Functional imaging shows how intestinal and liver diseases mutually influence each other

 A mechanism underlying several liver diseases involves bile produced in the liver that cannot be secreted into the intestine as intended. This leads to a backlog of bile, which can damage the liver tissue.

The research groups of Prof. Trautwein (University Hospital RWTH Aachen) and Prof. Hengstler (Leibniz Research Center for Working Environment and Human Factors in Dortmund) have made a surprising discovery about the interaction of the liver and the intestine. The course of cholestatic liver disease may be milder when the liver disease is accompanied by an additional disease of the intestine. The team discovered that an inflamed intestine influences the liver to produce less bile acids.

Primary sclerosing cholangitis (PSC) is a cholestatic (cholestasis = "stagnation of bile") liver disease characterized by chronic inflammation and progressive scarring of the bile ducts. Up to 80% of PSC patients simultaneously suffer from chronic inflammatory bowel disease, especially ulcerative colitis. This disease has been suggested to promote the development and progression of PSC. Since there are no effective drugs that improve the course of PSC, many patients develop cirrhosis of the liver—in which case liver transplantation remains the last therapeutic option.

Ulcerative colitis alleviates cholestatic liver disease

The results of the study, now published in Nature Communications, show that a local inflammation of the intestine, which is triggered by the molecule dextran sulfate (DSS), induces major changes in the signaling pathways of the liver.

Thus, the teams from Dortmund and Aachen were able to detect an upregulation of the inflammatory pathways and, surprisingly, a suppression of bile acid synthesis and transport. The study identifies a molecular regulatory circuit by which inflammation of the intestine reduces the production if bile and thus suppresses the progression of the cholestatic liver disease.

The discovered molecular mechanism may be used in the future to slow down the production of bile acids when the liver cells are already overloaded with these substances. The contribution of the IfADo team consisted of a special functional imaging technique with which the concentrations of bile acids and other metabolites in the tissue can be visualized and analyzed.

Diseases of the liver also affect other organs

The liver is the largest organ of the human body and is responsible for more than 500 specific functions in the organism, for example the detoxification of toxic substances. Diseases of the liver also have a negative impact on cells and other organs, especially the brain, kidney and immune functions.

The liver also works closely with the intestines. It releases messenger substances into the intestine via the bile and conversely also receives signals from the intestine via the blood of the portal vein.

More information: Wenfang Gui et al, Colitis ameliorates cholestatic liver disease via suppression of bile acid synthesis, Nature Communications (2023). DOI: 10.1038/s41467-023-38840-8

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Anti-viral cytokines can blunt the immune response to tuberculosis

 A new collaborative study recently published in the journal Cellular Immunology by researchers from Trinity's School of Medicine and the Trinity College Institute of Neuroscience (TCIN) is closing the research gap on the actions of an important protein of the immune system—type 1 interferon, whose actions remain poorly understood.

Type one interferons are cytokines responsible for killing viruses, including COVID-19. Cytokines are small proteins that are crucial in controlling the growth and activity of other immune and blood cells. When released, they signal the immune system to do its job.

Although cytokines play a positive, protective role, many patients suffer from diseases where chronic production of type 1 interferons make them sick. These include persons with the auto-immune disease systemic lupus erythematosus (SLE) and people suffering with chronic tuberculosis (TB).

It is not known though how type one 1 interferons impair the ability of the immune system to fight bacterial infection.

Dr. Gina Leisching, Senior Research Fellow, Clinical Medicine, School of Medicine has led the group to study the influence of type 1 interferons on the immune system, using an animal model. This study demonstrates that type 1 interferon treatment induces an inflammatory state characterized by the increased production of white cells, and inflammatory intermediate metabolites as well as immune cell metabolic rewiring—which interferes with the ability of macrophages to fight bacteria.

Specifically, the group have identified type one interferons as impairing the metabolic response to Mycobacterium tuberculosis, the bacteria that causes TB.

Dr. Leisching said, "This work has provided new evidence that chronic type I interferons blunt the immune response and explains why patients with diseases that are driven by these immune proteins are prone to infections.

"We now have new targets to test to see if we can reverse this poor response by either boosting immune cell function or limiting the effects of type I interferons. We are now working with immune cells from SLE patients to gain more insight into whether these effects are observed in all immune cells or only a select few."

These findings now identify type 1 interferons as a potential target for the development of host directed therapies in patients who suffer from excess production of this cytokine.

This approach is already used in treating SLE—an autoimmune disease in which the immune system attacks its own tissues, causing widespread inflammation and tissue damage in the affected organs—but might now be looked at in pre-clinical models of tuberculosis. The field of TB needs new adjuvant therapies that support the host, especially as antibiotics are rendered redundant by the increasing development of resistance in the Mycobacterium tuberculosis bacteria (XDR TB).

Anjali Yennemadi, Ph.D. candidate, Clinical Medicine, School of Medicine, said, "We are very excited by these findings as they help to close a gap in the literature by showing what a significant effect type I interferons have on altering immune cell metabolism. This is particularly interesting to us as we are now working with SLE patients to understand why they are more susceptible to infections, including TB.

"Going forward, with the use of more advanced experimental and computational techniques, we hope to uncover potential diagnostic and/or therapeutic targets specific to chronic production of type I interferons in SLE and TB."

More information: Anjali S. Yennemadi et al, Chronic IFNα treatment induces leukopoiesis, increased plasma succinate and immune cell metabolic rewiring, Cellular Immunology (2023). DOI: 10.1016/j.cellimm.2023.104741

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Study suggests resistance training can prevent or delay Alzheimer's

 Regular physical exercise, such as resistance training, can prevent Alzheimer's disease, or at least delay the appearance of symptoms, and serves as a simple and affordable therapy for Alzheimer's patients. This is the conclusion of an article published in Frontiers in Neuroscience by Brazilian researchers affiliated with the Federal University of São Paulo (UNIFESP) and the University of São Paulo (USP).

Although older people and dementia patients are unlikely to be able to do long daily runs or perform other high-intensity aerobic exercises, these activities are the focus for most scientific studies on Alzheimer's. The World Health Organization (WHO) recommends resistance exercise as the best option to train balance, improve posture and prevent falls. Resistance exercise entails contraction of specific muscles against an external resistance and is considered an essential strategy to increase muscle mass, strength and bone density, and to improve overall body composition, functional capacity and balance. It also helps prevent or mitigate sarcopenia (muscle atrophy), making everyday tasks easier to perform.

To observe the neuroprotective effects of this practice, researchers in UNIFESP's Departments of Physiology and Psychobiology, and the Department of Biochemistry at USP's Institute of Chemistry (IQ-USP), conducted experiments involving transgenic mice with a mutation responsible for a buildup of beta-amyloid plaques in the brain. The protein accumulates in the central nervous system, impairs synaptic connections and damages neurons, all of which are features of Alzheimer's disease.

During the study, the mice were trained to climb a 110 cm ladder with a slope of 80° and 2 cm between rungs. Loads corresponding to 75%, 90% and 100% of their body weight were attached to their tails. The experiment mimicked certain kinds of resistance training undertaken by humans in fitness centers.

At the end of a four-week period of training, blood samples were taken to measure plasma levels of corticosterone, the hormone in mice equivalent to cortisol in humans; rising levels in response to stress heighten the risk of developing Alzheimer's. Levels of the hormone were normal (equal to those found in the control group comprising animals without the mutation) in the exercise-trained mice, and analysis of their brain tissue showed a decrease in formation of beta-amyloid plaques.

"This confirms that physical activity can reverse neuropathological alterations that cause clinical symptoms of the disease," said Henrique Correia Campos, first author of the article.

"We also observed the animals' behavior to assess their anxiety in the open field test [which measures avoidance of the central area of a box, the most stress-inducing area] and found that resistance exercise reduced hyperlocomotion to similar levels to the controls among mice with the phenotype associated with Alzheimer's," said Deidiane Elisa Ribeiro, co-first author of the article and a researcher at IQ-USP's Neuroscience Laboratory. Agitation, restlessness and wandering are frequent early symptoms of Alzheimer's and other types of dementia.

"Resistance exercise is increasingly proving an effective strategy to avoid the appearance of symptoms of sporadic Alzheimer's [not directly caused by a single inherited genetic mutation], which is multifactorial and may be associated with aging, or to delay their emergence in familial Alzheimer's. The main possible reason for this effectiveness is the anti-inflammatory action of resistance exercise," said Beatriz Monteiro Longo, last author of the article and a professor of neurophysiology at UNIFESP.

The animal model study was based on a review of the literature published in Frontiers in Neuroscience, where the same group at UNIFESP compiled clinical evidence that the benefits of resistance exercise include positive effects on cognitive dysfunction, memory deficit and behavioral issues in Alzheimer's patients, concluding that it can be an affordable alternative or adjuvant therapy.

Researchers from the Federal University of Rio Grande do Norte (UFRN) and the Federal University of Ouro Preto (UFOP) in Brazil also took part in the study.

"Alzheimer's doesn't only affect the patient. The entire family is affected, especially in low-income households," said Caroline Vieira Azevedo, first author of the review article and a graduate student at UNIFESP. "Both articles offer information that can be used to stimulate the creation of public policies. Imagine the cost savings if the appearance of symptoms in older patients is deferred by ten years."

More information: Henrique Correia Campos et al, Neuroprotective effects of resistance physical exercise on the APP/PS1 mouse model of Alzheimer's disease, Frontiers in Neuroscience (2023). DOI: 10.3389/fnins.2023.1132825

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Dementia is not the end of learning

 People with dementia still have the ability to learn new things despite their illness. This is the conclusion of a doctoral thesis recently presented at Linköping University, Sweden. Its findings debunk the general belief that people with dementia are empty shells, according to Elias Ingebrand, who conducted the study.

Ingebrand let ten dementia sufferers, eight of whom lived in care facilities, try using computer tablets for the first time in their lives. A staff member or a loved one was there for support, but the only instruction given to participants was to use the tablet as they wished. It soon turned out that the device made them curious.

"I was rather surprised at this. I may have expected that it would just lie there and that they would talk about something else, but we saw that they focused their attention on it," he says.

The study lasted for 4-6 weeks. Although the participants suffered from severe memory decline, they gradually learned to use the tablet more independently. The explanation, Ingebrand believes, is that the body remembers the movements required even though the ability to talk about it has been lost. But it is important to arouse the person's interest.

A woman who used to do orienteering spontaneously started using the tablet to check competition results. A man who used to be restless and aggressive learned how to navigate to the Open Archive of SVT, the Swedish public television broadcaster. After a while, staff noted that he would sit and watch for a long time, calmly and focused. This was a side of him they had never seen before.

Ingebrand was surprised to find that people with dementia could solve the mysteries of the tablet also without help from staff or loved ones, by collaborating and learning from each other. Also in this context, they managed to focus on the task at hand. As far as he knows, no one has studied collaboration between dementia sufferers before.

There are however previous studies that have found that people with dementia have the ability to learn new things. This has involved remembering nonsense words or remembering the names of random people. But Ingebrand says that he has now shown that learning can take place even without any particular instructions, and that his results can also be immediately applied in dementia care.

"My thesis has an impact on how we look at people with dementia. They are not to be treated as children, but as people who still have a will and an incentive to do things. This is ultimately about having the opportunity to participate in meaningful activities based on the person's own interests and desires," he explains.

This of course presents a challenge to care facility staff, who are often too busy to sit down with just one person for any length of time. Letting people with dementia do things in collaboration could be a solution worth trying. And even though this study is about computer tablets, Ingebrand believes that its results are valid also for other forms of learning.

"I want to take my research further by finding out how to make use of the knowledge and expertise of people with dementia in creating meaningful activities. Maybe someone could initiate an activity and teach others in the care facility. Perhaps a small seminar, or knitting. The right to lifelong learning should include everyone; the important thing is getting a chance to learn," he says.

More information: Elias Ingebrand, Dementia and learning: The use of tablet computers in joint activities, Doctoral thesis (2023). DOI: 10.3384/9789180750714

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State medical cannabis laws not associated with reduced use of opioid or non-opioid pain treatments

 A study of commercially insured adults with chronic non-cancer pain has found that state medical cannabis laws did not affect receipt of opioid or non-opioid pain treatment. These findings suggest that cannabis use has not led to large shifts in pain treatment patterns at the population level. The study is published in Annals of Internal Medicine.

In the 37 states and the District of Columbia (D.C.) with medical cannabis laws, people with chronic non-cancer pain are eligible to use cannabis for pain management. The concern is that state medical cannabis laws may lead patients with chronic non-cancer pain to substitute cannabis in place of prescription opioid or recommended non-opioid prescription pain medications or procedures. However, the research is not clear.

Researchers from Weill Cornell Medicine studied insurance claims data from 12 states that implemented medical cannabis laws and 17 comparison states to assess the effects of such laws on receipt of prescription opioids, non-opioid prescription pain medications, and procedures for chronic non-cancer pain. The researchers found that in any given month during the 3 years of law implementation, medical cannabis laws had led to a negligible difference in the proportion of patients receiving any pain medication or chronic pain procedure.

According to the researchers, slow implementation could contribute to the study findings. Results also may be explained by reluctance among health system leaders and individual clinicians to recommend cannabis for pain.

More information: Effects of U.S. State Medical Cannabis Laws on Treatment of Chronic Noncancer Pain, Annals of Internal Medicine (2023). DOI: 10.7326/M23-0053

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Experimental monoclonal antibodies can coax aggressive prostate, breast cancers into submission

 Therapeutic antibodies that cause aggressive tumors to become susceptible to treatment are being studied with the hope of one day changing the fate of patients who either relapse soon after cancer therapy or whose stubborn tumors repel potent medications rendering the drugs useless.

Although immunotherapies and chemotherapies improve outcomes for cancer patients, many cancers don't respond well to treatment or thwart the drugs altogether. This is especially the case for aggressive prostate cancers, which are insensitive to immunotherapies.

A collaborative team of researchers throughout the United States, led by Chan School of Medicine scientists at the University of Massachusetts in Worchester, developed an antibody strategy that sensitizes prostate tumors to immunotherapy. The approach was tested in a mouse model using a monoclonal antibody dubbed aNRP2-28. Similar monoclonal antibodies, with the designation aNRP2-10, engineered for human cells, blocked the interaction between the growth factor VEGF (vascular endothelial growth factor) and its receptor neuropilin-2, thus sensitizing cells for treatment via immunotherapy.

Scientists found that by jamming the interaction between VEGF and neuropilin-2, they were able to render aggressive prostate cancers susceptible to treatment. This allowed use of the form of immunotherapy known as an immune checkpoint inhibitor. It's critical, team members say, that the programmed cell death ligand, PD-L1, a protein found in abundance on prostate cancer cells be inhibited, which in turn, allows T cells to attack the cancer.

Writing in Science Translational Medicine, researchers report that prostate cancer cells in the laboratory were coaxed into submission and successfully treated. A second study in the same issue tackled triple negative breast cancer using the same monoclonal antibody strategy in cell lines, organoids and mouse models. Scientists demonstrated that this aggressive tumor type, which is notorious for its capacity to repel chemotherapy, can also be coaxed into submission and successfully treated with the form of chemotherapy that it otherwise would repel.

The challenge now, is determining whether these promising laboratory findings will prove equally successful in human clinical trials.

Unlike other solid tumors, prostate cancers do not respond particularly well to immune checkpoint inhibitors, such as the PD-L1 blockade, reports the lead the author of the research, Mengdie Wang of the Chan School of Medicine's departments of molecular, cell and cancer biology.

"Prostate cancers are largely unresponsive to immune checkpoint inhibitors, and there is strong evidence that programmed death-ligand 1—PD-L1—expression itself must be inhibited to activate antitumor immunity," Wang asserted. "We report that neuropilin-2, which functions as a vascular endothelial growth factor receptor on tumor cells, is an attractive target to activate antitumor immunity in prostate cancer because VEGF-NRP2 signaling sustains PD-L1 expression."

Immune checkpoint inhibitor treatment is an innovative strategy that relies on the checkpoint blockade—blocking checkpoint proteins from binding with their partner proteins—preventing an "off" signal from being released. Checkpoint inhibitor treatments don't kill tumor cells. Instead, the checkpoint inhibitor engages the immune system to recognize and attack malignancies, allowing T cells to kill the cancer.

There are several immune checkpoint inhibitors available to oncologists for cancer treatment. They include Keytruda, Yervoy, Opdivo and Tecentriq. Among the benefits offered by an immune checkpoint inhibitor treatment strategy is increased survival time and highly potent activity against cancer cells—when the cancer is responsive to the treatment.

To coax prostate cancer into responsiveness to this form of immunotherapy, Wang and colleagues engineered antibodies to suppress PD-L1 expression and tested the antibodies in humanized mouse models of prostate cancer and in patient-derived organoids with prostate cancer. The team found that the antibodies reduced PD-L1 expression in mice and in patient-derived organoids.

By suppressing PD-L1 expression this way, scientists found they could boost the infiltration of T cells into cancers and potentiate antitumor responses in mice with prostate tumors. They also observed unusually high activity among genes that encode PD-L1 and neuropilin-2 in samples from patients, suggesting that neuropilin-2 is a viable treatment target for the antibodies in humans.

Using monoclonal antibodies isn't just for prostate cancers. In a second study, Zhiwen Xu of aTyr Pharma, Inc., a biotherapeutics company in San Diego, tested the efficacy of the monoclonal antibodies in cell lines, organoids, and mouse models of triple-negative breast cancer. Xu was also a member of Wang's team, which tested the antibodies in the prostate cancer research.

When Xu and colleagues exposed mouse models for triple negative breast cancer to the antibodies, these proteins had potent effects against the tumor-seeding of cancer stem cells and prevented an epithelial-to-mesenchymal transition, a cell transformation linked to the progression of cancer.

The antibodies also sensitized cancerous tumors to the chemotherapy drug cisplatin by causing the cancer stem cells to differentiate into a more drug-sensitive form, leading to less metastasis in the rodents. "Based on the proposed mechanism of action, addition of [the antibodies] may lead to a deeper and prolonged clinical response in [triple-negative breast cancer] patients," Xu concluded.

More information: Mengdie Wang et al, Therapeutic blocking of VEGF binding to neuropilin-2 diminishes PD-L1 expression to activate antitumor immunity in prostate cancer, Science Translational Medicine (2023). DOI: 10.1126/scitranslmed.ade5855

Zhiwen Xu et al, Inhibition of VEGF binding to neuropilin-2 enhances chemosensitivity and inhibits metastasis in triple-negative breast cancer, Science Translational Medicine (2023). DOI: 10.1126/scitranslmed.adf1128

https://medicalxpress.com/news/2023-07-experimental-monoclonal-antibodies-coax-aggressive.html

Tool that could improve liquid biopsy

 A research team led by Xianghong Jasmine Zhou, Ph.D., professor of Pathology and Laboratory Medicine at the David Geffen School of Medicine at UCLA, has made an important advancement to address one of the major challenges in cell-free DNA (cfDNA) testing, also known as liquid biopsy.

They've identified specific methylation patterns unique to each tissue, potentially helping to Identify the specific tissue or organ associated with cfDNA alterations picked up by testing, a critical challenge for accurate diagnosis and monitoring of diseases.

Cell-free DNA has significant potential in disease detection and monitoring. However, accurately quantifying tissue-derived cfDNA has proven challenging with current methods, among them determining the tissue origin of cfDNA fragments detected in these tests.

In a new study, published in Proceedings of the National Academy of Sciences, the team developed a comprehensive and high-resolution methylation atlas based on a vast dataset of 521 noncancerous tissue samples representing 29 major types of human tissues.

They call the approach cfSort, and showed it successfully identified specific methylation patterns unique to each tissue at the fragment level and validated these findings using additional datasets.

Going further, the team illustrated the clinical applications of cfSort through two potential uses: aiding in disease diagnosis and monitoring treatment side effects. By estimating the tissue-derived cfDNA fraction using cfSort, they were able to assess and predict clinical outcomes in patients.

"We have shown that the cfSort outperformed the existing methods in terms of accuracy and detection limit: making more accurate tissue fraction estimation and distinguishing a lower level of tissue-derived cfDNA," said first author Shuo Li.

"In addition, the cfSort demonstrated nearly perfect robustness toward the unseen local fluctuations of tissue compositions, indicating its wide applicability to diverse individuals."

More information: Shuo Li et al, Comprehensive tissue deconvolution of cell-free DNA by deep learning for disease diagnosis and monitoring, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2305236120

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