Category: 8. Health

Our intestines are home to trillions of microorganisms that produce substances capable of regulating all the body’s organs via the bloodstream and the gut’s nervous system. Yet, only little is known about the effects of most of the bacteria that make up our microbiome. Now, an international team of scientists led by the University of Copenhagen has identified a common specific bacterial strain that may open the door to an entirely new class of therapeutics.

This bacterium produces two proteins that partly resemble the hormone irisin. Irisin is released by muscles during physical activity and plays a role in fat metabolism.

The newly discovered signaling proteins, named RORDEP1 and RORDEP2, influence the body’s hormonal balance and affect weight, bone density, and blood sugar levels.

“We found that the number of RORDEP-producing bacteria can vary by up to 100,000 times between individuals, and that people with high levels of these bacteria tend to be leaner,” says Yong Fan, Assistant Professor at the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen and lead author of the study, which has just been published in the prestigious journal Nature Microbiology. 

Regulates body weight and blood sugar

In the study, the researchers describe how RORDEP-proteins increase the body’s own production of hormones such as GLP-1 and PYY, which help regulate appetite and blood sugar, as well as insulin, which is essential for maintaining stable blood sugar levels. At the same time, they suppress another hormone, GIP, which can contribute to weight gain. RORDEP-proteins also directly enhance fat burning.

In experiments with rats and mice that received either RORDEP-producing gut bacteria or the RORDEP proteins themselves, we observed reduced weight gain and lower blood sugar levels, along with increased bone density. What’s exciting is that this is the first time we’ve mapped gut bacteria that alter our hormonal balance.”

Yong Fan, Assistant Professor at the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen

A paradigm shift in treating chronic diseases

Research into the role of gut bacteria in human health has led the University of Copenhagen researchers to establish the biotech company GutCRINE already two years ago, with financial support from the university.

The first clinical trials are now underway. In one study, healthy participants are given live bacteria that produce RORDEPs to examine how they affect human biology. Another trial is testing the effects of the RORDEP1 protein.

We’re now translating our basic research into human studies to explore whether RORDEP-producing bacteria or the RORDEP proteins – either in their natural or chemically modified form – can serve as the foundation for a new class of biological drugs known as pharmabiotics.”

Professor Oluf Pedersen from the University of Copenhagen, project leader and senior author of the new study

He adds: “Looking 10 to 15 years ahead, our goal is to test the potential of RORDEP-producing bacteria for both prevention and treatment. We want to investigate whether they can function as a second-generation probiotic – used as a dietary supplement to prevent common chronic diseases – and whether RORDEP-proteins in modified forms can be developed into future medicines for cardiovascular disease, obesity, diabetes, and osteoporosis.”

The research was conducted in collaboration with scientists from the University of Copenhagen, Herlev-Gentofte Hospital, Zealand University Hospital, Novo Nordisk A/S, the Technical University of Denmark, Steno Diabetes Center, and Chongqing Medical University. 

We included 178,336 individuals with SLD in analysis (36.3% females, mean age 57.3 years; 73.5% MASLD, 19.0% MetALD, 6.4% ALD) (Fig. 1). About one in five (20.2%) of SLD participants had MM, higher in females than in males (24.4% vs. 17.8%). The prevalence of MM was 21.3%, 15.9% and 17.4% in people with MASLD, MetALD and ALD, respectively. Overall, compared to people without MM, people with MM were more likely to be older, living in socioeconomically deprived area, less educated, smokers and drink less. They were also more likely to have diabetes and low HDL cholesterol, but less likely to have hypertension and high TG (Table 1).

Disease clusters and their characteristics

Latent class analysis derived five distinct disease clusters for males and females, respectively, with some overlapping and some sex-specific patterns (Additional file 1: Fig. S1(A), Table S1). For males, although the clustering evaluation metrics indicated that an 8-cluster solution was statistically optimal, we opted against this model due to concerns on clinical redundancy and potential overfitting. Upon review, the 8-cluster solution included two highly similar respiratory clusters (one characterised by asthma and COPD, the other by asthma and other chronic respiratory disease), as well as two overlapping cardiovascular clusters (one with ischaemic heart disease, heart failure and arrhythmia, and another with ischaemic heart disease, heart failure and heart valve disease). A similar issue of cluster overlap was also observed in the 6-cluster solution. Therefore, to balance clinical interpretability and parsimony, we selected the 5-cluster model for subsequent analyses.

Table 2 summarises the characteristic diseases within each cluster. In both sexes, a respiratory cluster (characterised by asthma, COPD and other chronic respiratory diseases), a mental health cluster (dominated by depression and anxiety, with substance use disorder additionally present in males) and a cancer/osteoarthritis cluster (including solid organ cancers, chronic respiratory diseases and osteoarthritis) were observed. Among males, a heart cluster (characterised by ischaemic heart disease, arrhythmia and heart failure) and a stroke cluster (characterised by stroke and paralysis) were identified. In females, these two clusters merged into a single heart/stroke cluster, which included ischaemic heart disease, arrhythmia and stroke. Additionally, females had a unique thyroid cluster, consisting of thyroid disorders and connective tissue diseases. All these characteristic diseases showed high exclusivity (> 20%) and most showed high E/O ratio (> 2.0). Additional file 1: Table S2 shows more details on the LTCs in each cluster.

In males, the most common disease cluster to which individuals were assigned was the cancer/osteoarthritis cluster (30.0%), followed by respiratory cluster (27.7%), heart cluster (20.3%) and mental cluster (13.9%) while stroke cluster (8.1%) was the least common. In females, the most common cluster was respiratory cluster (26.0%), followed by mental cluster (21.9%), cancer/osteoarthritis cluster (21.5%) and thyroid cluster (19.6%), and the least common was heart/stroke cluster (11.0%) (Table 2). Across SLD subtypes, mental health cluster was more prevalent in ALD in both males and females, while heart/stroke and thyroid clusters were more prevalent in MASLD in females (Additional file 1: Fig. S2).

Additional file 1: Tables S3 and S4 present the baseline characteristics of males and females assigned to each disease cluster. In both males and females, clustering was associated with age, socioeconomic status, physical activity and CMRFs. Individuals in the respiratory and mental health clusters were younger, while those in the heart and/or stroke cluster were the oldest. Both sex-specific mental health and stroke clusters were more socioeconomically deprived, and the stroke clusters had lower level of physical activity. Both the stroke and heart clusters had higher prevalence of diabetes and low HDL than overall males. The heart cluster and stroke cluster also demonstrated differences in socioeconomic deprivation, physical activity level, diabetes, hypertension and low HDL cholesterol.

In females, the mental health and heart/stroke clusters were more likely to live in socioeconomically deprived area, with the heart/stroke cluster also less likely to have higher education, be never smokers or engage in high physical activity level. While diabetes was less common in the mental health cluster, it was more prevalent in the heart/stroke cluster, which also had higher TG and lower HDL levels. Mental health cluster was also more likely to be White ethnicity in females.

Disease clusters and all-cause mortality

During a median follow-up of 13.8 years, 14,595 (12.8%) and 6171 (9.5%) deaths were captured in males and females, respectively. Compared to males with SLD but without MM, males with MM had an excess mortality rate of 12.3/1000 person-years (20.0 vs. 7.7), yielding an HR estimate of 2.00 (95%CI 1.93, 2.08). Compared to females without MM, females with MM had an excess mortality rate of 6.0/1000 person-years (11.7 vs. 5.7), responding to an HR estimate of 1.80 (95%CI 1.71, 1.90).

People in all disease clusters showed higher all-cause mortality than people without MM. In males, heart and stroke clusters were associated with the highest mortality, with HR of 2.63 (2.48, 2.78) and 2.36 (2.16, 2.58); respiratory, mental health and cancer/osteoarthritis clusters showed HR of 1.62 (1.51, 1.73), 1.84 (1.69, 2.00) and 1.85 (1.75, 1.96), respectively. In females, heart/stroke cluster was associated with the highest mortality, with HR of 2.90 (2.64, 3.20). Respiratory, mental health, cancer/osteoarthritis and thyroid clusters showed HR of 1.73 (1.58, 1.89), 1.57 (1.42, 1.74), 1.85 (1.69, 2.02) and 1.42 (1.28, 1.58), respectively (Fig. 2, Additional file 1: Table S5). Sensitivity analyses by additional adjustment for CMRFs and removing the first 2 years of follow-up generated similar results (Additional file 1: Table S6).

Disease clusters and cause-specific mortality

Examining causes of death, 65% of all deaths were due to extrahepatic cancers, CVD and liver-related diseases, and the remaining 35% were due to other causes. More specifically, in males, 31.9% and 31.8% deaths were attributed to extrahepatic cancers and CVD, while only 1.1% to HCC and 4.4% to liver-related diseases. Similarly in females, 39.9%, 21.9%, 0.3% and 3.3% deaths were attributed to extrahepatic cancers, CVD, HCC and liver-related diseases, respectively. Extrahepatic cancer and CVD were the major causes of death across all clusters, contributing 58.1% to 67.3% of all deaths in males and 59.1% to 66.7% in females. CVD was the biggest cause of death in the stroke and heart clusters in males and in the stroke/heart cluster in females, while extrahepatic cancers remained the biggest cause of death for all other clusters (Additional file 1: Fig. S3).

Compared to people without MM, having MM was associated with higher mortality from extrahepatic cancers by 45% (1.45 (1.37, 1.54)), CVD by 173% (2.73 (2.56, 2.92)), HCC by 67% (1.67 (1.20, 2.32)) and liver-related diseases by 84% (1.84 (1.55, 2.18)) in males and extrahepatic cancers by 40% (1.40 (1.30, 1.52)), CVD by 130% (2.30 (2.04, 2.58)) and liver-related death by 46% (1.41 (1.06, 1.86)) in females. All five clusters were associated with increased mortality of extrahepatic cancers, with the highest risk in cancer clusters in males (1.77 (1.62, 1.92)) and females (1.74 (1.53, 1.98)). All five clusters were associated with mortality from CVD, with the highest risk in stroke and heart clusters in males (3.34 (2.86, 3.90) and 5.28 (4.83, 5.77)) and stroke/heart cluster (5.66 (4.75, 6.75)) in females. The disease clusters also showed general trend of positive associations with mortality of HCC and liver-related diseases, although non-significantly, likely due to the small number of events in these clusters (Table 3).

Stroke cluster males also had a lower mortality rate (26.9 vs. 30.1 per 1000 person-year) than heart cluster (Additional file 1: Table S5), with lower mortality of CVD but higher mortality of cancer compared to the heart cluster (Additional file 1: Fig. S3).

Cluster validation

To assess the clustering stability across subsamples, we applied LCA to randomly selected 80% and 50% subsets of the full sample and compared the results with the primary full-sample analysis. We observed that the aBIC plots demonstrated similar trends across all samples, and the optimal number of clusters remains unchanged at 5 when applying all three model selection criteria (Additional file 1: Fig. S1(B, C)). The disease profiles of the derived clusters were highly consistent with those identified in the full-sample analysis (Additional file 1: Table S7). The distributions of posterior probability for each cluster were also similar across the three sample analyses (Additional file 1: Table S8). Comparing the full and 80% sample analyses, 99.0% males and 98.2% females were assigned to the same clusters; compared the full and 50% sample analyses, 96.3% males and 96.2% females remained in the same clusters. These results supported the robustness and reproducibility of the clustering solution.

To evaluate the impact of individuals with low posterior probability on the association estimates, we conducted a sensitivity analysis excluding participants with a maximum posterior probability < 70% for cluster assignment. This resulted in the exclusion of 5995 (29.7%) males and 3511 (22.2%) females (Additional file 1: Table S9). Additional file 1: Table S10 shows the associations between disease clusters and all-cause and cause-specific mortality outcomes, which were largely consistent with those observed in the primary analysis, further supporting the stability of clustering assignments.

A fascinating study exploring the longevity of Black Death survivors in fourteenth century England has shone light on how famine and early life malnutrition can affect health well into adulthood.

The research, in Science Advances, reveals the biophysical trade-off made by the body to cope with severe nutritional stress in the womb or in childhood, which may still apply today.

While surviving famine increased the likelihood of reaching adolescence, it came at the cost of increased susceptibility to death later in life from common causes such as cardiovascular disease and cancer.

“What our findings suggest is that relationships between malnutrition early in life and poor health in middle and late adulthood have a very deep history,” researcher Sharon DeWitte, PhD, from the University of Colorado, told Inside Precision Medicine.

“This highlights the need to ensure that pregnant individuals and young children have access to nutritious diets in order to lessen the risks of poor health across the lifespan, and for people who know they experienced malnutrition as children to be really vigilant about diets and other healthy lifestyle habits as adults.”

The study examined the relationship between nutritional stress in childhood and health outcomes using skeletal remains from 275 people during and after the Black Death in London and rural Lincolnshire, from approximately 1000 to 1540 CE.

There were famines in England every 14 years on average in the eleventh to thirteenth centuries in the common era, with a slight decrease in the fourteenth to sixteenth centuries CE.

These are often attributed to the climate change at that time, with their effects exacerbated by social and economic factors, which tap into the concept of the “syndemic.”

This recognizes that diseases are not just biological and that outcomes are not simply the result of the interaction of a pathogen with a person’s immune system but operate with synergistic effects on a broader individual and societal level.

To therefore understand disease susceptibility and outcomes, careful attention needs to be paid to biological, environmental, physical, and social contexts that can include coinfections with multiple pathogens, malnutrition, wealth inequality, and social marginalization.

The team examined bones and teeth, focusing on isotopic profiles stored in dentine—a bony part of the tooth under the enamel layer that can reveal periods of nutritional stress.

Because teeth form in a well-understood and robust manner during childhood and adolescence and do not remodel, changes in the isotope ratios of carbon and nitrogen can be used to investigate changes in diet and physiology over set periods of life.

Restricting their analysis to people who died when they were less than 30 years of age, the researchers found that survivors of nutritional stress in utero and early childhood were resilient when it came to dying in childhood, adolescence, or early adulthood versus those without such stress signatures.

“However, in our study, the lack of a significant difference in hazards of death for those who died below the age of 30 with and without signatures of childhood nutritional stress cautions us against overinterpreting the survival analysis findings for this age group,” the authors caution.

Perhaps more meaningful was that, on looking at people older than 30 years, survivorship was significantly higher and hazards of death significantly lower for people without signatures of severe childhood nutritional stress than those who had these signatures.

“Perhaps the people in our study who suffered early-life nutritional stress underwent developmental adaptations as a result that shaped their physiology for a future of nutritional deprivations, but they subsequently experienced relative nutritional abundance in adulthood,” the authors speculated in their article.

“Thus, they may have suffered higher rates of diseases common in later adulthood, such as cardiovascular disease and other ‘degenerative’ diseases, as has been suggested to explain the relationships between early-life stress and noncommunicable disease outcomes for present-day people.”

Green unpacks the virus’s complex biology, highlighting how UAB researchers use molecular science to expose its vulnerabilities and explore new paths for treatment.It starts quietly, a bite or a scratch, and by the time symptoms surface, it is often too late. Rabies is not just a distant threat — it is alive and present here in Alabama. 

Prevention remains critical; but once symptoms appear, treatment options are extremely limited. Because rabies hides behind a complex molecular shield, it is nearly impossible to fight.

“For more than 30 years, my research has focused on the viral proteins that drive replication,” said Todd Green, Ph.D., structural biologist and virologist and associate professor in the University of Alabama at Birmingham Department of Microbiology. “By uncovering how these processes work in rabies and related viruses, we hope to open new doors for therapeutics, ones that can stop viral outbreaks before they become global threats.”

The challenge of treating rabies

Rabies is notoriously difficult to treat once symptoms begin, and that challenge starts at the molecular level. Unlike many viruses that immediately translate their genetic material into proteins, rabies belongs to a family of viruses with a far more complex replication process.

“The rabies virus and all negative-strand RNA viruses, or NSVs, have distinctive replication cycles,” Green said. “They rely on surface proteins that interact with various cell types and unique enzymes that drive transcription and replication.”

What sets these viruses apart is how tightly their genomes are bound to nucleocapsid, or N, proteins. This N protein-RNA complex acts as the template for both transcription and replication.

That means rabies must first transcribe its genetic material into messenger RNA before proteins can be made.

“This could offer an opportunity to target rabies at an earlier stage of replication, different from how we typically treat other viruses,” Green said. “There are only broad-spectrum antivirals, not rabies-specific ones, so there is potential to develop antivirals that directly target these early stages of replication.”

A weak spot in the rabies virus

Decoding rabies’ replication process has revealed one of its most significant vulnerabilities: a specialized polymerase enzyme the virus depends on to survive and multiply. While different viruses use various strategies to replicate, NSVs like rabies rely on this enzyme to generate mRNA and replicate their genomes.

Todd Green, Ph.D.“Two unique features of the polymerase are that it recognizes a protein-RNA complex as the viable template for both transcription and replication, and polymerases of NSVs have a different mechanism for capping viral mRNA,” Green said. “Capping is necessary for the stability of mRNA and efficient translation of mRNA to protein.”

In NSVs, the polymerase has a special region that carries out this capping through an enzymatic process distinct from the host’s process.

This molecular discovery offers a promising target for antiviral drugs that could disrupt the virus without harming human cells.

Decoding the structure

UAB has played a pivotal role in advancing research on NSVs. In the late 1980s and early 1990s, former faculty members and current adjunct professors Gail Wertz, Ph.D., and Andrew L. Ball, Ph.D., helped pioneer reverse genetics systems for NSVs. These tools allowed researchers to introduce targeted mutations into viral genomes, revolutionizing the study of viral behavior and replication.

“My work has focused on the structural biology of two related rhabdoviruses: vesicular stomatitis virus, or VSV, and rabies virus,” Green stated. “Working alongside Ming Luo, Ph.D., who retired in 2014, I helped determine the structure of the VSV nucleocapsid protein bound to RNA, and later studied its interaction with the phosphoprotein.”

Green’s lab defined parts of the polymerase structure and model polymerase complexes for VSV and rabies viruses.

“Over decades of research, we’ve mapped the structures and interactions of all major viral proteins,” he said. “This has given us a much deeper understanding of how these viruses assemble, replicate and transcribe their genomes.”

Building on this foundation, the department continues to expand its impact on viral research and antiviral development.

“By studying the detailed molecular makeup of viruses, researchers in our department can illuminate new paths for targeted antiviral therapies,” said J. Victor Garcia-Martinez, Ph.D., CPC, Charles H. McCauley Endowed Chair in Microbiology. “Their studies on virus replication mechanisms and structural vulnerabilities offer hope for the possible development of future treatments that could transform once-untreatable threats into preventable diseases.”

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Results from a recently published study demonstrated that a multicancer early detection test was able to identify circulating tumor DNA (ctDNA) 3 years or more before a cancer diagnosis.

Blood samples were collected from 52 patients in the observational Atherosclerosis Risk in Communities (ARIC) study (NCT00005131), of whom 26 had cancer diagnosed within 6 months of blood collection and 26 did not but were matched for age, race, and sex. A total of 8 patients had a positive early plasma sample: 7 were detected with a targeted panel and 1 with an aneuploidy analysis. All 8 patients were diagnosed with cancer within 4 months of the early plasma sample acquisition; the sensitivity was 31% (95% CI, 17%-50%).

Of the cases, 3 patients had colon cancer, and 1 each had pancreatic, rectal, lung, breast, and liver cancer. Cancer stage at diagnosis was unavailable for 5 patients, but in the 3 it was, stage I, II, and III were observed.

CancerNetwork® spoke with David L. Bartlett, MD, chair of the Allegheny Health Network Institute, past president of the Society of Surgical Oncology, and surgical oncologist, following the publication of the results.

CancerNetwork: What did this study find?

Bartlett: This study, very interestingly, identified patients who developed cancer, but were also on a study where they were getting serial blood drawn over a period of time, sometimes many years. What they were able to show, in retrospect, was that patients who developed cancer had cancer DNA or cell-free DNA or ctDNA in the blood up to 3 and a half years prior to the diagnosis of their cancer. It just opens that door that says we can detect cancer early using a blood test. That is the exciting aspect of this study, just showing there is a fingerprint of cancer early on, before it’’s detectable by other means.

What are the clinical implications of having extended notice if a patient may develop cancer?

The key to early detection, or the amazing results of early detection, is that you can [detect] the cancer early, and you can cure it. Most cancers that are [detected] in stage I or II are curable with surgical or other techniques; if you want to cure cancer, you have to [detect] early. If we can screen for cancer using blood tests, we’re going to [detect] it early. The problem with that is being able to detect cancer or ctDNA, but not knowing where that tumor is in the body. What are the implications for the health care system when we identify these cancer DNA mutations circulating in the blood? How are we going to apply that in terms of a workup? That’s the next step.

Once we have a reliable test, then we can start to look at what the workup is going to be, and the frequency of screening to [detect] that cancer as you start to see it on an imaging test, so that you can then go after it surgically.

There are some early detection tests that can identify the type of cancer as well. For instance, the GRAIL test is a multi-cancer early detection test that will specify the most likely primary site for that tumor. If it [detects] a pancreas cancer, then you know you need to focus on the pancreas, and you can do very focal imaging techniques on the pancreas to see if you can identify where the lesion is. Some tests will be able to pinpoint the origin of the cancer, whereas others are just going to say, “you have cancer DNA in your blood”. It could be anything, and it’s going to be up to us to figure out how to best work those patients up.

How should a physician care for a patient with a positive ctDNA signal?

It is a problem that if we identify that there’s cancer in the body, and cannot identify where that cancer is, that’s going to have a great psychological impact on the patients who have that positive test. One thing is, we need to have a very specific test. In other words, we can’t have a test that says you have cancer but could be wrong 20% to 30% of the time, because that’s going to create a lot of anxiety that may end up worse than not getting the test at all. We have to be very careful of the specificity.

If it is positive, we know there’s something going on, and then we’re going to have to put those patients through screening tests on a regular basis to identify where it’s coming from and take care of it right away. We can do whole-body PET scan imaging to look for metabolically active cancers, but even that has a threshold of detection that is going to be higher, most likely, than cell-free DNA. In those situations, you’re going to find positive tests with no correlation, and you’re going to have to educate the patients as to what that means. The hope is that you can educate patients and say, “As long as we’re following closely, we’re going to identify that cancer before it becomes a problem and while it’s still curable, whereas if you didn’t get the blood test by the time we knew it was there, it would be too advanced to cure.” There is an advantage, but you’re going to have to sit down and talk to the patients about the significance of the findings.

What are some of the logistical hurdles in integrating this as a pre-screening test in routine practice for oncologists?

The Delphi study is a good example of this because it’s not only educating patients about what this test is doing and what the significance of the test is, but it’s also educating practitioners who are used to getting a lung CT scan as a screening modality. Now they have to think about the blood test, they have to follow up on that blood test, and then get subsequent testing, as needed. There is a logistical hurdle around educating the practitioners about how to manage a positive or a negative test in these patients.

In general, the practitioners are very tuned in to cancer screening in general, and it’s part of all the metrics that they get judged by, from a quality perspective. There’s a lot of awareness around cancer screening in general. I don’t think it’s going to be too hard to implement new cancer screening blood tests, for instance, but [it may be] for the educational component because if they’re uncomfortable with those results, then they’re not going to order them. They’re going to have to do a lot of education in the communities.

How is this being applied at Allegheny Health Network?

The most commercially mature product is the GRAIL, a multicancer early detection blood test. This is not reimbursed by insurance companies, which is another big factor; if we get a test, we have to show that it has value, and, ultimately, get it approved by Medicare and other payers before it can be adopted widely because it’s expensive. Right now, the GRAIL test is available, and patients can pay for that to get screened for cancer, but it’s very important that those people understand the implications of the test. We do offer that test in our screening clinics, as well as at our free screening events on the weekends. We do free screening events at different cancer centers around the region on the weekends, and we have a comprehensive cancer screening clinic where patients can come in and get all their cancer screening done.

Reference

Wang Y, Joshu CE, Curtis SD, et al. Detection of cancers three years prior to diagnosis using plasma cell-free DNA. Cancer Discov. Published online July 04, 2025. doi:10.1158/2159-8290.CD-25-0375

In this interview, we spoke with Associate Professor Diana Mechtcheriakova about how lymphoid structures and germinal centers are unlocking new prognostic insights into colorectal cancer, and with Anastasiia Marchuk of TissueGnostics about the imaging technologies powering this research.

Can you please introduce yourself and your role at the Medical University of Vienna?

Diana Mechtcheriakova: I am Diana Mechtcheriakova, affiliated with the Institute of Pathophysiology and Allergy Research at the Medical University of Vienna, where I serve as head of the research group Molecular Systems Biology and Pathophysiology.

My recent presentation, titled “Unlocking the Lymphoid Structures with Germinal Centers: Architectural Complexity, Functionality, and Clinical Relevance,” reflects the core themes of our research.

Our group operates within a conceptual framework that transitions from systems biology to systems medicine, aligning with the broader vision of personalized medicine. This approach is based on the Aristotelian principle that “the whole is greater than the sum of its parts” and emphasizes a holistic methodology for deciphering biological complexity through a hierarchical flow from data to information to knowledge.

Our primary research areas include the development of systems biology approaches applied to various projects, with a focus on B-cell biology, immune oncology, lymphoid structures, AID/APOBEC-associated biological events, and the cellular sphingolipid/lysophosphatidate system in immunity and cancer.

In addition, I lead the Tissue Image Cytometry Unit at Austrian Bioimaging and serve as head of the Basic and Translational Research Module at the Austrian Platform for Personalized Medicine.

Could you tell us more about your recent research on lymphoid structures and their clinical relevance in cancer?

Diana Mechtcheriakova: My recent work focuses on the biology of lymphoid structures, which are highly organized formations characterized by dense cellular interactions and functional cooperation among various immune cell types. These include B-cell subsets, follicular helper T cells, and follicular dendritic cells.

When fully developed, these structures contain germinal centers, which are functional niches where B cells proliferate, differentiate, undergo affinity maturation, and switch antibody classes. A key marker of active germinal centers is activation-induced cytidine deaminase (AID), which can be visualized through tissue staining, such as in tonsil samples.

The germinal center reaction results in the production of plasma cells and memory B cells. These lymphoid structures are typically located in secondary lymphoid organs; however, they can also be assembled in ectopic locations within chronically inflamed tissues, including tumors. In such cases, they are referred to as ectopic lymphoid structures (ELS) or tertiary lymphoid structures (TLS).

A particularly important aspect of this research is the clinical relevance of B cells and ELS in cancer. It has been demonstrated—an insight I consider one of the major breakthroughs of recent years—that the local presence of B cells and ectopic lymphoid structures correlates with favorable patient prognosis in more than ten cancer types. Notable examples include non-small cell lung cancer, breast cancer, and colorectal cancer with liver metastases.

Can you describe your research findings on ectopic lymphoid structures in colorectal cancer with liver metastases?

Diana Mechtcheriakova: In the context of colorectal cancer with liver metastases, our research group was among the first to demonstrate the accumulation of B cells assembled in ectopic lymphoid structures (ELS) with active germinal centers in the liver. These ELS were observed forming a ring-like pattern around the metastases.

To investigate this further, we conducted a precise quantification of B cells and ELS at the tumor-liver interface, using defined zones extending both toward the tumor and into the adjacent liver tissue. This analysis was performed through quantitative tissue image cytometry, utilizing TissueFAXS-based computerized microscopy. Our findings revealed that a higher density of B cells and ELS at the tumor-liver border correlated with improved clinical outcomes, particularly in terms of patient survival.

This prognostic value exceeded that of conventional clinicopathological parameters. Based on these observations, we proposed the hypothesis that the anti-tumor immune response at the metastatic site in the liver may be pre-instructed either at the primary colorectal cancer site or potentially within the non-tumorous colon mucosa, where isolated lymphoid structures (ILS) are normally present.

Image Credit: Anusorn Nakdee/Shutterstock.com

What was the primary objective of your study on lymphoid structures in metastatic colorectal cancer?

Diana Mechtcheriakova: The main objective of our study was to determine whether specific characteristics of lymphoid structures across three distinct tissue entities influence the pathobiology of metastatic colorectal cancer (CRC). To investigate this, we developed a multi-modular approach called DIICO, which stands for Digital Immune Imaging to Clinical Outcome.

The first module of the DIICO strategy involved immunostaining tissue samples using a defined set of immune markers. These included CD20 as a general B-cell marker, AID to identify functionally active germinal centers, Ki67 for proliferating cells, CD27 for memory B cells and plasma cells, CD138 for plasma cells, and CD3 as a general T-cell marker.

We applied these markers to both colon cancer specimens and tonsil tissues to characterize the immune cell composition and assess the functional activity of lymphoid structures.

How did you implement the DIICO strategy, and what did your tissue analysis reveal?

Diana Mechtcheriakova: The second module of the DIICO strategy focused on assessing the immunological imprint using quantitative tissue image cytometry. Stained specimens were digitized through the automated microscope-based TissueFAXS platform, and quantitative analysis was performed using the HistoQuest and TissueQuest software packages.

Lymphoid structures were defined as distinct objects, and the analysis was carried out at the single-cell level with marker-positive cell detection based on specific expression profiles.

We have had the TissueFAXS platform at our institute since 2008, and in 2022, we were recognized as a Center of Excellence for Quantitative Digital Microscopy. For this project alone, we analyzed more than 700 colon cancer tissue slides and over 120 tonsil samples.

This analysis transformed tissue-encoded information into numerical variables, categorized by anatomical region and staining characteristics for each patient. These variables were then aligned with clinicopathological parameters to generate insights into disease mechanisms and patient outcomes.

What did your analysis reveal about the clinical importance of lymphoid structure characteristics in metastatic colorectal cancer?

Diana Mechtcheriakova: In our study, we identified 24 variables related to lymphoid structure characteristics. These included parameters such as anatomical site, number and size of lymphoid structures, cellular density, and the percentage of marker-positive cells for each defined immune marker.

A central question we addressed was the clinical relevance of these variables in characterizing the immune phenotype of lymphoid structures. Notably, in non-tumorous (NT) tissue, we found that variables reflecting the percentage of CD20-positive B cells and Ki67-positive proliferating cells—individually and in combination—demonstrated strong prognostic value.

This was supported by statistically significant patient stratification into low- and high-risk groups using Kaplan-Meier survival estimates. One of the most significant findings was that B-cell-enriched and highly proliferative isolated lymphoid structures (ILS) located in the non-tumorous colonic mucosa had a pronounced impact on patient survival outcomes.

This discovery indicates that the immunological imprint of lymphoid structures in normal colon tissue encodes valuable prognostic information for patients with colorectal cancer liver metastases.

What are the next steps in your research on lymphoid structures?

Diana Mechtcheriakova: Building upon our systems biology-based, multi-modular analysis strategy, we are now expanding our approach beyond quantitative tissue image cytometry—powered by the TissueFAXS platform—and transcriptomic data analysis through the GENEVESTIGATOR tool.

We have recently integrated two additional modules into our framework. The first is spatial transcriptomics using 10x Genomics Visium Spatial Gene Expression, which enables mRNA profiling directly within FFPE tissue sections, preserving spatial context.

The second is the application of artificial intelligence in biomedical research, introduced through our new ongoing project, LymphoidStructureMiner, in collaboration with AI specialists from Danube Private University in Austria.

Through the combined power of these technologies, we aim to develop advanced analytical models to further unravel germinal center biology. Our ultimate goal is the identification of novel biomarkers and therapeutic targets to enhance precision in cancer diagnosis and treatment.

Could you introduce TissueGnostics and explain how your technologies, especially tissue cytometry, support advanced research?

Anastasiia Marchuk: My name is Anastasiia Marchuk, and I represent TissueGnostics, a company headquartered in Vienna, Austria. We have been active in the field for over 20 years, specializing in whole slide imaging and image analysis. Our core focus is on a method we refer to as tissue cytometry, which involves detecting and phenotyping cells within their native tissue microenvironment.

The foundation of tissue cytometry is single-cell analysis, where individual cells—typically identified by nuclear staining—are detected and quantified. To define cell phenotypes, specific detection profiles are applied, allowing for quantification and characterization through spatial phenotyping. This process not only identifies cell types but also analyzes their spatial distribution within the tissue.

Tissue cytometry supports multicellular structure detection, enabling the analysis of anatomical features such as colon crypts, blood vessels, or glomeruli. It also facilitates the quantification of cellular pathogens and the detailed characterization of intracellular content.

We offer custom analysis solutions in the form of pre-configured, application-specific pipelines designed to address targeted research questions. For whole slide imaging, we provide TissueFAXS modular systems, which are fully automated platforms capable of processing immunofluorescence (IF) or immunohistochemistry (IHC) stained tissues or cells on glass slides, well plates, or tissue microarrays.

These systems are available in both upright and inverted configurations, with support for brightfield, fluorescence, or combined modalities, depending on research needs. Once a slide is placed and acquisition settings are selected, the automated system generates a fully digitized image, allowing researchers to focus on other tasks while the imaging is completed.

What advanced image analysis capabilities does TissueGnostics offer, and what innovations are you working on for the future?

Anastasiia Marchuk: TissueGnostics provides flexible and powerful imaging solutions designed to support a wide range of research needs. Users can define their own analysis pipelines and customize imaging settings, which can be saved and reused to ensure consistency across experiments.

As a modular and fully automated system, we also offer configurations for confocal, multispectral, and automated slide loading, depending on specific requirements. One of our most advanced image analysis platforms is StrataQuest, which includes modules for single-cell analysis, multicellular structure detection, neighborhood analysis, and more. Researchers can develop and save custom analysis workflows and reuse data for future studies.

To illustrate, in one example involving colon tissue stained with several immune markers, nuclei are detected using DAPI staining, followed by immune cell phenotyping and colon crypt detection. A distance map is then generated, which supports neighborhood analysis—examining the spatial proximity of immune cells to epithelial structures. This type of analysis yields critical insights into both cell identity and spatial organization.

In the latest version of our software, we have integrated advanced visualization and data interpretation tools, including 3D diagrams, violin plots, and manifold learning techniques such as SONG, UMAP, and t-SNE plots—all accessible directly within the platform.

Looking ahead, we are preparing to launch Colubris next year, an all-in-one acquisition and analysis system. Colubris will feature real-time AI-assisted image analysis and data mining, and is specifically engineered to handle high-volume data, delivering comprehensive solutions for modern biomedical imaging needs.

About Prof. Diana Mechtcheriakova

Assoc. Prof. Diana Mechtcheriakova is the head of the research group Molecular Systems Biology and Pathophysiology at the Medical University of Vienna. Her research interests include development of systems biology approaches, AI-powered solutions, with major focus on B-cell biology, immuno-oncology, lymphoid structures in immunity and cancer with translational perspectives.

About TissueGnostics

TissueGnostics (TG) is an Austrian company focusing on integrated solutions for high content and/or high throughput scanning and analysis of biomedical, veterinary, natural sciences, and technical microscopy samples.

TG has been founded by scientists from the Vienna University Hospital (AKH) in 2003. It is now a globally active company with subsidiaries in the EU, the USA, and China, and customers in 30 countries.

TissueGnostics portfolio

TG scanning systems are currently based on versatile automated microscopy systems with or without image analysis capabilities. We strive to provide cutting-edge technology solutions, such as multispectral imaging and context-based image analysis as well as established features like Z-Stacking and Extended Focus. This is combined with a strong emphasis on automation, ease of use of all solutions, and the production of publication-ready data.

The TG systems offer integrated workflows, i.e. scan and analysis, for digital slides or images of tissue sections, Tissue Microarrays (TMA), cell culture monolayers, smears, and other samples on slides and oversized slides, in Microtiter plates, Petri dishes and specialized sample containers. TG also provides dedicated workflows for FISH, CISH, and other dot structures.

TG analysis software apart from being integrated into full systems is fully standalone capable and supports a wide variety of scanner image formats as well as digital images taken with any microscope.

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Researchers at the University of Utrecht have discovered that respiratory viral infections, such as influenza and COVID-19, can trigger the reactivation of dormant cancer cells, leading to an increased risk of metastatic disease and cancer-related mortality. Animal studies and epidemiological data show these infections can disrupt the dormancy of disseminated cancer cells, particularly in the lungs, through inflammatory mechanisms involving the cytokine IL-6. The findings underscore the need to investigate further interventions that could mitigate the impact of viral infections on cancer progression in survivors.

Imagine cancer cells as seeds that can spread from an original tumor to other parts of the body. Sometimes, these seeds go to sleep, becoming dormant and inactive for extended periods, even years. While dormant, these cells are often undetectable through regular scans, lingering in the body post-treatment. Various factors, such as inflammation or changes in the immune system, can trigger these dormant cells to ‘wake up’ and start growing again. The study, published in Nature, reveals that respiratory viral infections like COVID-19 and influenza can act as such triggers, reawakening these dormant cancer cells.

This reactivation increases the risk of lung metastasis and, consequently, cancer-related deaths. In mouse models, infection with either the flu virus or SARS-CoV-2 led to a significant expansion—more than 100-fold—of previously dormant breast cancer cells in the lungs. Furthermore, Roel Vermeulen’s epidemiological team found similar connections in human data from the UK Biobank, reinforcing the relevance of these findings to human health.

Understanding the cancer comeback

The reawakening of dormant cancer cells is primarily driven by the inflammatory cytokine interleukin 6 (IL-6). Viral respiratory infections, including influenza A virus (IAV), can awaken dormant disseminated cancer cells (DCCs) in metastatic breast cancer through the production of IL-6. In experiments with MMTV-Her2 mice, IAV infection led to increased levels of IL-6 in the bronchoalveolar lavage fluid, activating the IL-6 signaling pathway in DCCs. By crossing MMTV-Her2 mice with IL-6 knockout (KO) mice, researchers demonstrated that IL-6 deficiency prevented the awakening and proliferation of dormant DCCs after IAV infection.

The relevance of these findings extends to human populations. An analysis of patient data from the UK and US indicated that individuals diagnosed with cancer five to ten years prior were three times more likely to die from their cancer if they contracted COVID-19 in 2020-2021, before vaccinations were available. Additional analyses also showed that COVID-19 infection significantly increased the risk of developing metastatic breast cancer in the lungs. Analysis of the Flatiron Health database showed that women with breast cancer who experienced COVID-19 had a 44% higher hazard ratio for subsequent diagnosis of metastatic breast cancer in the lungs, compared to those who did not have COVID-19.

Further research is planned to investigate the mechanisms of the reawakening process, explore preventive measures, and determine how the immune system can be engaged to eliminate awakened cancer cells. The Dutch Cancer Society (KWF Kankerbestrijding) will fund follow-up research, expected to start at the end of 2025 and run for two years, with initial results anticipated in 2027. Treatments already approved for managing severe COVID-19, like antagonistic antibodies against IL-6R and JAK1/2 inhibitors, could potentially reduce the risk of infection-induced metastatic cancer progression. However, further preclinical and clinical studies are necessary to ascertain the effectiveness, safety, and optimal timing of these interventions.

PULLMAN, Wash. — With a swab of their cat’s cheek, pet owners can now determine if their cat is at high risk of developing one of the most common chronic diseases years before any clinical signs emerge, and it could allow them to take measures to prolong their cat’s life.

The advancement is made possible by a genetic test that detects predisposition to progressive chronic kidney disease that has been developed by veterinarians at Washington State University’s College of Veterinary Medicine. The test, known as Feline Apoptosis Inhibitor Macrophages, or FAIM, is available to veterinarians and cat owners.

Chronic kidney disease is a progressive condition that causes deterioration of the kidneys and often results in kidney failure and death; about 30 to 50 percent of cats older than age 11 have some form of the disease. It can lead to cardiovascular disease, anemia, and hypertension. In extreme cases, it can cost thousands per year to manage cats with chronic kidney disease, for which there is no cure.

The test is made possible by a genetic variation that affects the productivity of a protein responsible for kidney repair. WSU associate professor Dr. Nicolas Villarino and collaborators from WSU’s Program in Individualized Medicine (PrIMe) identified the genetic marker in 2016.

Villarino and his colleagues then spent almost a decade developing the test, which is now available for about $100.

Now, pet owners and veterinarians can explore if the disease is likely to develop in their cat and patients and address it before their pet’s kidneys begin to deteriorate.

“Catching the disease early means cat owners can cut out certain foods and medications to maintain their pet’s health and slow the disease’s progression. That’s the big problem with this disease; you don’t know it is coming until it is too late,” Villarino said. “Once it is identified, there’s no way back, and those cats will likely require lifelong medical therapy.”

The test can be purchased now by emailing Villarino at nicolas.villarino@wsu.edu and will soon be available online through WSU’s (PrIMe). 

Once owners receive their sampling kit in the mail, they can swab their cat’s mouth and send their sample to the service center on the WSU Pullman campus.

Samples are processed using droplet digital PCR testing.

Villarino first noticed the genetic mutation during a WSU study examining biomarkers of kidney disease in cats.

“There was one cat that we noticed was behaving differently from the others,” Villarino said. “This cat was resistant to the disease.”

Looking closer, Villarino and colleagues discovered an alteration in a gene that codes for a protein responsible for kidney repair.

“I’m a scientist, and so we’re always doing studies, and so to get to a point where we can actually take the science and potentially help pets live a longer life, it’s a really great feeling,” Villarino said.

Villarino hopes the test opens the door to drug development and treatment of the disease. He said it could also be used by professional cat breeders to limit the number of cats with the disease.

The test would not have been possible without support from the WSU Office of Commercialization, the Washington Research Foundation, and dedicated donors Kay Fowler and Kay Yarborough Nelson, who were all determined to see the test come to fruition.

“This test aims to benefit the lives of so many cats and their owners, and there is no way we could have done this without donor support,” Villarino said.

A new study has found that, among women with a high desire to avoid becoming pregnant, those who drank heavily had a 50% higher risk of becoming pregnant than those who drank moderately or not at all. In contrast, participants who used cannabis were no more likely to have an undesired pregnancy than participants who did not use cannabis.

From a larger sample of over 2,000 non-pregnant women aged 15-34, researchers identified a subgroup of 936 who didn’t want to get pregnant. Within that subgroup, 429 reported heavy drinking (as measured using a standard alcohol screening questionnaire) and 362 reported using cannabis (including 157 who reported daily or almost daily use).

Those who drank heavily and those who used cannabis frequently had a higher overall desire to avoid pregnancy, compared with participants who drank moderately or not at all and participants who did not use cannabis.

Over the course of one year, 71 of the 936 women who most wanted to avoid pregnancy became pregnant. More than half of those undesired pregnancies (38) occurred among those who drank heavily, more than the combined number for those who drank moderately or not at all. In other words, heavy drinking was associated with a higher risk of undesired pregnancy compared with lower levels of drinking.

In contrast, less than half of the 71 undesired pregnancies (28) occurred among people who used cannabis, meaning that those who used cannabis did not show an elevated risk of undesired pregnancy compared with people who did not use cannabis. 

Lead author Dr Sarah Raifman, of the University of California, San Francisco, School of Medicine, comments: “This study made two important findings. First, non-pregnant women who drink heavily appear, on average, to have a higher desire to avoid pregnancy than those who drink moderately or not at all. Second, drinking heavily as opposed to moderately or not at all appears to put those who most want to avoid pregnancy at higher risk of becoming pregnant within one year. Finding out why those pregnancies happen is the next step in our research.”

“In the meantime, given the potentially life-altering effects of fetal alcohol spectrum disorders (which occur when a fetus is exposed to alcohol through the mother’s drinking) and the fact that the risk of FASD increases with the amount and duration of the mother’s drinking, it’s important for doctors and clinicians to support women who drink heavily to stop drinking as soon as they suspect an unintentional pregnancy.”