Mechanism that inhibits wide variety of viruses, similar to one already found in cancer drug

 TWINCORE researchers describe a mechanism that inhibits virus replication and protects cells from damage. Interestingly, a drug that has already been approved could prove useful in combating various viruses.

AIDS, the flu, COVID-19—time and again, viral infections overtake entire regions of the world and cost human lives. To date, there are no drugs with a broad antiviral effect. Researchers from Hannover want to change that.

In the journal PLOS Pathogens, Prof. Frank Peßler and his team at TWINCORE—Center for Experimental and Clinical Infection Research, a joint venture of the Helmholtz Center for Infection Research and the Hannover Medical School describe a way to effectively inhibit the multiplication of a wide variety of viruses.

For the study that has now been published, the researchers from the Biomarkers for Infectious Diseases working group worked together with teams from the universities in Gießen and Aarhus as well as the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS).

Therapeutic targets in humans

The fact that it is so tricky to fight viruses is partly due to their simple structure. They offer only a few points of attack for inhibiting agents. In addition, they repeatedly change in such a way that active agents no longer recognize their target.

Viruses, which consist of only a few components, use the body's own structures of their host, e.g. humans, for their reproduction. Also because severe effects of a viral infection are often due to an excessive reaction of the body's defense system, researchers are increasingly focusing their attention on the interaction between virus, human physiology and the defense system.

The goal is to find mechanisms in the body that can be therapeutically inhibited or enhanced to slow down a viral infection and alleviate its effects. Researchers led by Frank Peßler have now succeeded in influencing two mechanisms in human cells simultaneously so that both happen.

Correct active substance, but unexpected mechanism

Peßler and his colleagues are researching the body's own molecule itaconic acid. Some time ago, they discovered that a pharmacologically optimized variant of it, 4-octyl itaconate, is particularly efficient in activating a signaling pathway that controls various protective and defense mechanisms of human cells.

The switch for this signaling pathway is a protein called NRF2. However, their experiments repeatedly revealed evidence that 4-octyl itaconate directly impairs virus replication—independently of the NRF2 signaling pathway. To investigate these indications, they produced cells in the laboratory without NRF2 protein.

When the protective switch was missing, influenza viruses actually multiplied better. To their surprise, however, the researchers found that even without NRF2, 4-octyl itaconate inhibited the proliferation of influenza viruses just as strongly as in unmodified cells.

"When we saw the first results of these experiments, we were quite astonished," says Frank Peßler. "We had obviously been studying the right active ingredient all along, but only now got onto the trail of the decisive mechanism of action."

Transport path blocked

Peßler and his colleagues suspected that 4-octyl itaconate obstructed the transport of proteins and nucleic acids from the cell nucleus, which many viruses depend on.

To test their assumption, they compared the effect of 4-octyl itaconate with that of a cancer drug (selinexor) that blocks a transport channel from the cell nucleus. Both the cancer drug and the itaconic acid variant inhibited replication of an influenza virus. They prevented precursors of the newly formed virus particles from being transported out of the nucleus of the host cell. The unfinished viruses remained stuck in the cell nucleus, so to speak.

"We were very surprised how efficiently 4-octyl itaconate directly inhibits the multiplication of influenza viruses by this mechanism," says Peßler. The authors of the current study also provide an explanation for their observation: In the structure of the transport channel, they found a site to which both 4-octyl itaconate and the anticancer drug bind. It is similar to the site where 4-octyl itaconate interacts with the protein that controls the NRF2 switch.

Using biochemical methods, the researchers proved that 4-octyl itaconate actually binds to the nuclear transporter in human cells, thereby blocking it. Peßler and his colleagues also observed this effect with other substances that were previously only known as NRF2 activators.

Potential for broad efficacy

The now published findings open up new perspectives for the development of antiviral therapies. Interestingly, a wide variety of viruses with very different life cycles depend on the export of proteins or nucleic acids from the nucleus.

From the influenza virus, which causes seasonal flu, and SARS-CoV-2 to the respiratory syncytial virus (RSV), which hospitalized numerous infants last winter, to rabies, which is once again more widespread in many Asian and African (travel) countries—they all need the transport channel to replicate. In the case of different viruses, various steps of reproduction depend on the channel. Blocking this pathway therefore promises to counteract many different types of viruses.

Slowing down viruses, protecting cells

Newly emerging viruses could also possibly be slowed down in this way. "The next pandemic is bound to come," says Frank Peßler. "And wouldn't it be nice to have a pill that could help people quickly and curb the spread early—even before we know exactly which virus it is?"

The fact that an inhibitor of the transport channel has already been approved as a drug opens up prospects for a rapid adaptation of therapy to viral infections. However, this drug does not have the cell-protective properties of the NRF2 activators.

Peßler is therefore planning to optimize chemical variants of itaconic acid in such a way that they have equally virus-inhibiting and cell-protecting effects. The fact that itaconic acid occurs in the human naturally gives hope that this will result in drug candidates with as few undesired side effects as possible.

More information: Fakhar H. Waqas et al, NRF2 activators inhibit influenza A virus replication by interfering with nucleo-cytoplasmic export of viral RNPs in an NRF2-independent manner, PLOS Pathogens (2023). DOI: 10.1371/journal.ppat.1011506

https://medicalxpress.com/news/2023-08-mechanism-inhibits-wide-variety-viruses.html

Gene therapy for brain tumor shows promising early results in humans

 A new study from the University of Michigan Department of Neurosurgery and Rogel Cancer Center shows promising early results that a therapy combining cell-killing and immune-stimulating drugs are safe and effective in extending survival for patients with gliomas, a highly aggressive form of brain cancer.

The study was published in The Lancet Oncology.

This is a phase 1, first in human trial, and Rogel researchers Pedro Lowenstein M.D., Ph.D., and Maria Castro, Ph.D., lead authors of the study, previously developed and studied the adenoviral mediated gene therapies in their lab. Given gliomas' poor prognosis and limited response to treatments like chemotherapy and radiation, the team looked to using the protein Flt3L to recruit immune cells, typically absent from the brain. These immune cells are required to kick start a more effective cancer immune response.

"Being able to move a novel therapy from bench to bedside in such a streamlined fashion is exciting, and represents a tour-de-force in translational medicine," said Oren Sagher, M.D., professor of neurosurgery at U-M and author of this study.

The study focused on two types of genetic therapies in high-grade gliomas. The first was a combination of HSV-1-TK, a protein, and Valtrex, a drug used to treat viral infections like cold sores and chickenpox. HSV-1-TK turns Valtrex into a cytotoxic compound that kills actively dividing cancer cells. The second was Flt3L, a protein that recruits essential immune cells to the brain.

When used in combination, these therapies showed exciting early results, including improved survival. Of the 18 patients enrolled in the trial, six survived more than two years, three survived more than three years, and one patient, who is still alive at the time of publication, survived up to five years. With current standard-of-care, the life expectancy for a tumor of this kind of just over 14 months. Further, the study found that this treatment wasn't toxic to the patients, suggesting that the highest dose used in this trial could be used in future trials.

Though the adenoviral gene therapy vectors were supposed to be active for up to a month, work from three investigators—Maria Luisa Varela, Ph.D., Mohammad Faisal Syed, Ph.D., and Molly West, Ph.D.–discovered that activity from the adenoviral vector expressing the HSV1-TK was active for up to 17 months. This discovery changes expectations of adenoviral gene therapy in the brain and extends the potential time during which the combination HSV1-TK and Valtrex might be harnessed to combat tumor recurrence.

"This originated from a theoretical idea based on evolutionary hypotheses and was first tested in experimental models of the disease," said Lowenstein, Richard C. Schneider Collegiate Professor of Neurosurgery at U-M. "Finally, after many years, we're thrilled to report the results of testing this approach in human patients, obtaining results that will lead to better treatments for this group of brain tumor patients," said Maria Castro, Ph.D., Rogel member and professor of neurosurgery at U-M.

Although more work is needed before this is brought to the clinic, the significance of long term expression of HSV1-TK suggest implementation to improve treatment. The results of this study support the design of future phase 1b/2 clinical trials.

More information: Yoshie Umemura et al, Combined cytotoxic and immune-stimulatory gene therapy for primary adult high-grade glioma: a phase 1, first-in-human trial, The Lancet Oncology (2023). DOI: 10.1016/S1470-2045(23)00347-9

https://medicalxpress.com/news/2023-08-gene-therapy-brain-tumor-early.html

Adding complex component of milk to infant formula confers long-term cognitive benefits

 Breast milk is widely acknowledged as the most beneficial nutrition for infants, but many families face medical or logistical challenges in breastfeeding. In the U.S., just 45% of infants continue to be exclusively breastfed at 3 months of age, according to the Centers for Disease Control.

For decades, researchers have sought to create a viable complement or alternative to breast milk to give children their best start for healthy development. New research out of the University of Kansas has shown how a complex component of milk that can be added to infant formula has been shown to confer long-term cognitive benefits, including measures of intelligence and executive function in children.

The research by John Colombo, KU Life Span Institute director and investigator, along with colleagues at Mead Johnson Nutrition and in Shanghai, China, adds to the growing scientific support for the importance of ingredients found in milk fat globule membrane (MFGM) in early human development.

The study, which was published in the Journal of Pediatrics, showed that feeding infants formula supplemented with MFGM and lactoferrin for 12 months raised IQ by 5 points at 5 ½ years of age. The effects were most evident in tests of children's speed of processing information and visual-spatial skills. Significant differences were also seen in children's performance on tests of executive function, which are complex skills involving rule learning and inhibition.

All forms of mammalian milk contain large fat globules that are surrounded by a membrane composed of a variety of nutrients important to human nutrition and brain development, Colombo said. When milk-based infant formula is manufactured, the membrane has typically been removed during processing.

"No one thought much about this membrane," Colombo said, "until chemical analyses showed that it's remarkably complex and full of components that potentially contribute to health and brain development."

The 2023 study was a follow-up to one that Colombo also co-wrote with colleagues in Shanghai, China, published in the Journal of Pediatrics in 2019. That study showed that babies who were fed formula with added bovine MFGM and lactoferrin had higher scores on neurodevelopmental tests during the first year and on some aspects of language at 18 months of age.

The global nutrition research community has been looking at MFGM for about a decade, Colombo said. Because the membrane is made up of several different components, it isn't known whether one of the components is responsible for these benefits, or whether the entire package of nutrients act together to improve brain and behavioral development.

These benefits were seen in children long after the end of formula feeding at 12 months of age.

"This is consistent with the idea that early exposure to these nutritional components contribute to the long-term structure and function of the brain," said Colombo, who has spent much of his career researching the importance of early experience in shaping later development.

More information: John Colombo et al, Improved Neurodevelopmental Outcomes at 5.5 Years of Age in Children Who Received Bovine Milk Fat Globule Membrane and Lactoferrin in Infant Formula Through 12 Months: A Randomized Controlled Trial, The Journal of Pediatrics (2023). DOI: 10.1016/j.jpeds.2023.113483

https://medicalxpress.com/news/2023-08-adding-complex-component-infant-formula.html

Expanding impact of CAR T cell therapy: Immunotherapy strategy against all blood cancers

 A broad new strategy could hold hope for treating virtually all blood cancers with CAR T cell therapy, which is currently approved for five subtypes of blood cancer. Scientists in the Perelman School of Medicine at the University of Pennsylvania have demonstrated the potential efficacy of this approach in preclinical tests.

In the study, published today in Science Translational Medicine, the researchers used engineered CAR T cells to target CD45—a surface marker found on nearly all blood cells, including nearly all blood cancer cells. Because CD45 is found on healthy blood cells too, the research team used CRISPR base-editing to develop a method called "epitope editing" to overcome the challenges of an anti-CD45 strategy, which would otherwise result in low blood counts, with potentially life-threating side effects.

The early results represent a proof-of-concept for epitope editing, which involves changing a small piece of the target CD45 molecule just enough so that the CAR T cells don't recognize it, but it can still function normally within the blood immune system.

"Up to this point, we haven't had the tools to create a targeted cell therapy approach that could work across all different forms of blood and bone marrow cancers," said senior corresponding author Saar Gill, MD, Ph.D., an associate professor of Hematology-Oncology. "We're excited to create a new solution that could solve a major issue in immunotherapy, which is the inability to target surface markers that are found on both cancer cells and healthy cells."

Each of the currently available cell-based immunotherapies for blood cancer is designed to work against a narrow range of malignancies based on their target antigens. For example, the first CAR T cell therapy, developed at Penn by Carl June, MD, the Richard W. Vague Professor in Immunotherapy, targets the CD19 protein marker on B cells, to treat B-cell lymphomas and leukemias.

Four of the six CAR T cell therapies currently approved to treat blood cancers target CD19. The other two target the BCMA protein marker to treat multiple myeloma. While CAR T cell therapy has been remarkably successful, researchers at Penn and across the world are working to make it even more effective for more patients.

"One drawback of the current approach to CAR T cell therapy is that each therapy must be developed individually based on the targets for that cancer type," said June, co-senior author of the study, who also directs the Center for Cellular Immunotherapies at Penn. "This study lays the groundwork for a more universal approach that could potentially expand CAR T cell therapy to all blood cancers."

Because CD45 is found on nearly all blood cells—and is usually highly expressed on blood cancer cells—a treatment that wipes out all CD45-bearing cells would leave patients without any blood cells, including red blood cells, platelets, plasma, and even the marrow-based stem cells that generate new blood cells. Furthermore, since T cells are blood cells and normally express CD45, CAR T cells targeting CD45 effectively would kill each other before they could be infused into patients.

The team built on previous work to overcome this challenge, using CRISPR base-editing to develop a new strategy called epitope editing. This involves the genetic modification of both the CAR T cells and blood stem cells to alter a small piece of the CD45 structure or "epitope" where the CAR T cells bind to the CD45 molecule. The altered version of CD45 still works but differs enough from normal CD45 that the anti-CD45 CAR T cells do not recognize and attack it.

"It's essentially a blood stem cell transplant paired with CAR T cell therapy," said lead author Nils Wellhausen, a graduate student in Pharmacology and a member of Gill and June's labs. "The idea is that when the engineered cells are infused, the CAR T cells kill the cancer cells that bear normal CD45, but don't kill each other or the newly engineered blood stem cells. This allows the engineered blood stem cells to begin making new blood cells."

Because the strategy results in replacing the stem cells that create new blood cells, it also has potential use as a milder form of chemotherapy conditioning, which is given to patients before a bone marrow transplant to suppress the immune system.

The researchers tested the strategy in an extensive set of experiments in cell culture and mice models. They showed that the new approach not only keeps anti-CD45 CAR T cells from attacking each other or stem cells, but also enables swift destruction of blood cell cancers. In one test, the anti-CD45 CAR T cells eliminated leukemia cells within three weeks of infusion and were still present and capable of killing leukemia cells more than two months later.

Further toxicology studies and additional modeling studies are currently underway in preparation for an investigational new drug application before it can move into Phase I clinical trials.

More information: Nils Wellhausen et al, Epitope base editing CD45 in hematopoietic cells enables universal blood cancer immune therapy, Science Translational Medicine (2023). DOI: 10.1126/scitranslmed.adi1145. www.science.org/doi/10.1126/scitranslmed.adi1145

https://medicalxpress.com/news/2023-08-impact-car-cell-therapy-immunotherapy.html

Inflammation may influence weight loss surgery outcomes

 New research shows that higher levels of inflammation in the blood of patients with obesity undergoing bariatric surgery predicts poorer weight loss six months after the procedure.

Published in Psychological Medicine and led by researchers from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's College London, this is the first study to investigate the links between depression and inflammation in patients with obesity before and after bariatric surgery.

The analysis showed a strong relationship between depression and inflammation in obese patients before and after surgery, and it indicated that it was increased inflammation rather than depression that was driving poor weight loss after bariatric surgery.

Lead author and Clinical Professor of Psychoneuroimmunology at IoPPN, King's College London, Valeria Mondelli, said, "Our study has important clinical implications as it identifies specific targets for future personalized interventions which could improve physical and mental health outcomes after bariatric surgery. For example, our data showing that increased inflammation predicts lower weight-loss after bariatric surgery suggests that personalized treatments involving approaches that lower inflammation could enable better outcomes after surgery."

Obesity costs the NHS around £6 billion a year, and this figure is predicted to rise to £9.6 billion per year by 2050. Bariatric surgery physically alters the stomach and/or the bowel to reduce the amount of food people can eat and to reduce the absorption of nutrients.

Obese patients can lose up to 70% of excess weight after surgery, but there is variation in the outcomes. To help patients with obesity and ensure costly treatments are as effective as possible (private bariatric surgery can cost £4,000 to £10,000), it is important to understand the factors that can influence surgery.

Depression and obesity are known to often occur together, and previous research suggests the release of inflammatory proteins as part of the immune response may be a shared disease mechanism that is driving both conditions. To improve the understanding of this relationship and its potential role in obesity and bariatric surgery outcomes, the study investigated the differences in proteins released in the body during inflammation between obese patients with and without depression undergoing surgery.

The 85 participants in the study, enrolled from King's College Hospital NHS Foundation Trust in south London, were all obese (BMI >35) and part of the ongoing Bariatric Surgery & Depression study. Levels of proteins released during inflammation, such as C-Reactive Protein (CRP), and cytokines, such as interleukin-6 (IL-6) and interleukin-4 (IL-4), were measured before and after surgery in participants' blood and tissue.

Before surgery, 41 participants had symptoms of depression that reached the threshold of a clinical diagnosis, while in the remaining 44 participants, the symptoms of depression were below this threshold. The study showed that those with depression had higher levels of the inflammatory proteins CRP and IL-6 in the blood and lower levels of the anti-inflammatory protein IL-4. They also had higher levels of one inflammatory protein in their adipose tissue.

Six months after surgery, the bariatric patients who had depression before surgery continued to have higher levels of IL-6 and CRP in the blood, despite no difference in weight loss between those with and without depression.

Overall, bariatric surgery led to weight loss in all patients in line with what was expected, and the majority of patients who previously had depression before surgery also experienced a reduction in their symptoms so that they were no longer considered clinically depressed. Out of 44 patients who had depression before surgery, 29 completed the six-month follow-up, and only about one-third (34.5%;10 patients) of those still had clinical depression after surgery.

Researchers analyzed whether measures of inflammation and depression before surgery might be able to predict weight loss and depression after surgery. This showed that higher levels of CRP predicted reduced weight loss at six-month follow-up. However, levels of CRP in the blood before surgery did not predict levels of depression afterwards; instead, this was predicted by depression before surgery and experience of childhood trauma.

First author Dr. Anna McLaughlin, Postdoctoral Research Associate at IoPPN, King's College London, said, "Our study is the first to show that inflammation levels in the blood, rather than depression, play a significant role in weight loss outcomes after bariatric surgery. Additionally, our research aligns with previous findings, emphasizing that patients with childhood trauma may benefit from more psychological support after surgery. As we move forward, combining inflammation data with clinical insights will be crucial to pinpointing risk factors and improving outcomes for bariatric patients."

More information: Peripheral inflammation associated with depression and reduced weight loss: a longitudinal study of bariatric patients, Psychological Medicine (2023). DOI: 10.1017/S0033291723002283

https://medicalxpress.com/news/2023-08-inflammation-weight-loss-surgery-outcomes.html

Why Won't COVID Lockdown Tyrants Admit They Were Wrong?

 by Stephen Moore via The Epoch Times (emphasis ours),

COVID mania just won’t go away. The deadly strains of the virus have been gone for two years now, and yet the recent outbreak of a mild flu-like variant is again stoking panic on the Left.

Nearly 100 universities are requiring masks this fall.

Lionsgate movie studios in Los Angeles and Atlanta-based Morris Brown College this week stated they are reinstating not just mask mandates but social distancing measures and contact tracing.

CNN, which led the panic in 2020 and 2021—causing manic school, restaurant, and business shutdowns and vaccine mandates—recently put out a headline on its website that encouraged its readers not to go outside without a mask on. Really? The latest evidence finds this is less dangerous than a normal flu virus and tracking data suggest that the wave has already peaked.

What’s even more disturbing here is that the leftist medical community and the media aren’t renouncing their calls for mitigation strategies that were catastrophically wrong in the panic era of 2020 and 2021—but instead calling for more of these assaults on freedom in the future.

It is one thing for well-meaning medical experts to have disagreed about how to best combat a once-in-a-half-century deadly virus. We didn’t know exactly what we were dealing with. But now we know with concrete scientific evidence that most mandates and lockdowns had a small impact on the spread of the virus and on fatalities. It turns out there was almost no difference in death rates in states with strict lockdowns and no lockdowns at all. The same is true of cross-country evidence.

Healthy children were never at risk from COVID (something we knew early on), so shutting down schools for one or two years was a sop to the teachers unions but a disaster for this generation of kids. Test scores are the worst in 30 years.

Before the pandemic, only 15 percent of public school students were chronically absent—more than 18 or more days a year.

Stanford University education professor Thomas Dee’s data shows an estimated 6.5 million additional students are now chronically absent. In Connecticut and Massachusetts, chronic absenteeism remains double its pre-pandemic rate.

But polls show that Democrats—even those that are highly educated—generally still support the lockdowns that were mandated. These are the same people who lecture about “following the science.” The most comprehensive study by experts at Johns Hopkins University found death rates from lockdowns were reduced by 0.1 percent. But how many people died from the isolation of lockdowns, delayed health screening from cancer, the increase in drug overdoses?

Biden’s vaccine mandates only made Americans more resistant to get pricked. They backfired.

Worst of all, Anthony Fauci, who remains a hero of the Left, recently not only refused to admit the errors of his advice but said the “lockdown was absolutely justified.”

Why does this bizarre rewrite of recent history matter? Because the fearmongering Left can’t wait to install new lockdowns every time we have a new flu virus and health scare. They’ve even started putting out feelers for occasional climate change economic shutdowns.

Those who love freedom must strenuously resist this coming tyranny.

https://www.zerohedge.com/covid-19/why-wont-covid-lockdown-tyrants-admit-they-were-wrong

"Cartel-Run Theft Rings" Supercharge America's Retail Shrink Epidemic

 In a shocking but not surprising twist, a new report reveals a Mexican cartel connection in America's retail theft epidemic that cost companies like Walmart, Target, Kohl's, Home Depot, and Foot Locker, among others, $100 billion last year. Amid the chatter on earnings calls, the number of times CEOs mentioned "shrink" - the loss of inventory due to circumstances such as retail theft - surged to a record high. Yet again, this is another consequence of failed open border policies pushed by radicals in the Biden administration that flooded the nation with millions of illegal aliens. 

We've all seen the videos posted on X, formerly known as Twitter, of masked criminals raiding retailers. Now, the Washington Examiner explains some of those thieves are tied to Mexican cartels:

Mexican cartels are behind the spike in organized retail crime and are deeply entrenched in every level of the process, according to the federal government's chief investigative agency.

Retailers nationwide sustained nearly $100 billion worth of losses in 2021, the highest year on record, according to the National Retail Federation report published in September 2022. The growing number of cartel-run theft rings around the country drove that figure up from $70 billion in 2019.

"Organized retail crime exploded over the last few years as criminals exploited the anonymity of third-party online marketplaces to fence billions in stolen products," RILA Senior Executive Vice President of Public Affairs Michael Hanson said in a statement.

Cartels appear to have big presence in Democrat-controlled cities. 

One reason for the explosion is those criminal gang units are emboldened by failed social justice reform pushed by radical leftists in crime-ridden metro areas, such as ones in San Francisco, where shoplifting merchandise valued under $950 is now only a misdemeanor. Cartels recognized this opportunity: 

These retail crimes are perpetrated by people who work as part of a crime ring run by cartels. In recent years, cartels have gone from illicit drug manufacturing and smuggling, human smuggling and trafficking, and illegal firearm smuggling to commandeering crime in the retail environment.

Cartels are involved in every level of retail crime, from in-store theft and listing items in online marketplaces to shipping stolen merchandise worldwide and using US financial institutions to hold their profits. --Washington Examiner 

Texas alleges that Biden's open borders have flooded the nation with 6 million- more than the total population of Denmark or Finland or Norway Or New Zeland or Costa Rica- since he first took office in early 2021.

Still to this day, the Biden administration, with no regard for the safety of its own taxpayers, continues to flood the nation with illegals ahead of the 2024 presidential election cycle. The latest stunt was welding border gates wide open. 

https://www.zerohedge.com/political/open-border-blowback-report-warns-cartel-run-theft-rings-supercharge-americas-retail