Human 'molecular map' contributes to the understanding of disease mechanisms

 

Scientists at Weill Cornell Medicine in Qatar (WCM-Q) have created an intricate molecular map of the human body and its complex physiological processes based on the analysis of thousands of molecules in blood, urine and saliva samples from 391 volunteers. The data was integrated to create a powerful, interactive visual web-based tool called Connecting Omics (COmics) that can be used to investigate the complex molecular make-up of humans and discover underlying traits associated with various diseases.

The molecular processes of the human body refer to the chemical reactions and interactions occurring within cells and between different cells, including crucial functions like DNA replication, protein synthesis, energy production, cellular communication and various metabolic pathways, all governed by complex protein-protein, protein-DNA, and protein-RNA interactions, ultimately enabling the body's vital functions.

The exhaustive study, published Aug. 19 in Nature Communications, collated 12 years of data from the Qatar Metabolomics Study of Diabetes (QMDiab), a diabetes case-control study in the multiethnic population of Qatar, predominantly Arab, Filipino and Indian backgrounds.

"Our idea was to bring together everything we have learned over more than a decade of multiomics research to create a comprehensive molecular model of the human body and its processes," said senior author Dr. Karsten Suhre, professor of physiology and biophysics and a member of the Englander Institute of Precision Medicine. "This reference tool is free to access and use by researchers who want to investigate how the human body works at the molecular level and also for the formation of hypotheses to test with experimentation."

Through a collaboration with Hamad Medical Corporation, the researchers had collected multiple aliquots of blood, urine and saliva samples from volunteers, with and without diabetes. The samples were subsequently characterized on 18 different high-throughput analysis platforms, providing an extremely rich dataset including 6,300 individual molecular data points including genomic data (DNA), transcriptome (RNA), proteins and metabolites, such as amino acids, sugars and fats. In addition, they determined information on genetic variants, DNA methylation sites and gene expression for each of the participants.

This allowed the researchers to discover associations and pathways linking genetic characteristics with specific proteins, metabolic processes and diseases. They then painstakingly integrated the mass of data from all the individuals into an online web-based tool serving as the interface to 'The Molecular Human,' the molecular description of the human body.

The approach of combining genomic, transcriptomic, metabolomic, proteomic and other forms of so-called '-omics' research is known as 'multiomics.' This approach has emerged in recent years as a key strategy for biomedical researchers seeking to understand how the human body and diseases truly function, providing insights that could potentially enable the development of new drug therapies.

For instance, the study identified and described the proteins and metabolites which are signatures of subtypes of type 2 diabetes, shedding light on the different ways the disease manifests.

"Our integrative omics approach provides an overview of the interrelationships between different molecular traits and their association with a person's phenotype -- their observable traits, such as their physical appearance, biochemical processes and behaviors," said first author Dr. Anna Halama, assistant professor of research in physiology and biophysics. "The scale of the data integrated within the COmics web-tool enables access to hundreds of thousands of pathways and associations for researchers to explore, giving huge potential for discovery and investigation.

 

Journal Reference:

1. Anna Halama, Shaza Zaghlool, Gaurav Thareja, Sara Kader, Wadha Al Muftah, Marjonneke Mook-Kanamori, Hina Sarwath, Yasmin Ali Mohamoud, Nisha Stephan, Sabine Ameling, Maja Pucic Baković, Jan Krumsiek, Cornelia Prehn, Jerzy Adamski, Jochen M. Schwenk, Nele Friedrich, Uwe Völker, Manfred Wuhrer, Gordan Lauc, S. Hani Najafi-Shoushtari, Joel A. Malek, Johannes Graumann, Dennis Mook-Kanamori, Frank Schmidt, Karsten Suhre. A roadmap to the molecular human linking multiomics with population traits and diabetes subtypes. Nature Communications, 2024; 15 (1) DOI: 10.1038/s41467-024-51134-x

Courtesy:

Weill Cornell Medicine. "Human 'molecular map' contributes to the understanding of disease mechanisms." ScienceDaily. ScienceDaily, 11 September 2024. <www.sciencedaily.com/releases/2024/09/240911175947.htm>.

Some diabetes drugs tied to lower risk of dementia, Parkinson's disease

 

A class of drugs for diabetes may be associated with a lower risk of dementia and Parkinson's disease, according to a study published in the September 18, 2024, online issue of Neurology^®, the medical journal of the American Academy of Neurology.

The study looked at sodium-glucose cotransporter-2 (SGLT2) inhibitors, which are also known as gliflozins. They lower blood sugar by causing the kidneys to remove sugar from the body through urine.

"We know that these neurodegenerative diseases like dementia and Parkinson's disease are common and the number of cases is growing as the population ages, and people with diabetes are at increased risk of cognitive impairment, so it's encouraging to see that this class of drugs may provide some protection against dementia and Parkinson's disease," said study author Minyoung Lee, MD, PhD, of Yonsei University College of Medicine in Seoul, South Korea.

The retrospective study looked at people with type 2 diabetes who started diabetes medication from 2014 to 2019 in South Korea. People taking SGLT2 inhibitors were matched with people taking other oral diabetes drugs, so the two groups had people with similar ages, other health conditions and complications from diabetes. Then researchers followed the participants to see whether they developed dementia or Parkinson's disease. Those taking the SGLT2 inhibitors were followed for an average of two years and those taking the other drugs were followed for an average of four years.

Among the 358,862 participants with an average age of 58, a total of 6,837 people developed dementia or Parkinson's disease during the study.

For Alzheimer's disease, the incidence rate for people taking SGLT2 inhibitors was 39.7 cases per 10,000 person-years, compared to 63.7 cases for those taking other diabetes drugs. Person-years represent both the number of people in the study and the amount of time each person spends in the study.

For vascular dementia, which is dementia caused by vascular disease, the incidence rate for people taking the SGLT2 drugs was 10.6 cases per 10,000, compared to 18.7 for those taking the other drugs.

For Parkinson's disease, the incidence rate for those taking the SGLT2 drugs was 9.3 cases per 10,000, compared to 13.7 for those taking the other drugs.

After researchers adjusted for other factors that could affect the risk of dementia or Parkinson's disease, such as complications from diabetes and medications, they found that SGLT2 inhibitor use was associated with a 20% reduced risk of Alzheimer's disease and a 20% reduced risk of Parkinson's disease. Those taking the drugs had a 30% reduced risk of developing vascular dementia.

"The results are generally consistent even after adjusting for factors like blood pressure, glucose, cholesterol and kidney function," Lee said. "More research is needed to validate the long-term validity of these findings."

Lee said that since participants were followed for less than five years at the most, it's possible that some participants would later develop dementia or Parkinson's disease.

The study was supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare of Korea; Severance Hospital; and Yonsei University College of Medicine.

Journal Reference:

1. Hae Kyung Kim, Geert Jan Biessels, Min Heui Yu, Namki Hong, Yong-ho Lee, Byung-Wan Lee, Eun Seok Kang, Bong-Soo Cha, Eun Jig Lee, Minyoung Lee. SGLT2 Inhibitor Use and Risk of Dementia and Parkinson Disease Among Patients With Type 2 Diabetes. Neurology, 2024; 103 (8) DOI: 10.1212/WNL.0000000000209805 

Courtesy:

American Academy of Neurology. "Some diabetes drugs tied to lower risk of dementia, Parkinson's disease." ScienceDaily. ScienceDaily, 18 September 2024. <www.sciencedaily.com/releases/2024/09/240918165739.htm>.

 

 

 

 

Researchers combine the power of AI and the connectome to predict brain cell activity

With maps of the connections between neurons and artificial intelligence methods, researchers can now do what they never thought possible: predict the activity of individual neurons without making a single measurement in a living brain.

For decades, neuroscientists have spent countless hours in the lab painstakingly measuring the activity of neurons in living animals to tease out how the brain enables behavior. These experiments have yielded groundbreaking insights into how the brain works, but they have only scratched the surface, leaving much of the brain unexplored.

Now, researchers are using artificial intelligence and the connectome -- a map of neurons and their connections created from brain tissue -- to predict the role of neurons in the living brain. Using only information about the connectivity of a neural circuit gleaned from the fruit fly visual system connectome and a guess at what the circuit is supposed to do, researchers created an AI simulation of the fruit fly visual system that can predict the activity of every neuron in the circuit.

"We now have a computational method for turning measurements of the connectome into predictions of neural activity and brain function, without first starting with difficult-to-acquire measurements of neural activity for every neuron," says Janelia Group Leader Srini Turaga, a senior author on the new research.

The team of scientists from HHMI's Janelia Research Campus and the University of Tübingen used the connectome to build a detailed deep mechanistic network simulation of the fly visual system, where each neuron and synapse in the model corresponds to a real neuron and synapse in the brain. Although they didn't know the dynamics of every neuron and synapse, data from the connectome allowed the team to use deep learning methods to infer these unknown parameters. They combined this information with knowledge about the circuit's goal: motion detection.

"At that point, everything fell into place, and we could finally figure out if this connectome-constrained model gives us a good model of the brain," says Janne Lappalainen, a PhD student at the University of Tübingen who led the research.

The new model predicts the neural activity produced by 64 neuron types in the fruit fly visual system in response to visual input and accurately reproduces more than two dozen experimental studies performed over the past two decades.

By enabling researchers to predict the activity of individual neurons using only the connectome, the new work has the potential to transform how neuroscientists generate and test hypotheses about how the brain works. In principle, scientists can now use the model to simulate any experiment and generate detailed predictions that can be tested in the lab.

The new research provides more than 450 pages of predictions gleaned from the new model, including identification of cells not known to be involved in motion detection previously, which can now be examined in living flies.

The group's work provides a strategy for turning the wealth of connectome data being generated by Janelia and other research institutions into advanced understanding of the living brain, according to the researchers.

"There is a big gap between the static snapshot of the connectome and the dynamics of real-life computation in the living brain, and the question was, can we bridge that gap in a model? This paper, for the specific example of the fruit fly, shows a strategy for bridging that gap," says Jakob Macke, a senior author on the paper and a professor at the University of Tübingen.

 

Journal Reference:

1. Janne K. Lappalainen, Fabian D. Tschopp, Sridhama Prakhya, Mason McGill, Aljoscha Nern, Kazunori Shinomiya, Shin-ya Takemura, Eyal Gruntman, Jakob H. Macke, Srinivas C. Turaga. Connectome-constrained networks predict neural activity across the fly visual system. Nature, 2024; DOI: 10.1038/s41586-024-07939-3

Courtesy:

Howard Hughes Medical Institute. "Researchers combine the power of AI and the connectome to predict brain cell activity." ScienceDaily. ScienceDaily, 11 September 2024. <www.sciencedaily.com/releases/2024/09/240911111612.htm>.

 

 

 

Gut microbiome influences location of immune cells, study finds

 

Researchers at the Experimental and Clinical Research Center of Max Delbrück Center and Charité -- Universitätsmedizin Berlin (ECRC) have found that different anatomical sections of the gastrointestinal tracts of mice carry different compositions of microbial communities. Moreover, the specific makeup of the microbiota can influence the type and abundance of immune cells in any particular region. The study, which was published in Gut Microbes, maps the complex spatial organization of immune cells and microbial communities, providing a tool for studying the interaction between gut microbes and inflammatory diseases.

Previous research has hinted at the existence of "hotspots" along the GI tract where specific immune cells and microbes might interact more intensely.

But no one had systematically investigated this across the entire gut, says Dr. Hendrik Bartolomaeus, in the Immune-Microbial Dynamics in Cardiorenal Disease lab of Dr. Nicola Wilck, and an author of the study. 

"We were motivated by a simple question: How are immune cells organized along the gut, and how does the microbiome influence this organization?"

Microbial communities shape the immune system

The researchers compared the GI tracts of germ-free mice with conventionally colonized mice by dissecting their intestines into segments, and then extracting microbial DNA.

They used metagenomic sequencing to identify all the bacterial species present.

Concurrently, they isolated immune cells from the segments and analyzed them using flow cytometry, a commonly used technique to identify and quantify different immune cell types based on specific cellular markers.

They found that not only did the microbial communities in the GI tract of conventional mice vary depending on location.

But this also significantly influenced the distribution and type of immune cells found along the gut.

For instance, adaptive immune cells, which are acquired after exposure to antigens -- foreign substances that induce an immune response -- were more prominent in the lower parts of the intestine, while innate immune cells were more abundant in the upper segments.

This pattern was severely disturbed in germ-free mice, which lack bacterial antigens in their intestine.

Harithaa Anandakumar, PhD student and lead author of the study, then categorized the immune cells according to whether their presence and abundance is influenced only by location, by an interaction with the microbiota at that location, or both.

She then created an app that summarizes the information. "We built a go-to app so that anyone who is interested in a specific immune cell type can look it up and see where it's most abundant in the gut and whether it is influenced by the microbiome, the location, or an interaction of both."

Such a resource had been lacking, says Wilck, who is also a specialist at Charité's Department of Nephrology and Medical Intensive Care. Now any scientist working with mouse models can use it. His own lab studies how immune cells travel from the gut into tissues and organs in various mouse models of disease. "We can now use this resource to study whether the immune cells we find in organs damaged by hypertension or kidney disease come from the gut," he says.

Journal Reference:

1. Harithaa Anandakumar, Ariana Rauch, Moritz I. Wimmer, Alex Yarritu, Gudrun Koch, Victoria McParland, Hendrik Bartolomaeus, Nicola Wilck. Segmental patterning of microbiota and immune cells in the murine intestinal tract. Gut Microbes, 2024; 16 (1) DOI: 10.1080/19490976.2024.2398126 

Courtesy:

Max Delbrück Center for Molecular Medicine in the Helmholtz Association. "Gut microbiome influences location of immune cells, study finds." ScienceDaily. ScienceDaily, 12 September 2024. <www.sciencedaily.com/releases/2024/09/240912135820.htm>.

 

 

 

Antibody-drug conjugate found effective against brain metastases in patients with HER2-positive breast cancer

 

A drug that delivers chemotherapy directly to tumors has shown impressive activity against some of the hardest-to-reach cancer cells: those that have spread to the brain in patients with advanced HER2-positive breast cancer. The findings, from an international clinical trial led by Dana-Farber Cancer Institute researchers, reinforce earlier findings of the benefits of the drug -- trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate -- in these patients, trial leaders say.

The results of the trial, dubbed the DESTINY-Breast12 study, were presented today at the European Society of Medical Oncology (ESMO) Congress 2024 in Barcelona, Spain, and published simultaneously in a paper in the journal Nature Medicine.

The findings point to T-DXd as a valuable new treatment option for patients with a particularly challenging form of cancer, researchers say. "As many as half of patients with HER2-positive breast cancer develop brain metastases, which often has a poorer prognosis than breast cancer that hasn't spread to the brain," says Nancy Lin, MD, leader of the trial and senior author of the study in Nature Medicine. Lin is the associate chief of the Division of Breast Oncology, Dana-Farber, Susan F. Smith Center for Women's Cancers, and the director of the Metastatic Breast Cancer Program. Localized therapies such as surgery, radiosurgery, and radiation therapy to the brain, are used to treat brain metastases, but the disease usually progresses in the central nervous system -- the brain and spinal cord -- within six to 12 months of treatment.

Trastuzumab deruxtecan consists of the drug deruxtecan -- a chemotherapy agent -- linked to an antibody that targets the HER2 protein on breast cancer cells. Trastuzumab itself is a mainstay treatment of HER2-positive breast cancer that has spread to other parts of the body, including the brain. But as with treatments directed specifically at the brain, patients receiving trastuzumab usually have their disease progress, often in the central nervous system.

"Additional systemic therapies for patients with brain metastases are urgently needed," Lin remarks.

The DESTINY-Breast12 trial involved 504 patients with HER-2 positive breast cancer treated at 78 cancer centers in Western Europe, Japan, Australia, and the U.S. Two hundred sixty-three participants had active or stable brain metastases and 241 had no brain metastases. All had received at least one therapy before enrolling in the trial.

After a median follow-up of 15.4 months, progression-free survival of participants with brain metastases -- the length of time patients lived with the cancer before it worsened -- was a median of 17.3 months, investigators found. 12- month progression-free survival was 61.6%. Seventy-one percent of participants had an intracranial objective response -- a measurable decrease of their cancer in the central nervous system. As expected, there was also a high rate of response in tumors outside of the central nervous system in patients with or without brain metastases. Ninety percent of patients in both groups were alive a year after beginning T-DXd treatment.

The side effects associated with T-DXd were consistent with those reported in previous studies and included nausea, constipation, neutropenia (low levels of a type of white blood cells), fatigue, and anemia. Interstitial lung disease (ILD), a known risk of T-DXd, was observed at similar rates to prior studies, and vigilance to this potentially fatal side effect remains critical.

"Our data show that T-DXd has substantial and durable activity within the brain in patients with HER2-positive breast cancer that has metastasized there," Lin says. "These results support the use of the drug going forward in this patient population."

Journal Reference:

1. Nadia Harbeck, Eva Ciruelos, Guy Jerusalem, Volkmar Müller, Naoki Niikura, Giuseppe Viale, Rupert Bartsch, Christian Kurzeder, Michaela J. Higgins, Roisin M. Connolly, Sally Baron-Hay, María Gión, Valentina Guarneri, Giampaolo Bianchini, Hans Wildiers, Santiago Escrivá-de-Romaní, Manoj Prahladan, Helen Bridge, Nataliya Kuptsova-Clarkson, Nana Scotto, Sunil Verma, Nancy U. Lin. Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial. Nature Medicine, 2024; DOI: 10.1038/s41591-024-03261-7
   

 Courtesy:

Dana-Farber Cancer Institute. "Antibody-drug conjugate found effective against brain metastases in patients with HER2-positive breast cancer." ScienceDaily. ScienceDaily, 13 September 2024. <www.sciencedaily.com/releases/2024/09/240913105345.htm>.

 

 

 

 

 

Ignore antifungal resistance in fungal disease at your peril, warn top scientists

Without immediate action, humanity will potentially face further escalation in resistance in fungal disease, a group of scientists from the across the world has warned. The commentary -- published in The Lancet this week -- was coordinated by scientists at The University of Manchester, the Westerdijk Institute and the University of Amsterdam. According to the scientists most fungal pathogens identified by the World Health Organisation -- accounting for around 3.8 million deaths a year -- are either already resistant or rapidly acquiring resistance to antifungal drugs.

The authors argue that the currently narrow focus on bacteria will not fully combat antimicrobial resistance (AMR). September's United Nations meeting on antimicrobial resistance (AMR) must, they demand, include resistance developed in many fungal pathogens.

Devastating health impacts

Resistance is nowadays the rule rather than the exception for the four currently available antifungal classes, making it difficult -- if not impossible -- to treat many invasive fungal infections.

Fungicide resistant infections include Aspergillus, Candida, Nakaseomyces glabratus, and Trichophyton indotineae, all of which can have devastating health impacts on older or immunocompromised people.

Dr Norman van Rhijn from The University of Manchester coordinated the comment with Professor Ferry Hagen from the University of Amsterdam and the Westerdijk Institute in the Netherlands.

Dr van Rhijn said: "Most people agree that resistant bacterial infections constitute a significant part of the AMR problem. However many drug resistance problems over the past decades have also been the result of invasive fungal diseases largely underrecognized by scientists, governments, clinicians and pharmaceutical companies. The threat of fungal pathogens and antifungal resistance, even though it is a growing global issue, is being left out of the debate."

Unlike bacteria, the close similarities between fungal and human cells which, say the experts, means it is hard to find treatments that selectively inhibit fungi with minimal toxicity to patients.

Back to square one

Professor Ferry Hagen added: "Despite the huge difficulties in developing them, several promising new agents including entirely new classes of molecules, have entered clinical trials in recent years. But even before they reach the market after years of development, fungicides with similar modes of action are developed by the agrochemical industry resulting in cross-resistance. That sets us back to square one again. It is true many essential crops are affected by fungi, so antifungal protection is required for food security. But the question is, at what price?"

The scientists recommend:

• Worldwide agreement on restricting the use of certain classes of antifungal molecules for specific applications.
• Collaboration on solutions and regulations that ensure food security and universal health for animals, plants, and humans.
• Adding priority to AMR to fungal infections at the UN's meeting in September.

Journal Reference:

1. Norman van Rhijn, Sevtap Arikan-Akdagli, Justin Beardsley, Felix Bongomin, Arunaloke Chakrabarti, Sharon C-A Chen, Tom Chiller, Arnaldo Lopes Colombo, Nelesh P Govender, Ana Alastruey-Izquierdo, Sarah E Kidd, Michaela Lackner, Ruoyu Li, Ferry Hagen. Beyond bacteria: the growing threat of antifungal resistance. The Lancet, 2024; 404 (10457): 1017 DOI: 10.1016/S0140-6736(24)01695-7

 Courtesy:

Universiteit van Amsterdam. "Ignore antifungal resistance in fungal disease at your peril, warn top scientists." ScienceDaily. ScienceDaily, 13 September 2024. <www.sciencedaily.com/releases/2024/09/240913003332.htm>.

Novel study reveals how aging immune system fuels cancer growth, potentially opening new avenues for prevention

 

A novel study by researchers at the Icahn School of Medicine at Mount Sinai addresses a critical yet under-explored question in cancer research: Why is aging the biggest risk factor for cancer? The study reveals how an aging immune system spurs tumor growth, offering new insights into cancer prevention and treatment, especially for older adults.

Details on the findings were reported in the September 5 Online First Release of Science. In preclinical models, the research team found that anakinra, a drug typically used for inflammatory conditions such as rheumatoid arthritis, can be repurposed to block harmful signals between early lung cancer lesions and the bone marrow. This is critical, say the investigators, because as the immune system ages, it creates harmful inflammation that can drive cancer development.

"As the immune system ages, it triggers harmful inflammation that can drive cancer growth -- by promoting the accumulation of pro-tumor macrophages, a type of immune cell that suppresses the immune effector cells that normally kill tumor cells. This weakens the body's ability to fight cancer," says lead author Matthew D. Park, PhD, a sixth-year Icahn Mount Sinai MD/PhD student in the lab of Miriam Merad, MD, PhD, senior corresponding author of the study.

"We found that by blocking specific inflammatory pathways, especially those involving molecules called interleukin-1⍺ (IL-1⍺) and IL-1β, this damaging process could be reversed in mouse models, offering a potential new approach to preventing cancer development in humans," says Dr. Merad, Dean for Translational Research and Therapeutic Innovation, Director of the Marc and Jennifer Lipschultz Precision Immunology Institute, and Chair of Immunology and Immunotherapy at Icahn Mount Sinai.

Signaling between early lung cancer lesions and immune stem cells in bone marrow via IL-1⍺/β underscores how an aging immune system promotes cancer progression.

Cancer is a disease that becomes increasingly common as we age, with the risk rising sharply after the age of 60. Many theories have been proposed, including the cumulative effects of environmentally-induced damage and genetic mutations, but there has been little concrete data explaining why aging drives cancer, say the researchers.

As part of the study, the research team used mouse models to investigate how aging affects cancer progression. They injected tumor cells into mice and observed that lung, pancreatic, and colonic cancer grew more rapidly in older mice compared to younger ones. Using bone marrow transplants from either young or old mice, the investigators simulated the effects of the immune system's aging. The team found that an aged immune system accelerates cancer growth, even in young mice. More strikingly, they found that rejuvenating the immune system significantly reduced cancer growth in older mice.

Using high-dimensional analysis of murine and human cancer tissues, the team identified specific cells and immune-related factors that accelerate cancer growth in the elderly. They then successfully blocked these factors, specifically IL-1⍺/β, demonstrating that inhibiting these molecules can reduce cancer growth in aged mice.

"Our study shows that an aged immune system promotes cancer progression, independent of the age of the cancer cells or the surrounding tissue. We've long suspected that inflammation can suppress anti-tumor immunity, particularly in older individuals and cancer patients. However, this is the first robust evidence proving that chronic inflammation from an aging immune system predisposes to cancer," says Dr. Merad. "This research not only brings our lab into the field of immune aging but also lays the groundwork for future studies, exploring its links to cancer and other aging-related conditions like cardiovascular disease and infections."

"This study reveals that targeting the aging immune system could significantly reduce cancer risk in older adults. It suggests that enhancing the immune response through immunotherapy might be more effective than directly targeting tumors. The discovery that anakinra, which blocks the activity of IL-1⍺/β and is a drug already used for inflammatory conditions, can mitigate the harmful effects of immune aging on cancer opens the door to repurposing existing medications for cancer prevention," says co-senior author Thomas Marron, MD, PhD, Director of the Early Phase Trial Unit at Mount Sinai's Tisch Cancer Institute. "We're now focused on translating these findings into clinical practice. Based on these results, we have now designed early-phase clinical trials to use anakinra in high-risk patients."

The ongoing trials are investigating whether targeting the immune system can prevent cancer progression, while the researchers continue to explore additional therapeutic targets. Their ultimate goal is to develop preventive measures that reduce harmful inflammation in older adults, thus significantly reducing the incidence of cancer.

Story Source:

Materials provided by The Mount Sinai Hospital / Mount Sinai School of Medicine. Note: Content may be edited for style and length.

 

Journal Reference:

1. Matthew D. Park, Jessica Le Berichel, Pauline Hamon, C. Matthias Wilk, Meriem Belabed, Nader Yatim, Alexis Saffon, Jesse Boumelha, Chiara Falcomatà, Alexander Tepper, Samarth Hegde, Raphaël Mattiuz, Brian Y. Soong, Nelson M. LaMarche, Frederika Rentzeperis, Leanna Troncoso, Laszlo Halasz, Clotilde Hennequin, Theodore Chin, Earnest P. Chen, Amanda M. Reid, Matthew Su, Ashley Reid Cahn, Laura L. Koekkoek, Nicholas Venturini, Shira Wood-isenberg, Darwin D’souza, Rachel Chen, Travis Dawson, Kai Nie, Zhihong Chen, Seunghee Kim-Schulze, Maria Casanova-Acebes, Filip K. Swirski, Julian Downward, Nicolas Vabret, Brian D. Brown, Thomas U. Marron, Miriam Merad. Hematopoietic aging promotes cancer by fueling IL-1⍺–driven emergency myelopoiesis. Science, 2024; DOI: 10.1126/science.adn0327 

Courtesy:

The Mount Sinai Hospital / Mount Sinai School of Medicine. "Novel study reveals how aging immune system fuels cancer growth, potentially opening new avenues for prevention." ScienceDaily. ScienceDaily, 5 September 2024. <www.sciencedaily.com/releases/2024/09/240905154905.htm>.

 

Researchers map 50,000 of DNA's mysterious 'knots' in the human genome

 

Innovative study of DNA's hidden structures may open up new approaches for treatment and diagnosis of diseases, including cancer.

DNA is well-known for its double helix shape. But the human genome also contains more than 50,000 unusual 'knot'-like DNA structures called i-motifs, researchers at the Garvan Institute of Medical Research have discovered.

Published today in The EMBO Journalis the first comprehensive map of these unique DNA structures, shedding light on their potential roles in gene regulation involved in disease.

In a landmark 2018 study, Garvan scientists were the first to directly visualise i-motifs inside living human cells using a new antibody tool they developed to recognise and attach to i-motifs. The current research builds on those findings by deploying this antibody to identify i-motif locations across the entire genome.

"In this study, we mapped more than 50,000 i-motif sites in the human genome that occur in all three of the cell types we examined," says senior author Professor Daniel Christ, Head of the Antibody Therapeutics Lab and Director of the Centre for Targeted Therapy at Garvan. "That's a remarkably high number for a DNA structure whose existence in cells was once considered controversial. Our findings confirm that i-motifs are not just laboratory curiosities but widespread -- and likely to play key roles in genomic function."

Curious DNA i-motifs could play a dynamic role in gene activity

I-motifs are DNA structures that differ from the iconic double helix shape. They form when stretches of cytosine letters on the same DNA strand pair with each other, creating a four-stranded, twisted structure protruding from the double helix.

The researchers found that i-motifs are not randomly scattered but concentrated in key functional areas of the genome, including regions that control gene activity.

"We discovered that i-motifs are associated with genes that are highly active during specific times in the cell cycle. This suggests they play a dynamic role in regulating gene activity," says Cristian David Peña Martinez, a research officer in the Antibody Therapeutics Lab and first author of the study.

"We also found that i-motifs form in the promoter region of oncogenes, for instance the MYC oncogene, which encodes one of cancer's most notorious 'undruggable' targets. This presents an exciting opportunity to target disease-linked genes through the i-motif structure," he says.

I-motifs hold promise for new type of therapies and diagnostics

"The widespread presence of i-motifs near these 'holy grail' sequences involved in hard-to-treat cancers opens up new possibilities for new diagnostic and therapeutic approaches. It might be possible to design drugs that target i-motifs to influence gene expression, which could expand current treatment options," says Associate Professor Sarah Kummerfeld, Chief Scientific Officer at Garvan and co-author of the study.

Professor Christ adds that mapping i-motifs was only possible thanks to Garvan's world-leading expertise in antibody development and genomics. "This study is an example of how fundamental research and technological innovation can come together to make paradigm-shifting discoveries," he says.

This research was supported by funding from the National Health and Medical Research Council.

Professor Daniel Christ is a Conjoint Professor at St Vincent's Clinical School, Faculty of Medicine and Health, UNSW Sydney. Associate Professor Sarah Kummerfeld is a Conjoint Associate Professor at St Vincent's Clinical School, Faculty of Medicine and Health, UNSW Sydney.

Story Source:

Materials provided by Garvan Institute of Medical Research. Note: Content may be edited for style and length.

Journal Reference:

1. Cristian David Peña Martinez, Mahdi Zeraati, Romain Rouet, Ohan Mazigi, Jake Y Henry, Brian Gloss, Jessica A Kretzmann, Cameron W Evans, Emanuela Ruggiero, Irene Zanin, Maja Marušič, Janez Plavec, Sara N Richter, Tracy M Bryan, Nicole M Smith, Marcel E Dinger, Sarah Kummerfeld, Daniel Christ. Human genomic DNA is widely interspersed with i-motif structures. The EMBO Journal, 2024; DOI: 10.1038/s44318-024-00210-5 

Courtesy:

Garvan Institute of Medical Research. "Researchers map 50,000 of DNA's mysterious 'knots' in the human genome." ScienceDaily. ScienceDaily, 29 August 2024. <www.sciencedaily.com/releases/2024/08/240829132437.htm>.

 

 

 

One antibody to neutralize them all?

A monoclonal antibody appears effective at neutralizing the numerous variants of SARS-CoV-2, as well as related viruses in animals that could pose a threat if they were to begin spreading in people. The antibody, called SC27, was recently described in Cell Reports Medicine.

The finding opens the possibility of broader, more effective treatments to work against current and future COVID variants.

Monoclonal antibody SC27 was identified, developed and provisionally patented by a team of researchers led by Greg Ippolito, Ph.D., who recently joined Texas Biomedical Research Institute (Texas Biomed) from University of Texas at Austin. Other team leaders included Jason Lavinder, Ph.D., at UT and Ralph Baric, Ph.D., at University of North Carolina at Chapel Hill.

"Other COVID-19 antibodies have been rendered ineffective as SARS-CoV-2 has evolved over the past several years," says Dr. Ippolito, an Associate Professor. "Our new study suggests the virus is less likely to escape this treatment because SC27 targets and attaches to multiple parts of the virus's spike protein, including sections that are not mutating as frequently."

SC27 appears to work in two ways: it blocks the ACE2 binding site, which the virus uses to bind to, enter and infect cells. It also binds to a hidden or "cryptic" site on the underside of the spike protein that is largely unchanged or "conserved" between variants, which means SC27 can broadly recognize variants and related viruses. This is critical because if an antibody's shape does not match enough with a virus -- like two puzzle pieces that don't quite fit -- the antibody can't effectively neutralize the virus and the virus sneaks by the body's immune defense system.

The researchers tested SC27 against 12 viruses, from the original SARS-CoV-2 to currently circulating variants, as well as related SARS-1 and several other coronaviruses found in bats and pangolins. The antibody was effective against all of them in a petri dish and protected mice against both variants tested.

"This makes it broader and more effective than any other monoclonal antibody reported in scientific literature to date and the former FDA-approved cocktails," says Dr. Ippolito, adding the caveat that SC27 still needs to be tested in human clinical trials.

The team is looking to collaborate with industry to further develop the SC27 monoclonal antibody treatment, which could potentially benefit immunocompromised patients who are unable to get vaccines. It also could serve as an emergency treatment during future outbreaks of new variants or coronaviruses. Next steps would include preclinical studies in larger animal models, including nonhuman primates, which are the gold standard to evaluate how complete immune systems respond to a treatment before safely moving to human clinical trials.

Notably, SC27 was found in individuals following vaccination with mRNA COVID-19 vaccines. Previously, this type of "class 1/4" antibody -- which attaches to two distinct areas or "epitopes" of the spike protein -- was only detected following natural infection from SARS-1.

"This is fantastic news that vaccines can prompt the generation of these more robust and effective antibodies," explains Dr. Ippolito. "It means that future vaccine development can be tailored to generate these antibodies and have a clear metric for measuring which vaccines will be most effective."

 

Story Source:

Materials provided by Texas Biomedical Research Institute. Note: Content may be edited for style and length.

 

Journal Reference:

1. William N. Voss, Michael L. Mallory, Patrick O. Byrne, Jeffrey M. Marchioni, Sean A. Knudson, John M. Powers, Sarah R. Leist, Bernadeta Dadonaite, Douglas R. Townsend, Jessica Kain, Yimin Huang, Ed Satterwhite, Izabella N. Castillo, Melissa Mattocks, Chelsea Paresi, Jennifer E. Munt, Trevor Scobey, Allison Seeger, Lakshmanane Premkumar, Jesse D. Bloom, George Georgiou, Jason S. McLellan, Ralph S. Baric, Jason J. Lavinder, Gregory C. Ippolito. Hybrid immunity to SARS-CoV-2 arises from serological recall of IgG antibodies distinctly imprinted by infection or vaccination. Cell Reports Medicine, 2024; 5 (8): 101668 DOI: 10.1016/j.xcrm.2024.101668

Courtesy:

Texas Biomedical Research Institute. "One antibody to neutralize them all?." ScienceDaily. ScienceDaily, 6 September 2024. <www.sciencedaily.com/releases/2024/09/240906141718.htm>.

 

 

 

 

 

TB under the sea: A marine sponge microbe provides insights into the evolution of tuberculosis

The surprising discovery of a bacterium in a marine sponge from the Great Barrier Reef with striking similarity to Mycobacterium tuberculosis, the pathogen responsible for tuberculosis (TB), could unlock and inform future TB research and treatment strategies.

TB remains one of the world's deadliest infectious diseases, yet the origins of M. tuberculosis are still not fully understood.

In a new study published in PLOS Pathogens, research led by the Peter Doherty Institute for Infection and Immunity (Doherty Institute) details the newly identified bacterium, Mycobacterium spongiae, found in a marine sponge collected near Cooktown, Queensland.

Often referred to as 'chemical factories', marine sponges are a valuable source of bioactive compounds with potent anticancer, antibacterial, antiviral and anti-inflammatory properties.

While studying a sponge specimen for its chemical-producing bacteria, researchers at the University of Queensland found a bacterium that puzzled them.

The sample was sent to the Doherty Institute, where the team conducted extensive analyses of the genes, proteins and lipids of M. spongiae. They discovered that it shares 80 per cent of its genetic material with M. tuberculosis, including some key genes associated with the bacteria's ability to cause disease.

However, the researchers found that, unlike M. tuberculosis, M. spongiae does not cause disease in mice, making it non-virulent.

The University of Melbourne's Dr Sacha Pidot, a Laboratory Head at the Doherty Institute and co-lead author of the paper, said it was an exciting and important find.

"We were astounded to discover that this bacterium is a very close relative of M. tuberculosis," said Dr Pidot.

"This finding provides new insights into the evolution of M. tuberculosis, suggesting that these pathogens may have originated from marine mycobacteria."

The University of Melbourne's Professor Tim Stinear, a Laboratory Head at the Doherty Institute and co-lead author of the paper, said that that this new knowledge is an important building block for future research.

"While there is more work to be done in this space, this discovery is a valuable piece in the puzzle of understanding how TB came to be such a serious disease," said Professor Stinear.

"Our findings could help find weak links in M. tuberculosis to inform the development of new strategies such as vaccines to prevent and combat tuberculosis."

Authors were from Bio21 Institute, University of Queensland, Institut Pasteur, UK Health Security Agency, University of Otago and WEHI.

Story Source:

Materials provided by University of Melbourne. Note: Content may be edited for style and length.

Journal Reference:

1. Sacha J. Pidot, Stephan Klatt, Louis S. Ates, Wafa Frigui, Fadel Sayes, Laleh Majlessi, Hiroshi Izumi, Ian R. Monk, Jessica L. Porter, Vicki Bennett-Wood, Torsten Seemann, Ashley Otter, George Taiaroa, Gregory M. Cook, Nicholas West, Nicholas J. Tobias, John A. Fuerst, Michael D. Stutz, Marc Pellegrini, Malcolm McConville, Roland Brosch, Timothy P. Stinear. Marine sponge microbe provides insights into evolution and virulence of the tubercle bacillus. PLOS Pathogens, 2024; 20 (8): e1012440 DOI: 10.1371/journal.ppat.1012440

Courtesy:

University of Melbourne. "TB under the sea: A marine sponge microbe provides insights into the evolution of tuberculosis." ScienceDaily. ScienceDaily, 30 August 2024. <www.sciencedaily.com/releases/2024/08/240829140836.htm>.

Scientists discover how the body's killer cells attack cancer

Scientists are on the verge of a cancer breakthrough after working out how the body's immune system targets cells devastated by the disease.

A new study has discovered that our natural killer cells, from the immune system which protect against disease and infections, instinctively recognise and attack a protein that drives cancer growth.

The experts say that by hijacking this protein, known as XPO1, they may be able to activate more killer cells to destroy the disease.

Scientists from the University of Southampton, working with experts worldwide, led the study and now believe it could offer new and less invasive forms of treatments.

The findings have been published in the Science Advances journal.

Lead author Professor of Hepatology Salim Khakoo, from Southampton, said it was previously believed that killer cells attack cancer cells in a random manner.

He added: "Our findings actually show how our body's immune system recognises and attacks these cancer cells.

"Killer cells are an emerging form of immunotherapy that shows huge promise.

"They don't attack healthy tissue in the way chemotherapy and other immunotherapies do, so are safer and have less side-effects than traditional forms of cancer treatment."

The XPO1 protein examined by the scientists is essential for normal cell function.

However, in many cancers, it becomes overactive and allows malignant cells to multiply unchecked.

The Southampton scientists found that a peptide -- short chains of amino acids -- derived from the XPO1 protein attracted the natural killer cells.

This, they say, triggers the body's immune response against the cancerous cells.

Prof Khakoo added: "Patients with cancer who had both active killer cells and high levels of XPO1 had significantly better survival rates.

"This holds true for a range of cancers including those with higher rates of death such as liver cancer, which has an average survival rate of only 18 months.

"As well as liver cancer, killer cell treatment in the future could be used to treat head and neck cancers, endometrial, bladder or breast cancer."

Previous studies have linked natural killer cells to the body's protection against cancer.But the latest study is the first of its kind to highlight a viable technique of activating killer cells -- to target the XPO1 protein -- to fight the disease.

Co-author Professor Ralf Schittenhelm, from Monash University in Australia, said the discovery could change the course of immunotherapy.

"We hope it could lead to personalised cancer treatment, especially in cases where traditional therapies have failed.

"The potential to develop targeted therapies that utilise the body's own immune system is incredibly exciting."

The scientific team at Southampton are now working on the development of the world's first vaccine that uses natural killer cells to fight cancer.

Story Source:

Materials provided by University of Southampton. Note: Content may be edited for style and length.

Journal Reference:

1. Matthew D. Blunt, Hayden Fisher, Ralf B. Schittenhelm, Berenice Mbiribindi, Rebecca Fulton, Sajida Khan, Laura Espana-Serrano, Lara V. Graham, Leidy Bastidas-Legarda, Daniel Burns, Sophie M.S. Khakoo, Salah Mansour, Jonathan W. Essex, Rochelle Ayala, Jayajit Das, Anthony W. Purcell, Salim I. Khakoo. The nuclear export protein XPO1 provides a peptide ligand for natural killer cells. Science Advances, 2024; 10 (34) DOI: 10.1126/sciadv.ado6566

Courtesy:

University of Southampton. "Scientists discover how the body's killer cells attack cancer." ScienceDaily. ScienceDaily, 28 August 2024. <www.sciencedaily.com/releases/2024/08/240828224237.htm>.

How beetle juice led to the discovery of a virus and solved the mystery of a superworm die-off

Rutgers University-New Brunswick scientists have discovered a virus that caused a nationwide die-off of superworms, a common food for birds, reptiles, other pets and, more and more so, even for humans as an alternative protein source. In doing so, they pioneered a different way to search for and identify emerging viruses and pathogens in humans, plants and animals.

Using chopped up beetle carcasses forming a slurry and an electron microscope cooled by liquid nitrogen, the scientists reported today in Cell that they have discovered what they have titled Zophobas morio black wasting virus. The name is derived from the virus' deadly effect on a species of darkling beetle, Zophobas morio, native to the subtropics,particularly in the insect's immature larval stage when it emerges from its eggs as large, brown superworms. This species was named "superworm" because its larvae are bigger, at about 2 inches in length, than any others grown as feed.

The protein-rich larvae of Z. morio, which are dietary staples for captive, often exotic reptiles, birds, fish and amphibians worldwide, mysteriously began dying off in 2019, puzzling pet food suppliers and pet owners.

Jason Kaelber, an author of the study and an associate research professor at the Institute for Quantitative Biomedicine (IQB) at Rutgers-New Brunswick, worked with Judit Penzes, the first author of the study and a postdoctoral associate at IQB.

"Judit was looking to identify the reason beetle farmers were losing all their superworm colonies to a deadly disease and I was looking to develop ways of discovering new viruses that don't depend on DNA or RNA sequencing," Kaelber said. "We ended up discovering the virus that has been sweeping the country and killing superworms."

The scientific investigation began more than a year ago, when Penzes, a molecular virologist, was contacted by beetle farm owners whose superworms were mysteriously dying off at alarming rates. Penzes was already well known in the industry because of earlier work where she isolated a virus that was killing crickets, another popular food for pets.

She started by collecting superworms at pet stores in New Jersey. "Whenever I went to a pet store, I immediately went to the feeder insect section, opened the containers and looked at the worms," she said. "They were all infected. I told the owners of the stores what I was seeing that I was researching this virus, and asked if I could have the container. They were immediately on board. They told me to take as many as I needed."

She returned to her lab, took a Magic Bullet blender, dropped the worm carcasses in and blended them at a high speed. The process created a slurry of beetle juice which she took and processed using a virus purification method that separates the virus out due to its density. In the final step, she shined a fluorescent light on the centrifuge tube and the virus glowed blue.

"I said, 'I got you,' when I saw it," Penzes said. "I knew then it was, indeed, a virus."

Next, Penzes worked with Kaelber, a fellow electron microscopist, to examine the virus using a cryo-electron microscope, which allows a three-dimensional view of the virus, including its interior.

"You're taking a virus, a protein, a cell, etc., and you're freezing it so quickly that the water solidifies without turning into ice crystals," Kaelber said. "We actually can figure out what the amino acid sequence of the protein is without analyzing the DNA, and just by looking at that 3D structure, because we have such sharp resolution."

They compared the structure of the protein with all known proteins using the database of the Protein Data Bank hosted at Rutgers and found that it is similar to a virus affecting cockroaches, but not identical, and part of a family of animal viruses known as parvoviruses.

"It's a new one, different from anything that's been sequenced or imaged before," Penzes said.

The scientists are also grateful to superworm farmers nationwide who sent samples voluntarily, once word of the study got out. "The eagerness of the farmers to help us out researching the virus had an enormous role in helping this published study to be born," Penzes said.

The effort, Kaelber said, provided a "proof of concept" that cryo-electron microscopy can be employed to directly discover and characterize new pathogens.

"In the future, if there's ever a really important outbreak, we're going to want to throw every tool we can at it to see what we can find," Kaelber said. "We'd like to make diagnostic cryo-electron microscopy routinized, so that when there's some unknown infectious disease, we have a lot of options for same-day identification of the causative agent."

Cryo-electron microscopy has gained popularity in recent years, becoming a more prevalent method for 3D analysis of known specimens. However, the Rutgers work represents the first time the method was used on an unknown pathogen.

After discovering the virus, the researchers tested a way to protect the Z. morio beetles from disease, by injecting a closely related virus from another species that doesn't cause symptoms. They are developing a vaccine based on that work.

"The discovery is important for two reasons," Kaelber said. "First, beetle farmers can use this information to protect their colonies and understand which actions will be effective or ineffective at managing the epidemic. Second, the beetle epidemic was a real-world test of the technology that we hope can be useful to rapidly investigate future outbreaks in humans, plants or animals."

Scientists Martin Holm of the Rutgers Institute for Quantitative Biomedicine and Samantha Yost of REGENXBIO Inc., in Rockville, Md., also authored the study.

Story Source:

Materials provided by Rutgers University. Original written by Kitta MacPherson. Note: Content may be edited for style and length.

ournal Reference:

1. Judit J. Penzes, Martin Holm, Samantha A. Yost, Jason T. Kaelber. Cryo-EM-based discovery of a pathogenic parvovirus causing epidemic mortality by black wasting disease in farmed beetles. Cell, 2024; DOI: 10.1016/j.cell.2024.07.053

Courtesy:

Rutgers University. "How beetle juice led to the discovery of a virus and solved the mystery of a superworm die-off." ScienceDaily. ScienceDaily, 28 August 2024. <www.sciencedaily.com/releases/2024/08/240828224243.htm>.