevent frontotemporal dementia or slow its progression in a mouse model linked with the condition.

The team is aiming to use a novel gene therapy called DNAzymes to target pathological tau aggregates, which cause frontotemporal dementia and its resulting cognitive impairment and progressive neuropathological symptoms. The team is examining the effective dose, frequency, and duration of treatment as well as its potential in reducing neurodegeneration and behavioral deficits in mice.

Our preliminary data suggest that DNAzyme is a novel therapeutic approach and has a great potential for preventing the accumulation of pathological tau. The results of this proposal would be foundational for future studies examining the clinical use of DNAzyme for other neurological diseases associated with traumatic brain injury and other tauopathies.”

Dr. Mohammad Moshahid Khan, PhD, associate professor in the Department of Neurology

“DNAzyme is a powerful gene therapy technique that can be used to prevent production of proteins associated with diseases, like tau protein in Alzheimer’s disease and dementia,” Dr. Pourmotabbed said. “We have used DNAzyme as a potential therapy for breast cancer, glioma, and Huntington’s disease in preclinical animal models with great success. Hopefully, with the use of DNAzyme technology, we would be able to reduce the risk of dementia after traumatic brain injury in veterans and other individuals that deal with this debilitating disease.”

Source:

University of Tennessee Health Science Center

Microbiology

Genes encoding T cell receptors vary greatly between persons and populations, study reveals

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Reviewed by Emily Henderson, B.Sc.Feb 16 2023

Researchers from Karolinska Institutet have discovered that the genes encoding our T cell receptors vary greatly between persons and populations, which may explain why we respond differently to for example infections. The findings, presented in the journal Immunity, also demonstrate that some gene variants are inherited from Neanderthals.

T-cells that are part of our immune system are central in the protection against infections and cancer. With the help of TCRs, the cells recognize foreign invaders and tumor cells.

“It was previously unknown how variable human TCR genes are”, says Gunilla Karlsson Hedestam, professor at the department of microbiology, tumor and cell biology at Karolinska Institutet and the study’s lead author.

Using deep sequencing of blood samples, the researchers examined TCR genes in 45 people originating from sub-Saharan Africa, East Asia, South Asia and Europe. The researchers showed that these genes vary greatly between different persons and population groups. The results were confirmed by analyses of several thousand additional cases from the 1000 Genomes project.

We found that every individual, other than identical twins, has a unique set of TCR gene variants. These differences reveal possible mechanisms underlying the wide range of responses to infections and vaccines that we observe at the population level.”

Martin Corcoran, first author of the study

“We discovered 175 new gene variants, which doubles the number of known TCR gene variants. An unexpected and surprising finding is that certain gene variants originate from Neanderthals and one of these is present in up to 20% of modern humans in Europe and Asia.”

Gunilla Karlsson Hedestam explains that the variation in these genes cannot be detected with the standard methods used in whole genome sequencing, but with the development of specialized deep sequencing methods and analysis software that allow highly precise definition of B- and T-cell receptor genes, this is now possible.

“As these genes are among the most variable in our genome, the results also provide new information about how our immune system has developed over the course of history, says Martin Corcoran. We are particularly interested in uncovering the function of the TCR variants we have inherited from Neanderthal ancestors. The frequency of these variants in modern humans suggests an advantageous function in our biology and we are keen to understand this”, adds Martin Corcoran.

The findings and the new TCR gene database the researchers now publish can be of great importance in the development of new therapeutic approaches in the future.

“Understanding human genetics is fundamental for the development of targeted treatments. The methods described in the study provide new opportunities, not the least in the cancer field where T-cells are central to several promising forms of immunotherapy”, says Gunilla Karlsson Hedestam.

The results can also shed light on other areas of research.

“The findings can lead to the development of new diagnostics and therapies in a range of medical disciplines, including precision medicine”, says Gunilla Karlsson Hedestam.

What is the next step in your research?

“We are now investigating the functional significance of several of the newly discovered gene variants and how this variation impacts our T-cell responses. We are also planning extended studies involving large groups of individuals to examine the role of TCR gene variation in diseases we know involve T cells, such as infectious diseases, cancer, and autoimmune disorders”, says Gunilla Karlsson Hedestam.

Main funding for the study comes from an ERC Advanced Grant and the Swedish Research Council.

Source:

Karolinska Institutet

Journal reference:

Corcoran, M., et al. (2023) Archaic humans have contributed to large-scale variation in modern human T cell receptor genes. Immunity. doi.org/10.1016/j.immuni.2023.01.026.