Ukraine Shoots Down 'Decoy' Russian Balloons As Moldova, Romania Report High-Altitude Objects

 Following last week's balloon shootdown incidents over the United States, there have been a slew of fresh reports involving high-altitude balloon activity over eastern Europe, including incidents involving objects over Moldova, Romania, as well as potential 'weaponized' balloons over Ukraine. 

"Ukraine's army has said Russia fired 36 cruise missiles on Thursday, a day after six apparently radar-reflecting balloons were spotted over Kyiv," BBC reports. Ukraine authorities have said the balloon activity is related to a change in Russian tactics, which have of late included sending wind-propelled reflective balloons over the capital and other cities in order to provoke an anti-air response. 

"These objects could carry radar reflectors and certain reconnaissance equipment," Ukrainian air force spokesman Yurii Ihnat said. "The balloons were launched to detect and exhaust our air defense forces."

The military further described that most balloons had been shot down, and they are intentionally designed to be picked up on radar as decoys. 

"Balloons with reflectors have also been spotted over the eastern region of Dnipropetrovsk in recent days," BBC continues, also referencing photographs which surfaced on social media in recent days.

Tiny Moldova was among those earlier this week to close its airspace due to an unidentified object, now believed to be a balloon, and Romania even scrambled fighter jets in response to "an object resembling a weather balloon was spotted at a height of around 11,000 ft (3,350m)," according to official statements.

In a briefing, Romania's defense ministry said the object wasn't a threat upon closer review, and the it had "characteristics similar to a weather balloon" - but had been picked up on radar and warranted investigation. 

Via Telegram: deflated balloon tied to a reflector, believed used by the Russian military to trigger Ukrainian air defense.

The dispatched jets had surveyed the area for about 30 minutes, but "did not confirm the presence of the aerial target, neither visually nor on the onboard radars," and afterward returned to base without incident, defense officials said.

https://www.zerohedge.com/geopolitical/ukraine-shoots-down-decoy-russian-balloons-moldova-romania-report-high-altitude

New generation of light-activated cancer treatments

 Scientists at the University of East Anglia are a step closer to creating a new generation of light-activated cancer treatments. The futuristic-sounding treatment would work by switching on LED lights embedded close to a tumor, which would then activate biotherapeutic drugs.

These new treatments would be highly targeted and more effective than current state-of-the-art cancer immunotherapies.

New research published today in Nature Chemical Biology reveals the science behind this innovative idea. It shows how the UEA team have engineered antibody fragments—which not only "fuse" with their target but are also light activated.

It means that in future, immunotherapy treatments could be engineered to attack tumors more precisely than ever before.

The principal scientist for this study, Dr. Amit Sachdeva, from UEA's School of Chemistry, said, "Current cancer treatments like chemotherapy kill cancer cells, but they can also damage healthy cells in your body such as blood and skin cells. This means that they can cause side effects including hair loss, feeling tired and sick, and they also put patients at increased risk of picking up infections.

"There has therefore been a very big drive to create new treatments that are more targeted and don't have these unwanted side-effects.

"Several antibodies and antibody fragments have already been developed to treat cancer. These antibodies are much more selective than the cytotoxic drugs used in chemotherapy, but they can still cause severe side effects, as antibody targets are also present on healthy cells."

Now, the UEA team has engineered one of the first antibody fragments that binds to, and forms a covalent bond with, its target—upon irradiation with UV light of a specific wavelength. Dr. Sachdeva said, "A covalent bond is a bit like melting two pieces of plastic and fusing them together. It means that drug molecules could for example be permanently fixed to a tumor.

"We hope that our work will lead to the development of a new class of highly targeted light-responsive biotherapeutics. This would mean that antibodies could be activated at the site of a tumor and covalently stick to their target upon light activation.

"In other words, you could activate antibodies to attack tumor cells by shining light—either directly on to the skin, in the case of skin cancer, or using small LED lights that could be implanted at the site of a tumor inside the body. This would allow cancer treatment to be more efficient and targeted because it means that only molecules in the vicinity of the tumor would be activated, and it wouldn't affect other cells.

"This would potentially reduce side effects for patients, and also improve antibody residence time in the body. It would work for cancers like skin cancer, or where there is a solid tumor—but not for blood cancers like leukemia.

"Development of these antibody fragments would not have been possible without pioneering work from several other research groups across the globe who developed and optimized methods for site-specific incorporation of non-natural amino acids into proteins expressed in live cells. We employed some of these methods to site-specifically install unique light-sensitive amino acids into antibody fragments."

If the researchers are successful in the next stages of their work, they hope to see the "next generation" light-activated immunotherapies being used to treat cancer patients within 5 to 10 years.

More information: Amit Sachdeva, Site-specific encoding of photoactivity and photoreactivity into antibody fragments, Nature Chemical Biology (2023). DOI: 10.1038/s41589-022-01251-9 . www.nature.com/articles/s41589-022-01251-9

https://medicalxpress.com/news/2023-02-scientists-breakthrough-generation-cancer-treatment.html

Small molecule drug reverses ADAR1-induced cancer stem cell cloning capacity

 Researchers at University of California San Diego School of Medicine, Sanford Stem Cell Institute and Moores Cancer Center report that a late-stage, pre-clinical small molecule inhibitor, called rebecsinib, reverses malignant hyper-editing by an inflammation-induced protein isoform, known as ADAR1 p150. This malignant protein isoform of ADAR1 promotes immune silencing, metastasis and therapeutic resistance in 20 different cancer types.

The findings are published in Cell Stem Cell.

The ADAR1 protein is involved in making changes to RNA, a chemical cousin of DNA. Specifically, it alters the RNA-building block adenosine into a different a building block called inosine. The process is known as A-to-I editing.

Normally, ADAR1 is involved in the control of innate immune response—the body's early response to foreign invaders. A-to-I editing performed by ADAR1 changes certain aspects of the body's RNA so that it won't be attacked by the immune system. ADAR1 is also thought to inhibit replication and spread of certain viruses, such as human immunodeficiency virus and hepatitis C, by modifying their RNA. Unbridled ADAR1 overexpression, however, allows cancer cells to evade host innate immune responses.

Previous research by Jamieson and colleagues has shown that disruptive inflammatory signaling in malignant microenvironments causes ADAR1p150 overexpression, inducing chronic myeloid leukemia (CML) and malignant reprogramming of certain hematopoietic (blood) stem and progenitor cells that drive progression of pre-leukemic disorders, such as myelofibrosis, to become acute myeloid leukemia (AML). Additionally, ADAR1p150 has also emerged as both a driver of therapeutic resistance and an immune silencer in 20 different malignancies.

Both AML and CML are relatively uncommon cancers, but both can be deadly, particularly secondary AML (sAML), which has a 5-year survival rate of just 26%. More than half of patients succumb to sAML in the first year after diagnosis (10,590 deaths out of 21,380 new cases in 2017), according to the latest available data.

"Despite advances in molecularly targeted therapy, the mortality rate has remained roughly the same for more than four decades," said senior study author Catriona Jamieson, MD, Ph.D., director of the UC San Diego Sanford Stem Cell Institute, deputy director at UC San Diego Moores Cancer Center and professor of Medicine at UC San Diego School of Medicine.

"Inflammatory cytokine-induced A-to-I hyper-editing by ADAR1 has been linked to therapeutic resistance in AML, CML, multiple myeloma, myelofibrosis and 14 different solid tumor types."

In the latest study, Jamieson and co-authors sought to determine the specific drivers of malignant ADAR1 splicing and whether it could be reversed. They developed a non-invasive imaging tool using glowing firefly luciferase and green fluorescent protein technologies and assay tools, then observed that rebecsinib inhibited malignant ADAR1 splicing in a humanized mouse model of sAML.

"The goal is to stop cancer before it takes off," said Jamieson. "In these studies, rebecsinib appears to have great potential for stopping and reversing ADAR1 hyper-editing that leads from non-invasive pre-cancer to invasive cancer able to resist therapy, evade immunity and metastasize."

The authors noted that rebecsinib has been shown to be well tolerated and effective in completed pre-investigational new drug application (pre-IND) animal studies and is currently undergoing IND enabling studies.

"This study lays the foundation for clinical development of rebecsinib as a promising way to remove therapeutic resistance and relapse in patients with high-risk sAML and myelofibrosis," said Jamieson.

More information: Leslie A. Crews et al, Reversal of malignant ADAR1 splice isoform switching with Rebecsinib, Cell Stem Cell (2023). DOI: 10.1016/j.stem.2023.01.008

https://medicalxpress.com/news/2023-02-small-molecule-drug-reverses-adar1-induced.html

Off-label drugs prescribed in addition to insulin for type 1 diabetes

 Two classes of drugs prescribed off-label for some patients with type 1 diabetes can provide significant benefits, but also come with health concerns, according to a study by UT Southwestern Medical Center researchers. The findings, published in The Journal of Clinical Endocrinology & Metabolism, provide a rare view of real-world use of these medications, which are growing in popularity among patients with type 1 diabetes as adjuvants to insulin.

"These findings, from our real clinic experience, show both benefits and some risk to patients with type 1 diabetes who take these medications in addition to insulin treatment," said study leader Ildiko Lingvay, M.D., M.P.H., M.S.C.S., Professor of Internal Medicine in the Division of Endocrinology and in the Peter O'Donnell Jr. School of Public Health at UT Southwestern.

Nearly 1.5 million Americans have type 1 diabetes, an autoimmune disease that destroys insulin-producing cells in the pancreas. Without this hormone, cells can't take in glucose, leading to dangerously high blood sugar levels that can cause a host of short- and long-term problems. These can include diabetic coma, blindness, neuropathy, and a condition called diabetic ketoacidosis (DKA), in which the blood becomes dangerously acidic, necessitating emergency care.

Type 1 diabetes is universally treated with insulin injections. However, explained Dr. Lingvay, because only a fifth of patients with type 1 diabetes in the U.S. achieve the blood sugar control that the American Diabetes Association recommends, doctors are increasingly prescribing medications known as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and/or sodium-glucose cotransporter-2 inhibitors (SGLT2is) to help patients reach this goal.

Furthermore, both classes of medications have been shown in patients with type 2 diabetes to decrease the risk of cardiac and renal events and help promote weight loss, effects that also would greatly benefit patients with type 1 diabetes. However, the risk-benefit ratio of these medications has not been fully vetted in this patient population.

In fact, both classes of drugs have been associated with increased risk of severe hypoglycemia and DKA when used in patients with type 1 diabetes. Because both positive and negative effects of GLP-1RAs and SGLT2is were shown in strictly regulated clinical trials, their real-world effects have been unclear.

To examine their efficacy, Dr. Lingvay, along with colleagues Khary Edwards, M.D., a former Endocrinology fellow at UTSW, and Xilong Li, M.B.A., Senior Database Analyst at UTSW, searched medical records for type 1 diabetes patients treated at UT Southwestern who used any GLP-1RAs and/or SGLT2is for at least 90 days before Oct. 31, 2021. Their search turned up 104 patients: 65 who had used GLP-1RAs exclusively, 28 who had used SGLT2is exclusively, and 11 who had used both either concurrently or sequentially.

After a year of use, patients on GLP-1RAs had significant reductions in weight, glycated hemoglobin A1C (a three-month average measure of blood sugar), and total daily dose of insulin. SGLT2i users had significant reductions in hemoglobin A1C and basal insulin, a baseline dose delivered outside of meals.

However, SGLT2i users were about three times more likely than GLP-1RA users to experience DKA. Just over a quarter of patients taking either class of drugs stopped due to side effects such as gastrointestinal problems.

The study authors say these results suggest both types of drugs can be beneficial to patients with type 1 diabetes, but close monitoring is required. Specifically when using SGLT2is, extreme caution is advised in selecting patients with the lowest risk of DKA, performing detailed education about the risk of DKA, and ensuring careful monitoring to prevent its occurrence.

"When viewed holistically at the person level, all of these small changes can add up to substantial overall clinical benefits, especially considering that improving glycemic control in patients with long-standing T1DM [type 1 diabetes mellitus] can be challenging," the researchers wrote.

More information: Khary Edwards et al, Clinical and Safety Outcomes With GLP-1 Receptor Agonists and SGLT2 Inhibitors in Type 1 Diabetes: A Real-World Study, The Journal of Clinical Endocrinology & Metabolism (2022). DOI: 10.1210/clinem/dgac618

https://medicalxpress.com/news/2023-02-off-label-drugs-addition-insulin-diabetes.html

A broad-spectrum synthetic antibiotic that does not evoke bacterial resistance

 In a potential game changer for the treatment of superbugs, researchers have developed a new class of antibiotics that cured mice infected with bacteria deemed nearly "untreatable" in humans—and resistance to the drug was virtually undetectable.

Developed by a research team of UC Santa Barbara scientists, the study was published in the journal eBioMedicine. The drug works by disrupting many bacterial functions simultaneously—which may explain how it killed every pathogen tested and why a low level of bacterial resistance was observed after prolonged drug exposure.

The project was led by professors Michael Mahan, David Low, Chuck Samuel and their research team, Douglas Heithoff, Scott Mahan, Lucien Barnes and Cyril George. Additional contributors include professors Guillermo Bazan (UC Santa Barbara) and Andrei Osterman (Sanford Burnham Prebys Medical Discovery Institute).

The discovery was serendipitous. The U.S. Army had a pressing need to charge cell phones while in the field—essential for soldier survival. Because bacteria are miniature power plants, compounds were designed by Bazan's group to harness bacterial energy as a "'microbial"' battery. Later the idea arose to repurpose these compounds as potential antibiotics.

"When asked to determine if the chemical compounds could serve as antibiotics, we thought they would be highly toxic to human cells, similar to bleach," said Mahan, the project lead investigator. "Most were toxic—but one was not—and it could kill every bacterial pathogen we tested."

What makes the drug unique is the failure of bacteria to become resistant to it. And bacterial resistance is typically a major barrier to antibiotic development since it limits a drug's potential value in the marketplace.

"The key finding was that bacterial resistance to the drug was virtually undetectable," said lead author Heithoff. "Most drugs fail at this stage of development and never get to clinical practice."

The antibiotic has a unique mechanism of action. Contrary to most drugs (like penicillin) that target a specific germ function, the new drug targets many functions simultaneously.

"The drug appears to affect the bacterial membrane, which in turn, disrupts multiple bacterial functions," explained Low, the co-project lead. "This may account for the broad-spectrum antibacterial activity and low level of bacterial resistance."

"This class of antibiotics has potential as a new versatile therapy for antimicrobial resistant pathogens," Samuel said.

Additional drug safety and efficacy studies will need to be conducted to fully understand the clinical benefits and risks before the drug can be used in clinical practice.

More information: Douglas M. Heithoff et al, A broad-spectrum synthetic antibiotic that does not evoke bacterial resistance, eBioMedicine (2023). DOI: 10.1016/j.ebiom.2023.104461

https://medicalxpress.com/news/2023-02-broad-spectrum-synthetic-antibiotic-evoke-bacterial.html

Chemically 'poisoned' protein acts as a molecular switch to spur cancer formation

 Scientists at Scripps Research, with collaborators in Japan, have discovered how a "poisoned" form of a protein could set off a cascade of events that encourage the growth of some cancers. The research, published in Nature Communications on February 4, also triggered development of a drug candidate that can revert the protein to its normal form. In mice with colon cancer, the drug prevented or dramatically slowed formation of tumors.

"This is a potentially very important and druggable link between the environment, genes and cancer," says senior author Stuart Lipton, MD, Ph.D., professor and Step Family Foundation Endowed Chair in the Department of Molecular Medicine at Scripps Research and a clinical neurologist in La Jolla, Calif.

The study was a collaboration with a team led by Takashi Uehara at Okayama University in Japan.

Lipton's research group previously discovered a process called protein S-nitrosylation, in which a molecule related to nitric oxide (NO) binds to sulfur atoms within proteins to change those proteins' functions. NO is found naturally within the body and produced in response to inflammation. But it also can form from nitrates and nitrites that are eaten (in the form of processed meats) or breathed in (through cigarette smoke or air pollution). Recently, the team showed how S-nitrosylation might contribute to Alzheimer's disease, as well as Parkinson's disease, Lewy body dementia, Lou Gehrig's disease (ALS) and some forms of autism.

Separately, scientists know that many genes can be turned on or off by proteins called DNA methyltransferases (a process known as epigenetic control of gene expression). When these proteins add a methyl group—a kind of chemical marker—to a strand of DNA, they keep nearby genes from being activated. In some cancers, those methyl "silencers" are removed, and genes involved in tumor growth and spread get abnormally turned on.

"If you block methylation, genes get turned on when they shouldn't be, and that's been known to be an important driver of some cancers," says Lipton. "But no one knew the prime trigger for this process."

In the work, Lipton, with Scripps Research investigator Tomohiro Nakamura and their colleagues in Japan, showed that when DNA methyltrasferase 3B (DNMT3B) is S-nitrosylated—which can happen in the presence of high levels of NO—it no longer adds methyl groups to DNA. This then enables certain those cancer-causing genes to turn on. The findings suggest one way that processed meats, air pollution, cigarette smoke and inflammation—all linked to some forms of cancer—could flip DNMT3B to its cancer-promoting form.

"It's like a poisoned form of DNMT3B," says Lipton.

The group went on to show that when DNMT3B is "poisoned" in this way, expression levels of 173 different genes in human cells changed. Among these genes is Ccnd2, which was already known to be involved in the formation of gastric and colon cancers in humans.

The research group in Japan then designed a drug that would prevent DNMT3B from being S-nitrosylated, but not block its normal function or affect the S-nitrosylation of any other proteins. This prevented NO, even when present at high levels, from converting DNMT3B into the "poisoned" form.

Lipton and Uehara's teams found that the drug, known as DBIC, prevented isolated precancerous colon cells from turning into full-blown colon cancer in the lab. Moreover, when they gave DBIC to mice prone to colon cancer, the drug virtually prevented tumors from forming, even when inflammation produced high levels of NO.

The researchers think that the S-nitrosylation of DNMT3B is likely associated with other cancers, including brain and breast cancer. They're planning more research on the full list of genes that are impacted by S-nitrosylated DNMT3B.

"We still don't know the full panoply of tumor types that this molecular switch might be associated with," says Lipton. "We'll be pursuing that in the future, as well as trying to move DBIC toward human clinical trials."

More information: Kosaku Okuda et al, Pivotal role for S-nitrosylation of DNA methyltransferase 3B in epigenetic regulation of tumorigenesis, Nature Communications (2023). DOI: 10.1038/s41467-023-36232-6

https://medicalxpress.com/news/2023-02-chemically-poisoned-protein-molecular-spur.html

Cell type key to successful immunotherapies for chronic viral infections identified

 An international study led by researchers from the Infection Biology Laboratory at the UPF Department of Medicine and Life Sciences (MELIS) establishes that one type of dendritic cell is crucial for the success of immunotherapeutic treatments to control chronic viral infections. These dendritic cells have been found to be key in reactivating exhausted lymphocytes responsible for clearing infected cells to keep the viral load low.

Chronic viral infections, such as those caused by human immunodeficiency virus (HIV) or hepatitis B and C viruses, are characterized by a persistent viral load. This is maintained by a balance between the expansion of the virus and the expansion of exhausted T lymphocytes, which—once the viral load increases—become active, multiply and eliminate infected cells.

In HIV-infected patients, infection has been controlled with antiviral therapy that reduces the viral load to below detectable levels. However, this is transitory, as the viral load increases dramatically when treatment is stopped. With 650,000 people worldwide dying from HIV and 1.5 million acquiring the virus each year, there is a need to find a functional cure that controls the virus without causing disease and avoids the side effects and burden on health systems that antiviral therapy entails.

Hence, immunotherapies based on checkpoint inhibitors that block proteins preventing the immune system from attacking infected cells are considered a promising therapy.

The study published in Cell Reports determines that the various types of dendritic cells differ in their ability to reactivate exhausted lymphocytes during checkpoint immunotherapy. It also identifies XCR1+ cross-presenting dendritic cells as key elements that trigger exhausted lymphocyte reactivation in checkpoint inhibitor-based immunotherapies. Therefore, XCR1+ cross-presenting dendritic cells are a promising therapeutic target to improve virus control during chronic viral infection.

The study, performed in a mouse model of the chronic lymphocytic choriomeningitis virus—which partly resembles human chronic HIV and hepatitis virus infections—opens the possibility of considering combination immunotherapies including checkpoint inhibitors that target cross-presenting dendritic cells as an interesting therapy option for HIV-infected individuals.

"Our findings are an important step forward in understanding the requirements for cure strategies in chronic infections," says Eva Domenjo, first author of the manuscript. "The next steps now are to improve the duration of the therapeutic benefits and translate the data from the model system to the clinical practice," adds Andreas Meyerhans, who coordinated the work together with Jordi Argilaguet.

Considering analogous findings in cancer immunotherapy, this not only argues for immunological similarities between chronic infections and cancers, but also gives hope for a timely translation into clinical applications.

More information: Eva Domenjo-Vila et al, XCR1+ DCs are critical for T cell-mediated immunotherapy of chronic viral infections, Cell Reports (2023). DOI: 10.1016/j.celrep.2023.112123

https://medicalxpress.com/news/2023-02-cell-key-successful-immunotherapies-chronic.html